A survey for Management of Drug Safety Evaluation System for Investigational Product

Objective@#To gather the opinions of hands-on workers for successful introduction of the Development Safety Update Report (DSUR) according to a five-year comprehensive plan for clinical trial development [Ministry of Food and Drug Safety, 2019]. @*Methods@#We conducted a survey on considerations that industry stakeholders may have related to the enforcement of the DSUR. A questionnaire was distributed among pharmacovigilance specialists from 13 pharmaceutical companies in South Korea on June 4, 2020. The questionnaire comprised two sections: 1) current status of the Drug Safety Data Management System and 2) considerations on the implementation and management of the DSUR. @*Results@#All respondents have agreed the introduction of DSUR is inevitable for regulatory harmonization and safety of trial subject. However, most respondents (85%) felt concern about additional workload with DSUR implementation. They answered that format and operation system of DSUR should be harmonized with those of international standards and authorities need to minimize double burden due to related report. @*Conclusion@#All respondents asserted that domestic DSUR should be harmonized with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E2F guidelines. Respondents from global companies also suggested regulatory authorities allow DSUR written in English to replace Korean version considering their deadline for submission.Moreover, every respondent agreed regulatory authorities need delicate effort when implementing mandatory submission of DSUR to ensure that even small pharmaceutical companies with no experience in DSUR can comply with the system.

A survey for Management of Drug Safety Evaluation System for Investigational Product

Objective@#To gather the opinions of hands-on workers for successful introduction of the Development Safety Update Report (DSUR) according to a five-year comprehensive plan for clinical trial development [Ministry of Food and Drug Safety, 2019]. @*Methods@#We conducted a survey on considerations that industry stakeholders may have related to the enforcement of the DSUR. A questionnaire was distributed among pharmacovigilance specialists from 13 pharmaceutical companies in South Korea on June 4, 2020. The questionnaire comprised two sections: 1) current status of the Drug Safety Data Management System and 2) considerations on the implementation and management of the DSUR. @*Results@#All respondents have agreed the introduction of DSUR is inevitable for regulatory harmonization and safety of trial subject. However, most respondents (85%) felt concern about additional workload with DSUR implementation. They answered that format and operation system of DSUR should be harmonized with those of international standards and authorities need to minimize double burden due to related report. @*Conclusion@#All respondents asserted that domestic DSUR should be harmonized with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E2F guidelines. Respondents from global companies also suggested regulatory authorities allow DSUR written in English to replace Korean version considering their deadline for submission.Moreover, every respondent agreed regulatory authorities need delicate effort when implementing mandatory submission of DSUR to ensure that even small pharmaceutical companies with no experience in DSUR can comply with the system.

Risk Factors for Distant Metastasis as a Primary Site of Treatment Failure in Early-Stage Breast Cancer / 전남의대학술지

The aim of this study was to evaluate the risk factors for distant metastasis (DM) as a primary site of failure in early-stage breast cancer. Data from 294 patients diagnosed with pathologic stage I or II breast cancer between January 2000 and December 2005 were reviewed retrospectively. Median follow-up duration was 81.0 months (range, 18-135 months). The total number of patients with DM without evidence of locoregional recurrence was 20 and the median time between surgery and DM was 29 months (range, 9-79 months). Median survival time was 38 months (range, 22-77 months) after operation. HER-2 positivity (p=0.015), T stage of tumor (p=0.012), and number of involved lymph nodes (p=0.008) were significant predictors of DM in the univariable analysis. Number of involved lymph nodes [p=0.005, hazards ratio (HR): 1.741; 95% confidence interval (CI): 1.178-2.574] and HER-2 positivity (p=0.018, HR: 2.888; 95% CI: 1.201-6.941) had a statistically significant effect on DM-free survival in the multivariable analysis. A cautious evaluation may be helpful when patients with risk factors for DM have symptoms implying the possibility of DM. To reduce DM, applying intensive therapy is needed after curative surgery for patients with high risk for DM.

