La aprobación de CoronaVac en Brasil y Chile: algunas lecciones sobre los retos regulatorios de vacunas / Approval of CoronaVac in Brazil and Chile: some lessons on vaccine regulatory challenges / A aprovação da CoronaVac no Brasil e no Chile: algumas lições sobre os desafios regulatórios de vacinas

RESUMEN Este análisis compara y sistematiza algunos hitos de la aprobación en Brasil y Chile de la vacuna CoronaVac del laboratorio chino Sinovac, desde diciembre 2020 hasta octubre 2021, respecto de cómo se fundamentó su eficacia e inmunogenicidad. A tal fin se realizó un análisis exhaustivo de la documentación oficial pública sobre la aprobación de la vacuna en ambos países; asimismo, se consideraron artículos técnicos pertinentes sobre la materia, y la divulgación y discusión realizada en los medios de comunicación. En uno y otro caso se expresó nítidamente una puja de una amplia gama de actores privados y públicos en torno a la medición y difusión de las cifras de eficacia. Esto permite visualizar los sendos retos que enfrentan y enfrentarán los países de medianos ingresos para certificar la calidad de productos en una era epidemiológica pandémica, y la necesidad de fortalecer institucionalmente las autoridades regulatorias, para viabilizar una evaluación proba y certera de la calidad de las vacunas, en cuanto a su seguridad y eficiencia.

ABSTRACT This analysis compares and systematizes some of the milestones (between December 2020 and October 2021) in the approval by Brazil and Chile of the CoronaVac vaccine made by the Chinese laboratory Sinovac, with regard to how the efficacy and immunogenicity of the vaccine was determined. To this end, a comprehensive analysis was conducted of official public documentation of the vaccine's approval in both countries; likewise, relevant technical articles on the subject, as well as dissemination and discussion in the media were considered. In both cases, a wide range of private and public actors expressed clearly competing interests in the measurement and dissemination of figures on the vaccine's efficacy. This reveals the challenges that middle-income countries face—and will continue to face—when certifying the quality of products in a pandemic period, and the need to institutionally strengthen regulatory authorities to ensure a sound and accurate evaluation of vaccine quality, in terms of safety and efficiency.

RESUMO Esta análise compara e sistematiza alguns marcos da aprovação, no Brasil e no Chile, da vacina CoronaVac, do laboratório chinês Sinovac, de dezembro de 2020 a outubro de 2021, especificamente sobre como sua eficácia e imunogenicidade foram fundamentadas. Para tanto, foi realizada uma análise exaustiva da documentação pública oficial sobre a aprovação da vacina em ambos os países. Da mesma forma, foram considerados artigos técnicos pertinentes sobre o assunto, e divulgações e discussões realizadas na mídia. Em ambos os casos, uma disputa de interesses de uma ampla gama de atores privados e públicos em torno da medição e divulgação dos números referentes à eficácia foi claramente expressa. Isso permite visualizar os enormes desafios que os países de renda média enfrentam e enfrentarão para certificar a qualidade dos produtos em um contexto epidemiológico de pandemia e a necessidade de fortalecer institucionalmente as autoridades reguladoras para viabilizar uma avaliação íntegra e acertada da qualidade das vacinas em relação a sua segurança e eficiência.

Seguridad de las vacunas contra la COVID-19 / COVID-19 vaccine safety

RESUMEN El desarrollo y producción de vacunas seguras y eficaces contra la enfermedad por coronavirus 2019 (COVID-19) ofrece la esperanza para el control de la pandemia actual. Los eventos adversos posteriores a la inmunización son respuestas indeseadas o acontecimientos involuntarios que siguen a la vacunación, y que deben ser cuidadosamente vigilados, ya que todas las vacunas, incluyendo las desarrolladas contra el SARS-CoV-2, requieren cumplir con los criterios de seguridad para su administración en humanos. Se recopiló la información de la base de datos de PubMed/Medline durante los meses de agosto de 2020 a noviembre de 2021. La mayoría de los eventos adversos identificados en los ensayos clínicos fueron leves o moderados; sin embargo, se identificaron eventos trombóticos asociados a algunas vacunas basadas en vectores virales contra la COVID-19 en estudios de seguimiento, aunque se requiere la conclusión de los distintos estudios en curso y vigilancia poscomercialización para determinar todos los posibles eventos adversos y de especial interés.

