Current status of intensity-modulated radiation therapy for prostate cancer: History, clinical results and future directions.

External beam radiotherapy has changed dramatically over several decades with the improvement of computer hardware and software, and machinery developments. Intensity-modulated radiation therapy is the most sophisticated technique for all cancer treatment with radiation therapy, and is widely disseminated and available for daily use in many countries. Several retrospective and prospective studies have shown that intensity-modulated radiation therapy reduces the radiation dose in the organs at risk with diminished rates of acute and late toxicity, even with higher doses (>74 Gy). An important technique for the clinical use of intensity-modulated radiation therapy is image-guided radiation therapy. The clinical benefit for prostate image-guided radiation therapy has been assessed by comparing the outcomes of patients with either the image-guided radiation therapy or non-image-guided radiation therapy technique. These studies have shown that image-guided radiation therapy significantly decreases acute and late rectal and bladder toxicities. Randomized trials and meta-analysis have shown that higher doses result in better biochemical control. More recently, hypofractionated radiation therapy comparing hypofractionated radiation therapy versus conventional fractionated radiation therapy have shown that hypofractionated radiation therapy produces biochemical control and toxicity rated similar to those produced by conventional fractionated radiation therapy. The clinical use of ultrahypofractionated radiation therapy and simultaneous integrated boost technique is necessary to evaluate its further safety and benefits. Intensity-modulated radiation therapy is also widely accepted in the field of salvage therapy and for the patients with distant oligometastases. The purpose of the present review is to summarize the history of intensity-modulated radiation therapy, new techniques for intensity-modulated radiation therapy, hypofractionation and future directions for prostate cancer.

Therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate-risk and high-risk prostate cancer.

OBJECTIVES: To investigate the therapeutic outcomes of neoadjuvant and concurrent androgen-deprivation therapy and intensity-modulated radiation therapy with gold marker implantation for intermediate- and high-risk prostate cancer. METHODS: This was a retrospective study of 325 patients with intermediate- or high-risk prostate cancer according to the National Comprehensive Cancer Network guidelines who underwent androgen-deprivation therapy and intensity-modulated radiation therapy (76 Gy) after gold marker implantation between 2001 and 2010. RESULTS: The 5-year distant metastasis-free survival rate was significantly lower for very high-risk patients than for intermediate- and high-risk patients (82.6% vs 99.4% and 96.5%, respectively; P < 0.01). The 5-year biochemical relapse-free survival rates significantly declined with increasing prostate cancer risk (P < 0.01), and were 95.9%, 87.2%, and 73.1% for the intermediate-risk, high-risk and very high-risk patients, respectively. Acute genitourinary and gastrointestinal toxicity grade ≥3 were not observed in any of the patients. Late grade 3 genitourinary toxicity occurred in 0.3% of patients. CONCLUSION: Combination androgen-deprivation therapy and 76-Gy intensity-modulated radiation therapy with gold marker implantation offers good therapeutic outcomes with few serious complications in patients with intermediate- and high-risk prostate cancer.

Novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals.

SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including ß-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC(90)s of ≤ 1 µg/ml. Unlike tebipenem (MIC(50), 8 µg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC(50), ≥ 128 µg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren. The therapeutic efficacies of intravenous administrations of SM-295291 and SM-369926 against experimentally induced infections in mice caused by penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae were equal or superior to that of tebipenem and greater than that of cefditoren, respectively, reflecting their in vitro activities. SM-295291 and SM-369926 showed intravenous pharmacokinetics similar to those of meropenem in terms of half-life in monkeys (0.4 h) and were stable against human dehydropeptidase I. SM-368589 and SM-375769, which are medoxomil esters of SM-295291 and SM-369926, respectively, showed good oral bioavailability in rats, dogs, and monkeys (4.2 to 62.3%). Thus, 2-aryl carbapenems are promising candidates that show an ideal broad spectrum for the treatment of community-acquired infections, including infections caused by penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae, have low selective pressure on antipseudomonal carbapenem-resistant nosocomial pathogens, and allow parenteral, oral, and switch therapies.

Patterns of practice in intensity-modulated radiation therapy and image-guided radiation therapy for prostate cancer in Japan.

