Recurrence patterns and progression-free survival after chemoradiotherapy with or without consolidation durvalumab for stage III non-small cell lung cancer.

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM.

The safety and efficacy of durvalumab consolidation therapy in the management of patients with stage III non-small-cell lung cancer and preexisting interstitial lung disease.

BACKGROUND: Some lung cancer patients have preexisting interstitial lung disease (ILD), which is considered a risk factor for lung cancer treatment. This study investigated the safety and efficacy of durvalumab consolidation therapy for patients with stage III non-small-cell lung cancer (NSCLC) and preexisting ILD. METHODS: Fifty consecutive patients who were judged to be tolerable to concurrent chemoradiotherapy (CCRT) for stage III NSCLC were enrolled. Differences in the incidence rate of radiation pneumonitis (RP) and progression-free survival (PFS) were assessed in patients with or without ILD of which CT showed non-usual interstitial pneumonia pattern between the durvalumab consolidation group and chemotherapy (combination of carboplatin and paclitaxel [CP]) consolidation group. RESULTS: The incidence of RP was higher in patients with preexisting ILD (40% and 20% in the durvalumab and CP groups, respectively) than in those without ILD (26% and 8% in the durvalumab and CP groups, respectively). Univariate analysis showed that durvalumab therapy tended to increase the incidence of RP; however, preexisting ILD did not significantly increase the incidence of RP. The condition of all patients who developed RP improved with the administration of oral prednisolone. Among patients without ILD, the median PFS was 17 and 16 months in the durvalumab and CP groups, respectively. Among patients with preexisting ILD, median PFS was not achieved in the durvalumab group and was 8 months in the CP group. CONCLUSIONS: Although durvalumab consolidation therapy tended to increase the incidence of RP, it might be tolerable in stage III NSCLC patients with preexisting ILD.

Long-term outcomes of an esophagus-preserving chemoradiotherapy strategy for patients with endoscopically unresectable stage I thoracic esophageal squamous cell carcinoma.

BACKGROUND AND PURPOSE: To assess the long-term outcomes of a multimodal approach for maximum esophagus preservation in operable patients with endoscopically unresectable stage I thoracic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The medical records of patients with stage I thoracic ESCC treated with our protocol between 1992 and 2005 were retrospectively reviewed. Our protocol consisted of neoadjuvant concurrent chemoradiotherapy, followed by either additional definitive chemoradiotherapy for good responders (CRT group) or surgery for moderate or poor responders (CRT-S group) after an interim appraisal. RESULTS: A total of 51 patients were analysed. The median age of the patients was 67 years. The median follow-up period was 124.8 months. After the interim assessment, 49 and 2 cases were assigned to the CRT and CRT-S groups, respectively. In the intent-to-treat analyses, overall survival (OS), disease-free survival (DFS), cumulative incidence for death from esophageal cancer, and that for loss of esophageal function were 78.9%, 53.5%, 10.5%, and 20.4% at 5 years, and 55.2%, 27.8%, 18.2%, and 22.9% at 10 years, respectively. Grade 3 late toxicities occurred with the following incidences: esophageal stenosis in 1 case, esophageal ulcer in 1 case, and pericardial effusion in 2 cases. No grade 4 or higher toxicities were observed. CONCLUSION: Long-term survival and esophagus preservation outcomes were favorable, with acceptable toxicities. Our results suggest that CCRT is an alternative treatment for majority of operable patients with endoscopically unresectable stage I thoracic ESCC in combination with salvage therapy.

Incidence and Risk Factors of Symptomatic Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy and Consolidation Durvalumab.

