Cancer Research and Treatment

Original Article

General

The Survival and Financial Benefit of Investigator-Initiated Trials Conducted by Korean Cancer Study Group: Bum Jun Kim, Chi Hoon Maeng, Bhumsuk Keam, Young-Hyuck Im, Jungsil Ro, Kyung Hae Jung, Seock-Ah Im, Tae Won Kim, Jae Lyun Lee, Dae Seog Heo, Sang-We Kim, Keunchil Park, Myung-Ju Ahn, Byoung Chul Cho, Hoon-Kyo Kim, Yoon-Koo Kang, Jae Yong Cho, Hwan Jung Yun, Byung-Ho Nam, Dae Young Zang; Cancer Res Treat. 2025;57(1):39-46. Published online July 10, 2024; DOI: https://doi.org/10.4143/crt.2024.421

Abstract PDF PubReader ePub: Purpose
The Korean Cancer Study Group (KCSG) is a nationwide cancer clinical trial group dedicated to advancing investigator-initiated trials (IITs) by conducting and supporting clinical trials. This study aims to review IITs conducted by KCSG and quantitatively evaluate the survival and financial benefits of IITs for patients.
Materials and Methods
We reviewed IITs conducted by KCSG from 1998 to 2023, analyzing progression-free survival (PFS) and overall survival (OS) gains for participants. PFS and OS benefits were calculated as the difference in median survival times between the intervention and control groups, multiplied by the number of patients in the intervention group. Financial benefits were assessed based on the cost of investigational products provided.
Results
From 1998 to 2023, KCSG conducted 310 IITs, with 133 completed and published. Of these, 21 were included in the survival analysis. The analysis revealed that 1,951 patients in the intervention groups gained a total of 2,558.4 months (213.2 years) of PFS and 2,501.6 months (208.5 years) of OS, with median gains of 1.31 months in PFS and 1.58 months in OS per patient. When analyzing only statistically significant results, PFS and OS gain per patients was 1.69 months and 3.02 months, respectively. Investigational drug cost analysis from six available IITs indicated that investigational products provided to 252 patients were valued at 10,400,077,294 won (approximately 8,046,481 US dollars), averaging about 41,270,148 won (approximately 31,930 US dollars) per patient.
Conclusion
Our findings, based on analysis of published research, suggest that IITs conducted by KCSG led to survival benefits for participants and, in some studies, may have provided financial benefits by providing investment drugs.

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Erratum

ERRATUM: Comparison of Surgery Plus Chemotherapy and Palliative Chemotherapy Alone for Advanced Gastric Cancer with Krukenberg Tumor: Jang Ho Cho, Jae Yun Lim, Ah Ran Choi, Sung Min Choi, Jong Won Kim, Seung Ho Choi, Jae Yong Cho; Cancer Res Treat. 2018;50(1):302-302. Published online December 6, 2017; DOI: https://doi.org/10.4143/crt.2013.175.2; Corrects: Cancer Res Treat 2015;47(4):697

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Original Articles

Overexpression of Endoplasmic Reticulum Oxidoreductin 1-α (ERO1L) Is Associated with Poor Prognosis of Gastric Cancer: So-Young Seol, Chul Kim, Jae Yun Lim, Sun Och Yoon, Soon Won Hong, Jong Won Kim, Seung Ho Choi, Jae Yong Cho; Cancer Res Treat. 2016;48(4):1196-1209. Published online February 26, 2016; DOI: https://doi.org/10.4143/crt.2015.189

Abstract PDF PubReader ePub

Purpose
Gastric cancer is the second leading cause of cancer-related death worldwide. Although surgery is the standard curative treatment for gastric cancer, relapse occurs in a large number of patients, except in the case of early diagnosed gastric cancer. Following previous studies that identified endoplasmic reticulum oxidoreductin 1-α (ERO1L) as a potential marker for gastric cancer, we investigated the functional role of ERO1L in gastric cancer.
Materials and Methods
For validation of microarray data, the mRNA expression level of ERO1L was measured by quantitative real-time reverse transcription polymerase chain reaction in 56 independent stage III gastric cancer patients. Immunohistochemical staining was performed to examine the protein expression level of ERO1L in 231 gastric cancer patients. Correlation between gene expression and cancer prognosis was evaluated.
Results
Patients with high ERO1L expression had poorer survival than those with low expression (p < 0.01). Functional assays demonstrated that ERO1L knockdown inhibited cell proliferation, migration, invasion, and chemoresistance. In addition, involvement of inactivation of Akt and JNK signaling in molecular mechanisms of ERO1L inhibition was demonstrated.
Conclusion
High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer.

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Comparison of Surgery Plus Chemotherapy and Palliative Chemotherapy Alone for Advanced Gastric Cancer with Krukenberg Tumor: Jang Ho Cho, Jae Yun Lim, Ah Ran Choi, Sung Min Choi, Jong Won Kim, Seung Ho Choi, Jae Yong Cho; Cancer Res Treat. 2015;47(4):697-705. Published online November 27, 2014; DOI: https://doi.org/10.4143/crt.2013.175; Correction in: Cancer Res Treat 2018;50(1):302

Abstract PDF PubReader ePub

Purpose
This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival. Materials and Methods Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone. Results Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival. Conclusion Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.

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Gemcitabine Combined with Capecitabine Compared to Gemcitabine with or without Erlotinib as First-Line Chemotherapy in Patients with Advanced Pancreatic Cancer: Jae Yun Lim, Jang Ho Cho, Se Joon Lee, Dong Ki Lee, Dong Sup Yoon, Jae Yong Cho; Cancer Res Treat. 2015;47(2):266-273. Published online August 29, 2014; DOI: https://doi.org/10.4143/crt.2013.158

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Purpose
The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy—gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)—in patients with advanced pancreatic cancer. Materials and Methods There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and capecitabine 850 mg/m2 twice daily for 2 weeks followed by 1 week’s rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated. Results The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2. Conclusion GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment.