Risk Factors for Distant Metastasis as a Primary Site of Treatment Failure in Early-Stage Breast Cancer / 전남의대학술지

The aim of this study was to evaluate the risk factors for distant metastasis (DM) as a primary site of failure in early-stage breast cancer. Data from 294 patients diagnosed with pathologic stage I or II breast cancer between January 2000 and December 2005 were reviewed retrospectively. Median follow-up duration was 81.0 months (range, 18-135 months). The total number of patients with DM without evidence of locoregional recurrence was 20 and the median time between surgery and DM was 29 months (range, 9-79 months). Median survival time was 38 months (range, 22-77 months) after operation. HER-2 positivity (p=0.015), T stage of tumor (p=0.012), and number of involved lymph nodes (p=0.008) were significant predictors of DM in the univariable analysis. Number of involved lymph nodes [p=0.005, hazards ratio (HR): 1.741; 95% confidence interval (CI): 1.178-2.574] and HER-2 positivity (p=0.018, HR: 2.888; 95% CI: 1.201-6.941) had a statistically significant effect on DM-free survival in the multivariable analysis. A cautious evaluation may be helpful when patients with risk factors for DM have symptoms implying the possibility of DM. To reduce DM, applying intensive therapy is needed after curative surgery for patients with high risk for DM.

Esophageal tolerance to high-dose stereotactic radiosurgery

PURPOSE: Esophageal tolerance is needed to guide the safe administration of stereotactic radiosurgery (SRS). We evaluated comprehensive dose-volume parameters of acute esophageal toxicity in patients with spinal metastasis treated with SRS. MATERIALS AND METHODS: From May 2008 to May 2011, 30 cases in 27 patients with spinal metastasis received single fraction SRS to targets neighboring esophagus. Endpoints evaluated include length (mm), volume (mL), maximal dose (Gy), and series of dose-volume thresholds from the dose-volume histogram (volume of the organ treated beyond a threshold dose). RESULTS: The median time from the start of irradiation to development of esophageal toxicity was 2 weeks (range, 1 to 12 weeks). Six events of grade 1 esophageal toxicity occurred. No grade 2 or higher events were observed. V15 of external surface of esophagus was found to predict acute esophageal toxicity revealed by multivariate analysis (odds radio = 1.272, p = 0.047). CONCLUSION: In patients with spinal metastasis who received SRS for palliation of symptoms, the threshold dose-volume parameter associated with acute esophageal toxicity was found to be V15 of external surface of esophagus. Restrict V15 to external surface of esophagus as low as possible might be safe and feasible in radiosurgery.

Treatment outcome in patients with triple negative early stage breast cancers compared with other molecular subtypes

PURPOSE: To determine whether triple negative (TN) early stage breast cancers have poorer survival rates compared with other molecular types. MATERIALS AND METHODS: Between August 2000 and July 2006, patients diagnosed with stage I, II early stage breast cancers, in whom all three markers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor [HER]-2) were available and treated with modified radical mastectomy or breast conserving surgery followed by radiotherapy, were retrospectively reviewed. RESULTS: Of 446 patients, 94 (21.1%) were classified as TN, 57 (12.8%) as HER-2 type, and 295 (66.1%) as luminal. TN was more frequently associated with young patients younger than 35 years old (p = 0.002), higher histologic grade (p 0.05). CONCLUSION: We found that patients with TN early stage breast cancers had no difference in survival rates compared with other molecular subtypes. Prospective study in homogeneous treatment group will need for a prognosis of TN early stage breast cancer.

Permanent Brachytherapy of Localized Prostate Cancer: Preliminary Results / 대한방사선종양학회지