INTRODUCTION: Data on the risk factors for symptomatic radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemoradiotherapy (CCRT) and consolidation durvalumab are limited; we aimed to investigate these risk factors. MATERIALS AND METHODS: This multicenter retrospective study, conducted at 15 institutions in Japan, included patients who were ≥20 years of age; who started definitive CCRT for NSCLC between July 1, 2018, and July 31, 2019; and who then received durvalumab. The primary endpoint was grade 2 or worse (grade 2+) RP. RESULTS: In the 146 patients analyzed, the median follow-up period was 16 months. A majority of the patients had stage III disease (86%), received radiation doses of 60 to 66 Gy equivalent in 2-Gy fractions (93%) and carboplatin and paclitaxel/nab-paclitaxel (77%), and underwent elective nodal irradiation (71%) and 3-dimensional conformal radiotherapy (75%). RP grade 2 was observed in 44 patients (30%); grade 3, in four patients (3%); grade 4, in one patient (1%); and grade 5, in one patient (1%). In the multivariable analysis, lung V20 was a significant risk factor, whereas age, sex, smoking history, irradiation technique, and chemotherapy regimen were not. The 12-month grade 2+ RP incidence was 34.4% (95% confidence interval [CI], 26.7%-42.1%); the values were 50.0% (95% CI, 34.7%-63.5%) and 27.1% (95% CI, 18.8%-36.2%) in those with lung V20 ≥ 26% and < 26%, respectively (P = .007). CONCLUSION: The incidence of grade 2+ RP was relatively high in this multicenter real-world study, and its risk increased remarkably at elevated lung V20. Our findings can aid in RP risk prediction and the safe radiotherapy treatment planning.

Phase I/II Study of Cisplatin plus Nab-Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.

Application and limitation of radiomics approach to prognostic prediction for lung stereotactic body radiotherapy using breath-hold CT images with random survival forest: A multi-institutional study.

PURPOSE: To predict local recurrence (LR) and distant metastasis (DM) in early stage non-small cell lung cancer (NSCLC) patients after stereotactic body radiotherapy (SBRT) in multiple institutions using breath-hold computed tomography (CT)-based radiomic features with random survival forest. METHODS: A total of 573 primary early stage NSCLC patients who underwent SBRT between January 2006 and March 2016 and met the eligibility criteria were included in this study. Patients were divided into two datasets: training (464 patients in 10 institutions) and test (109 patients in one institution) datasets. A total of 944 radiomic features were extracted from manually segmented gross tumor volumes (GTVs). Feature selection was performed by analyzing inter-segmentation reproducibility, GTV correlation, and inter-feature redundancy. Nine clinical factors, including histology and GTV size, were also used. Three prognostic models (clinical, radiomic, and combined) for LR and DM were constructed using random survival forest (RSF) to deal with total death as a competing risk in the training dataset. Robust models with optimal hyper-parameters were determined using fivefold cross-validation. The patients were dichotomized into two groups based on the median value of the patient-specific risk scores (high- and low-risk score groups). Gray's test was used to evaluate the statistical significance between the two risk score groups. The prognostic power was evaluated by the concordance index with the 95% confidence intervals (CI) via bootstrapping (2000 iterations). RESULTS: The concordance indices at 3 yr of clinical, radiomic, and combined models for LR were 0.57 [CI: 0.39-0.75], 0.55 [CI: 0.38-0.73], and 0.61 [CI: 0.43-0.78], respectively, whereas those for DM were 0.59 [CI: 0.54-0.79], 0.67 [CI: 0.54-0.79], and 0.68 [CI: 0.55-0.81], respectively, in the test dataset. The combined DM model significantly discriminated its cumulative incidence between high- and low-risk score groups (P < 0.05). The variable importance of RSF in the combined model for DM indicated that two radiomic features were more important than other clinical factors. The feature maps generated on the basis of the most important radiomic feature had visual difference between high- and low-risk score groups. CONCLUSIONS: The radiomics approach with RSF for competing risks using breath-hold CT-based radiomic features might predict DM in early stage NSCLC patients who underwent SBRT although that may not have potential to predict LR.

Agreement between patients' and radiation oncologists' cancer diagnosis and prognosis perceptions: A cross sectional study in Japan.