ABSTRACT The development and production of safe and effective vaccines against coronavirus disease 2019 (COVID-19) provides hope for controlling the current pandemic. Adverse events following immunization are unwanted responses or unintended events that must be carefully monitored, as all vaccines, including those developed against SARS-CoV-2, are required to meet safety criteria for administration in humans. Information was collected from the PubMed/Medline database during the months of August 2020 to November 2021. Most adverse events reported in clinical trials were mild or moderate; however, thrombotic events associated with some viral vector-based vaccines against COVID-19 were identified in follow-up studies, although completion of the various ongoing studies and post-marketing surveillance is required to determine all potential adverse events, as well as those of special interest.

Vacunas SARS CoV-2, estudios en fase III / SARS CoV-2 vaccine studies currently in phase III

Resumen La enfermedad por coronavirus 2019, causada por el virus SARS-CoV2, fue declarada pandemia en marzo de 2020 por la OMS. La proteína S, de la superficie viral ha sido identificada como antígeno óptimo para el desarrollo de vacunas. En pandemia, el proceso tradicional de desarrollo de vacunas ha debido acelerarse para avanzar en una respuesta adecuada al problema, acortando los tiempos. La seguridad, inmunogenicidad, protección frente a la infección, fenómeno de "aumento dependiente de anticuerpos", duración de la protección se estudian en paralelo, a diferencia de la manera tradicional en que se llevaba a cabo en etapas sucesivas. Actualmente en Fase III hay 4 tipos vacunas: inactivadas; en base a proteínas purificadas o recombinantes, en base a ácidos nucleicos ADN/ARN y en base a vectores virales. El objetivo de esta revisión es conocer los estudios que preceden a las vacunas que actualmente están en estudios de Fase III y describir las características principales de estos estudios. Actualmente el mundo se encuentra en una situación inédita en el último siglo. Dentro las opciones para enfrentar este hecho, una vacuna o idealmente varias, seguras, eficaces e inmunogénicas, parecen ser una de las mejores alternativas para retomar en un plazo razonable la normalidad perdida.

Abstract The coronavirus disease 2019, caused by the SARS-CoV2 virus, was declared a pandemic in March 2020 by the WHO. Protein S from the viral surface has been identified as the optimal antigen for vaccine development. In a pandemic, the traditional vaccine development process has had to be accelerated to advance in an adequate response to the problem, shortening the times. Safety, immunogenicity, protection against infection, antibody dependent enhancement phenomena and duration of protection are studied in parallel, unlike the traditional way in which it was carried out in successive stages. Currently in Phase III there are 4 types of vaccines: inactivated; based on purified or recombinant proteins, based on DNA / RNA nucleic acids and based on viral vectors. The objective of this review is to understand the studies that precede the vaccines that are currently in Phase III studies and to describe the main characteristics of these studies. Currently the world is in a situation unprecedented in the last century. Among the options to face this fact, one vaccine or, ideally, several, safe, effective and immunogenic, seem to be one of the best alternatives to regain lost normality within a reasonable time.

Vacuna terapéutica racotumomab en un anciano con cáncer avanzado de pulmón / Racotumomab therapeutic vaccine in an elderly with advanced lung cancer

Se presenta el caso clínico de un anciano de 84 años de edad, fumador, con diagnóstico de cáncer de pulmón en etapa IV, quien fue incluido en el ensayo clínico de fase III para ser tratado con racotumumab. Se observó mejoría clínica y del estado general del paciente, pues según la escala funcional concluyó el estudio con ECOG 0. Por tanto, es oportuno destacar que esta vacuna incrementa la supervivencia de los afectados por cáncer de pulmón de células no pequeñas recurrentes o en estadios avanzados.

The case report of a 84 years elderly smoker, is presented with diagnosis of lung cancer in stage IV who was included in the phase III clinical trial to be treated with racotumomab. Clinical improvement and recovery of the patient's general state was observed, because according to the functional scale the study concluded with ECOG 0. Therefore, it is opportune to highlight that this vaccine increases the survival of those affected by recurrent non-small cells lung cancer or in advanced stages.

