Late genitourinary toxicity in salvage radiotherapy for prostate cancer after radical prostatectomy: impact of daily fraction doses.

OBJECTIVE: To evaluate the impact of daily fraction doses on late genitourinary (GU) toxicity after salvage radiotherapy (SRT) for prostate cancer. METHODS: This multi-institutional retrospective study included 212 patients who underwent SRT between 2008 and 2018. All patients received image-guided intensity-modulated SRT at a median dose of 67.2 Gy in 1.8-2.3 Gy/fraction. The cumulative rates of late grade ≥2 GU and gastrointestinal (GI) toxicities were compared using Gray test, stratified by the ≤2.0 Gy/fraction (n = 137) and ≥2.1 Gy/fraction groups (n = 75), followed by multivariate analyses. The total dose was represented as an equivalent dose in 2-Gy fractions (EQD2) with α/ß = 3 Gy. RESULTS: After a median follow-up of 63 months, the cumulative rates of 5-year late grade ≥2 GU and GI toxicities were 14% and 2.5%, respectively. The cumulative rates of 5-year late grade ≥2 GU toxicity in the ≥2.1 Gy/fraction and ≤2.0 Gy/fraction groups were 22% and 10%, respectively (P = .020). In the multivariate analysis, ≥2.1 Gy/fraction was still associated with an increased risk of late grade ≥2 GU toxicity (hazard ratio, 2.37; 95% confidence interval, 1.12-4.99; P = .023), while the total dose was not significant. CONCLUSION: The present results showed that ≥2.1 Gy/fraction resulted in a higher incidence of late grade ≥2 GU toxicity in SRT. ADVANCES IN KNOWLEDGE: The impact of fraction doses on late GU toxicity after SRT remains unknown. The results suggest that higher fraction doses may increase the risk of late GU toxicity in SRT.

Impact of radiation doses on clinical relapse of biochemically recurrent prostate cancer after prostatectomy.

The relationship between radiation doses and clinical relapse in patients receiving salvage radiotherapy (SRT) for biochemical recurrence (BCR) after radical prostatectomy (RP) remains unclear. We identified 292 eligible patients treated with SRT between 2005 and 2018 at 15 institutions. Clinical relapse-free survival (cRFS) between the ≥ 66 Gy (n = 226) and < 66 Gy groups (n = 66) were compared using the Log-rank test, followed by univariate and multivariate analyses and a subgroup analysis. After a median follow-up of 73 months, 6-year biochemical relapse-free survival, cRFS, cancer-specific survival, and overall survival rates were 58, 92, 98, and 94%, respectively. Six-year cRFS rates in the ≥ 66 Gy and < 66 Gy groups were 94 and 87%, respectively (p = 0.022). The multivariate analysis revealed that Gleason score ≥ 8, seminal vesicle involvement, PSA at BCR after RP ≥ 0.5 ng/ml, and a dose < 66 Gy correlated with clinical relapse (p = 0.015, 0.012, 0.024, and 0.0018, respectively). The subgroup analysis showed the consistent benefit of a dose ≥ 66 Gy in patients across most subgroups. Doses ≥ 66 Gy were found to significantly, albeit borderline, increase the risk of late grade ≥ 2 GU toxicity compared to doses < 66 Gy (14% vs. 3.2%, p = 0.055). This large multi-institutional retrospective study demonstrated that a higher SRT dose (≥ 66 Gy) resulted in superior cRFS.

Comparison of intensity-modulated radiotherapy with the 5-field technique, helical tomotherapy and volumetric modulated arc therapy for localized prostate cancer.