BACKGROUND: The purpose of this study was to compare the prevalence of treatment techniques including intensity-modulated radiation therapy and image-guided radiation therapy in external-beam radiation therapy for prostate cancer in Japan. METHODS: A national survey on the current status of external-beam radiation therapy for prostate cancer was performed in 2010. We sent questionnaires to 139 major radiotherapy facilities in Japan, of which 115 (82.7%) were returned. RESULTS: Intensity-modulated radiation therapy was conducted at 67 facilities (58.3%), while image-guided radiation therapy was conducted at 70 facilities (60.9%). Simulations and treatments were performed in the supine position at most facilities. In two-thirds of the facilities, a filling bladder was requested. Approximately 80% of the facilities inserted a tube or encouraged defecation when the rectum was dilated. Some kind of fixation method was used at 102 facilities (88.7%). Magnetic resonance imaging was routinely performed for treatment planning at 32 facilities (27.8%). The median total dose was 76 Gy with intensity-modulated radiation therapy and 70 Gy with three-dimensional radiation therapy. The doses were prescribed at the isocenter at the facilities that conducted three-dimensional radiation therapy. In contrast, the dose prescription varied at the facilities that conducted intensity-modulated radiation therapy. Of the 70 facilities that could perform image-guided radiation therapy, 33 (47.1%) conducted bone matching, 28 (40.0%) conducted prostate matching and 9 (12.9%) used metal markers. Prostate or metal marker matching tended to produce a smaller margin than bone matching. CONCLUSIONS: The results of the survey identified current patterns in the treatment planning and delivery processes of external-beam radiation therapy for prostate cancer in Japan.

A consensus-based guideline defining clinical target volume for primary disease in external beam radiotherapy for intact uterine cervical cancer.

OBJECTIVE: To develop a consensus-based guideline to define clinical target volume for primary disease (clinical target volume primary) in external beam radiotherapy for intact uterine cervical cancer. METHODS: The working subgroup of the JCOG Radiation Therapy Study Group began developing a guideline for primary clinical target volume in November 2009. The group consisted of 10 radiation oncologists and 2 gynecologic oncologists. The process started with comparing the contouring on computed tomographic images of actual cervical cancer cases among the members. This was followed by a comprehensive literature review that included primary research articles and textbooks as well as information on surgical procedures. Extensive discussion occurred in face-to-face meetings (three occasions) and frequent e-mail communications until a consensus was reached. RESULTS: The working subgroup reached a consensus on the definition for the clinical target volume primary. The clinical target volume primary consists of the gross tumor volume, uterine cervix, uterine corpus, parametrium, vagina and ovaries. Definitions for these component structures were determined. Anatomical boundaries in all directions were defined for the parametrium. Examples delineating these boundaries were prepared for the posterior border of the parametrium for various clinical situations (i.e. central tumor bulk, degree of parametrial involvement). CONCLUSIONS: A consensus-based guideline defining the clinical target volume primary was developed for external beam radiotherapy for intact uterine cervical cancer. This guideline will serve as a template for radiotherapy protocols in future clinical trials. It may also be used in actual clinical practice in the setting of highly precise external beam radiotherapy, including intensity-modulated radiotherapy.

Radiotherapy quality assurance of the Japanese Gynecologic Oncology Group study (JGOG1066): a cooperative phase II study of concurrent chemoradiotherapy for uterine cervical cancer.

BACKGROUND: To assess radiotherapy protocol compliance in a multi-institutional phase II study of concurrent chemoradiotherapy for patients with locally advanced cancer of the uterine cervix (JGOG1066). METHODS: For study protocol development, various radiotherapy parameters were examined and consensus was reached by Japanese radiation oncologists with cervical cancer treatment expertise. Quality assurance (QA) was also discussed and included in the protocol. A credentialing process was used to select institutions for participation in the study. Individual case reviews referring to 18 QA items were undertaken for each patient. Radiotherapy data were submitted to the Japanese Gynecologic Oncology Group (JGOG) data center and reviewed by the members of the radiotherapy committee. The QA evaluation was classed as per protocol, deviation, and violation. RESULTS: Individual case reviews were performed on 69 of 72 patients entered in the study. In 24 patients (35%), there were no deviations for any QA items. There were also no deviations seen for 5 of the 18 items in 69 patients evaluated. Deviations of 64 QA items were seen in 45 cases, and violations were seen in 4 cases (4 items). The most common deviation concerned appropriate application for the external beam radiotherapy (EBRT) boost to involved nodes or parametrium (32 cases). The 4 violations were identified in the QA items regarding high-dose rate intracavitary brachytherapy. CONCLUSIONS: Radiotherapy protocol compliance was favorable except for the EBRT boost indications. The results of this study validate the quality of radiotherapy in JGOG1066, and indicate that the final analysis will provide meaningful results.

Toward global standardization of conducting fair investigations of allegations of research misconduct.

