Cancer Research and Treatment

Case Reports

Fatal Ifosfamide-Induced Metabolic Encephalopathy in Patients with Recurrent Epithelial Ovarian Cancer: Report of Two Cases: You-Jung Shin, Ji-Young Kim, Jei-Won Moon, Rae-Mi You, Jeong-Yeol Park, Joo-Hyun Nam; Cancer Res Treat. 2011;43(4):260-263. Published online December 27, 2011; DOI: https://doi.org/10.4143/crt.2011.43.4.260

Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment.

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New metabolic insights into the mechanism of ifosfamide encephalopathy
Diren Beyoğlu, Paul Hamberg, Nikki S. IJzerman, Ron H.J. Mathijssen, Jeffrey R. Idle
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Rare Delayed Ifosfamide Encephalopathy: A Case Report of Chemotherapeutic Neurotoxicity
Ambika Menon, Chidiebele A. Enunwa, William L. Read, Kyle P. James
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Potential of Cytochrome P450, a Family of Xenobiotic Metabolizing Enzymes, in Cancer Therapy
Ragini D. Singh, Avadhesh Avadhesh, Gaurav Sharma, Sagar Dholariya, Rima B. Shah, Bela Goyal, Subash Chandra Gupta
Antioxidants & Redox Signaling.2023; 38(10-12): 853. CrossRef
Ifosfamide - History, efficacy, toxicity and encephalopathy
Jeffrey R. Idle, Diren Beyoğlu
Pharmacology & Therapeutics.2023; 243: 108366. CrossRef
A Case of Encephalopathy Caused by Drug Interaction between Ifosfamide and Aprepitant
Tomomi Sano, Nokitaka Setsu, Eisuke Kobayashi, Akira Kawai
YAKUGAKU ZASSHI.2023; 143(6): 541. CrossRef
Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies
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Ifosfamide-induced Encephalopathy With Rapid Response to Thiamine: A Pediatric Case
Eren Müngen, İnci Yaman Bajin, Sibel Öz, Ceren Günbey, Banu Anlar, Burca Aydin
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Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?
Halima Abahssain, Badreddine Moukafih, Hajar Essangri, Hind Mrabti, Bouchra Meddah, Fadila Guessous, Fatima Zahra Fadhil, Amine Souadka, Hassan Errihani
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Effect of Berberis vulgaris L. root extract on ifosfamide-induced in vivo toxicity and in vitro cytotoxicity
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Ifosfamide-related encephalopathy with severe clinical presentations in children with cancer
Eda Ataseven, Şebnem Önen Göktepe, Mehmet Kantar
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Neurotoxicity of antineoplastic drugs: Mechanisms, susceptibility, and neuroprotective strategies
Claudia Pellacani, Georgios Eleftheriou
Advances in Medical Sciences.2020; 65(2): 265. CrossRef
Delayed Ifosfamide Neurotoxicity
Jill Yeager, Alina Basnet
American Journal of Therapeutics.2020; 27(6): e613. CrossRef
Clinical and EEG Characteristics of Ifosfamide-Related Encephalopathy
Aaron M. Gusdon, Rachna Malani, Xi Chen
Journal of Clinical Neurophysiology.2019; 36(2): 150. CrossRef
Incidence et facteurs de risque de l’encéphalopathie à l’ifosfamide chez les patients suivis pour un sarcome
Natacha Stern, Ilyes Sakji, Anne-Sophie Defachelles, Cyril Lervat, Thomas Ryckewaert, Guillaume Marliot, Charlotte Peugniez, Dominique Deplanque, Nicolas Penel
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Risk factors of ifosfamide-related encephalopathy in adult patients with cancer: A retrospective analysis
Yin Lo, Li-Jiuan Shen, Wen-Hwei Chen, Yaa-Hui Dong, Fe-Lin Lin Wu
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The Neurotoxicity and Pharmacokinetics of Oral Ifosfamide
Martin S. Highley, Guido Momerency, Diane Sawyers, Ernst A. De Bruijn, Hans Prenen, Gunther Guetens, Gert De Boeck, Allan T. Van Oosterom, Janine L. Mansi, Peter R. Blake, Tim Mant, Robert A.A. Maes , Peter G. Harper
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Two Cases of Fatal Encephalopathy Related to Ifosfamide: An Adverse Role of Aprepitant
Alice Séjourné, Sabine Noal, Mathieu Boone, Céline Bihan, Marion Sassier, Michel Andrejak, Bruno Chauffert
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Reversible Proximal Renal Tubular Dysfunction after One-Time Ifosfamide Exposure: Young Il Kim, Ju Young Yoon, Jun Eul Hwang, Hyun Jeong Shim, Woo Kyun Bae, Sang Hee Cho, Ik-Joo Chung; Cancer Res Treat. 2010;42(4):244-246. Published online December 31, 2010; DOI: https://doi.org/10.4143/crt.2010.42.4.244