The outcomes of three methods of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. Between 2010 and 2018, 308 D'Amico intermediate- or high-risk patients were treated with 2.2 Gy daily fractions to a total dose of 74.8 Gy in combination with hormonal therapy. Overall, 165 patients were treated with 5-field IMRT using a sliding window technique, 66 were then treated with helical tomotherapy and 77 were treated with volumetric modulated arc therapy (VMAT). The median age of patients was 71 years. The median follow-up period was 75 months. Five-year overall survival (OS) and biochemical or clinical failure-free survival (FFS) rates were 95.5 and 91.6% in the 5-field IMRT group, 95.1 and 90.3% in the tomotherapy group and 93.0 and 88.6% in the VMAT group, respectively, with no significant differences among the three groups. The 5-year cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 7.3 and 6.2%, respectively, for all patients. Late grade ≥2 gastrointestinal toxicities were less frequent in patients undergoing VMAT (0%) than in patients undergoing 5-field IMRT (7.3%) and those undergoing tomotherapy (11%) (P = 0.025), and this finding appeared to be correlated with the better rectal DVH parameters in patients undergoing VMAT. Other toxicities did not differ significantly among the three groups, although bladder dose-volume parameters were slightly worse in the tomotherapy group than in the other groups. Despite differences in the IMRT delivery methods, X-ray energies and daily registration methods, all modalities may be used as IMRT for localized prostate cancer.

Changes in pulmonary function and their correlation with dose-volume parameters in patients undergoing stereotactic body radiotherapy for lung cancer.

It is desirable to estimate the degree of the decrease in pulmonary function before lung stereotactic body radiation therapy (SBRT) especially for patients with poor pulmonary function. The purpose of this study was to investigate whether decreases in pulmonary function after SBRT may be predicted from radiation dose-volume parameters. A total of 70 patients undergoing SBRT were evaluated for changes in pulmonary function. Of these, 67 had primary lung cancer and 3 had lung metastasis. Twenty-six (37%) patients had chronic obstructive pulmonary disease. Pulmonary function tests (PFTs) were performed shortly before and at 18-24 months after SBRT. Radiation pneumonitis was Grade 2 in 10 patients and Grade 3 in 1. Mean forced vital capacity (FVC) decreased from 2.67 to 2.51 L (P < 0.01) and mean forced expiratory volume in 1 s (FEV1) decreased from 1.80 to 1.72 L (P < 0.01). Planning target volume (PTV) was correlated with changes in FVC. Changes in percent predicted FVC were correlated with %V5Gy (% of lung volume receiving > 5 Gy) and %V40Gy. Although the correlation was not significant, the %V20Gy value was the closest to the percent reduction in predicted FVC; %V20Gy of 10% tended to be associated with ~10% reduction in predicted FVC. Patients with poor pulmonary function did not necessarily show greater decreases in each PFT parameter. Decreases in FVC and FEV1 were within previously reported ranges. PTV was associated with decreases in FVC. The %V20Gy value was closest to the percentage decrease in predicted FVC.

Early salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy: Its impact and optimal candidate.

AIM: We aimed to identify the optimal candidates for early salvage radiotherapy (SRT) among patients with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: This multi-institutional retrospective study included 371 patients treated using SRT after RP. The median (range) PSA level at BCR was 0.36 (0.10-2.00) ng/mL. The association between early SRT (ie, starting PSA level < 0.50) and BCR after SRT was tested in each subgroup according to our own risk stratification. RESULTS: The median follow-up time was 51 months. By multivariate analysis, pT3b, Gleason score ≥ 8, negative surgical margins, PSA doubling time < 6 months, and non-early SRT were associated with BCR after SRT. Patients were stratified by four risk factors other than non-early SRT: (1) low risk (0 risk factor), (2) intermediate risk (1 risk factor), and (3) high risk (≥2 risk factors). The BCR-free survival was higher in the early SRT group than the nonearly SRT group in the high-risk subgroup (P = 0.020), whereas that was similar between two groups in the low-risk and intermediate-risk subgroups (P = .79 and .18, respectively). Multivariate analysis revealed that early SRT was beneficial for the high-risk subgroup (P = .032), whereas early SRT was not associated with improved outcomes in the low-risk and intermediate-risk subgroups (P = .92 and 1.0, respectively). CONCLUSIONS: This study suggested that early SRT seemed to contribute to better biochemical control for patients with more adverse features, whereas no benefit was observed in men with no adverse features.

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy.