This study assessed agreement between radiation oncologist- and cancer patient-reported perceptions about cancer diagnosis, time since diagnosis, treatment purpose, and whether life expectancy had been discussed; and described preferences for prognosis discussions. Adult cancer patients receiving radiotherapy at a Japanese hospital were invited to complete a touchscreen tablet survey. Patient survey responses were linked and comparisons made with a survey completed by their radiation oncologist. Among 146 cancer patient-oncologist dyads, there was almost perfect agreement on cancer diagnosis (ĸ = 0.88, 95% CI: 0.82-0.94), substantial agreement on time since diagnosis (ĸ = 0.70, 95% CI: 0.57-0.83) and moderate agreement on whether treatment goal was curative or palliative (ĸ = 0.44, 95% CI: 0.28-0.57; all p's < 0.0001). Agreement about whether a life expectancy discussion had occurred was less than expected by chance (κ = -0.06, p = 0.9). Radiation oncologists reported that they had spoken to over two thirds of patients about this, whilst less than one third of patients stated that this discussion had occurred with their radiation oncologist. Over half of the patients who had not discussed life expectancy wanted to. Patients had variable preferences for whether they (80%), their radiation oncologist (78%) or their partner/family (52%) should decide whether they discuss their life expectancy. Although patient self-reported information about diagnosis and time since diagnosis appears to be reasonably accurate (compared with clinician-reported information), limitations of self-reported data about prognostic discussions were highlighted by poor agreement between patient- and clinician-reported information about whether prognostic discussions have occurred. Additional support is needed to improve prognosis communication and understanding in radiation oncology settings.

The Use of External-beam Radiotherapy for Muscle-invasive Bladder Cancer in Elderly or Medically-fragile Patients.

AIM: To evaluate the clinical results of external-beam radiotherapy (EBRT) for muscle-invasive bladder cancer (MIBC) in elderly or medically-fragile patients. PATIENTS AND METHODS: Twenty-five consecutive patients with MIBC (cT2-4N0-1M0) receiving EBRT were retrospectively analyzed. Their median age was 82 years. Radiotherapy median dose was 60 Gy administered in 30 fractions. RESULTS: Median follow-up period was 14.7 months. Median overall survival (OS) and progression-free survival (PFS) were 14.7 months and 7.8 months, respectively. The OS, cause-specific survival (CSS), and PFS rates at 1-year were 56.0%, 68.5%, and 40.0%, respectively. The local progression-free rates (LPFR) at 6 months and 1 year were 89.3% and 59.5%, respectively. Performance status 3 was a significantly unfavorable factor for OS, CSS, and progression-free survival; clinical N stage was a significantly unfavorable factor for progression-free survival; and lower irradiation dose (≤50.4 Gy) was a significantly unfavorable factor for LPFR. CONCLUSION: EBRT for elderly or medically-fragile patients is feasible, and achieves acceptable local progression-free status.

Regional recurrence in breast cancer patients with one to three positive axillary lymph nodes treated with breast-conserving surgery and whole breast irradiation.

Radiotherapy with breast-conserving therapy plays a crucial role in the treatment of early breast cancer. However, optimal radiotherapy targets have been controversial. We therefore evaluated regional recurrence in breast cancer patients with one to three positive lymph nodes (LNs) treated with breast-conserving surgery (BCS) followed by whole-breast irradiation (WBI). From 1993 to 2010, 121 breast cancer patients with one to three positive LNs who underwent BCS followed by WBI were analyzed. All patients underwent radiotherapy with two tangential fields to the whole breast. To evaluate the radiation dose to the axillary LNs, we contoured axillary LNs area and evaluated the dose-volumetric parameters. The median follow-up time was 112.4 months (range, 15.6-248.1 months). The 5-year overall survival and disease-free survival rates were 95.6% and 86.6%, respectively. The 5-year regional recurrence-free rate (RRFR) was 97.4%. During follow-up, six patients had regional recurrence. The pathological T stage was the factor best associated with the 5-year RRFR using the log-rank test, with 100.0% in the pT1 cohort versus 94.7% in the pT2-4 cohort (P < 0.01). The radiation dose to the axillary LNs did not contribute to the RRFR. In conclusion, while the pathological T stage was the prognostic factor best associated with regional recurrence, few regional recurrences were observed in early breast cancer patients with one to three LNs treated with BCS followed by WBI. Unintentional radiation doses to the axillary LNs using standard WBI were not related to the RRFR after axillary dissection.

Improvement of registration accuracy in accelerated partial breast irradiation using the point-based rigid-body registration algorithm for patients with implanted fiducial markers.