Embarazos y sus resultados en las participantes de ensayos clínicos de fase III y IV en el Perú / Pregnancies and their results in phase III and IV clinical trial participants in Peru

Resumen Objetivos: Identificar la ocurrencia de casos de embarazo, nacimientos y aborto en participantes de ensayos clinicos en fases III y IV, en Perú. Material y métodos: Estudio de análisis de datos secundarios, retrospectivo, de todos los casos de embarazo ocurridos durante la realización de ensayos clínicos, en el periodo 2010 al 2015. Los datos se obtuvieron del sistema virtual REAS-NET, del Instituto Nacional de Salud para el reporte de eventos adversos serios. Se utilizó la prueba de Fisher y Chi cuadrado para el análisis de las variables. Resultados: Se encontraron 30 casos de embarazos de pacientes enroladas en los ensayos clínicos, 24 de ellos en ensayos de fase III. El rango de edad fue 19 a 44 años, 21 casos terminaron en aborto. Ninguna de las variables estudiadas presentó asociación significativa con el resultado del embarazo: aborto y nacido vivo normal. Conclusiones: Se encontraron embarazos en las participantes en ensayos clínicos de fase III y IV, la edad correspondió a la edad fértil de las mujeres.

Summary Objectives: To identify the occurrence of cases of pregnancy, births and abortion in participants of clinical trials in phases III and IV, in Peru. Methods: Retrospective secondary data analysis study of all cases of pregnancy that occurred during clinical trials, in the period 2010 to 2015. The data were obtained from the virtual system REAS-NET, of the National Institute of Health for the report of serious adverse events. The Fisher and Chi square test was used to analyze the variables. Results: 30 cases of pregnancies of patients enrolled in clinical trials were found, 24 of them in phase III trials. The age range was 19 to 44 years, 21 cases ended in abortion. None of the variables studied presented a significant association with the outcome of pregnancy: abortion and normal live birth. Conclusions: Pregnancies were found in the participants in phase III and IV clinical trials, the age corresponded to the fertile age of the women.

Effect of self-designed closed negative pressure drainage combined with sponge dressing on refractory wounds / 现代临床护理

Objective To investigate the effect of self-designed closed negative pressure drainage combined with sponge dressings on refractory wounds.Methods Sixty patients with phase III-IV pressure ulcers were randomly divided into experiment group and control group in equal number.The self-designed closed negative pressure drainage combined with sponge dressing was applied in the experiment group and in the control group the conventional dressings were used.The two groups were compared in terms of hyperplasia of fresh granulation tissue,time for filling the defect and the healing time and the medical expense.Results Compared to the control group,the time for hyperplasia of fresh granulation tissue,the time for filling the defect and the healing time in the experiment group were all significantly shorter,and the medical expense of the experiment group was significantly less(all P<0.01). Conclusion The self-designed closed negative pressure drainage combined with sponge dressings in the treatment of phase III-IV refractory pressure ulcers may effectively shorten the healing time,improve the curative effects and reduce the economic burden of patients.

Empleo del adhesivo tisular Tisuacryl en la síntesis de heridas de complejo bucofacial / Use of the tissular adhesive Tisuacryl in the synthesis of injuries of buccofacial complex

Fundamento: El método ideal para el cierre de heridas traumáticas debe ser rápido, fácil de realizar, barato y poco doloroso. El adhesivo Tisuacryl desarrollado por el Centro Nacional de Biomateriales de la Universidad de La Habana permite sellar las heridas recientes y tiene además propiedades hemostáticas y bactericidas. Objetivo: Evaluar la efectividad del adhesivo tisular Tisuacryl, en la síntesis de heridas bucofaciales. Método: Se realizó un ensayo clínico fase III, de extensión terapéutica, unicéntrico no controlado, en el Servicio de Cirugía Maxilofacial del Hospital Provincial Docente Clínico Quirúrgico «Manuel Ascunce Domenech¼ de Camagüey desde octubre de 2003 a marzo de 2005. La muestra estuvo constituida por 110 pacientes seleccionados según criterios de inclusión. El tratamiento fue ambulatorio, se aplicó el adhesivo tisular Tisuacryl sobre los bordes afrontados de las heridas bucofaciales, con el objetivo de determinar la aparición de dehiscencia e infección, de evaluar la calidad de la cicatrización de las heridas tratadas, determinar la conformidad del paciente e investigador, así como la presencia de reacciones adversas. Resultados: Lasheridas tratadas fueron más frecuentes en el sexo masculino en las edades comprendidas entre 29 y 38 años, las heridas traumáticas faciales fueron predominantes, con una buena cicatrización en la mayoría de los pacienteas, sin complicaciones (dehiscencia e infección). Conclusiones: Resultó ser un tratamiento efectivo y seguro en la síntesis de heridas faciales cutáneas y de la mucosa bucal de naturaleza traumática y quirúrgica. Se logró una oclusión hermética, rápida recuperación de los tejidos, oclusión con una buena calidad de la cicatrización y conformidad con los resultados de los investigadores y la mayoría de los pacientes. No se presentaron reacciones adversas con la aplicación del producto.