The safety and efficacy of dose-escalated radiotherapy with intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) remain unclear in salvage radiotherapy (SRT) after radical prostatectomy. We examined the impact of these advanced radiotherapy techniques and dose intensification on the toxicity of SRT. This multi-institutional retrospective study included 421 patients who underwent SRT at the median dose of 66 Gy in 2-Gy fractions. IMRT and IGRT were used for 225 (53%) and 321 (76%) patients, respectively. At the median follow-up of 50 months, the cumulative incidence of late grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicities was 4.8% and 24%, respectively. Multivariate analysis revealed that the non-use of either IMRT or IGRT, or both (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.8-5.4, p < 0.001) and use of whole-pelvic radiotherapy (HR 7.6, CI 1.0-56, p = 0.048) were associated with late GI toxicity, whereas a higher dose ≥68 Gy was the only factor associated with GU toxicities (HR 3.1, CI 1.3-7.4, p = 0.012). This study suggested that the incidence of GI toxicities can be reduced by IMRT and IGRT in SRT, whereas dose intensification may increase GU toxicity even with these advanced techniques.

Low-dose Gamma Knife radiosurgery plus whole-brain radiation therapy for patients with 5 or more brain metastases with or without meningeal dissemination.

PURPOSE/OBJECTIVE(S): Radiosurgery plus whole-brain radiotherapy (WBRT) has been reported to be useful for patients with ≤ 4 brain metastases (BM), but we hypothesized that similar treatment may be applicable to patients with ≥ 5 BM with or without meningeal dissemination. The purpose of this study was to evaluate the efficacy and toxicity of low-dose Gamma Knife (GK) followed by WBRT for patients with advanced BM. MATERIALS/METHODS: Major eligibility criteria for this phase II study were: (1) ≥ 5 BM with or without meningeal dissemination and (2) the largest tumor diameter ≤ 4 cm. During 2013-2016, 40 patients (13 men and 27 women) entered the study. Nineteen had meningeal dissemination. The GK dose was 12 Gy at the periphery when the longest diameter was 3-4 cm and 14 Gy when it was < 3 cm. The WBRT dose to the isocenter was 30 Gy in 10 fractions, or 37.5 Gy in 15 fractions for two patients, with an expected survival of > 12 months. The median number of target BM was 17.5. RESULTS: After GK plus WBRT for 40 patients, 31 did not develop further intracranial recurrence until death or last follow-up, whereas 9 developed recurrence. With a follow-up period up to 24 months, the overall survival rate was 36% at 12 months and median survival time was 8 months. The cumulative incidence of intracranial recurrence was 25% at 12 months. Toxicity was considered acceptable. CONCLUSION: Treatment with low-dose GK followed by WBRT for advanced-stage BM appeared to contribute to local control.

Long-term results of intensity-modulated radiotherapy with three dose-fractionation regimens for localized prostate cancer.

We evaluated long-term outcomes of three protocols of intensity-modulated radiation therapy (IMRT) for localized prostate cancer. Between 2005 and 2014, 348 patients were treated with 5-field IMRT. The first 74 patients were treated with a daily fraction of 2.0 Gy to 74 Gy (low-risk prostate cancer) or 78 Gy (intermediate- or high-risk prostate cancer); then 101 patients were treated with 2.1-Gy daily fractions to 73.5 or 77.7 Gy. More recently, 173 patients were treated with 2.2-Gy fractions to 72.6 or 74.8 Gy. The median age of all patients was 70 years and the median follow-up period was 82 months. The median follow-up periods were 124 months in the 2.0-Gy group, 98 months in the 2.1-Gy group, and 69 months in the 2.2-Gy group. The overall and prostate-specific antigen (PSA) failure-free survival (PSA-FFS) rates were, respectively, 89 and 68% at 10 years for the 2.0-Gy group, 91 and 84% at 8 years for the 2.1-Gy group, and 93 and 92% at 6 years for the 2.2-Gy group. The PSA-FFS rate for high-risk patients in all groups was 80% at 7 years. The cumulative incidences of Grade ≥2 late genitourinary (GU) and gastrointestinal (GI) toxicity were, respectively, 7.2 and 12.4% at 10 years for the 2.0-Gy group, 7.4 and 14.1% at 8 years for the 2.1-Gy group, and 7.1 and 7.9% at 6 years for the 2.2-Gy group. All three fractionation schedules yielded good tumor control with acceptable toxicities.

[Making Patient-focused Information Provision a Reality: One Company's Approach].