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Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer: Ji Soo Park, Jae Yun Lim, Seung Kyo Park, Min Kyung Kim, Hee Sung Ko, Sun Och Yoon, Jong Won Kim, Seung Ho Choi, Jae Yong Cho; Cancer Res Treat. 2011;43(4):236-243. Published online December 27, 2011; DOI: https://doi.org/10.4143/crt.2011.43.4.236

Abstract PDF PubReader ePub

PURPOSE
The aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response.
MATERIALS AND METHODS
Fifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study. Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI.
RESULTS
The median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy.
CONCLUSION
It is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles. Development of individualized chemotherapy regimens based on gene expression profiles is warranted.

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Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease
Daniel V.T. Catenacci, Stephanie Moya, Samantha Lomnicki, Leah M. Chase, Bryan F. Peterson, Natalie Reizine, Lindsay Alpert, Namrata Setia, Shu-Yuan Xiao, John Hart, Uzma D. Siddiqui, D. Kyle Hogarth, Oliver S. Eng, Kiran Turaga, Kevin Roggin, Mitchell C.
Cancer Discovery.2021; 11(2): 308. CrossRef
Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer
Minkyu Jung, Kyu Hyun Park, Hyun Myong Kim, Tae Soo Kim, Xianglan Zhang, Sun-Mi Park, Seung-Hoon Beom, Hyo Song Kim, Jae-Ho Cheong, Hyun Cheol Chung, John Soong, Shu-chuan Lin, Sun Young Rha
Gastric Cancer.2019; 22(6): 1153. CrossRef
Advanced gastric cancer: is there an optimal chemotherapy regimen?
Kalliopi Andrikou, Massimiliano Salati, Annalisa Fontana, Andrea Spallanzani, Stefania Pipitone, Fabio Gelsomino, Monica Barbolini, Stefano Cascinu
Expert Review of Quality of Life in Cancer Care.2017; 2(2): 123. CrossRef
Third-line chemotherapy in advanced gastric cancer
Yu Zheng, Xu-Qing Zhu, Xiao-Gang Ren
Medicine.2017; 96(24): e6884. CrossRef
Melatonin pre-treatment mitigates SHSY-5Y cells against oxaliplatin induced mitochondrial stress and apoptotic cell death
Mohammad Waseem, Upasana Sahu, Mohd. Salman, Arnab Choudhury, Sudeshna Kar, Heena Tabassum, Suhel Parvez, Saeid Ghavami
PLOS ONE.2017; 12(7): e0180953. CrossRef
Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy
Valentina Fanotto, Mario Uccello, Irene Pecora, Lorenza Rimassa, Francesco Leone, Gerardo Rosati, Daniele Santini, Riccardo Giampieri, Samantha Di Donato, Gianluca Tomasello, Nicola Silvestris, Filippo Pietrantonio, Francesca Battaglin, Antonio Avallone,
The Oncologist.2017; 22(12): 1463. CrossRef
Therapeutic effect of apatinib on overall survival is mediated by prolonged progression-free survival in advanced gastric cancer patients
Lihong Huang, Yongyue Wei, Sipeng Shen, Qianwen Shi, Jianling Bai, Jin Li, Shukui Qin, Hao Yu, Feng Chen
Oncotarget.2017; 8(17): 29346. CrossRef
Apatinib for the treatment of gastric cancer
Giandomenico Roviello, Andrea Ravelli, Anna Ida Fiaschi, Maria Rosa Cappelletti, Angela Gobbi, Chiara Senti, Laura Zanotti, Karol Polom, Andrew R. Reynolds, Stephen B. Fox, Daniele Generali
Expert Review of Gastroenterology & Hepatology.2016; : 1. CrossRef
Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction
Jin Li, Shukui Qin, Jianming Xu, Jianping Xiong, Changping Wu, Yuxian Bai, Wei Liu, Jiandong Tong, Yunpeng Liu, Ruihua Xu, Zhehai Wang, Qiong Wang, Xuenong Ouyang, Yan Yang, Yi Ba, Jun Liang, Xiaoyan Lin, Deyun Luo, Rongsheng Zheng, Xin Wang, Guoping Sun,
Journal of Clinical Oncology.2016; 34(13): 1448. CrossRef
Efficacy and Safety of FOLFIRI as Second-line Chemotherapy in Advanced Gastric Cancer
Sung Chul Park, Hoon Jai Chun
The Korean Journal of Gastroenterology.2015; 66(1): 1. CrossRef
Efficacy and Safety of FOLFIRI after Failure of FOLFOX-4 in Advanced Gastric Cancer
Hye Jung Kwon, Moo In Park, Seun Ja Park, Won Moon, Sung Eun Kim, Hae Won Lee, Youn Jung Choi, Jae Hyun Kim
The Korean Journal of Gastroenterology.2015; 66(1): 10. CrossRef
Strategies and Advancements in Harnessing the Immune System for Gastric Cancer Immunotherapy
Vinod Vijay Subhash, Mei Shi Yeo, Woei Loon Tan, Wei Peng Yong
Journal of Immunology Research.2015; 2015: 1. CrossRef
Impact of the availability of active cytotoxic agents on the survival of patients with advanced gastric cancer
BYUNG HA CHO, HYE SOOK HAN, JIHYUN KWON, JOUNG-HO HAN, SOON MAN YOON, DAE HOON KIM, HYO YUNG YUN, KI HYEONG LEE, SEI JIN YOUN, SEUNG TAIK KIM
Oncology Letters.2015; 10(4): 2481. CrossRef
Design of precise third-line therapy for gastric cancer: target or chemotherpy?
Jae Yong Cho
The Korean Journal of Internal Medicine.2013; 28(3): 297. CrossRef
Sequential Chemotherapies for Advanced Gastric Cancer: A Retrospective Analysis of 111 Patients
Christoph Elsing, Christina Herrmann, Carla Verena Hannig, Wolfgang Stremmel, Dirk Jäger, Thomas Herrmann
Oncology.2013; 85(5): 262. CrossRef

