• Communications for Statistical Applications and Methods
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• 제29권4호
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• pp.421-439
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• 2022

Phase I dose-finding trials are essential in drug development. By finding the maximum tolerated dose (MTD) of a new drug or treatment, a Phase I trial establishes the recommended doses for later-phase testing. The primary toxicity endpoint of interest is often a binary variable, which describes an event of a patient who experiences dose-limiting toxicity. However, there is a growing interest in dose-finding studies regarding non-binary outcomes, defined by either the weighted sum of rates of various toxicity grades or a continuous outcome. Although several novel methods have been proposed in the literature, accessible software is still lacking to implement these methods. This study introduces a newly developed R package, UnifiedDoseFinding, which implements three phase I dose-finding methods with non-binary outcomes (Quasi- and Robust Quasi-CRM designs by Yuan et al. (2007) and Pan et al. (2014), gBOIN design by Mu et al. (2019), and by a method by Ivanova and Kim (2009)). For each of the methods, UnifiedDoseFinding provides corresponding functions that begin with next that determines the dose for the next cohort of patients, select, which selects the MTD defined by the non-binary toxicity endpoint when the trial is completed, and get oc, which obtains the operating characteristics. Three real examples are provided to help practitioners use these methods. The R package UnifiedDoseFinding, which is accessible in R CRAN, provides a user-friendly tool to facilitate the implementation of innovative dose-finding studies with nonbinary outcomes.

• Asian Pacific Journal of Cancer Prevention
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• 제14권3호
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• pp.1781-1786
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• 2013

Objective: The study was designed to assess the skin and subcutaneous toxicity in patients with advanced colorectal carcinoma treated with four different schedules of FOLFOX. Methods: The patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study as per specified inclusion criteria. Toxicity was graded according to CTC v2.0. The frequency of grade 3 and 4 adverse effects were comparatively assessed in each treatment arm. Results: Very severe toxicity was attributed to the FOLFOX7 schedule. The difference between the incidence rate of grade 4 toxicity with all other grades for all parameters of skin and subcutaneous toxicity was highly significant (p=0.00<0.001). Grade 4 hand and foot syndrome was reported only in the FOLFOX7 treatment arm. The most frequent adverse symptom of skin and subcutaneous toxicity reported in the patients treated with modified schedule of FOLFOX was pruritus (grade 1). Frequency and onset of skin and subcutaneous toxic symptoms like alopecia (p=0.000), nail discoloration (p=0.021) and pruritis (p=0.000) was significantly different in each FOLFOX treatment arm. A few cases of oncholysis were also reported in the FOLFOX7 treatment arm. Hand and foot syndrome was fast progressing in patients with grade 1 toxicity. Conclusion: Higher frequency and severity of hand and foot syndrome and pruritus wasa found in the FOLFOX7 treatment arm. Skin and subcutaneous toxicity was comparatively low in the FOLFOX6 treatment arm.

• Asian Pacific Journal of Cancer Prevention
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• 제15권3호
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• pp.1145-1148
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• 2014

Background: Single pegylated liposomal doxorubicin (PLD) is commonly used as a salvage treatment in platinum-resistant ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma (PPA) with a satisfactory outcome. However, the data for second generation PLD administered in this setting are still limited. We conducted a retrospective study to evaluate the outcome of patients who received single-agent second generation PLD (LIPO-DOX) after the development of clinical platinum resistance. The study period was between March 2008 and March 2013. LIPO-DOX was administered intravenously 40 $mg/m^2$ every 28 days until disease progression, but for not more than six cycles. The response rate was evaluated using the Gynecologic Cancer Intergroup (GCIG) criteria while the toxicity was evaluated according to WHO criteria. Twenty-nine patients met the inclusion criteria in the study period with an overall response rate of 13.8%. The median progression free survival and overall survival were three and eleven months, respectively. With the total of 96 cycles of chemotherapy, the patients developed grades 3 and 4 hematologic toxicity as follows: anemia, 0%, leukopenia, 9.6%, neutropenia, 32.3% and thrombocytopenia, 0%. In conclusion, the single agent second generation PLD demonstrated modest efficacy in patients with platinum-resistant ovarian cancer, fallopian tube cancer and PPA without serious toxicity.