　In recent years, as the market has seen the appearance of innovative medical products with novel mechanisms of action, adverse reactions that cannot be expected from the approved product label are being detected in the postmarketing phase. It is increasingly important to undertake timely product label updates and other drug safety measures through the monitoring, early detection, and reporting of adverse reactions. In 2013, the risk management plan (RMP) system was introduced in Japan. An RMP documents efforts to ensure the safety of a medical product, and sharing the RMP with stakeholders results in enhanced postmarketing safety measures. Healthcare providers have already started to utilize RMPs, but issues with perception and utilization remain. The industry, regulators, and academia are also working together to facilitate the use of RMPs. With the implementation of the RMP requirement, pharmaceutical companies are seeking to improve safety assurance by enhancing their drug safety functions, including the collection, assessment, and dissemination of drug safety information. Chugai Pharmaceutical is starting a completely new approach to patient-focused information provision, exemplified by the "PMS & SAFETY DB Tools," designed to give healthcare providers quick access to its extensive database of real-world drug safety information. This paper introduces Chugai Pharmaceutical's new efforts to manage adverse reactions and raises issues for future consideration.

Robustness of the neurological prognostic score in brain metastasis patients treated with Gamma Knife radiosurgery.

OBJECTIVE The neurological prognostic score (NPS) was recently proposed as a means for predicting neurological outcomes, such as the preservation of neurological function and the prevention of neurological death, in brain metastasis patients treated with Gamma Knife radiosurgery (GKRS). NPS consists of 2 groups: Group A patients were expected to have better neurological outcomes, and Group B patients were expected to have poorer outcomes. NPS robustness was tested in various situations. METHODS In total, 3040 patients with brain metastases that were treated with GKRS were analyzed. The cumulative incidence of the loss of neurological function independence (i.e., neurological deterioration) was estimated using competing risk analysis, and NPS was compared between Groups A and B by employing Gray's model. NPS was tested to determine if it can be applied to 5 cancer categories-non-small cell lung cancer, small cell lung cancer, gastrointestinal tract cancer, breast cancer, and other cancers-as well as if it can be incorporated into the 5 major grading systems: recursive partitioning analysis (RPA), score index for stereotactic radiosurgery (SIR), basic score for brain metastases (BSBM), graded prognostic assessment (GPA), and modified-RPA (M-RPA). RESULTS There were 2263 patients in NPS Group A and 777 patients in Group B. Neurological deterioration was observed in 586 patients (19.2%). The cumulative incidences of neurological deterioration were 9.5% versus 21.0%, 14.1% versus 25.4%, and 17.6% versus 27.8% in NPS Groups A and B at 1, 2, and 5 years, respectively. Significant differences were detected between the NPS groups in all cancer categories. There were significant differences between NPS Groups A and B for all classes in terms of the BSBM, GPA, and M-RPA systems, but the differences failed to reach statistical significance in terms of RPA Class I and SIR Class 0 to 3. CONCLUSIONS The NPS was verified as being highly applicable to all cancer categories and almost all classes for the 5 grading systems in terms of neurological function independence. This NPS system appears to be quite robust in various situations for brain metastasis patients treated with GKRS.

Fractionated stereotactic radiotherapy for metastatic brain tumors that recurred after gamma knife radiosurgery results in acceptable toxicity and favorable local control.

BACKGROUND: To treat local recurrence of brain metastases after gamma knife radiosurgery (GKS), we have used fractionated stereotactic radiotherapy (SRT). The purpose of this study was to evaluate the efficacy and toxicity of SRT in these patients. METHODS: Fifty locally recurrent metastatic brain tumors in 47 patients were treated with SRT. The median prescribed dose of GKS was 20 Gy at the periphery. The median interval between the GKS (the last session in cases in which multiple GKS procedures were performed) and recurrence was 7.5 (range 1-33) months. Several dose-fractionation protocols were used for SRT, depending on the size and location of the tumor and previous GKS dose. The median prescribed dose of the SRT at the isocenter was 30 Gy with a median of ten fractions. RESULTS: Among the 50 lesions treated with SRT, 26 did not recur locally before the patient's death or the last follow-up examination, and 24 recurred locally. The median follow-up period for the surviving patients was 24 months after the first GKS procedure, and the overall survival rate was 80% at 1 year and 57% at 2 years. The median time to local re-recurrence after the SRT (16 months) was significantly longer than the median interval between the last GKS and recurrence (7.5 months; P < 0.001). Only two patients developed ≥grade 2 radiation necrosis. CONCLUSIONS: Stereotactic radiotherapy appeared to be an effective treatment for recurrent metastatic brain tumors and yielded relatively good local control. The associated adverse events were generally acceptable.