Abstract PDF PubReader ePub

The alkylating agent ifosfamide is an anti-neoplastic used to treat various pediatric and adult malignancies. Its potential urologic toxicities include glomerulopathy, tubulopathy and hemorrhagic cystitis. This report describes a case of proximal renal tubular dysfunction and hemorrhagic cystitis in a 67-year-old male given ifosfamide for epitheloid sarcoma. He was also receiving an oral hypoglycemic agent for type 2 diabetes mellitus and had a baseline glomerular filtration rate of 51.5 mL/min/1.73 m². Despite mesna prophylaxis, the patient experienced dysuria and gross hematuria after a single course of ifosfamide plus adriamycin. The abrupt renal impairment and serum/urine electrolyte imbalances that ensued were consistent with Fanconi's syndrome. However, normal renal function and electrolyte status were restored within 14 days, simply through supportive measures. A score of 8 by Naranjo adverse drug reaction probability scale indicated these complications were most likely treatment-related, although they developed without known predisposing factors. The currently undefined role of diabetic nephropathy in adult ifosfamide nephrotoxicity merits future investigation.

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Ifosfamide-induced nephrotoxicity in oncological patients
Juan Eduardo Quiroz-Aldave, María Del Carmen Durand-Vásquez, Freddy Shanner Chávez-Vásquez, Alexandra Noelia Rodríguez-Angulo, Sonia Elizabeth Gonzáles-Saldaña, Carlos César Alcalde-Loyola, Julia Cristina Coronado-Arroyo, Francisca Elena Zavaleta-Gutiérre
Expert Review of Anticancer Therapy.2024; 24(1-2): 5. CrossRef
Conditioning Regimens for Relapsed/Refractory Lymphoma Patients Undergoing Autologous Stem Cell Transplantation: BEAM Versus High Dose ICE
Ahmet Kursad Gunes, Simten Dagdas, Funda Ceran, Mehmet Ali Ucar, Mesude Falay, Cenk Sunu, Meltem Ayli, Nurullah Zengin, Gulsum Ozet
Indian Journal of Hematology and Blood Transfusion.2021; 37(1): 82. CrossRef
Cancer treatment-induced bone loss (CTIBL): Pathogenesis and clinical implications
S. D’Oronzo, S. Stucci, M. Tucci, F. Silvestris
Cancer Treatment Reviews.2015; 41(9): 798. CrossRef
Tubulointerstitial nephritis and cancer chemotherapy: update on a neglected clinical entity
M. Airy, R. Raghavan, L. D. Truong, G. Eknoyan
Nephrology Dialysis Transplantation.2013; 28(10): 2502. CrossRef

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Original Articles

A Phase II Trial of Docetaxel and Ifosfamide for Patients with Platinum-Resistant or Refractory Non-Small Cell Lung Cancer in a Salvage Setting: Gyeong-Won Lee, Jung-Hun Kang, Seok-Hyun Kim, Hea Yong Lee, Ho-Cheol Kim, Won-Sup Lee, Jong-Duk Lee, Young-Sil Hwang, Joung-Soon Jang, Jong-Seok Lee; Cancer Res Treat. 2004;36(5):287-292. Published online October 31, 2004; DOI: https://doi.org/10.4143/crt.2004.36.5.287

Abstract PDF PubReader ePub

Purpose

We conducted a phase II study of docetaxel and ifosfamide chemotherapy for patients with platinum-resistant or refractory non-small-cell lung cancer (NSCLC) to evaluate the response and toxicity profiles as a salvage treatment.