PURPOSE: To investigate image-registration errors when using fiducial markers with a manual method and the point-based rigid-body registration (PRBR) algorithm in accelerated partial breast irradiation (APBI) patients, with accompanying fiducial deviations. METHODS: Twenty-two consecutive patients were enrolled in a prospective trial examining 10-fraction APBI. Titanium clips were implanted intraoperatively around the seroma in all patients. For image-registration, the positions of the clips in daily kV x-ray images were matched to those in the planning digitally reconstructed radiographs. Fiducial and gravity registration errors (FREs and GREs, respectively), representing resulting misalignments of the edge and center of the target, respectively, were compared between the manual and algorithm-based methods. RESULTS: In total, 218 fractions were evaluated. Although the mean FRE/GRE values for the manual and algorithm-based methods were within 3 mm (2.3/1.7 and 1.3/0.4 mm, respectively), the percentages of fractions where FRE/GRE exceeded 3 mm using the manual and algorithm-based methods were 18.8%/7.3% and 0%/0%, respectively. Manual registration resulted in 18.6% of patients with fractions of FRE/GRE exceeding 5 mm. The patients with larger clip deviation had significantly more fractions showing large FRE/GRE using manual registration. CONCLUSIONS: For image-registration using fiducial markers in APBI, the manual registration results in more fractions with considerable registration error due to loss of fiducial objectivity resulting from their deviation. The authors recommend the PRBR algorithm as a safe and effective strategy for accurate, image-guided registration and PTV margin reduction.

Assessment of interfractional prostate motion in patients immobilized in the prone position using a thermoplastic shell.

The aim of this study was to evaluate the interfractional prostate motion of patients immobilized in the prone position using a thermoplastic shell. A total of 24 patients with prostate calcifications detectable using a kilo-voltage X-ray image-guidance system (ExacTrac X-ray system) were examined. Daily displacements of the calcification within the prostate relative to pelvic bony structures were calculated by the ExacTrac X-ray system. The average displacement and standard deviation (SD) in each of the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were calculated for each patient. Based on the results of interfractional prostate motion, we also calculated planning target volume (PTV) margins using the van Herk formula and examined the validity of the PTV margin of our institute (a 9-mm margin everywhere except posteriorly, where a 6-mm margin was applied). In total, 899 data measurements from 24 patients were obtained. The average prostate displacements ± SD relative to bony structures were 2.8 ± 3.3, -2.0 ± 2.0 and 0.2 ± 0.4 mm, in the SI, AP and LR directions, respectively. The required PTV margins were 9.7, 6.1 and 1.4 mm in the SI, AP and LR directions, respectively. The clinical target volumes of 21 patients (87.5%) were located within the PTV for 90% or more of all treatment sessions. Interfractional prostate motion in the prone position with a thermoplastic shell was equivalent to that reported for the supine position. The PTV margin of our institute is considered appropriate for alignment, based on bony structures.

Initial and cumulative recurrence patterns of glioblastoma after temozolomide-based chemoradiotherapy and salvage treatment: a retrospective cohort study in a single institution.

PURPOSE: To analyze initial recurrence patterns in patients with newly diagnosed glioblastoma after radiotherapy plus concurrent and adjuvant temozolomide, and to investigate cumulative recurrence patterns after salvage treatment, including surgery, stereotactic radiotherapy, and chemotherapy. METHODS: Twenty-one patients with glioblastoma that recurred after concurrent temozolomide and localized radiotherapy were retrospectively analyzed (11 male, 10 female; median age, 57 years; range, 27-74). Disease progression was assessed by new response criteria proposed by the Response Assessment in Neuro-Oncology Working Group of the American Society of Clinical Oncology. The pattern of recurrence was determined by relationships between locations of recurrent tumors and irradiated doses. Central, in-field, marginal, and out-field recurrences were defined relative to the prescribed isodose line. Distant recurrence was operationally defined as subependymal or disseminated disease. Initial and cumulative patterns of recurrence were evaluated in each patient. RESULTS: The median follow-up of the recurrent patients was 501 (range, 217-1815) days after initial surgery. Initial recurrences were central in 14 patients (66.7%), in-field in four patients (19.0%), marginal in no patient (0%), out-field in two patients (9.5%), and distant in four patients (19.0%). One patient had both central and in-field recurrences simultaneously, and two had both central and distant recurrences. In the analysis of cumulative recurrence patterns, five patients, who had no scans after initial recurrences, were excluded and the remaining 16 were included. Cumulative recurrences were central in 11 patients (68.8%), in-field in five patients (31.3%), marginal in three patients (18.8%), out-field in five patients (31.3%), and distant in 14 patients (87.5%). Regarding salvage treatments, 11 (52.4%), 11 (52.4%) and 17 (81.0%) patients underwent surgery, stereotactic radiotherapy and chemotherapy, respectively. Eighteen (85.7%) patients had died at the time of analysis, and 16 of them (88.9%) had suffered distant recurrences, which could have been the immediate causes of death. CONCLUSIONS: Recurrence patterns of glioblastoma after radiotherapy plus concomitant and adjuvant temozolomide were mainly central at first, and distant recurrences were often detected during the clinical course. Much better local control and prevention of distant recurrence, including effective salvage treatment, seem to be important.