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Phase II Study of Gemcitabine and Vinorelbine as Second-Line Chemotherapy in Non-Small Cell Lung Cancer: Yoon Jae Kim, Joo Hyuk Sohn, Chul Kim, Yong Tai Kim, Hai Jin Kim, Joong Bae Ahn, Se Kyu Kim, Joon Chang, Nae Choon Yoo, Joo Hang Kim, Jae Yong Cho; Cancer Res Treat. 2003;35(4):294-298. Published online August 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.4.294

Abstract PDF: PURPOSE
With the increased use of chemotherapy for non small cell lung cancer (NSCLC), a growing group of patients can now be considered for second-line chemotherapy. However, guidelines for the second line treatment remain to be developed. The objective of this study was to evaluate the efficacy and safety of the gemcitabine and vinorelbine combination therapy in patients with advanced NSCLC, pretreated with taxane and platinum based regimens. Gemcitabine has already demonstrated activity in this patient group, with the combination therapy having been reported to be well tolerated in previous phase I/II studies.
MATERIALS AND METHODS
Forty two patients with advanced NSCLC (stages III/IV), having received prior taxane and platinum based chemotherapy, with an ECOG performance status (PS) 0~2, and unimpaired hematopoietic and organ function, were treated with vinorelbine, 20 mg/m2, followed by gemcitabine, 1, 000 mg/m2, both administered on days 1, 8 and 15, every 4 weeks.
RESULTS
Out of the 42 patients enrolled, 41 were evaluable for their response, and all 42 for their toxicity. The patient's characteristics were as follows; median age=60 years (42~73), median PS=1 (range 0~2), a gender ratio 31: 11 males/females, with stages IIIA, IIIB and IV in 3, 14 and 25 cases. The objective responses included a partial response (PR) 8/41 (19.5%), a stable disease 15/41 (36.6%) and a progressive disease 18/41 (43.9%). The median time-to progression (TTP) and survival were 4 months, ranging from 2 to 14 months, and 8 months, ranging from 2 to 17+ months, respectively. Grade 3 neutropenia was seen in 19% of the patient, and there was no grade 4 neutropenia or episodes of febrile neutropenia. No grade 4 thrombocytopenia or other grade 3/4 non-hematological toxicities were observed.
CONCLUSION
The combination of gemcitabine/vinorelbine is active and well tolerated in patients with advanced NSCLC having failed prior taxane/platinum therapy.

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Phase II Study of Topotecan and Etoposide as Second-line Treatment in Chemotherapy-refractory Small-cell Lung Cancer: Chul Kim, Joo Hyuk Sohn, Joo Hang Kim, Se Kyu Kim, Young Sam Kim, Joon Chang, Jae Yong Cho; Cancer Res Treat. 2002;34(5):334-338. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.334

Abstract PDF

PURPOSE
Refractory small-cell lung cancer (SCLC) has a poor prognosis, and current salvage chemotherapy for refractory SCLC, such as CAV (cyclophosphamide, adriamycin, vincristine) or topotecan, has an unsatisfactory outcome, with a response rate and overall survival of less than 10% and 6 months, respectively. This phase II study evaluated the role of topotecan combined with etoposide in SCLC patients that have progressed, or relapsed, within 3 months following completion of the initial chemotherapy.
MATERIALS AND METHODS
Twenty-seven patients were entered into this study. Eligible patients had an ECOG performance status of less than, or equal to, 2, at least one bidimensionally measurable lesion and adequate end organ function. IV topotecan, 1.0 mg/m2/d for 5 consecutive days, and etoposide, 100 mg/m2/d through days 1 to 3, were administered every 3 weeks until disease progression or undue toxicity.
RESULTS
The major toxicity was myelosuppression. Grade 3/4 anemia, granulocytopenia, and thrombocy-topenia occurred in 14.2, 34.8, and 27.3% of cycles, respectively. There was no treatment-related death, and other non-hematologic toxicities were generally mild. Four patients achieved partial responses, with a response rate RR of 14.8%. The progression-free survival PFS ranged from 1 to 7 months, with a median of 2.0 months (95% confidence interval 1.22~2.78 months). Twenty-five patients died, with a median overall survival of 5.5 months (ranging from 1 to 21 months, 95% CI 4.32~6.68 months), and the 6-month survival rate was 32.1% (95% confidence interval 14.4~49.8%).
CONCLUSION
The combination of topotecan and etoposide chemotherapy showed a modest response rate, but failed to prolong survival of refractory SCLC patients compared to topotecan monotherapy.

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Real-World Outcomes with Lurbinectedin in Second Line and Beyond for Extensive Stage Small Cell Lung Cancer in Korea
Joo Sung Shim, Youhyun Kim, Taeho Yuh, Jii Bum Lee, Hye Ryun Kim, Min Hee Hong, Byoung Chul Cho, Sun Min Lim
Lung Cancer: Targets and Therapy.2024; Volume 15: 149. CrossRef

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Effects of Interleukin-2 Transduction into the Human Hepatoma Cell Lines Using Retroviral Vector: Soo Jung Gong, Nae Chun Yoo, Joo Hang Kim, Dong Hwan Shin, Hyo Dong Uhm, Sook Jung Jeong, Jae Yong Cho, Sun Young Rha, Yeon Soo Kim, Hyun Cheol Chung, Jae Kyung Roh, Jin Sik Min, Byung Soo Kim; J Korean Cancer Assoc. 1997;29(4):555-564.

