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.

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.

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.

A questionnaire-based survey on 3D image-guided brachytherapy for cervical cancer in Japan: advances and obstacles.

The purpose of this study is to survey the current patterns of practice, and barriers to implementation, of 3D image-guided brachytherapy (3D-IGBT) for cervical cancer in Japan. A 30-item questionnaire was sent to 171 Japanese facilities where high-dose-rate brachytherapy devices were available in 2012. In total, 135 responses were returned for analysis. Fifty-one facilities had acquired some sort of 3D imaging modality with applicator insertion, and computed tomography (CT) and magnetic resonance imaging (MRI) were used in 51 and 3 of the facilities, respectively. For actual treatment planning, X-ray films, CT and MRI were used in 113, 20 and 2 facilities, respectively. Among 43 facilities where X-ray films and CT or MRI were acquired with an applicator, 29 still used X-ray films for actual treatment planning, mainly because of limited time and/or staffing. In a follow-up survey 2.5 years later, respondents included 38 facilities that originally used X-ray films alone but had indicated plans to adopt 3D-IGBT. Of these, 21 had indeed adopted CT imaging with applicator insertion. In conclusion, 3D-IGBT (mainly CT) was implemented in 22 facilities (16%) and will be installed in 72 (53%) facilities in the future. Limited time and staffing were major impediments.

Methionine Uptake and Required Radiation Dose to Control Glioblastoma.

PURPOSE: The purpose of this study was to retrospectively assess the feasibility of radiation therapy planning for glioblastoma multiforme (GBM) based on the use of methionine (MET) positron emission tomography (PET), and the correlation among MET uptake, radiation dose, and tumor control. METHODS AND MATERIALS: Twenty-two patients with GBM who underwent MET-PET prior to radiation therapy were enrolled. MET uptake in 30 regions of interest (ROIs) from 22 GBMs, biologically effective doses (BEDs) for the ROIs and their ratios (MET uptake:BED) were compared in terms of whether the ROIs were controlled for >12 months. RESULTS: MET uptake was significantly correlated with tumor control (odds ratio [OR], 10.0; P = .005); however, there was a higher level of correlation between MET uptake:BED ratio and tumor control (OR, 40.0; P < .0001). These data indicated that the required BEDs for controlling the ROIs could be predicted in terms of MET uptake; BED could be calculated as [34.0 × MET uptake] Gy from the optimal threshold of the MET uptake:BED ratio for tumor control. CONCLUSIONS: Target delineation based on MET-PET was demonstrated to be feasible for radiation therapy treatment planning. MET-PET could not only provide precise visualization of infiltrating tumor cells but also predict the required radiation doses to control target regions.

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.

[Application of the PET for Radiation Therapy].

Because radiotherapy is local treatment, it is very important to define target volume and critical organs based on accurate lesion area. The PET using an index such as the SUV is quantifiable noninvasively with information of the molecular biology for individual case/lesion. In particular, PET with 18F-fluorodeoxyglucose (FDG-PET) has been used for the diagnosis and treatment evaluation of various tumors. The radiation therapy based on PET enables the treatment planning that reflected metabolic activity of the lesion. The PET produce an error by various factors, therefore, we must handle the PET image in consideration of this error when apply PET to radiotherapy.

Impact of intraluminal brachytherapy on survival outcome for radiation therapy for unresectable biliary tract cancer: a propensity-score matched-pair analysis.

PURPOSE: To determine whether adding intraluminal brachytherapy (ILBT) to definitive radiation therapy (RT) for unresectable biliary tract cancer has a positive impact on survival outcome. METHODS AND MATERIALS: The original cohort comprised 209 patients, including 153 who underwent external beam RT (EBRT) alone and 56 who received both ILBT and EBRT. By matching propensity scores, 56 pairs (112 patients) consisting of 1 patient with and 1 patient without ILBT were selected. They were well balanced in terms of sex, age, performance status, clinical stage, jaundice, and addition of chemotherapy. The impact of ILBT on overall survival (OS), disease-specific survival (DSS), and local control (LC) was investigated. RESULTS: The 2-year OS rates were 31% for the ILBT+ group and 40% for theILBT- group (P=.862). The 2-year DSS rates were 42% for the ILBT+ group and 41% for the ILBT- group (P=.288). The 2-year LC rates were 65% for the ILBT+ group and 35% for the ILBT- group (P=.094). Three of the 4 sensitivity analyses showed a significantly better LC for the ILBT+ group (P=.010, .025, .049), and another showed a marginally better LC (P=.068), and none of the sensitivity analyses showed any statistically significant differences in OS or DSS. CONCLUSIONS: In the treatment for unresectable biliary tract cancer, the addition of ILBT to RT has no impact on OS or DSS but is associated with better LC. Therefore, the role of ILBT should be addressed by other measures than survival benefit, for example, by less toxicity, prolonged biliary tract patency decreasing the need for further palliative interventions, or patient quality of life.