In the United States, through nation-wide discussions, the procedures for handling allegations of research misconduct are now well established. Procedures are geared toward carefully treating both complainants and respondents fairly in accordance with the US framework. Other countries, which have their own cultural and legal framework, also need fair and legally compatible procedures for conducting investigations of allegations of research misconduct. Given the rapid growth of international collaboration in research, it is desirable to have a global standard, or common ground, for misconduct investigations. Institutions need clear guidance on important subjects such as what information should be included in the investigation reports, how the investigation committee should be organized once research misconduct allegation has been received, how to conduct the investigation, how the data and information obtained should be taken as evidence for vs. against misconduct, and what policies the investigation committee should follow. We explore these issues from the viewpoint of members of committees investigating accusations of research misconduct (hereafter referred to as "investigation committees") as well as persons overseeing the committees in Japan. We hope to engender productive discussions among experts in misconduct investigations, leading to a formulation of international standards for such investigation.

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma.

In the management of patients with newly diagnosed glioblastoma, there is no standard duration for adjuvant temozolomide treatment. This study aimed to assess the feasibility of finalizing adjuvant temozolomide treatment on the basis of methionine uptake in methionine positron emission tomography (Met-PET). We conducted a retrospective review of glioblastoma patients who underwent more than twelve cycles of temozolomide (extended temozolomide) treatment after resection and concomitant chemoradiotherapy with no evidence of recurrence on MRI. In addition to the methionine uptake value at the completion of extended temozolomide, local and distant recurrence and progression-free survival were also analyzed. Forty-four patients completed the extended temozolomide treatment. Among these, 18 experienced some type of tumor recurrence within one year. A Tmax/Nave value of 2.0 was the optimal cut-off value indicating progression. More than 80% of the patients with low methionine uptake completed the temozolomide treatment, and subsequent basic MRI observations showed no recurrence within one year after Met-PET. Subgroups with high uptake (≥2.0), even with continuation of temozolomide treatment, showed more frequent tumor progression than patients with low uptake (<2.0) who completed the extended temozolomide treatment (p < 0.001, odds ratio 14.7, 95% CI 3.46-62.3). The tumor recurrence rate increased in stepwise manner according to methionine uptake. Finalization of the extended temozolomide treatment on the basis of low uptake value was feasible with a low recurrence rate. Compared to MRI, Met-PET shows better ability to predict tumor progression in long-term glioblastoma survivors with extended temozolomide use.

Reference dosimetry condition and beam quality correction factor for CyberKnife beam.

This article is intended to improve the certainty of the absorbed dose determination for reference dosimetry in CyberKnife beams. The CyberKnife beams do not satisfy some conditions of the standard reference dosimetry protocols because of its unique treatment head structure and beam collimating system. Under the present state of affairs, the reference dosimetry has not been performed under uniform conditions and the beam quality correction factor kQ for an ordinary 6 MV linear accelerator has been temporally substituted for the kQ of the CyberKnife in many sites. Therefore, the reference conditions and kQ as a function of the beam quality index in a new way are required. The dose flatness and the error of dosimeter reading caused by radiation fields and detector size were analyzed to determine the reference conditions. Owing to the absence of beam flattening filter, the dose flatness of the CyberKnife beam was inferior to that of an ordinary 6 MV linear accelerator. And if the absorbed dose is measured with an ionization chamber which has cavity length of 2.4, 1.0 and 0.7 cm in reference dosimetry, the dose at the beam axis for a field of 6.0 cm collimator was underestimated 1.5%, 0.4%, and 0.2% on a calculation. Therefore, the maximum field shaped with a 6.0 cm collimator and ionization chamber which has a cavity length of 1.0 cm or shorter were recommended as the conditions of reference dosimetry. Furthermore, to determine the kQ for the CyberKnife, the realistic energy spectrum of photons and electrons in water was simulated with the BEAMnrc. The absence of beam flattening filter also caused softer photon energy spectrum than that of an ordinary 6 MV linear accelerator. Consequently, the kQ for ionization chambers of a suitable size were determined and tabulated as a function of measurable beam quality indexes in the CyberKnife beam.

Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: discovery of FR264205.

We describe herein the synthesis and biological evaluation of a series of novel cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led to the discovery of FR264205 (15) with excellent anti-bacterial activity and weak convulsion effect by direct intracerebroventricular injection assay.

Structural requirements for the stability of novel cephalosporins to AmpC beta-lactamase based on 3D-structure.

AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC=1 microg/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC=16 microg/mL) and ceftazidime (CAZ) (MIC=128 microg/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model.

Overproduction of a metallo-beta-lactamase by a strong promoter causes high-level imipenem resistance in a clinical isolate of Pseudomonas aeruginosa.