Abstract PDF: PURPOSE
We compared the differences between parent hepatoma cell lines and interleukin-2 (IL-2) transduced hepatoma cell lines using N2A/IL-2 and LNC/IL-2 retrovirus with regards to in vitro sensitivity to peripheral blood monocytes and in vivo tumorigenic activity.
MATERIALS AND METHODS
Retroviral vector and producer cell line were constructed and IL-2 gene was transduced into the human hepatoma cell lines (SK-Hep1, Hep-G2, Hep-3B). IL-2 secretion after IL-2 transduction was measured by ELISA. MTT assay for in vitro sensitivity to peripheral blood monocytes was performed and the tumorigenic activity was observed in BALB/c mice and nude mice.
RESULTS
IL-2 secretion was 186 pg/10 degrees C cells/24 hrs in SK-Hep1 cell line and was 147 pg/10 (6) cells/24 hrs in Hep-3B cell line with N2A/IL-2 retroviral vector and was 55,000 pg/10 (6) cells/24 hrs with LNC/IL-2 retroviral vector. In vitro sensitivity to peripheral blood monocytes was increased by 163.8~254% in IL-2 transduced hepatoma cell lines (Hep -3B/N2A/IL-2, Hep-G2/N2A/IL-2) compared to those of the parent cell lines. The tumorigenicity was observed in 1 of 3 BALB/c mice and all 3 nude mice. Simultaneous injection of 1 X 10 (7) cells of the parent cell line (Hep-3B) into the right flank and IL-2 transduced cell line (Hep-3B/LNC/IL-2) into the left flank of the three BALB/c mice and of 5 X 10 (5) cells for the three nude mice resulted in a complete regression of the IL-2 modified tumor cell line (Hep-3B/LNC/IL-2) in 3 weeks and the parent cell line (Hep-3B) in 5 weeks. But, after the injection of 1.5 X 10 (7) cells for other five nude mice, the tumor of the IL-2 transduced hepatoma cell line (Hep-3B/LNC/IL-2) was gradually disappeared, and the tumor of the parent hepatoma cell line (Hep-3B) was initially decreased and then gradually regrew 20 days later.
CONCLUSION
IL-2 transduced hepatoma cell lines secreting IL-2 became more sensitive to peripheral blood monocytes and resulted in the increased antigenicity to the tumors formed by IL-2 transduced hepatoma cell line and parent cell line, and finally resulted in the regression of the tumors in experimental animals.

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Evaluation of Biologic Phenotype by Midkine Gene Expression in Gastric Cancer as a Target for Biotherapy: Hyun Cheol Chung, Sun Young Rha, Hei Cheol Chung, Hyun Joo Kwak, Jae Yong Cho, Soo Jung Gong, Sung Hoon Noh, Joo Hang Kim, Jae Kyung Roh, Jin Sik Min, Byung Soo Kim; J Korean Cancer Assoc. 1997;29(1):69-80.

Abstract PDF: PURPOSE
We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor, midkine (MK) expression.
MATERIALS AND METHODS
Nine gastric cancer cell lines and 25 gastric cancer tissues were tested for MK expression by Northern blot analysis. Soft agar assay for in vitro tumorigenesis, cross- feeding assay for paracrine angiogenic activity, ELISA for uPA and PAI-1 measurement were performed.
RESULTS
MK expression was found in 67% (6/9) of the gastric cancer cell lines, and 56% (14/25) of the primary gastric cancer tissues. Gastric cancer cell lines with MK expression were more tumorigenic in soft agar assay and endothelial cell growth stimulatory in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity.
CONCLUSION
Gastric cancer cells with increased MK gene expression showed increased tumorigenic and angiogenic activity. Therefore, this proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer treatment.

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Therapeautic effect of hepatic arterial infusion of cisplatin in primary hepatocelluar carcinoma: Jae Yong Cho, Jin Hyuk Choi, Nae Choon Yoo, Ho Young Lim, Joo Hang Kim, Jae Kyung Roh, Jong Tae Lee, Byung Soo Kim; J Korean Cancer Assoc. 1993;25(6):865-872.

Abstract PDF: No abstract available.

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Four cases of primary malignant lymphoma of the breast: Jin Ahn Kim, Jin Hyuk Choi, Jae Yong Cho, Hee Yong Moon, Bum Soo Kim, Ho Young Lim, Joo Hang Kim, Jae Kyung Roh, Byung Soo Kim; J Korean Cancer Assoc. 1993;25(5):773-779.

Abstract PDF: No abstract available.

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A Retrospective Comparison of Infusional 5-Fluorouracil , Doxorubicin , Mitomycin - C ( Modified FAM ) Combination Chemotherapy Versus Palliative Therapy in: Joon Oh Park, Jae Kyung Roh, Hyun Cheol Chung, Hyun Jin Noh, Jae Yong Cho, Sun Young Rha, Chong In Lee, Cheol Woo Kim, Joo Hang Kim, Choong Bai Kim, Sung Hoon Noh, Kyong Sik Lee, Jin Sik Min, Byung S; J Korean Cancer Assoc. 1995;27(2):165-175.