Materials and Methods

Between July 2000 and July 2004, 40 patients who had previously received platinum-based regimen as the first-line or second-line therapy were enrolled in this study. The treatment consisted of a docetaxel 75 mg/m² intravenous infusion on day 1 and intravenous ifosfamide 3 g/m² with Mesna® uroprotectione on day 1 through 3. This regimen was repeated every 3 weeks.

Results

One hundred thirty cycles of treatment were given, with a median of 3 cycles (range: 2~6 cycles). All the patients were evaluable for the response rate and toxicity profile. The major toxicity was myelosuppression. Grade 3~4 neutropenia occurred in 30 patients (75%) during treatment. Febrile neutropenia occurred in 16 patients (40%). Five of 40 patients (12.5%) had a partial response (95% confidence interval, 3.3~21.7%). The median time to disease progression was 2.65 months (range: 2.02~3.20 months), and the median survival was 5.24 months (range: 2.99~7.49 months).

Conclusion

Salvage chemotherapy with docetaxel and ifosfamide showed a low efficacy and a high proportion of severe neutropenia in patients with platinum-resistant or refractory advanced NSCLC.

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The Safety and Efficacy of Second-line Single Docetaxel (75 mg/m2) Therapy in Advanced Non-Small Cell Lung Cancer Patients who were Previously Treated with Platinum-based Chemotherapy
Byoung Yong Shim, Chi Hong Kim, So Hyang Song, Meyung Im Ahn, Eun Jung Hong, Sung Whan Kim, Suzy Kim, Min Seop Jo, Deog Gon Cho, Kyu Do Cho, Jinyoung Yoo, Hoon-Kyo Kim
Cancer Research and Treatment.2005; 37(6): 339. CrossRef

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Oral Etoposide, Ifosfamide and Cisplatin in the Treatment of Extensive Disease Small Cell Lung Cancer: Seok Jin Kim, Hwa Jung Sung, Kyong Hwa Park, So Young Yoon, Sang Cheul Oh, Jae Hong Seo, Chul Won Choi, Byung Soo Kim, Sang Won Shin, Yeul Hong Kim, Kwang Taek Kim, Young Ho Choi, Jun Suk Kim; Cancer Res Treat. 2002;34(6):421-425. Published online December 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.6.421

Abstract PDF: PURPOSE
The combination of cisplatin and etoposide has been a common first line regimen for the treatment of small cell lung cancer (SCLC). The schedule dependence, and equal efficacy, of the oral and intravenous dosing of etoposide has led to prolonged administration of oral etoposide, which is known to produce an encouraging response in SCLC. To improve the efficacy of the cisplatin/etoposide combination, we administered oral etoposide, with added ifosfamide, which had significant single agent activity against SCLC. We conducted this study to evaluate the efficacy and toxicity of the cisplatin, ifosfamide and oral etoposide (PIE) combination in patients with extensive small cell lung cancer.
MATERIALS AND METHODS
Twenty-five patients with histologically confirmed extensive small cell lung cancer were enrolled into this study between January 2000 and May 2002. They were treated with, cisplatin at 20 mg/ m2/day, ifosfamide 1.5 g/m2/day, with mesna (all given intravenously on Days 1~3), and oral etoposide 50 mg/m2 on days 4~17. This cycle was repeated every 4 weeks for up to 6 cycles. We evaluated the corresponding disease responses and toxicities.
RESULTS
The patients' characteristics were as follows: median age 65 years (32~75), 19 males and 6 females. The performance stati were ECOG 0 in 3 patients, ECOG 1 in 12 and ECOG 2 in 10. Sixteen patients had a partial response, 2 had a stable disease and 4 had a progressive disease. Thus, the overall objective response rate was 72.7% (95% CI: 49.6~88.4%), with a median response duration of 7 months (95% CI: 3.5~10.5 months). Myelosuppression was the major observed toxicity. Grades III and IV neutropenia were observed in 42 (46.1%) of the 91 cycles. Significant non-hematological toxicities (>or=Grade III) were uncommon, with the exception of nausea and vomiting.
CONCLUSION
The response rate to the combination of cisplatin, ifosfamide and oral etoposide was similar to that of other combination chemotherapy studies in patients with extensive disease small cell lung cancer. The toxicity of the regimen was considered acceptable.