BACKGROUND: Metallo-beta-lactamase is one of the feared resistance mechanisms in Pseudomonas aeruginosa. METHODS: beta-Lactamase activity was determined using crude enzymes. Cloned plasmids were transformed in P. aeruginosa KG2505, PAO1 derivative without an AmpC beta-lactamase and a MexAB-OprM efflux pump. RESULTS: P. aeruginosa No. 20232 was highly resistant to imipenem (minimum inhibitory concentration >512 microg/ml). It possessed IMP-10 and the activity was 1.89 +/- 0.42 micromol/min/mg of protein, which was 5-8 times higher than other tested isolates. The bla(IMP-10) promoter was strong (-35 region, TTGACA; -10 region, TAAACT); on the other hand, bla(IMP) of other isolates had a hybrid promoter. Transformants with plasmid encoding bla(IMP-10) with a strong promoter had higher enzymatic activity and were less susceptible to imipenem than those encoding bla(IMP-10) with a hybrid promoter. CONCLUSIONS: The high metallo-beta-lactamase activity caused by a strong promoter was a major determinant for high-level imipenem resistance of P. aeruginosa No. 20232.

In vitro antibacterial activity of a new cephalosporin, FR295389, against IMP-type metallo-beta-lactamase-producers.

FR295389 is a novel dihydroimidazopyrazolium cephalosporin. Although all previously reported cephalosporins had been ineffective against metallo-beta-lactamase (MBL)-producers, FR295389 showed moderate activity against these strains. The MIC values of FR295389 at which 50% and 90% of 21 clinical isolates of IMP-type MBL-producing Pseudomonas aeruginosa were inhibited were 8.0 and 32 mug/ml, respectively. The kinetic study of IMP-1 MBL showed that the K(m) and the k(cat) values against FR295389 were over 20-fold-higher and 12-fold-lower than those against ceftazidime, respectively, suggesting that FR295389 is a poor substrate for IMP-type MBL. This is the first report of a cephalosporin with activity against IMP-type MBL-producers.

[Contribution to survival rate improvement].

For patients with locally advanced HNSCC, where the outcome with conventional radiotherapy is poor, meta-analysis and collective data showed a high level of evidence of loco-regional control improvement by altered fractionated radiotherapy, chemo-radiotherapy with a concomitant approach. For these patients, much evidence indicates overall survival may be improved by concomitant chemo-radiotherapy or hyper-fractionated radiotherapy delivered with increased total dose. There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years. The benefit was significantly higher with hyper-fractionated radiotherapy (8% at 5 years)than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years). The effect was greater for the primary tumor than for nodal disease. The effect was also more pronounced in younger patients and in those with good performance status. Hyper-fractionation seemed to yield a more consistent advantage for survival than accelerated fractionated radiotherapy. However, accelerated radiotherapy might be associated with higher non-cancer-related death. Despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for altered fractionation regimens, type of chemo-radiotherapy association, and radiation of chemotherapy dose schedule. We have to evaluate whether the benefit of hyper-fractionated radiotherapy versus standard radiotherapy persists when combined with concomitant chemotherapy and the benefit of IMRT compared with altered fractionation.

Treatment and prognosis of squamous cell carcinoma of the external auditory canal and middle ear: a multi-institutional retrospective review of 87 patients.

PURPOSE: To examine the relative roles of surgery, radiotherapy, and chemotherapy in the management of patients with squamous cell carcinomas of the external auditory canal and middle ear. METHODS AND MATERIALS: The records of 87 patients with histologically confirmed squamous cell carcinoma who were treated between 1984 and 2005 were reviewed. Fifty-three patients (61%) were treated with surgery and radiotherapy (S + RT group) and the remaining 34 patients with radiotherapy alone (RT group). Chemotherapy was administered in 34 patients (39%). RESULTS: The 5-year actuarial overall and disease-free survival (DFS) rates for all patients were 55% and 54%, respectively. On univariate analysis, T stage (Stell's classification), treatment modality, and Karnofsky performance status had significant impact on DFS. On multivariate analysis, T stage and treatment modality were significant prognostic factors. Chemotherapy did not influence DFS. The 5-year DFS rate in T1, T2, and T3 patients was 83%, 45%, and 0 in the RT group (p < 0.0001) and 75%, 75%, and 46% in the S + RT group (p = 0.13), respectively. The 5-year DFS rate in patients with negative surgical margins, those with positive margins, and those with macroscopic residual disease was 83%, 55%, and 38%, respectively (p = 0.007). CONCLUSIONS: Radical radiotherapy is the treatment of choice for early-stage (T1) diseases, whereas surgery (negative surgical margins if possible) with radiotherapy is recommended as the standard care for advanced (T2-3) disease. Further clarification on the role of chemotherapy is necessary.