Abstract PDF: In Korea, gastric cancer is the most common cancer and the leading cause of cancer death. About one-third of the patients with gastric cancer is unresectable at the time of diagnosis. Their median survival is less than 6 months with very poor prognosis. Accordingly, various regimens of chemotherapy have been proposed as intensive treatment for unresectable patients. After MacDonald et aL reported 42% response rate and 9 months response duration using combination of 5-Fluorouracil, Doxorubicin and Mitomycin-CFAM), it became the most widely used regimen in the treatment of advanced gastric cancer. However, despite of high initial response rate, there was no survival benefit in randomised comparative trials. To increase the drug effect, we modified the standard FAM regimen by continuously infusing the 5- Fluorouracil instead of bolus injection(modified FAM). We retrospectively reviewed the clinical recoreds of 409 patients with histologically proven advanced gastric cancer in Yonsei University Medical Center and Yonsei Cencer Center between Jan. 1, 1991 and Dec. 31, 1993. The purpose of this study is to assess the efficacy of infusional FAM combination chemotherapy compared with other palliative therapy in advanced gastric cancer. Among 409 patients, 266 were male and 143 were female with a median age of 57-year(range: 15~75). There were 202 patients in mFAM-treated group and 207 patients in control group. In mFAM-treated group, 140 patients had no surgery, 30 patients underwent a palliative bypass and 32 patients underwent a palliative resection. In control group, 151 patients had no surgery, 33 patients underwent a palliative bypass and 23 patients underwent a palliative resection. In preoperative staging, 257 patients had locally advanced disease, 48 had carcinomatosis and 104 had distant metastasis. There was no difference of distribution in age, sex, perfomance status, preoperative stege and treatment modalities between mFAM-treated and control group. 1) Among 154 of evaluable patients, no CRs were observed. PR were seen in 17.5% of patients in mFAM-treated group. The median response duration was 30 weeks and progression free survival was 23 weeks. 2) Higher 1-year survival rate was demonstrated in mFAM-treated group comparing to control group(34.1% vs 22.5)(p=0.0135). 3) Median survival was longer in mFAM-treated group than that of control group(40 week vs 28 week). 4) The toxicities were relatively tolerable and reversible. This results proposed that the infusional FAM combination chemotherapy showed a probalbility of survival pralongation, especially combined with palliative surgery in advanced gastric cancer. Further prospective randomized study will be warranted.

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Detection of Soluble c-erbB-2 Oncoproteins in the Serum of Gastric Cnacer patients as a Tumor Marker: Hyung Cheol Chung, Joong Bae Ahn, Joon Oh Park, Jae Yong Cho, Sun Young Rha, Chong In Lee, Hye Ran Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Sung Hoon Noh, Jin Sik Min, Byung Soo Kim, Ho Yeon; J Korean Cancer Assoc. 1995;27(2):175-184.

Abstract PDF: A soluble fragment of the c-erbB-2 oncoprotein become detectable in the serum of the breast cancer petients by enzyme-linked immunosorbent assay(ELISA). To evaluate the clinical sig- nificance of soluble c-erbB-2 in gastric cancer, we measured the serum levels in 45 normal healthy persons and in 86 gastric cancer patients. Fifty-five patients were underwent surgery(47 curative surgery, 8 palliative surgery) and thirty-one patients were inoperable(18 advanced, 8 relapsed, 6 progressed after palliative surgery). The c-erbB-2 serum levels were below 14 U/ml in normal persons. Three of 86(3.5%) sam- ples from gastric cancer patients had elevated serum c-erbB-2 leveL In 55 operated patients, all serum samples were negative for c-erbB-2. Elevated serum levels were predominantly found in patients with initially advanced cancers(3/18: 16.7%). In 22 operated cases, immunohisto- chemical staining showed 36.4% c-erbB-2 positive ratio(8/22) in tissues. Comparing the results from sera and tissues studies, the sensitivity of serum ELISA assay was too low even if the specificity was high. Our data suggest that the soluble c-erbB-2 oncoprotein can be a tumor marker only in advanced stage of gastric cancer. Further studies are warrented to elucidate the discrepancy between the serum and tissue results in oprable early stage gastric cancer.

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Prognostic Factors in Node - Negative Breast Cancer: Kyung Hee Lee, Hyun Cheol Chung, Jae Yong Cho, Sun Young Rha, Joong Bae Ahn, Chong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Byung Soo Kim, Kyung Sik Lee, Kyl Beom Lee, Ho Yeong Lim, Jin Hy; J Korean Cancer Assoc. 1995;27(2):265-275.

Abstract PDF: Breast cancer is the third most common malignant neoplasm in Korean women. The effect of postoperative adjuvant systemic therapy in the treatment of primary breast cancer with pathologic involvement of the axillary lymph nodes has been well established. But, 20 30% of node-negative breast cancer patients will develop recurrent disease and risk death within 10 years after initial local therapy without adjuvant treatment. Therfore, it is reasonable to identify those node-negative breast cancer patients at significant risk for recurrence and who could be treated with adjuvant therapies. A clinical study was perofrmed in 184 cases of primary node-negative breast cancers from January 198l to December 1991 to study the natural course of the diaease and to find-out the prognostic factors. The following results were obtained; l) During 73 monthe(9-143) of follow-up duration, 5-year and 10-year relapse free survival rates were 88%, 77% respectively, and overall survival rates were 89%, 88%, respectively. 10 year recurrence rate was 19%. 2) Median disease-free and survival durations were 80 month, 17 months, respectively, in tumor size<2 cm group and 68.5 months, 62 months respectively in tumor size 2-5 cm group. 3) Median disease-free and overall survival durations were 73 months, 61 months, respectively, in premenopause patients and 74 months, 73 months in postmenopause patients. 4) No differences were found in disease-free and survival duration based on types of operation. 5) With adjuvant treatment, there was a decreasing tendency of systemic relapse. In conclusion, continuous relapse was found in node-negative breast cancer even after 5 years of operation. Even if decreasing tendency of systemic relapse was induced with adjuvant treatment, no clinically useful prognostic factors were found from surgical and pathologic factors until now. Further study of biological factors in node-negative breast cancer is warrented.

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Expression and Significance of c-erbB-2 in Radically Resected Colorectal Cancer: Hyun Cheol Chung, Sun Young Rha, Joon Oh Park, Seung Hun Song, Jae Yong Cho, Jung Bae Aha, Hye Ran Lee, Chong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Jin Sil Seong, Gwi Eon Kim, Jin Sik M; J Korean Cancer Assoc. 1995;27(3):389-403.