Patterns of practice in the radiation therapy for bladder cancer: survey of the Japanese Radiation Oncology Study Group (JROSG).

OBJECTIVE: To retrospectively analyze the clinical outcomes of radiation therapy with or without chemotherapy for bladder cancer in Japan. METHODS: A questionnaire-based survey of patients with pathologically proven bladder cancer treated by definitive radiation therapy between 2002 and 2006 was conducted by the Japanese Radiation Oncology Study Group, and the clinical records of 159 patients were collected from 17 institutions. Concurrent intra-arterial chemoradiotherapy and concurrent systemic chemoradiotherapy were administered in 51 and 33 patients, respectively. RESULTS: The 5-year overall survival and bladder preservation rates were 48 and 39%, respectively. Eighty-nine (56%) patients developed recurrence (bladder, 48; regional lymph nodes, 4; distant sites, 41). The results of multivariate analysis revealed that adoption of chemotherapy was the only significant prognostic factor for overall survival (relative risk = 0.615 [95% confidence interval: 0.439-0.862], P = 0.005). The type of chemotherapy administered did not significantly affect the local control or overall survival rates. The actuarial 5-year overall survival rates and bladder preservation in the radiation therapy combined with intra-arterial chemotherapy group were 64 and 58%, respectively, and the corresponding rates in the radiation therapy combined with systemic chemotherapy group were 67 and 42%, respectively. CONCLUSIONS: The results of this survey revealed the current status of practice of radiation therapy for bladder cancer in Japan. A multi-institutional prospective study is needed based on the results of this study to determine the optimal radiotherapeutic approach, including the need for concurrent chemotherapy and the appropriate chemotherapy regimen for invasive bladder cancer.

Adjuvant radiotherapy after prostatectomy for prostate cancer in Japan: a multi-institutional survey study of the JROSG.

In Japan, the use of adjuvant radiotherapy after prostatectomy for prostate cancer has not increased compared with the use of salvage radiotherapy. We retrospectively evaluated the outcome of adjuvant radiotherapy together with prognostic factors of outcome in Japan. Between 2005 and 2007, a total of 87 patients were referred for adjuvant radiotherapy in 23 institutions [median age: 64 years (54-77 years), median initial prostate-specific antigen: 11.0 ng/ml (2.9-284 ng/ml), Gleason score (GS): 6, 7, 8, 9, 10 = 13.8, 35.6, 23.0, 27.6, 0%, respectively]. Rates of positive marginal status, seminal vesicle invasion (SVI) and extra-prostatic extension (EPE) were 74%, 26% and 64%, respectively. Median post-operative PSA nadir: 0.167 ng/ml (0-2.51 ng/ml). Median time from surgery to radiotherapy was 3 months (1-6 months). A total dose of ≥ 60 Gy and <65 Gy was administered to 69% of patients. The median follow-up time was 62 months. The 3- and 5-year biochemical relapse-free survival (bRFS) rates for all patients were 66.5% and 57.1%, respectively. The GS and marginal status (P = 0.019), GS and SVI (P = 0.001), marginal status and EPE (P = 0.017), type of hormonal therapy and total dose (P = 0.026) were significantly related. The 5-year bRFS rate was significantly higher in SVI-negative patients than SVI-positive patients (P = 0.001), and significantly higher in patients with post-operative PSA nadir ≤ 0.2 than in patients with post-operative PSA nadir >0.2 (P = 0.02), and tended to be more favorable after radiotherapy ≤ 3 months from surgery than >3 months from surgery (P = 0.069). Multivariate analysis identified SVI and post-operative PSA nadir as independent prognostic factors for bRFS (P = 0.001 and 0.018, respectively).