Background: The ideal method for the closure of traumatic injuries should be fast, easy to carry out, cheap and little painful. The Tisuacryl adhesive developed by the Biomaterial National Center of Havana University permits to seal the recent injuries and has besides bactericide and hemostatic properties. Objective: To evaluate the effectiveness of the tissular adhesive Tisuacryl, in the synthesis of buccofacial injuries. Method: A clinical trial phase III, of therapeutic extension, unicentric not controlled was conducted at «Manuel Ascunce Domenech¼ Surgical Clinical Educational Provincial Hospital of Camagüey in the Maxillofacial Surgery service, from October 2003 to March 2005. The sample was constituted by 110 patients selected according to inclusion criteria. The treatment was ambulatory, the tissular adhesive Tisuacryl was applied on the edges confronted of the buccofacial injuries, with the objective to determine the apparition of dehiscence and infection, to evaluate the quality of the cicatrization of the treated injuries, to determine the patient and investigator conformity, as well as the presence of adverse reactions. Results: The treated injuries were more frequent in the male sex in ages between 29 and 38 years, the facial traumatic injuries were predominant, with a good cicatrization in the majority of patients, without complications (dehiscence and infection). Conclusions: It resulted to be an effective and save treatment in the synthesis of cutaneous facial injuries and of the oral mucous membrane of surgical and traumatic nature. An hermetic occlusion was achieved, fast recovery of the tissues, occlusion with a good quality of cicatrization and conformity with the results of the investigators and the majority of patients. Not adverse reactions with the application of the product were presented.

Phase III Clinical Trial Comparing Iopamidol 250 mgI/mL and Iopamidol 300mgI/mL in Cerebral Angiography: Multicenteric, Randomized and Double Blind Study

PURPOSE: To evaluate and compare the safety, tolerance and the image quality of cerebral angiography images with the use of the nonionic monomeric contrast agent, iopamidol at 250 mgI/mL or 300 mgI/mL. MATERIALS AND METHODS: This study was approved by the institutional review board and was performed from December 2005 to March 2006. A total of 90 patients undergoing an elective cerebral angiography were studied during a phase III clinical trial to compare the safety and diagnostic efficacy of iopamidol at 250 mgI/ml and 300 mgI/ml. The overall quality of cerebral angiography images was independently graded into three categories: good, bad and nondiagnostic by two radiologists. RESULTS: The image quality of the cerebral angiography was good in 100% of the patients in both groups. A total of 4.44% of the patients experienced adverse events (4.44% in the iopamidol 250 group and 4.44% in the iopamidol 300 group). No statistically significant differences were observed between the two studied groups for either the proportion of patients with one or more adverse events or the intensity of the adverse events. CONCLUSION: The safety and efficacy (quality of the radiographic diagnostic visualization) of Iopamidol at 250 and 300 mg I/ml did not reveal any significant differences and thus are comparable.

Phase III Clinical Trial of Revaprazan (Revanex(R)) for Gastric Ulcer / 대한소화기내시경학회지

BACKGROUND/AIMS: This randomized, double-blind, phase III, multicenter trial was carried out to compare the efficacy and safety of revaprazan, a novel acid pump antagonist, with that of omeprazole in patients with more than one of gastric ulcers. METHODS: Two hundred and ninety two subjects were randomized to 4~8 weeks of treatment with either revaprazan 200 mg or omeprazole 20 mg. The primary efficacy parameter was the cumulative healing rate determined by endoscopy after 4 and 8 weeks of treatment, and the secondary efficacy parameter was an improvement rate of pain. RESULTS: The intention-to-treat analysis revealed revaprazan and omeprazole to have similar cumulative healing rates (93.0% and 89.6%, respectively; p=0.3038). The per-protocol analysis revealed revaprazan and omeprazole to also have similar cumulative healing rates (99.1% and 100%, respectively; p= 0.3229). In both analyses, there were no significant differences in an improvement rate of pain between the two groups. Both drugs were well tolerated. CONCLUSIONS: Revaprazan has similar efficacy to omeprazole in the treatment of patients with gastric ulcer with a once a day application of revaprazan 200 mg or omeprazole 20 mg over a 4 to 8-week period. In terms of safety, revaprazan was well tolerated.