Efficacy of intraoperative radiotherapy targeted to the abdominal lymph node area in patients with esophageal carcinoma.

We investigated whether intraoperative radiotherapy (IORT) during curative surgery for esophageal carcinoma is useful or not. The cases of 117 patients diagnosed with thoracoabdominal esophageal carcinoma who underwent curative surgery between 1986 and 2007 were reviewed: 72 patients received IORT (IORT group) and 45 did not (non-IORT group). Upper abdominal lymphadenectomy was performed in 115 patients (98.5%). Seventy patients (59.8%) received chemotherapy and 80 patients (68.4%) received external radiotherapy. IORT encompassed the upper abdominal lymph node area. A single-fraction dose of 20-30 Gy was delivered using high-energy electrons. Median follow-up duration for patients was 7.4 years. The 5-year overall survival rate did not significantly differ between the IORT and non-IORT groups. However, the 5-year abdominal control rate was significantly higher in the IORT group (89.2%) than in the non-IORT group (72.9%; P = 0.022). We next focused on a patient subgroup with a primary lesion in the lower thoracic or abdominal esophagus or measuring >6 cm in length since this subgroup is probably at high risk of upper abdominal lymph node metastasis. Of the 117 patients, 75 belonged to this subgroup, and among them 45 received IORT. Both univariate and multivariate analysis revealed the survival rate was significantly higher in patients who received IORT than in those who did not (P = 0.033 univariate; 0.026 multivariate). There were no obvious perioperative complications solely attributed to IORT. IORT for esophageal carcinoma will likely be effective for patients with a primary lesion in the lower thoracic or abdominal esophagus, or with a long lesion.

Outcomes of hypofractionated stereotactic radiotherapy for metastatic brain tumors with high risk factors.

The present study aimed to analyze outcomes of hypofractionated stereotactic radiotherapy (HFSRT) delivered in five fractions to metastatic brain tumors. Between June 2008 and June 2011, 39 consecutive patients with 46 brain metastases underwent HFSRT at Kyoto University Hospital. Selection criteria included high risk factors such as eloquent location, history of whole-brain radiotherapy (WBRT), or large tumor size. Given these factors, fractionated schedules were preferable in terms of radiobiology. The prescribed dose at the isocenter was basically 35 Gy in five fractions. Brainstem lesions with a history of WBRT were treated with 20-25 Gy in five fractions. Planning target volume was covered by the 80 % isodose line of the prescribed dose to the isocenter. Local-control probability and overall survival were estimated using the Kaplan-Meier method. For the analysis of local control, the response criteria were defined as follows: complete response (CR) was defined as no visible gross tumor or absence of contrast enhancement, partial response (PR) as more than a 30 % decrease in size, progressive disease as more than a 20 % increase in size, and stable disease (SD) as all other responses. Local control was defined as a status of CR, PR, or SD. Only patients with at least 3 months or longer follow-up (21 patients, 27 tumors) were included in the analysis. Median age and Karnofsky performance status were 59 years (range, 39-84 years) and 90 (range, 40-100), respectively. Tumor volumes and maximum diameters ranged from 0.08 to 15.38 cm(3) (median, 3.67 cm(3)) and from 3 to 34 mm (median, 18 mm), respectively. The median follow-up period was 329 days (range, 120-1,321 days). Local-control probabilities at 6 and 12 months were 92.1 and 86.7 %, respectively. Overall survival after HFSRT at 6 and 12 months was 85.4 and 64.5 %, respectively. Grade 3 radiation necrosis was observed in one patient according to the Common Terminology Criteria for Adverse Events version 3.0. The patient was successfully managed conservatively. HFSRT for metastatic brain tumors yields high local-control probabilities without increasing severe adverse events despite high risk factors.