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A Phase II Study of Ifosfamide, Carboplatin, and Epirubicin (ICE) Combination Chemotherapy for Extensive Disease of Small Cell Lung Cancer: Jae Ho Byun, In Sook Woo, Hun Ho Song, Keun Seok Lee, Jin Seok Ahn, Dae Young Jang, Jung Ae Lee, Young Lee Park, Young Suk Park; Cancer Res Treat. 2002;34(6):416-420. Published online December 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.6.416

Abstract PDF: PURPOSE
To evaluate the efficacy and safety of ifosfamide, carboplatin and epirubicin (ICE) combination chemotherapy for extensive disease small cell lung cancer (SCLC) patients, who had received no previous chemotherapy, we performed phase II trial between August 1998 and January 2001.
MATERIALS AND METHODS
The study group comprised of 21 patients. Ifosfamide, 1,500 mg/m2, was given with mesna, 900 mg/m2, intravenously for 12 hours on days 1, 2 and 3, and carboplatin, 4.5 mg/ml/min, for target AUC, and epirubicin, 60 mg/m2, were given intravenously for 90 minutes on day 1. The cycle of treatment was repeated at 4 week intervals.
RESULTS
Twenty-one patients with extensive disease SCLC were treated at Hallym University between August 1998 and January 2001. One patient was unable to be evaluated because of lost to follow-up. Of the 20 patients able to be evaluated, an objective response was observed in 13 (65%). There were no complete responses. The median response duration, time to progression and median overall survival were 15.4, 18.3 and 34 weeks, respectively. Toxicities were acceptable, with dose reduction for myelosuppression necessary in only a minority of the patients. A total of 85 cycles of chemotherapy were given to the patients. The median number of cycles completed was 4. Grade III and IV hematological toxicities included anemia (4.7%), neutropenia (3.5%) and thrombocytopenia (3.5%). Most non-hematological toxicities were grade I or II.
CONCLUSION
These results suggested that ICE combination chemotherapy for extensive disease SCLC is effective, and can be safely administered with acceptable toxicities.

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Effect of Vinorelbine, Ifosfamide and Cisplatin Combination Chemotherapy in Stage III-IV Non-Small-Cell Lung Cancer: Young Chul Kim, So Young Lee, Hong Joo Cho, Jung A Kim, So Hyang Song, Chi Hong Kim, Hoon Kyo Kim, Meyung Im Ahn, Jin Young You, Sung Whan Kim, Deng Gon Cho, Kyu Do Cho, Jin Hyung Kang; Cancer Res Treat. 2002;34(5):352-356. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.352

Abstract PDF: PURPOSE
To evaluate the response rates, toxicitiesy, and survival rates, to vinorelbine (Navelbine(R)), cisplatin and ifosfamide combination chemotherapy, of the patients with inoperable NSCLC (stage III and IV), who received vinorelbine (Navelbine(R)), cisplatin, ifosfamide combinationthe mentioned chemotherapy every 4 weeks.
MATERIALS AND METHODS
This study included 26 patients with inoperable NSCLC (stage III and IV), who attended St. Vincent's Hospital Bbetween April 1999 and December 2001, 26 patients were included at St.Vincent's Hospital. The chemotherapy regimen consisted of vinorelbine (25 mg/m2 on days 1 and 8), ifosfamide (1,500 mg/m2 on days 1- and 2 with mesna), and cisplatin (30 mg/m2 on days 1- to 3). The cycles were administered every 4 weeks. A 25% reduction in the doses reduction was applied into subsequent courses if there werewas grade 3~4 neutropenia.
RESULTS
The median age was 63 (range, 44~73) years and the male : to female ratio was 19 : 7. One patient had stage IIIa, 6 had stage IIIb and 19 had stage IV. Twenty two patients had an ECOG performance status of 0 or 1, andwith 4 hadhave one of 2. Eighteen of the patients had adenocarcinoma, 7 had squamous cell carcinomas, and 1 had an undifferentiated NSCLC. Two patients were innot able to be evaluatedble due to follow-up loss. Among Of the 24 patients able to be evaluatedble patients, 1 patient had a complete response and 9 patients hada partial responses, and thewith an overall response rate wasof 41.7%. During a total of 104 cycles, grade 3 neutropenia occurred in 29%, grade 4 neutropenia in 12%, grade 3~4 thrombocytopenia in 4%, grade 3 anemia in 11%, and grade 3~4 mucositis in 2%. The mean time to progression was 6.4 months (range 1~13) and the median overall survival was 10 months (range 1.5~32).
CONCLUSION
The combination of vinorelbine, ifosfamide and cisplatin, in the dose and schedule employed in this study, shows an response rate of 41.7%, but, because grade 3- or 4 neutropenia occurred in 41%, a careful investigation is needed.