• Journal of Society of Preventive Korean Medicine
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• 제19권2호
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• pp.123-133
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• 2015

The new formular for herbal medicine-safety classification in terms of evidence-based medicine was developed and applied to evaluate various herbal medicines in the previous study. This study is aimed to evaluate the frequently-used herbal medicines inducing toxic metabolites or reactive intermediates(RI), such as Ligusticum wallichii Franch, Angelica sinensis, Glycyrrhizae Radix, Rehmanniae Radix, based on 6 safety grades calculated from human equivalent dose(HED)-based MOS(margin of safety). HED-based MOS can be explained as the ratio of theoretical ALD(approximate lethal dose) of human as $LD_1$(lethal dose of 1%)/ clinical maximum dose as $ED_{99}$(Effective dose of 99%). The herbal medicine showing the ratio less than 1 belongs to Class 1, but the herbal medicine showing the ratio more than 500 belongs to Class 6 with the lowest toxicity. As a result, they were evaluated as class 2 for Angelica sinensis and Glycyrrhizae Radix, class 3 for Ligusticum wallichii Franch and Rehmanniae Radix. These resultant grades for 4 herbal medicines were lower than the grade expected under consideration that these herbal medicines are used very frequently in oriental clinics. These low grades would be due to their ingredients which is biotransformed to toxic metabolites.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8089-8093
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• 2014

Background: To assess the frequency and severity of gastrointestinal adverse effects in advanced colorectal carcinoma patients treated with four different schedules of FOLFOX. Materials and Methods: Patients (median age 61 years) who underwent surgery were included in the study. All had measureable disease at CT scan, ultrasonography or clinical examination. Toxicity was graded on a scale of 1-5 according to the general grade definition of CTC v2.0. The severity of adverse effects (Grade 3 and 4) assessed in each treatment arm was compared. Results: Differences between the incidence rates of 3 and 4 toxicity and all grades of toxicity for all parameters in GI toxicity were very highly significant (p<0.001). Severe gastrointestinal symptoms of toxicity were noted with FOLFOX7 (oxaliplatin $130mg/m^2$). Grade 3 diarrhea was reported in 25% patients and grade 4 diarrhea in 4% in the FOLFOX7 treatment arm. Grade 2 vomiting was very frequently reported in the FOLFOX4 treatment arm (oxaliplatin $85mg/m^2$). Grade 2 stomatitis was reported in 42% patients treated with mFOLFOX6 (oxaliplatin $100mg/m^2$). Differences in the incidence rate of nausea, diarrhea and stomatitis among all treatment arms of FOLFOX were significant (p<0.05). Conclusions: Severe diarrhea is associated with FOLFOX7 treatment. No grade 3 or 4 GI toxicity was reported in patients of the mFOLFOX6 arm.

• Journal of The Korean Society of Clinical Toxicology
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• 제9권2호
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• pp.49-55
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• 2011

Purpose: Acetanilide has been in widespread use as an amide herbicide compound. However, available data regarding acute human poisoning is scarce. The aim of this study was to analyze the clinical characteristics of acetanilide poisoning in order to identify the risk factors associated with severity. Methods: We conducted a retrospective observational study encompassing the period January 2005 to December 2010, including adult ED patients suffering from acetanilide intoxication. Toxicological history, symptoms observed, clinical signs of toxicity, and laboratory test results were collected for each patient. The patients were classified into two groups for analysis, according their poisoning severity score (PSS). Resulting clinical data and prognostic variables were compared between mild-to-moderate poisoning (PSS 1/2 grades), and severe poisonings and fatalities (PSS 3/4 grades). Results: There were a total of 37 patients, including 26 alachlor, 6 s-metolachlor, 4 mefenacet, and 1 butachlor cases. The majority of patients (81.1%) were assigned PSS 1/2 grades. Changes in mental status and observation of adverse neurologic symptoms were more common in the PSS 3/4 group. The median ingested volume of amide herbicide compound was 250 ml (IQR 200-300 ml) in the PSS 3/4 group, and 80 ml (IQR 50-138 ml) in the PSS 1/2 group. Also, the median GCS observed in the PSS 3/4 group was 13 (IQR 10-14), which was markedly low as compared to a median GCS of 15 in the PSS 1/2 group. Overall mortality rate was 5.4%, and profound cardiogenic shock was observed prior to death in all fatalities. Conclusion: When compared to previous reports, acute acetanilide poisoning resulted in relatively moderate severity. The presence of neurologic manifestations, hypotension, lower GCS score, and larger ingested volumes was associated with more serious effects and mortalities.