Abstract PDF: Overexpression of c-erbB-2 oncoprotein has been shown to correlate with poor prognosis and drug-resistance to the conventional chemotherapy with 5-fluorouracil in breast and gastric cancers. To evaluate the clinical significance of c-erbB-2 overexpreseion in colorectal cancer, immunohistochemical staining was performed with the paraffin-embedded tiasues of 141 colorectal cancer patients with curative surgery. The follow-up duration ranged from 7 to 61 months(median 30 months). Two-year disease- free and overall survival rate of the total patients were 77%, 91%, respectively. The c-erbB-2 positive rate was 24.8%, Even if patients with c-erbB-2 overexpression showed a tendency of poor prognosis than c-erbB-2 negative patients, T-factor and the TNM stage were independent prognostic factors in multivariate analysis. In subset analysis with c-erbB-2 negative patienta, there were no differences in recurrence rate and 2-year disease-free survival rate between pa- tients with chemotherapy and without chemotherapy(20.0% versus 26.1%)(80.0% versus 82.0%). However, in c-erbB-2 positive patients, those subgroup with chemotherapy showed tendencies toward advantages in relapse rate and 2-year disease-free survival rate than those of subgroup without chemotherapy(21.0% versus 50.0%; p=0.09)(76.0% versus 50.0%: p=0.06). Also, there was a tendency of increased time to relapse in patients with chemotherapy comparing to that of the patients without chemotherapy(7.5 months versus l7.0 months; p = 0.09). In stage III, patients with c-erbB-2 overexpression showed increased 2-year disease-free survival rate with chemotherapy as comparing to that of patients without chemotherapy(81.0% versus 29.0%; p= 0.003). Again, this survival benefit was not found in c-erbB-2 negative stage III patients regard- less of chemotherapy. In conclusion, c-erbB-2 overexyression might be a marker of relative drug resistance to 5-FU which will be converted with the high dose treatment of modulation with leucovorin. A prospective randomized trial is warrented to confirm this suggestion and for the clinical applica- tion of c-erbB-2 overexpression.

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Expression in Matrix - Metalloproteinases ( MMP-2 , MMP-9 ) in Gastric Cancer as new Targets for Biotherapy: Hyun Cheol Chung, Jae Yong cho, Sun Young Rha, Joon Oh Park, Joong Bae Ahn, Choong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Sung Hoon Noh, Jin Sik Min, Byung Soo Kim, Ho Yeong Lim, Jin Hyu Choi; J Korean Cancer Assoc. 1995;27(6):897-907.

Abstract PDF: The proteolytic processes are thought to be the critical point in tumor invasion and metastasis, mainly by matrix-metalloproteinases (MMPs) and serine proteases. We measured the activities of MMP-9 and MMP-2 in the 120 normal and cancer tissue samples from the same patients using gelatin zymography. Inactive MMP-9(92 kD) was expressed in 73.3% of the normal and 87.5% of the cancer tissues, respectively (p=0.009), while active MMP-9(82 kD) was expressed in 24.2% and 53.3%, respectively (p=0.0001). Inactive MMP-2 (72kD) was expressed in 33.3% of the normal and 55.0% of the cancer tissues, respectively (p=0.001), while active MMP-2(62kD) was expressed in 4.2% and 31.7%, respectively (p=0.0001). In Tl state, only frequency of expression and enzymatic activity of the active MMP-2(62kD) were increased, while from T2 stage, the expression and the activation of the both MMP-9 and MMP-2 were increased as the cancer progressed. The expression frequency of the MMP-9 was more common than of the MMP-2. The co-expression rate of the active forms (82 kD, 62 kD), activites of 82 kD and 62 kD, and the activation rates of the both MMPs were increased as the cancer invades and metastasizes to distant lymph node areas. In conclusion, MMP-2 activation was the main causes of the increased MMPs activity during the Tl phase of the gastric cancer, while production and activation of the both MMP-9 and MMP-2 were increased as the cancer progressed. Therefore, we suggest that the different expression and activation of the MMPs in the gastric cancer progression can be a potential therapeutic target in gastric cancer biotherapy.

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A Comparative Study of Intravenous granistron Versus Intravenous / Oral Ondansetron in the Prevention of Nausea and Vomiting Associated with Moderately: Joon Oh Park, Hyun Cheol Chung, Yong Seok Yoon, Woong Chol Kang, Sang Hak Lee, Heui Cheul Chung, Jae Yong Cho, Sun Young Rha, Chong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Jin Sik Min, By; J Korean Cancer Assoc. 1995;27(6):1048-1061.

Abstract PDF: Nausea and vomiting are common and the most distressing side effects of cancer chemotherapy. As these symtoms can cause emotional instability and malnutrion from poor oral intake, which further lead to decrease the effect of chemotherapy, it is important to prevent emesis adequately and effectively. Ondansetron is a selective 5-HT, receptor antagonist and is reported to be effective in preventing cisplatin-induced emesis, Granisetron is a potent and the most selective 5-HT, receptor antagonist currently available. We conducted a prospective, randomized, open, single center, parallel group study to compare the antiemetic effect and safety of granisetron versus ondansetron in patients receiving moderately emetogenic chemotherapy. Form December l994 to May 1995, 65 consecutive patients who planned to receive moderately emetogenic chemotherapy(80 to 100 mg/§³ of cisplatin or 40 mg/§³of doxorubicin) were enrolled in this study. Granisetron was administered intravenously prior to chemotherapy at a dose of 3mg, and up to two doses of granisetron could be administered as rescue therapy within the first 24 hour period. Ondansetron 8 mg was given intravenously prior to chemotherapy followed by 2 more doses at 8 and 16 hours after chemotherapy. Finally, we evaluated 63 patients(32 receiving granisetron and 31 receiving ondansetron). In the first 24 hours after chemotherapy, complete and major response were achieved in 78.1 % of patients receiving granisetron and 74.2 % of patients receiving ondansetron(P=0.7163). There were also no differences in the control of delayed nausea and vomiting between two groups(56.3% vs 45.2%, P=0.3826). There were no differences in percentages of patients who received rescue therapy across the treatment groups: 3I.5% for granisetron vs. 45.2% for ondansetron during the study(P=0.3803). During the first 24 hours following chemotherapy, there were no differences in time to first episodes of nausea(granisetron 14 hours 20 minutes vs ondansetron 13 hours) and vomiting(granisetron 20 hours vs ondansetron 19 hours 20 minutes) between two groups. There were no significant adverse effects or toxicities with these antiemetics. We concluded that single dose granisetron was as effective in prophylaxis of emesis induced by moderatly emetogenic chemotherapy as triple doses of ondansetron and oral maintainence combination. For the non-responders to granisetron, combination of granisetron with other antiemetics of different action mechanism or maintainence granisetron trials are warranted.