Long-term outcomes of three-dimensional conformal radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with T1c-T2N0M0 prostate cancer.

BACKGROUND: The outcomes of three-dimensional conformal radiation therapy (3D-CRT) combined with neoadjuvant hormonal therapy (NAHT) in Japanese patients with T1c-T2N0M0 prostate cancer, with initiation of salvage hormonal therapy (SHT) at a relatively early phase, were analyzed. METHODS: Fifty-nine Japanese patients with T1c-T2N0M0 prostate cancer who received radical 3D-CRT between January 1999 and January 2003 were evaluated. The median age, initial prostate-specific antigen (PSA) level, and duration of NAHT were: 72 years, 9.4 ng/ml, and 6 months, respectively. Seventy Gy was given in 35 fractions confined to the prostate ± seminal vesicles. AHT was not administered after 3D-CRT in any patients. RESULTS: The median follow-up period was 89 months. The median PSA value at the time of initiation of SHT was 4.7 ng/ml (range 0.1-21.6 ng/ml). The overall, disease-specific, PSA failure-free (based on the Phoenix definition), and SHT-free survival rates at 8 years were 82.8% (95% confidence interval [CI] 72.4-93.2), 100%, 62.4% (47.1-77.8), and 82.6% (71.3-94.0), respectively. Only one patient developed grade 3 late toxicity. CONCLUSIONS: The PSA control rates in our series of Japanese patients with stage T1c-T2N0M0 prostate cancer treated with the standard dose of 3D-CRT combined with NAHT seemed at least comparable to those reported from Western countries; as well, the patients had excellent outcomes. The present outcomes can be used as basic data for evaluating the impact of dose escalation with intensity-modulated radiation therapy for Japanese patients with prostate cancer in the future.

External-beam radiotherapy for localized or locally advanced prostate cancer in Japan: a multi-institutional outcome analysis.

BACKGROUND: The outcomes of patients with localized or locally advanced prostate cancer treated with external-beam radiotherapy are not well known in Japan. METHODS: Thirty-four institutions combined data on 679 patients with localized or locally advanced prostate cancer treated with a total dose >/=60 Gy between 1995 and 2002. RESULTS: With a median follow-up of 46 months, the 5-year overall, clinical progression-free, and biochemical relapse-free survival rate were 93.0, 95.3 and 71.9% for all patients, respectively. The 5-year progression-free, and biochemical relapse-free survival rates according to the risk group were 100%, 90.8% in the low-risk group, 98.3%, 75.7% in the intermediate-risk group and 93.6%, 67.6% in the high-risk group, respectively. The multivariate analysis for biochemical relapse-free survival revealed that prostate-specific antigen (relative risk, 1.002; 95% CI, 1.001-1.003; P = 0.0041), Gleason score (relative risk, 1.166; 95% CI, 1.046-1.302; P = 0.0055), T classification (relative risk, 2.897; 95% CI, 1.999-4.230; P = 0.0000), pelvic irradiation (relative risk, 2.042; 95% CI, 1.328-3.273; P = 0.0008), and androgen abletion (relative risk, 0.321; 95% CI, 0.240-0.427; P = 0.0000) were significant prognostic factors. Only 1.1% of patients experienced late morbidity of Grade 3. CONCLUSION: Radiotherapy for prostate cancer seemed to be effective, with little risk of normal tissue complications.

A tumor-specific gene therapy strategy targeting dysregulation of the VHL/HIF pathway in renal cell carcinomas.