• Asian Pacific Journal of Cancer Prevention
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• 제13권2호
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• pp.517-520
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• 2012

Single original gemcitabine is commonly used as salvage treatment in platinum-resistant ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma (PPA) with a satisfactory outcome. However, efficacy data fro this regimen are limited. We therefore conducted a retrospective study to evaluate the outcome of patients who received single-agent generic gemcitabine (GEMITA) after development of clinical platinum resistance. The study period was between May 2008 and December 2010. Gemcitabine was administered intravenously in two different schedules: 1,000 $mg/m^2$ on day 1,8, and 15 every 28 days; and on days 1 and 8 every 21 days with the same dosage. Administration was until disease progression was noted. The response rate was evaluated using the Gynecologic Cancer Intergroup (GCIG) criteria while toxicity was evaluated according to WHO criteria. Sixty-six patients met the inclusion criteria in the study period. Two-thirds of them received gemcitabine as the second and third line regimen. The overall response rate was 12.1%. The median progression free survival and overall survival was 2 and 10 months, respectively. With the total 550 courses of chemotherapy,the patients developed grades 3 and 4 hematologic toxicity as follows: anemia, 1.5%; leukopenia, 13.7%; neutropenia, 27.3%; and thrombocytopenia, 3.0%. In conclusion, single agent generic gemcitabine revealed a modest efficacy in patients with platinum-resistant ovarian cancer, fallopian tube cancer and PPA without serious toxicity.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3587-3592
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• 2014

Burden of cancer is progressively increasing in developing countries like India which has also led to a steep rise in toxicity due to anti-cancer therapy. A cross-sectional analysis was here conducted for patients with different malignancies (except leukaemia) who while undergoing radical anti-cancer therapy were admitted to our oncology ward from January-July 2013. In a total of 280 patients, the total number of toxicity events was 473. Nine patients expired over this time period. Among the events, grade 2 anaemia the most common (n=189) while the most common grades of neutropenia and thrombocytopenia were grade 4 (n=114) and grade 2 (n=48), respectively. Among the tracable microbial etiologies, gram negative bacteria were the most commonly found pathogens. Treatment interruptions took place in 240 patients (median duration=8.8 days). Prolonged hospital admission, intensive care and artificial ventilation support was needed to be given in 48, 7 and 13 patients respectively. Advanced NSCLC, KPS <70, pancytopenia and artificial ventilation requirement were found to have a significant impact on death. Such studies show the prevailing practice from institutes of our country and may guide us formulating a guideline for managing such toxicities for this part of the world.

• Environmental Analysis Health and Toxicology
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• 제25권1호
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• pp.41-55
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• 2010

The aims of this study were to develop the suitable "system software" in chemical ranking and scoring (CRS) for the food hazardous chemicals associated with environmental emission and to suggest the priority lists of food contamination by environmental-origined pollutants. Study materials were selected with reference to the priority pollutants list for environment and food management from domestic and foreign research and the number of study materials is 103 pollutants (18 heavy metals, 10 PBTs, 10 EDs, and 65 organic compounds). The Food-CRS-Korea system consisted of the environmental fate model via multimedia, transfer environment to food model, and health risk assessment by contaminated food intake. We have established that health risks of excess cancer risks, hazard quotients (HQs) by chronic toxicity and HQs by reproductive toxicity convert to score, respectively. The creditable scoring system was designed to consider uncertainty of quantitative risk assessment based on VOI (Value-Of-Information). The predictability of the Food-CRS-Korea model was evaluated by comparing the presumable values and the measured ones of the environmental media and foodstuffs. The priority lists based on emissions with background-level-correction are 15 pollutants such as arsenic, cadmium, and etc. The priority lists based on environmental monitoring date are 17 pollutants including DEHP, TCDD, and so on. Consequently, we suggested the priority lists of 13 pollutants by considering the several emission and exposure scenarios. According to the Food-CRS-Korea system, arsenics, cadmium, chromes, DEHP, leads, and nickels have high health risk rates and reliable grades.

• Hwankyungkyoyuk
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• 제11권2호
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• pp.144-155
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• 1998

This research aims to perceive the present state of science experimental education practiced in middle school and also to improve the laboratorial environment. Accordingly, this study surveyed 297 middle school science teachers in Seoul to examine the risks and accidents occurred during lab sessions, the conditions of chemical waste disposal, and whether or not teacher's manual clearly states cautions on toxic chemicals. About 70%(69.6%) of science teachers were highly concerned about risks and toxicity of chemicals used in classes, 59.9% experienced actual accidents, and 83.2% were anxiety of incidents caused by chemicals. Besides, 55.2% of science teachers answered that they have little knowledge about caring noxious chemicals used in lab sessions. So it turns out that they need more specific education on handling toxic chemicals. More than one third(36.7%) answered that they disposed of chemical waste water without any special care or kept it in the lab after experiments. The number of chemicals as well used in middle school curriculum is increasing as grades gets higher toxic chemicals. However, there are few teachers' manual covering how to handle noxious chemicals. Therefore, in middle school curriculum the number of poisonous chemicals should be minimized as much as possible, and in case the toxic chemicals have to be used, teacher's guide book should state precautions on handling chemicals in detail. Also government should make it obligatory on schools to instate ventilator for chemical waste, or to transport the waste to proper disposal systems.