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Expression and Clinical Relevance of c-erbB-3 in Rectal Cancer: Chong In Lee, Sun Young Rha, Jin Oh Park, Hyun Cheol Chung, Jae Yong Cho, Joong Bae Ahn, Nae Choon Yoon, Tae Soo Kim, Joo Hang Kim, Jae Kyung Roh, Jin Sup Choi, Jin Sik Min, Byung Soo Kim, Woo Ick Ja; J Korean Cancer Assoc. 1996;28(1):50-63.

Abstract PDF: Recently, there is an increasing tendency of colorectal cancer in Korea, probably due to changes of diet pattern to western style. In rectal cancer, as the local recurrence is a common and major problem despite of radical resection, it is recommended to use 5-fluorouracil(5-FU)- based chemotherapy in combination with pelvic radiation after radical operation in MAC B,-C, cancers. But until now, there are many controversies about the effective chemotherapeutic agent, radiation dose, route, and chemoradiation schedule. There is increasing evidence that genes involved in normal cell growth and differentiation(oncogenes) or genes that encode for growth factor are important in determining the development and biologic aggressiveness of various cancers. Among many oncogenes thought to be related with cancer, c-erbB-2 is a relatively well known protein to be associated with cancers, especially in breast and colorectal cancers. In addition to c-erbB-2 and Epidermal Growth Factor Receptor(EGFR), c-erbB-3 belongs to Type -I Growth Factor Receptor Family(EGFR-related Family) and is the most recently identified protein in EGFR-related Family. There have been a few reports about the prognostic value of c-erbB-3 in breast and prostate cancers. In this study we performed immunohistochemical staining of 114 surgically resected specimens of rectal cancers to investigate the expression rate and clinical relevance of c-erbB-3 as a prognostic factor and drug selection marker. c-erbB-3 expression rate was 46% in 114 rectal cancers and there were significant differences in recurrence rate and survival rate between c- erbB-3 positive and negative group. Twenty-one cases(40%) recurred in 52 c-erbB-3 positive cases and 10 cases(16%) recurred in 62 c-erbB-3 negative cases(p=0.004). The difference in recurrence rate between c-erbB-3 positive and negative group was significant exclusively in MAC stage C(p=0.0126), but not in MAC stage B(p=0.4357). In c-erbB-3 positive and negative group, 2-year disease free survival rate was 66% and 87%, respectively(p=0.0052), and 2-year overall survival rate was 84% and 95%, respectively(p=0.005). Again, the difference in 2-year disease free survival rate between the two groups was significant only in MAC stage C(p=0. 0137), not in stage B(p=0.4182). There were no significant differences in recurrence rate and 2- year disease free survival rate in chemo-radiation group regardless of c-erbB-3 expression and stage. But in adjuvant radiotherapy alone group, increased recurrence rate and decreased survival rate were found in c-erbB-3 positive group. This finding suggested c-erbB-3 as a possible relative radioresistance marker, in whom a higher radiotherapy dose is needed. In conclusion, c-erbB-3 may be regared as a prognostic marker and as a possible indicator of radioresistance in the treatment of rectal cancer.

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Expression of Urokinase - type Plasminogen Activator a New Biologic Marker of the Invasion and Metastasis in Gastric Cancer: Sung Hoon Noh, Jae Yong Cho, Sun Young Rha, Hyun Cheol Chung, Joon Oh Park, Chong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Jin Sup Choi, Jin Sik Min, Byung Soo Kim; J Korean Cancer Assoc. 1996;28(2):198-207.

Abstract PDF: Mortality in gastric cancer is related to invasion and metastasis. Evidence has accumulated that invasion and rnetastasis in solid tumors require the action of tumor associated proteases, which promotes the dissolution of the surrounding tumor matrix and the basement membrane. The serine protease urokinase-type plasminogen activator(uPA), which is elevated in solid tumors, appears to play a key role in these processes. We used enzymelinked immunoabsorbent assays(ELISA) to test uPA antigen expression in tissue extracts of normal and cancer tissue of 160 gastric cancer patients. uPA level was significantly higher in cancerous tissue than normal gastric tissue(9.4 vs 5.3 ng/mg protein cytosol: p<0.001). When the uPA level was correlated to other prognostic parameters, uPA positivity is associated with grade of anaplasia(p=0.005). Univariate analysis showed that a uPA positivity is significantly associated with short. disease-free survival(p=0.005). Multivariate analysis with known prognostic parameters revealed that the uPA positivity was an independent prognostic parameter for short disease-free survival. These data indicate that uPA is a potentially important prognostic factor in gastric cancer. Consequently, we suggest that modulation of uPA is needed to prevent invasion and metastasis in gastric cancer patients.

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A Phase 1 Clinical Trial and Pharmacokinetic Evaluation of DA-125 ( A Novel Anthracycline Derivative ) in Advanced Carcer Patients: Jae Kyung Roh, Sun Young Rha, Jong In Lee, Kyung Hee Lee, Joon Oh Park, Jae Yong Cho, Nae Chun Yoo, Hyun Cheol chung, Joo Hang Kim, Jin Sik Min, Byung Soo Kim, Myung Geol Lee, Won Bae Kim, Joong Ik Y; J Korean Cancer Assoc. 1996;28(6):961-973.