Hypoxia-inducible factors, key transcription factors for hypoxia-dependent gene expression, play important roles in angiogenesis and tumor growth. The VHL protein binds to the alpha subunit of (HIF-alpha) for its oxygen-dependent degradation. VHL mutations are found frequently in sporadic RCC. Disruption of VHL results in an abnormal accumulation of HIF-alpha, leading to the upregulation of downstream genes such as the vascular endothelial growth factor gene. We constructed a luciferase reporter vector driven by hypoxia-responsive elements (5HRE/luc) and a therapeutic vector expressing a herpes simplex virus thymidine kinase gene (5HRE/tk). In the transient transfection assay using VHL-deficient 786-O cells, constitutive luciferase expression was detected under both aerobic and hypoxic conditions. In contrast, 786-O cells transfected with a wild-type VHL showed hypoxia-inducible luciferase activity. In in vitro MTS assay, 50% of growth inhibition of 786-O cells stably transfected with 5HRE/tk was achieved with exposure to 0.2 microg/mL of GCV under both aerobic and hypoxic conditions. Xenografts of the stable clone in SCID mice exhibited a marked regression on daily injections of GCV (50 mg/kg) for 10 days. In conclusion, a hypoxia-responsive vector may have therapeutic potential for RCC with VHL mutations.

Real-time imaging of hypoxia-inducible factor-1 activity in tumor xenografts.

Hypoxia-inducible factor-1 (HIF-1) is responsible for various gene expressions related to tumor malignancy, such as metastasis, invasion and angiogenesis. Therefore, monitoring HIF-1 activity in solid tumors is becoming increasingly important in clinical and basic studies. To establish a convenient system for visualizing HIF-1 activity in tumor xenografts, we employed a promoter consisting of five copies of hypoxia response elements (5HRE), whose activity depends on HIF-1, and used a derivative of green fluorescence protein (d2EGFP) as a reporter gene. A human melanoma cell line, Be11, which contains the 5HRE-d2EGFP gene, showed fluorescence in response to hypoxia. The fluorescent intensity correlated inversely with the surrounding oxygen tension, and was time-dependent for the hypoxic treatment. Reoxygenation resulted in a rapid decrease in fluorescence due to the signal sequence for protein degradation encoded in d2EGFP, which enabled monitoring of HIF-1 activity in real-time. Heterogeneous fluorescence was observed in the solid tumor of a non-sacrificed tumor-bearing mouse. Immunohistochemical analysis confirmed that d2EGFP-expressing regions overlapped with the ones stained with a hypoxia marker, pimonidazole. These results suggest that the 5HRE-d2EGFP gene is suitable for the real-time imaging of HIF-1-activating cells in vivo, due to the short half-life of the d2EGFP protein as well as the specificity of the 5HRE promoter for HIF-1 activity.

Influences of the p53 status on hypoxia-induced gene expression.

The p53 tumor-suppressor gene is one of the most frequently mutated genes in human cancers, and its genetic alterations may play critical roles in oncogenesis, tumor progression, and angiogenesis. To clarify the influence of the p53 status on hypoxia-inducible gene expression, we first performed transfection assays with a hypoxia-responsive vector carrying 5 hypoxia-responsive elements upstream of the human CMV minimal promoter driving transcription of the luciferase gene in various human tumor cell lines with wild-type (wt) or mutant (mut) p53. As a result, hypoxia responsiveness considerably varied between cell lines, and we could not obtain clear evidence that the hypoxia-inducible factor-1 (HIF-1) mediated gene expression in the wt-p53 cells was lower than that in cells with mut-p53. It is interesting that SaOS2 cells (p53 null) showed the highest luciferase activities under both aerobic and hypoxic conditions among tested cells. Next, to elucidate the effects of endogenous wt- and mut-p53s, a transfection assay and Northern blot analysis for VEGF transcription under hypoxia were performed by using isogenic variants of HT1080 cells differing in their p53 status. The luciferase and the endogenous VEGF mRNA expression were apparently lower in a variant carrying mutations in both p53 alleles than in a parental line harboring wt-p53, implying that some types of mutant p53 constitutively accumulated in cells can decrease both the basal and the hypoxia-induced expressions in addition to wt-p53.