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MINE (mesna, ifosfamide, mitoxantrone, etoposide) Chemotherapy as a Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma: Seong Hoon Chang, Yang Soo Kim, Wan Kyu Eo; Cancer Res Treat. 2002;34(2):145-152. Published online April 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.2.145

Abstract PDF

PURPOSE
The prognosis of non-Hodgkin's lymphoma (NHL) is disappointing for patients who experience primary treatment failure or relapse after an initial response. Patients in relapse may respond again to chemotherapy, however the time to disease progression becomes shorter and eventually the disease becomes resistant. The aim of this study was to evaluate the efficacy and safety of the MINE regimen in the treatment of patients with relapsed or refractory NHL. Material and Methods: Forty-three pretreated patients with a median age of 56 years were enrolled into the study between October 1995 and June 2000. Most patients (60.5%) had a performance status of 0 to 1, and a diffuse large cell subtype (55.8%). Seventy-four percent of patients had stage III or IV disease at the start of MINE treatment. Eighteen (41.9%) patients had complete response, 5 (11.6%) had partial response, and 20 (46.5%) had failed to respond to prior therapy. Ifosfamide 4 g/m2 was divided over 3 days and administered IV over a 1 hour period. Mitoxantrone 8 mg/m2 was administered as a short IV infusion on day 1. Etoposide (65 mg/m2/day) was infused over 1 hour on days 1 to 3. A total of 144 cycles was administered, with a mean of 3.34 cycles per patient (range, 1-8). The mean relative dose intensity was 87.4%.
RESULTS
1) Nine patients achieved a complete response and nine patients achieved a partial response, resulting in an overall response rate of 43.8% of the 41 assessable patients. 2) The median survival time was 6 months (95% CI, 4 to 8 months), and the median time to failure was 5 months (95% CI, 3 to 7 months). 3) A statistically significant association with complete response rates was found for complete response to prior therapy (p=0.049). The significant factors for overall survival were a complete response after MINE chemotherapy and serum 2-microglobulin (p=0.003, p=0.012, respectively). The significant factors for time to treatment failure were a complete response after MINE chemotherapy and serum 2-microglobulin (p=0.003, p=0.044, respectively). 4) The main result of toxicity of MINE was bone marrow suppression.
CONCLUSION
The response to MINE chemotherapy and serum 2-microglobulin were both independent prognostic factors for overall survival and time to treatment failure. As the median time to treatment failure for complete responses was 14 months, the best use of this regimen could be in a strategy that includes prompt consolidation of a complete response with intense chemotherapy, with or without hematopoietic stem cell rescue.

Citations

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Clinical feasibility of oral low-dose etoposide and sobuzoxane for conventional chemotherapy–intolerant lymphoma patients
Akihiro Ohmoto, Shigeo Fuji
Expert Review of Anticancer Therapy.2021; 21(7): 715. CrossRef

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Combination Chemotherapy with Vinorelbine and Ifosfamide in Patients with Advanced Non-Small Cell Lung Cancer: Seong Geun Kim, Sung Hyun Kim, Hyuk Chan Kwon, Kee Hyun Lee, Jae Seok Kim, Hyo Jin Kim; J Korean Cancer Assoc. 2001;33(2):163-167.