Revaprazan (Revanex(R)), a Novel Acid Pump Antagonist, for Duodenal Ulcer: Results of a Double-Blind, Randomized, Parallel, Multi-Center Phase III Clinical Trial / 대한소화기내시경학회지

BACKGROUND/AIMS: To assess the comparative efficacy and safety of revaprazan, a novel acid pump antagonist, versus omeprazole in patients with duodenal ulcer, we performed a randomized, double-blind, phase III, multicenter trial. METHODS: Two hundred and twenty eight patients were randomized to 4 weeks of treatment with either revaprazan 200 mg or omeprazole 20 mg once daily. Primary efficacy parameter was complete ulcer healing by endoscopy, and secondary parameter was the improvement in the severity of daytime and nighttime pain. RESULTS: Healing rates at 4 weeks (intention-to-treat analysis) were 91.7% with revaprazan 200 mg and 91.3% with omeprazole 20 mg; there were no significant differences between two groups (p=0.9228). In per-protocol analysis, healing rates of revaprazan 200 mg and omeprazole 20 mg were 94.4% and 92.3%, respectively. There was no significant difference in healing rate between two groups (p=0.5666). There was no significant difference between two groups in improvement rates of daytime and nighttime pain. Both drugs were well tolerated. CONCLUSIONS: Revaprazan 200 mg was equivalent to omeprazole 20 mg for both ulcer healing and symptom relief, and was well tolerated in patients with duodenal ulcer.

Preoperative Chemotherapy in Gastric Cancer

Gastric cancer is the most prevalent cancer in Korea and comprises the second cause of cancer death. Surgery only can provide chance of cure, but most locally advanced cancers recur after a curative resection, even though important advances in the surgical and nonsurgical treatments of gastric cancer have taken place. Preoperative chemotherapy theoretically can provide the advantages of reducing the bulk of tumor, which might improve the R0 resection rate, and of treating micrometastases early. Also, preoperative chemotherapy is expected to render unresectable tumors resectable without increasing postoperative morbidity and mortality. There are many new chemotherapeutic agents available for the treatment of advanced gastric cancer, but still the most effective agent, the optimal time and number of cycle for administration are still not known. The addition of postoperative chemotherapy through an intraperitoneal route and/or radiotherapy might affect the outcome of surgery favorably, but that hasn't been proved yet. A multicenter prospective randomized phase III trial should be performed to answer for those questions and to improve the curability of gastric cancer treatment.

Randomized Phase III Trial of Cisplatin, Epirubicin, Leucovorin, 5-Fluorouracil (PELF) Combination versus 5-fluorouracil Alone as Adjuvant Chemotherapy in Curative Resected Stage III Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The combination of cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) administration, as adjuvant chemotherapy after curative resection for gastirc cancer, was compared with 5-fluorouracil (5-FU) administration alone. This paper reports the results of a prospective randomized comparison of the two regimens, PELF and 5-FU. METHODS: From August 1996 to July 1999, 54 patients were selected subsequent to being diagnosed with stage III cancer after a curative resection for gastric cancer. The patients were stratified according to stage IIIA/IIIB and subtotal/total gastrectomy, and then they were randomized into each treatment group, i.e. the PELF or 5-FU alone groups. RESULTS: 54 assessable patients were enrolled in this study: 28 received PELF and 26 received 5-FU alone. 12 patients relapsed in each group and the median follow-up duration was 42 months (range: 10~77 months). The overall survival rate and disease-free survival rate (DFS) were not significantly different between two groups, (5-year survival of PELF vs. 5-FU: 57% vs. 64%, 5-year DFS: 54% vs. 51%). The PELF combination was more toxic in terms of anemia, anorexia, nausea and diarrhea than the 5-FU. CONCLUSIONS: This study showed that the PELF combination, as an adjuvant therapy for gastric cancer after a curative resection, was a less effective treatment, and it had more toxic effects than the 5-FU.