Stability of FR264205 against AmpC beta-lactamase of Pseudomonas aeruginosa.

FR264205 is a novel parenteral 3'-aminopyrazolium cephalosporin. Here, we compared the stability of FR264205 against AmpC beta-lactamase of Pseudomonas aeruginosa with that of ceftazidime. The effect of ampD inactivation, which causes a moderate degree of hyperinducible AmpC expression, on the minimum inhibitory concentration (MIC) of FR264205 was eight-fold less than that on the MIC of ceftazidime. Hydrolysis efficiency (k(cat)/K(m)) towards FR264205 was substantially lower than that towards ceftazidime owing to a 20-fold-higher K(m) value. These results indicate that FR264205 is more stable against AmpC beta-lactamase than ceftazidime because of its low affinity.

In vitro antimicrobial activity of telavancin against methicillin-resistant Staphylococcus aureus clinical isolates from Japan (2006).

In vitro antimicrobial activity of telavancin, a rapidly bactericidal lipoglycopeptide, was evaluated against 1500 strains of MRSA recently isolated in Japan. Telavancin had potent activity, with MIC values that ranged from 0.12 microg/ml to 0.5 microg/ml and a MIC90 value of 0.5 microg/ml. The MIC90s of vancomycin and linezolid were 1.0microg/ml and 2 microg/ml, respectively. No vancomycin intermediate resistant or vancomycin-resistant MRSAs were detected in this surveillance study.

Verification of the tumor volume delineation method using a fixed threshold of peak standardized uptake value.

We aimed to determine the difference in tumor volume associated with the reconstruction model in positron-emission tomography (PET). To reduce the influence of the reconstruction model, we suggested a method to measure the tumor volume using the relative threshold method with a fixed threshold based on peak standardized uptake value (SUVpeak). The efficacy of our method was verified using 18F-2-fluoro-2-deoxy-D-glucose PET/computed tomography images of 20 patients with lung cancer. The tumor volume was determined using the relative threshold method with a fixed threshold based on the SUVpeak. The PET data were reconstructed using the ordered-subset expectation maximization (OSEM) model, the OSEM + time-of-flight (TOF) model, and the OSEM + TOF + point-spread function (PSF) model. The volume differences associated with the reconstruction algorithm (%VD) were compared. For comparison, the tumor volume was measured using the relative threshold method based on the maximum SUV (SUVmax). For the OSEM and TOF models, the mean %VD values were -0.06 ± 8.07 and -2.04 ± 4.23% for the fixed 40% threshold according to the SUVmax and the SUVpeak, respectively. The effect of our method in this case seemed to be minor. For the OSEM and PSF models, the mean %VD values were -20.41 ± 14.47 and -13.87 ± 6.59% for the fixed 40% threshold according to the SUVmax and SUVpeak, respectively. Our new method enabled the measurement of tumor volume with a fixed threshold and reduced the influence of the changes in tumor volume associated with the reconstruction model.

Hypofractionated high-dose irradiation for the treatment of malignant astrocytomas using simultaneous integrated boost technique by IMRT.

PURPOSE: We evaluated the clinical significance of hypofractionated high-dose irradiation using simultaneous integrated boost technique with intensity-modulated radiation therapy (IMRT) for the treatment of malignant astrocytomas (MAs). METHODS AND MATERIALS: Twenty-five patients with MAs were treated by IMRT. Three layered planning target volumes (PTVs) were contoured. PTV-1 was the area of enhanced lesion with 5-mm margin; PTV-2 was the area with 15-mm margin surrounding the PTV-1; PTV-3 was the area of perifocal edema. Irradiation was performed in 8 fractions, and only the dose for PTV-1 was escalated from 48 Gy to 68 Gy while maintaining the dose for PTV-2 (40 Gy) and PTV-3 (32 Gy). The clinical outcome of IMRT was compared with 60 MA patients treated by conventional external beam irradiation (EBI). RESULTS: The progression-free survival of patients in the IMRT group was significantly longer than that in the EBI group (p < 0.0001). No distant failure was observed in both groups. In the IMRT group, dissemination was the most frequent cause of death (70%). The overall survival of patients in the IMRT group was better than that in the EBI group (p = 0.043). CONCLUSIONS: Our regimen of IMRT contributed to the control of both the regional and infiltrating tumors, resulting in better survival of patients.

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.