Toxicity and efficacy of three dose-fractionation regimens of intensity-modulated radiation therapy for localized prostate cancer.

Outcomes of three protocols of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. A total of 259 patients treated with 5-field IMRT between 2005 and 2011 were analyzed. First, 74 patients were treated with a daily fraction of 2.0 Gy to a total of 74 Gy (low risk) or 78 Gy (intermediate or high risk). Then, 101 patients were treated with a 2.1-Gy daily fraction to 73.5 or 77.7 Gy. More recently, 84 patients were treated with a 2.2-Gy fraction to 72.6 or 74.8 Gy. The median patient age was 70 years (range, 54-82) and the follow-up period for living patients was 47 months (range, 18-97). Androgen deprivation therapy was given according to patient risk. The overall and biochemical failure-free survival rates were, respectively, 96 and 82% at 6 years in the 2.0-Gy group, 99 and 96% at 4 years in the 2.1-Gy group, and 99 and 96% at 2 years in the 2.2-Gy group. The biochemical failure-free rate for high-risk patients in all groups was 89% at 4 years. Incidences of Grade ≥ 2 acute genitourinary toxicities were 9.5% in the 2.0-Gy group, 18% in the 2.1-Gy group, and 15% in the 2.2-Gy group (P = 0.29). Cumulative incidences of Grade ≥ 2 late gastrointestinal toxicity were 13% in the 2.0-Gy group at 6 years, 12% in the 2.1-Gy group at 4 years, and 3.7% in the 2.2-Gy group at 2 years (P = 0.23). So far, this stepwise shortening of treatment periods seems to be successful.

Treatment and prognosis of patients with late rectal bleeding after intensity-modulated radiation therapy for prostate cancer.

BACKGROUND: Radiation proctitis after intensity-modulated radiation therapy (IMRT) differs from that seen after pelvic irradiation in that this adverse event is a result of high-dose radiation to a very small area in the rectum. We evaluated the results of treatment for hemorrhagic proctitis after IMRT for prostate cancer. METHODS: Between November 2004 and February 2010, 403 patients with prostate cancer were treated with IMRT at 2 institutions. Among these patients, 64 patients who developed late rectal bleeding were evaluated. Forty patients had received IMRT using a linear accelerator and 24 by tomotherapy. Their median age was 72 years. Each patient was assessed clinically and/or endoscopically. Depending on the severity, steroid suppositories or enemas were administered up to twice daily and Argon plasma coagulation (APC) was performed up to 3 times. Response to treatment was evaluated using the Rectal Bleeding Score (RBS), which is the sum of Frequency Score (graded from 1 to 3 by frequency of bleeding) and Amount Score (graded from 1 to 3 by amount of bleeding). Stoppage of bleeding over 3 months was scored as RBS 1. RESULTS: The median follow-up period for treatment of rectal bleeding was 35 months (range, 12-69 months). Grade of bleeding was 1 in 31 patients, 2 in 26, and 3 in 7. Nineteen of 45 patients (42%) observed without treatment showed improvement and bleeding stopped in 17 (38%), although mean RBS did not change significantly. Eighteen of 29 patients (62%) treated with steroid suppositories or enemas showed improvement (mean RBS, from 4.1 ± 1.0 to 3.0 ± 1.8, p = 0.003) and bleeding stopped in 9 (31%). One patient treated with steroid enema 0.5-2 times a day for 12 months developed septic shock and died of multiple organ failure. All 12 patients treated with APC showed improvement (mean RBS, 4.7 ± 1.2 to 2.3 ± 1.4, p < 0.001) and bleeding stopped in 5 (42%). CONCLUSIONS: After adequate periods of observation, steroid suppositories/enemas are expected to be effective. However, short duration of administration with appropriate dosage should be appropriate. Even when patients have no response to pharmacotherapy, APC is effective.

Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR).