A Phase III Clinical Trial of Stillen(TM) for Erosive Gastritis / 대한소화기내시경학회지

BACKGROUND/AIMS: Phase IIb clinical study of Stillen(TM), a novel cytoprotectant, for gastritis showed 180 mg of Stillen, t.i.d. for 2 weeks results in a significant increase of cure rate when compared with a placebo group. It is reported that antioxidative effect and strengthening the endogenous cytoprotective molecules of the gastric mucosa play a pivotal role for cytoprotective action of Stillen(TM). The aim of this phase III multicenter, double-blind comparative study was to assess the efficacy of Stillen(TM) for the treatment of erosive gastritis. METHODS: Five hundred and twelve patients with erosive gastritis were enrolled and divided into three groups. Each group received 180 mg or 360 mg of Stillen(TM) or 600 mg of cetraxate (Neuer(TM)) t.i.d. for 2 weeks, respectively and a follow-up endoscopic examination for evaluation. RESULTS: Patients treated with 180 mg and 360 mg of Stillen(TM) had a significantly improved endoscopic cure rate of gastritis (55.6% and 57.5%, respectively) compared with patients treated with 600 mg of cetraxate (35.5%, p<0.001). Endoscopic improvement rate was also significantly higher in 180 mg group (67.3%) and 360 mg group (65.0%) of Stillen(TM) treated patients than cetraxate treated group (46.4%, p<0.001). During the study, both Stillen(TM) and cetraxate were well tolerated. CONCLUSIONS: These results clearly demonstrate that Stillen(TM) is an efficacious, safe, and well-tolerated treatment for gastritis.

Preliminary Results of the Prospective Randomized Phase III Trial on the Induction Chemotherapy in the Concurrent Chemoradiotherapy for the Locally Advanced Non-small Cell Lung Cancer

PURPOSE: To investigate the role of induction chemotherapy in relation to the treatment results and toxicities of concurrent chemoradiotherapy (CCRT) for locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with unresectable and pathologically confirmed Stage III NSCLC were eligible. According to the stage and pathological subgroup, the patients were randomized into two arms. Arm A received two cycles of the induction chemotherapy composed of gemcitabine, 1,000 mg/m2 (D1 and D8), and cisplatin, 70 mg/m2 (D1), followed by CCRT with weekly paclitaxel, 50 mg/m2, and cisplatin, 20 mg/m2. Arm B received immediate CCRT without the induction chemotherapy. A daily 2.2 Gy radiation dose was delivered to the isodose line covering the planned target volume, which was defined as the gross tumor volume plus a 1.0 cm margin from the planning CT, using a 3-D conformal radiation therapy technique. RESULTS: Between May 2003 and 2004, 63 patients were enrolled. Forty four patients (Arm A 23, Arm B 21) were evaluable, with follow-up periods exceeded 1 month after the end of the assigned treatment. The median follow-up periods were 6 and 7 months for Arms A and B, respectively. The patients' characteristics, including gender, age, weight loss, performance status, pulmonary function and stage, were well balanced between the two arms. The median largest tumor diameters were 4.8 cm (3.0~15 cm) and 5.0 cm (2.5~10 cm) for Arms A and B, respectively. The one-year survival rates were 58 and 63% for Arms A and B respectively, which showed no statistical significance (p=0.6667). The compliance of the induction chemotherapy was 96% (22/23 patients), and those of the CCRT were 86% for both arms (18/21 patients). The response rate of the induction chemotherapy was 64% (14/22 patients) and those of the CCRT were 83 (15/18 patients) and 89% (16/18 patients) for Arms A and B, respectively, which showed no statistical significance (p=0.630). In the 23 patients of Arm A, 8 (35%) suffered grade 3~4 neutropenia during the induction chemotherapy and 1 expired due to sepsis. CCRT caused grade 3~4 neutropenia in 6 and 1 patients of Arms A (29%) and B (5%), respectively, showing statistical significance (p=0.038). Grade 3~4 radiation pneumonitis developed in 2 and patients from Arms A (10%) and B (5%), respectively, (p=0.464) and grade 3~4 acute esophagitis developed in 7 (Arm A) and 5 patients (Arm B) (p=0.495). CONCLUSION: Both treatment schemes showed acceptable treatment compliance and toxicities. However, the induction chemotherapy resulted in a higher incidence of severe neutropenia. The treatment outcomes, as yet, have shown no statistical significance. To evaluate the role of induction chemotherapy on the survival prolongation in CCRT for locally advanced NSCLC, more patients and a longer follow-up are mandatory