Abstract PDF: PURPOSE
We conducted a phase II study of vinorelbine and ifosfamide combination chemotherapy in patients with advanced or recurrent non-small cell lung cancer (NSCLC) to evaluate response rate, response duration, and toxicities of this regimen.
MATERIALS AND METHODS
From June 1998 to March 2000, twenty seven patients with advanced or recurrent non- small cell lung cancer (stage IIIB and IV) who had no prior systemic chemotherapy were enrolled in this study. All patients were treated with vinorelbine and ifosfamide combination chemotherapy (vinorelbine 25 mg/m2 i.v. days 1 & 8, and ifosfamide 2 g/m2 i.v. days 1~3 with Mesna 1600 mg/m2). Each cycle was repeated every 21 days.
RESULTS
All twenty seven patients were eligible and assessable. Age ranged from 41 to 72 (median 57 years). 14 patients were male and 13 were female. Overall response rate was 33.3%. One complete response (3.7%) and 8 partial responses (29.6%) were observed. Stable disease was 15 (55.6%) and progressive disease was 3 (11.1%). Overall median survival duration was 7.8 months. The median progression-free and response durations were 6.6 months and 3.5 months respectively. World Health Organization grade 3 to 4 neutropenia occurred in 6.5%. Nonhematologic toxicities including nausea/vomiting, nephropathy and hepatopathy were generally grade 1 or 2.
CONCLUSION
The combination chemotherapy with vinorelbine and ifosfamide in the patients with advanced or recurrent non-small cell lung cancer can be considered as an effective and safe treatment.

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Phase I Clinical Trial of Paclitaxel Plus Ifosfamide for the Patients with Refractory Ovarian Cancer: Ho Sawk Saw, Jae Kwan Lee; J Korean Cancer Assoc. 2000;32(5):895-903.

Abstract PDF: PURPOSE
Patients with advanced ovarian carcinoma and refractory to platinum based chemotherapy have a very poor prognosis and effective salvage regimens are needed. This study was conducted in order to determine the maximum tolerated dose (MTD) and dose limiting toxicity of combination with paclitaxel and ifosfamide.
MATERIALS AND METHODS
After premedication, patients received paclitaxel (110~225 mg/m2) as a 24 hour IV infusion on day 1. Ifosfamide (1,000~1,500 mg/m2) was given as a 12 hour IV infusion with standard dose of mesna on day 2~6. All patients received G-CSF (granulocyte colony stimulating factor) on day 6~15.
RESULTS
12 patients with advanced ovarian cancer entered this trial. Toxicity included bone marrow suppression, neuromuscular toxicity, urothelial toxicity, gastrointestinal toxicity, which occurred in 84.6%, 65.3%, 30.7%, 88.4% of cycles.
CONCLUSION
Neuromuscular toxicity was dose limiting toxicity. Maximum tolerated dose in com bination with paclitaxel and ifosfamide was 175 mg/m2 of paclitaxel and 1,500 mg/m2 of ifosfamide.

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Efficacy of Combination Chemotherapy with Vinorelbine, Ifosfamide, and Cisplatin in Patients with Advanced Non-Small Cell Lung Cancer: Heung Moon Chang, Jung Ae Lee, Jin Seok Ahn, In Sook Woo, Young Iee Park, Jee Woong Son, Seung Joon Lee, Dong Kyu Kim, Eun Kyung Mo, Myung Jae Park, Myung Goo Lee, In Gyu Hyun, Ki Suck Jung, Young Suk Park; J Korean Cancer Assoc. 2000;32(3):612-618.

Abstract PDF: PURPOSE
To evaluate the efficacy and toxicity of combination chemotherapy with vinorelbine, ifosfamide, and cisplatin in patients with advanced non-small cell lung cancer.
MATERIALS AND METHODS
Patients with unresectable, pathologically proven non-small cell lung cancer who had no prior chemotherapy were eligible. Patients received vinorelbine (25 mg/m2, iv., D1 & 8), ifosfamide (1.5 g/m2, iv., D1-3 with mesna), and cisplatin (60 mg/m2, iv., D1). The treatment was repeated every 3 weeks.
RESULTS
Between degrees Ctober, 1997 and June, 1999, 26 patients were enrolled. Median age was 61. 1 patient had stage IIIA, 13 had stage IIIB, and 12 had stage IV. Patients with adendegrees Carcinoma were 15, squamous cell carcinoma were 11. Of 22 evaluable patients, objective responses were observed in 9 patients (response rate: 40.9%, CR: 1 (4.5%), PR 8 (36.4%)). Median duration of response was 48 weeks. Median overall survival was 52 weeks. Grade 3-4 leukopenia was observed in 10.2% of the 88 courses. There was 1 death related to febrile neutropenia. Non- hematologic toxicities were mild.
CONCLUSION
We concluded that combination chemotherapy with vinorelbine, ifosfamide, and cisplatin was effective and tolerable in patients with advanced non-small cell lung cancer, and phase III randomized trial is needed to compare this regimen to other cisplatin-based regimens.