Abstract PDF: Background
DA-125 {(7-0-12.6-dioxy-2-fluoro-2-L-talopyranosyl)- adriamycinone-14-b-alaninate HC1}, is a novel water soluble derivative of fluorinated doxorubicin. Our previous studies showed that DA-125 is more stable and effective than doxorubicin, especially to doxorubicin resistant tumor cell lines in vitro and in vivo. We initiated phase I clinical trial to evaluate the toxicities and the pharmacokinetics of DA-l25 in advanced cancer patients. Method: Advanced cancer patients who were refractory to the standard treatment with normal hepatic and renal functions were eligible after informed consent. Drug was administered intravenously for 5 minutes with initial starting dose of 20 mg/§³(10% of murine LD10). For each dose level, 3 patients were enrolled and the next increased dose was administered if there were no toxicities greater than WHO grade III. Blood, urine and bile (if possible) were collected for the pharmacokinetic evaluation. Result: Twenty three patients were enrolled with 22 evaluable patients (3 at 20 mg/§³, 3 at 40 mg/§³, 3 at 60 mg/§³, 6 at 80 mg/§³ and 7 at 100 mg/§³ of DA-125). All treated patients did not suffer from life-threatening side effects. Hematologic alterations especially neutropenia were major toxicities. Up to 60 mg/§³ dose, toxicities greater than WHO grade II were not observed. At 80 mg/§³ dose, one heavily pretreated patient developed grade III neutropenia. At 100 mg/§³ dose, one patient developed grade IV thrombocytopenia without evidence of clinical bleeding and 2 patients showed grade III neutropenia Grade I and II nausea and vomiting were observed at 80 mg/§³ and 100 mg/§³ dose level. Cardiac toxicities did not occur in any patient. DA-125 was rapidly hydralized to Ml(active metabolite), after IV administration. The plasma half life of M1 was 1.1~2.6 hours and that of M2 was 7.8~9.4 hours. The AUC of both metabolites were dose dependent(Ml: 0.154~0.638ug.hr/ml, M2: 0.684~3.07 ug.hr;ml). Urinary excretion of Ml wss less than 1% of administered dose until 96 hours and that of M2 was 10~22%. In one patient with periampullary cancer, 52.3% of the metabolites were excreted through bile. Conclusion: The results of the present study demonstrated that DA-125 was well tolerable to the advanced cancer patients and 100 mg/§³ was considered as maximally tolerated dose. We are planning the phase II trial on the basis of these results.

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Effect of Combined Modality Treatment and Clinical Significance of P-Glycoprotein Overexpression in Patients with Osteosarcoma: Yong Seok Yun, Jae Kyung Roh, Hyun Cheol Chung, Jae Yong Cho, Kyoo Ho Shin, Soo Bong Han, Beom Seok Kim, Joon Oh Park, Soo Jung Gong, Sun Young Rha, Nae Choon Yoo, Joo Hang Kim, Jin Sik Min, Byung So; J Korean Cancer Assoc. 1996;28(6):1104-1117.

Abstract PDF: Osteosarcoma is a highly malignant bone tumor and usually encountered in the first three decades of life. The Prognosis of osteasarcoma treated with surgery alone had been poor, with 20% of the patients surviving 5 years. The addition of adjuvant chemotherapy after surgery has siginificantly improved the outcome of osteosarcoma. The new concept of pre-operative chemotherapy has permitted histological assessment of treatment effect and limb salvage procedures. As the role of chemotherapy has been raised, the resistance of tumors to multiple drugs, such as p-glycoprotein overexpression, has become a major problem in the treatment of osteosarcoma. We retrospectively reviewed the clinical records of 53 patients with stage IIB osteosarcoma who were treated at Yonsei Medical Center and Yonsei Cancer Center between March 1, 1986 and June 30, 1996. The purpose of this study was to assess the efficacy and toxicity of cisplatin(IA)-adriamycin(IV) combination pre-operative chemotherapy and the clinical significance of p-glycoprotein status and histologic response as prognostic factors. Among 53 patients, 33 were male and 20 were female with a median age of 21 years(range: 5~61). The tumor locations were as follows: distal femur 24(45.3%), proximal tibia 17(32.1%), humerus 7(13.2%), proximal femur 3(5.4%), fibular 1(1.9%), radius 1(1.9%). Histologic subclassifications were as follows: osteoblastic type 42(78.2%), telangiectatic type 4(7.5%), chondrablastic type 3(5.7%), fibroblastic type 2(3.8%) and undetermined 2(2.8%). The three year overall survival and disease-free survival rates were 66.1% and 61.9% respectively in all patients. Thirty-two patients were treated by pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy and 21 patients were taken only post-operative adjuvant chemotherapy. No significant difference was found between the two groups in probability of survival and recurrence rates. The histological response ta pre-operative chemotherapy was scored by degree of tumor necrosis. Twenty-two patients had a good response [grade IV, 13(40.6%);grade III, 8(25.0%)] and 11 patients had a poor response [grade II, 6(18.8%);grade I, 5(15.6%)]. The histological response was not significantly related to the probability of the survival rate. However, the recurrence rate was higher in the poor-response group(p=0.04). Overexpression of p-glycoprotein was found in tumors from 11 of l8 patients(61.1%) who were given only post-operative adjuvant chemotherapy. No relation was found between the p-glycoprotein expression and survival rate. The degree of tumor necrosis after pre-operative chemotherapy and initial serum alkaline-phosphatase level were considered as prognositic factors. Other clinicopathologic features including age, gender, anatomical site, histological subclassification,operation types,tumor size.p-glycoprotein expression were not associate with patient outcome. Treatment-related side effects were relatively tolerable and reversible by conservative treatment. Pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy in our study did not show improved survival than conventional post-operative chemotherapy with limited follow-up duration. The degree of histologic response after chemotherapy and the initial alkaline phosphatase level were found to be the major predictor for tumor recurrences, while p-glycoprotein overexpression did not alter the clinical outcome. Further studies are warranted to improve the efficacy of adjuvant chemotherapy and to evaluate the significance of multiple resistance gene overexpression in osteosarcoma.

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