Current Status and Future Prospects of Post-Marketing Clinical Trials / 薬剤疫学

Good Post-Marketing Surveillance Practice (GPMSP) defines “post-marketing clinical trials” as industry-initiated studies constituting a part of Post-Marketing Surveillance (PMS). Post-marketing clinical studies play the role of gathering further information on appropriate drug use. This is why the proper conduct of medically required post-marketing clinical trials would facilitate the proposal of new treatments with improved efficacy and/or safety over existing therapies, thereby contributing to the promotion of EBM and to the advance of healthcare. In the case of anticancer drugs, in particular, post-marketing clinical trials are of great importance, because they also serve as Phase III studies. In reality, however, pharmaceutical companies are not very active in conducting these studies because of the many issues involved. To solve or alleviate these problems, the Japan Pharmaceutical Manufacturers Association and COTEC are making aggressive efforts.

Optimal Scheme of Postoperative Chemoradiotherapy in Rectal Cancer: Phase III Prospective Randomized Trial / 대한방사선종양학회지

PURPOSE: To determine the optimal scheme of postoperative chemoradiotherapy in rectal cancer by comparing survival, patterns of failure, toxicities in early and late radiotherapy groups using a phase III randomized prospective clinical trial. MATERIALS AND METHODS: From January 1996 to March 1999, 307 patients with curatively resected AJCC stage II and III rectal cancer were assigned randomly to an 'early (151 patients, arm I)' or a 'late (156 patients, arm II)' and were administered combined chemotherapy (5-FU 375 mg/m2/day, leucovorin 20 mg/ m2, IV bolus daily, for 3 days with RT, 5 days without RT, 8 cycles with 4 weeks interval) and radiation therapy (whole pelvis with 45 Gy/25 fractions/5 weeks). Patients of arm I received radiation therapy from day 1 of the first cycle of chemotherapy and those of arm II from day 57 with a third cycle of chemotherapy. The median follow-up period of living patients was 40 months. RESULTS: Of the 307 patients enrolled, fifty patients did not receive scheduled radiation therapy or chemotherapy. The overall survival rate and disease free survival rate at 5 years were 78.3% and 68.7% in arm I, and 78.4% and 67.5% in arm II. The local recurrence rate was 6.6% and 6.4% ( p=0.46) in arms I and II, respectively, no significant difference was observed between the distant metastasis rates of the two arms (23.8% and 29.5%, p=0.16). During radiation therapy, grade 3 diarrhea or more, by the NCI common toxicity criteria, was observed in 63.0% and 58.2% of the respective arms ( p=N.S.), but most were controlled with supportive care. Hematologic toxicity (leukopenia) greater than RTOG grade 2 was found in only 1.3% and 2.6% of patients in each respective arm. CONCLUSION: There was no significant difference in survival, patterns of failure or toxicities between the early and late radiation therapy arms. Postoperative adjuvant chemoradiation was found to be a relatively safe treatment but higher compliance is needed.

A Prospective Randomized Trial Comparing the Sequence of Adjuvant Chemotherapy and Radiotherapy following Curative Resection of Stage II, III Rectal Cancer / 대한방사선종양학회지