PURPOSE: To evaluate the biochemical control rate and the rate of side effects after performing permanent brachytherapy of localized prostate cancer. MATERIALS AND METHODS: 67 patients with localized prostate cancer were treated with brachytherapy between April 2007 and December 2008. Of these, 43 patients who were followed up and did not receive external radiotherapy were evaluated for the change in prostate specific antigen (PSA) level and the occurrence of side effects. In total, 18 patients were classified as low risk, 19 patients as intermediate risk, and 6 patients as high risk. The prescription dose was 145 Gy. RESULTS: A PSA increase greater than 2 ng/mL occurred in 2 patients (4.7%). Radiation Therapy Oncology Group (RTOG) grade 1 and 2 acute urologic complications (UC) occurred in 40 and 3 patients, respectively. Further, 5 patients had RTOG grade 1 acute rectal complication (RC). The numbers of RTOG grade 1, 2, and 3 chronic UC were 1, 4, and 1, respectively. The numbers of RTOG grade 1, 2, and 4 chronic RC were 5, 10, and 3, respectively. The statistically significant risk factors (RF) of acute RC were the minimal dose in the most irradiated 0.1 cc volume (D0.1CC, p=0.041) and absolute volume receiving 150% of the prescribed dose (V150cc, p=0.038) in the entire rectum (ER). The percentage (V100%, p=0.019) and absolute volume (V100cc, p=0.047) in the involved rectum (IR) were also statistically significant. The RF of chronic RC were V100% (p=0.011) in the ER and the D0.1cc (p=0.049), V100cc (p=0.023) in the IR. The number of used seeds were related with acute UC (p=0.028). CONCLUSION: Permanent brachytherpy of localized prostate cancer showed a favorable short term biochemical control rate. As such, selective intermediate and high risk patients can be managed with permanent brachytherapy. The effort to reduce rectal complication is also necessary.

A Correction Method of Dose to Attenuation Rate of Transmitting Photon Beam Through Couch Top for Radiosurgery Using Novalis / 의학물리

This study has its own goal to deliver the accurate dose on the target volume by calculating and modifying the attenuation rate of photon beam transmitting the couch top with geometric model. The experiment was that the transmission rate and attenuation rate of photon beam transmitting the couch top was predicted by the geometric model, then compared and analyzed with what was measured experimentally based on that. The result showed that the predicted value by the geometric model accorded closely with the experimental value. In addition, in order to judge whether the practical clinical application is available, the point dose, measured after modifying the attenuation rate modelinged according to the treatment plan of a patient of spine radiosurgery, was compared with the one done nothing. The result was that the former showed decreased error range with treatment planned one than the latter. This papers calculated the transmission and attenuation rate with the geometric model transmitting the couch top and verified it experimentally. This method is expected to be very useful in not only the radiosurgery using Novalis but also the general radiation therapy.

A comparison of preplan MRI and preplan CT-based prostate volume with intraoperative ultrasound-based prostate volume in real-time permanent brachytherapy

PURPOSE: The present study compared the difference between intraoperative transrectal ultrasound (iTRUS)-based prostate volume and preplan computed tomography (CT), preplan magnetic resonance imaging (MRI)-based prostate volume to estimate the number of seeds needed for appropriate dose coverage in permanent brachytherapy for prostate cancer. MATERIALS AND METHODS: Between March 2007 and March 2011, among 112 patients who underwent permanent brachytherapy with 125I, 60 image scans of 56 patients who underwent preplan CT (pCT) or preplan MRI (pMRI) within 2 months before brachytherapy were retrospectively reviewed. Twenty-four cases among 30 cases with pCT and 26 cases among 30 cases with pMRI received neoadjuvant hormone therapy (NHT). In 34 cases, NHT started after acquisition of preplan image. The median duration of NHT after preplan image acquisition was 17 and 21 days for cases with pCT and pMRI, respectively. The prostate volume calculated by different modalities was compared. And retrospective planning with iTRUS image was performed to estimate the number of 125I seed required to obtain recommended dose distribution according to prostate volume. RESULTS: The mean difference in prostate volume was 9.05 mL between the pCT and iTRUS and 6.84 mL between the pMRI and iTRUS. The prostate volume was roughly overestimated by 1.36 times with pCT and by 1.33 times with pMRI. For 34 cases which received NHT after image acquisition, the prostate volume was roughly overestimated by 1.45 times with pCT and by 1.37 times with pMRI. A statistically significant difference was found between preplan image-based volume and iTRUS-based volume (p < 0.001). The median number of wasted seeds is approximately 13, when the pCT or pMRI volume was accepted without modification to assess the required number of seeds for brachytherapy. CONCLUSION: pCT-based volume and pMRI-based volume tended to overestimate prostate volume in comparison to iTRUS-based volume. To reduce wasted seeds and cost of the brachytherapy, we should take the volume discrepancy into account when we estimate the number of 125I seeds for permanent brachytherapy.