Factors influencing survival outcome for radiotherapy for biliary tract cancer: a multicenter retrospective study.

PURPOSE: To seek for the possible factors influencing overall survival (OS) with radiotherapy (RT) for biliary tract cancer. MATERIALS AND METHODS: Data were collected retrospectively from RT database of 31 institutions in Japan. All patients underwent at least external beam RT. The factors influencing OS were investigated. RESULTS: Data of 498 patients were analyzed. Median OS of the 212 patients who underwent surgery was significantly better than that of the 286 patients without surgery (31 vs. 15 months, p<0.001). The OS for the R0 or R1 resection group was significantly longer than that for the R2 or non-surgery group, as well as for n0 compared to n1 (all p<0.001). Chemoradiotherapy (CRT), both sequential and concurrent, resulted in a better OS than RT alone for the n1 group (31 vs. 13 months, p<0.001), and marginally better for the R0/R1 group (p=0.065; p=0.054 for concurrent CRT). However, no such benefit was observed for the R2/non-surgical patients. Multivariate analysis identified performance status, clinical stage, and surgery as significant factors. CONCLUSION: Surgery, especially R0/R1 resection, seemed as the gold standard for treatment of biliary tract cancer including RT, even in the highly heterogeneous population obtained from the multicenter retrospective study. The possibility was shown that CRT yielded better survival benefit especially for n1 patients. We recommend that future prospective trials include an arm of adjuvant CRT at least for n1 and possibly R0/R1 patients.

Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma.

PURPOSE/OBJECTIVES: To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m(2)/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. RESULTS: No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. CONCLUSIONS: Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

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.

Surveillance on interfacility differences in dose-prescription policy of intensity-modulated radiation therapy plans for prostate cancer.

Intensity-modulated radiation therapy (IMRT) has recently become popular in Japan. Prostate cancer is indisputably one of the main targets of IMRT. However, the current status and interfacility differences in dose-prescription policies for prostate IMRT are unknown. Therefore, a nationwide survey of 43 institutions that had implemented prostate IMRT was conducted by sending a questionnaire regarding the above-mentioned issues. Thirty-three institutions (77%) had responded to the questionnaire by the end of October 2010. A total of 5245 patients with localized prostate cancer had been treated with IMRT by the end of 2009. Regular multileaf collimator-based techniques were the most common beam delivery method. Dose-prescription policies were divided into four major categories: isocenter-based (@isocenter), dose delivered to 95% of the planning target volume (PTV) (D95)-based (D95@PTV), mean dose to the PTV-based (Mean@PTV), and mean dose to the clinical target volume (CTV)-based (@CTV). The mean doses of the CTV and PTV, and the volume of the PTV receiving 95% of the dose (V95) were significantly higher with the D95@PTV policy than with the other prescription policies. Low-dose areas and hot spots were observed within the PTV in plans with @isocenter and @CTV policies. In conclusion, there are currently considerable differences among institutions in Japan regarding target doses for prostate IMRT. The D95@PTV prescription policy resulted in significant dose escalation compared with the other policies. These differences should be taken into consideration when interpreting treatment outcomes and creating multi-institutional protocols in the future.

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.

Comparison of intensity modulated radiotherapy and dynamic three-dimensional conformal radiotherapy with regard to dose distribution and sparing of organs at risk.

Dose escalation to the target while sparing the organs at risk near the lesion has been difficult over the last decade. However, recent radiotherapy techniques can deliver more sophisticated doses to the target. This study evaluated whether intensity modulated radiotherapy can deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy while sparing organs at risk near the lesion in 13 patients with central nervous system tumors and other tumors around the central nervous system. Dynamic three-dimensional conformal radiotherapy and intensity modulated radiotherapy plans were calculated and dose distributions were compared for all patients with regard to the planning target volume and organs at risk. The plan of intensity modulated radiotherapy was significantly superior to that of dynamic three-dimensional conformal radiotherapy in target dose conformity (p = 0.0006) and organs at risk sparing (p = 0.0257). Intensity modulated radiotherapy could deliver more homogeneous and conformal doses to the target than dynamic three-dimensional conformal radiotherapy with sparing organs at risk near the lesion and may improve local control of radioresistant tumors via dose escalation.

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.

Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer.

PURPOSE: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m(2)/day from day 1 to 14 and 22 to 35. Two weeks after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. RESULTS: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. CONCLUSIONS: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.

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.

[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.