PURPOSE: To evaluate the side effects, pattern of failure, and survival rate according to the sequence of postoperative adjuvant radiotherapy and chemotherapy, patients with stages II and lll rectal cancer who had undergone curative resection were randomized to early radiotherapy group (arm I) or 'late radiotherapy group (arm II)', then we intend to determine the most effective sequence of the radiotherapy and chemotherapy. MATERIALS AND METHODS: From January 1996 to March 1999, 3 13 patients with curatively resected stages II and III rectal cancer have been randomized to early' or late radiation therapy group and recei ved combined chemotherapy (5-FU 375 mg/m/day, leucovorin 20 mg/m, IV bolus daily D1-5, 8 cycles) and radiation therapy (whole pelvis with 45 Gy/25 fractions/5 weeks). Arm I received radiation therapy from day 1 with first cycle of chemotherapy and arm II received radiation therapy from day 57 with third cycle of chemotherapy after completion of first two cycles. Preliminary analysis was performed with 228 patients registered up to Jun 1998. Two out of the 228 patients were excluded because of double primary cancer. Median follow-up period was 23 months. RESULTS: Local recurrence occurred in 11 patients (9.7%) for arm I and 9 patients (8%) for arm II. There was no significant difference between both groups (p=0.64). However, distant metastasis was found in 22 patients (19.5%) for arm I and 35 patients (31.0%) for arm II and which showed statistically significant difference between the two groups (p=0.046). And neither 3-year disease-free survival (70.2% vs 59.2%, p=0.2) nor overall survival (89.4% vs 88.0%, p=0.47) showed significant differences. The incidence of leukopenia during radiation therapy and chemotherapy was 78.3% and 79.9% respectively but leukopenia more than RTOG grade 3 was only 2.1% and 6.0% respectively. The incidence of diarrhea more than 10 times per day was significantly higher in the patients for arm I than for arm II (71.2% vs 4 1.6%, p=0.02) but this complication was controlled with supportive cares. CONCLUSION: Regardless of the sequence of postoperative adjuvant radiation therapy and chemotherapy a fter curative resection for rectal cancer, local recurrence rate was low with combined chemoradiotherapy. But distant metastasis rate was lower in early radiation therapy group than in late radiation therapy group and the reason is unclear. Most patients completed these treatments without severe complication, so these were thought to be safe treatments but the treatment compliance should be improved.

Phase III Study of Pirarubicin / Cyclophosphamide / CDDP(CTP) vs. Doxorubicin / Cyclophosphamide / CDDP(CAP) Combination Chemotherapy in Advanced Epithelial Ovarian Cancer / 대한부인종양콜포스코피학회잡지

Backgrouad & Aims: Cyclophosphamide, adriamycin and cisplatin(CAP) combination chemo- therapy improved the response rate in the treatment of advanced epithelial ovarian cancer, and it has been the gold standard. However, adriamycin is a rather toxic drug, and there is still confusion concerning the choice of adriamycin to be included in optimal regimen. The present study was designed to compare the activity and toxicity of combination regimens in advanced epithelial ovarian cancer between CAP and CTP which substitutes adriamycin with pirarubicin(THP- adriamycin). PATIENTS AND METHODS: From March 1995 to December 1997, 47 patients with FIGO stage III-IV epithelial ovarian cancer who were diagnosed after initial cytoreductive surgery were divided into two groups at random: (1) The case group were treated with CTP(500/40/50 mg/m2) as a first line chemotherapy. (2) The control group were treated with CAP(500/50/50 mg/m2) as that of case group. Clinical characteristics, response rates and toxicities according to Gynecologic Oncology Group criteria were compared between those treated with CAP and CTP respectively. RESULTS: Forty one patients out of 47 were evaluable and the number of patients in case and control group was 22 and 19 respectively. There was no significant differences in patient characteristics such as age, stage, histologic type between two groups. Clinical complete response rate was 50.0%(11/22) in patients treated with CTP regimen and 47.4%(9/19) with CAP regimen and there was no significant difference between two groups. Second look operation was undergone in 10 patients of CTP group and 7 patients of CAP group who showed clinical complete response and the pathologic complete response rate was 27.3%(6/22) with CTP and 21.1%(4/19) with CAP. The incidence of leukocytopenia of grade 3 or 4 was more frequently occurred in CAP group(52.6%, 10/19) than CTP group(22.7%, 5/22). There was no significant difference in the incidence of other toxicitied such as hepatic, renal and G-I toxicities. Suspicious cardiac toxicity according to the finding of EKG was seen in 15.8%(3/19) only with CAP regimen and all of them showed decreased cardiac function in gated blood pool scan. There were no significant differences in risponse rates between two groups, but the incidence of cardiac toxicity and leukocytopenia o f grade 3 or 4 was more frequently occurred in CAP group than CTP group. CONCLUSION : CTP regimen has comparable response rates to CAP regimen, with lower incidence of hematolohic and cardiac toxicity.