INTRODUCTION: Interstitial lung disease (ILD) is an adverse drug reaction (ADR) of concern in Japanese patients with non-small-cell lung cancer (NSCLC) receiving erlotinib. To investigate erlotinib safety and efficacy in Japanese patients, a large-scale surveillance study was implemented. METHODS: All patients with recurrent/advanced NSCLC receiving erlotinib in Japan were enrolled (December 2007-October 2009). During the 12-month observation period, adverse-event data were collected; any adverse event where erlotinib could not be excluded as a causative factor was termed an ADR. An independent review committee assessed ILD-like events. Overall survival and progression-free survival were also assessed. Interim data were analyzed for patients registered before June 30, 2008. RESULTS: In total, 10,708 patients were enrolled, 3743 by June 30, 2008, with data available for 3488 patients. Overall ADR incidence was 81.8% (mostly grade 1/2); skin disorders (68.5%) including rash (63.0%) were most common. However, 81.8% of patients who experienced rash recovered or improved. ILD-like events, diagnosed by local physicians, were reported in 189 patients. The independent review committee confirmed ILD (all grades) in 158 patients (4.5% of interim population) with a mortality rate of 1.6% (55 patients). Significant ILD risk factors included concomitant or previous ILD, smoking history, concomitant or previous lung infection, and Eastern Cooperative Oncology Group performance status 2 to 4. Median overall survival and progression-free survival were 260 and 64 days, respectively. CONCLUSIONS: These interim data support the clinical benefits of erlotinib in Japanese NSCLC patients with no new safety signals. The risk/benefit balance for erlotinib in recurrent/advanced NSCLC remains favorable.

Progression of non-small-cell lung cancer during the interval before stereotactic body radiotherapy.

PURPOSE: To investigate the relationship between waiting time (WT) and disease progression in patients undergoing stereotactic body radiotherapy (SBRT) for lung adenocarcinoma (AD) or squamous cell carcinoma (SQ). METHODS AND MATERIALS: 201 patients with Stage I AD or SQ undergoing SBRT between January 2004 and June 2010 were analyzed. The WT was defined as the interval between diagnostic computed tomography before referral and computed tomography for treatment planning or positioning before SBRT. Tumor size was measured on the slice of the longest tumor diameter, and tumor volume was calculated from the longest diameter and the diameter perpendicular to it. Changes in tumor volume and TNM stage progression were evaluated, and volume doubling time (VDT) was estimated. RESULTS: The median WT was 42 days (range, 5-323 days). There was a correlation between WT and rate of increase in volume in both AD and SQ. The median VDTs of AD and SQ were 170 and 93 days, respectively. Thirty-six tumors (23%) did not show volume increase during WTs >25 days. In 41 patients waiting for ≤4 weeks, no patient showed T stage progression, whereas in 25 of 120 (21%) patients waiting for >4 weeks, T stage progressed from T1 to T2 (p = 0.001). In 10 of 110 (9.1%) T1 ADs and 15 of 51 (29%) T1 SQs, T stage progressed (p = 0.002). N stage and M stage progressions were not observed. CONCLUSION: Generally, a WT of ≤4 weeks seems to be acceptable. The WT seems to be more important in SQ than in AD.

Statistical and theoretical investigations on the directionality of nonbonded S...O interactions. Implications for molecular design and protein engineering.

Weak nonbonded interactions between a divalent sulfur (S) atom and a main-chain carbonyl oxygen (O) atom have recently been characterized in proteins. However, they have shown distinctly different directional propensities around the O atom from the S...O interactions in small organic compounds, although the linearity of the C-S...O or S-S...O atomic alignment was commonly observed. To elucidate the observed discrepancy, a comprehensive search for nonbonded S.O interactions in the Cambridge Structural Database (CSD) and MP2 calculations on the model complexes between dimethyl disulfide (CH(3)SSCH(3)) and various carbonyl compounds were performed. It was found that the O atom showed a strong intrinsic tendency to approach the S atom from the backside of the S-C or S-S bond (in the sigma(S) direction). On the other hand, the S atom had both possibilities of approach to the carbonyl O atom within the same plane (in the n(O) direction) and out of the plane (in the pi(O) direction). In the case of S...O(amide) interactions, the pi(O) direction was significantly preferred as observed in proteins. Thus, structural features of S...O interactions depend on the type of carbonyl groups involved. The results suggested that S.O interactions may control protein structures to some extent and that the unique directional properties of S...O interactions could be applied to molecular design.