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Combination Chemotherapy with VP - 16 , Ifosfamide , and Cisplatin ( VIP ) in the Advanced Non - Small Cell Lung Cancer: Yong Seon Cho, Si Young Kim, Jeong Hee Kim, Hwi Joong Yoon, Kyung Sam Cho; J Korean Cancer Assoc. 2000;32(1):86-92.

Abstract PDF: PURPOSE
We conducted a phase II study in previously untreated patients with unresectable stage IIIB or IV non-small cell lung cancer to evaluate the response rate and toxicity of the combination chemotherapy regimen of etoposide, ifosfamide and cisplatin. MATERIALS AND METHODS: From September 1993 to December 1996, twenty patients with advanced non-small cell lung cancer (stage IIIB 5 and IV 15) (squamous cell 8, adeno- carcinoma 12), were enrolled in this study. There were 13 (65%) males and 7 (35%) females, and median age of patients were 56 years (range: 34~66). Eighteen patients had performance status (ECOG) 0~1, two patients had performance status 2. Treatment was consisted of cisplatin (20 mg/m2 i.v., day 1~4), VP-16 (etoposide) (75 mg/m2 i.v., day 1~4), ifosfamide (1000 mg/m2 i.v., day 1~4) with mesna. This treatment was repeated every four weeks.
RESULTS
The overall response rate was 25%. Complete response rate was 5% (1/20) and partial response rate was 20% (4/20). The median cycle of response was 4 (2~6) cycles. The median overall survival time was 28 weeks (9~98 weeks). The median time to progression was 10 weeks (3~50 weeks). Toxicities were evaluated by WHO criteria. Toxicity > GradeIII included: leukopenia 1.6%, thrombocytopenia 3.2%, nausea and vomiting 15%, alopecia 30%, stomatitis 10%. These toxicities were tolerable and reversible.
CONCLUSION
VIP regimen was not superior to previous regimens for advanced non-small all lung cancer, and the toxicities were tolerable.

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The Effect of Combination Chemotherapy with Vinorelbine, Carboplatin, and Ifosfamide in Patients with Advanced Non-Small Cell Lung Cancer: Young Woo Lee, Baek Yeol Ryoo, Tae You Kim, Bong Seog Kim, Yeon Hee Park, Hyun Ju Hong, Jin Young Kwag, Sang Won Lee, Yoon Koo Kang; J Korean Cancer Assoc. 1999;31(6):1227-1235.

Abstract PDF: PURPOSE
Despite recent advances in chemotherapy, the treatment outcome of advanced non-small cell lung cancer (NSCLC) remains poor and NSCLC is still the predominant source of cancer-related mortality in worldwide. Thus, we evaluated the efficacy and safety of a combination chemotherapy with vinorelbine, carboplatin, and ifosfamide (NCI) in advanced NSCLC patients.
MATERIALS AND METHODS
A total of 26 patients was enrolled in this study between December 1997 and June 1998. All entered patients were treated with NCI combination chemotherapy (vinorelbine 25 mg/m2/day i.v. days 1 and 8; carboplatin 300 mg/m2/day i.v. day 1; ifosfamide 3 g/m2/day i.v. day I; and mesna 2.4 g/m2/day i.v. day 1 after completion of ifosfamide infusion, treatment repeated every 4 weeks).
RESULTS
Among 26 patients, 23 patients were evaluable. Nine out of 23 evaluable patients had a partial response (response rate 39%; 95% confidence interval 19~59%). The median survival of the total 23 evaluable patients was 7.4 (range; 3~9.3+) months. The median progression-free survival was 2.8 (range; 0~7.7+) months. Among total 70 cycles of chemotherapy, leukopenia of grade II or more was observed in 6%, and tbrombo- cytopenia of grade II or more in 1%. There was no treatment-related death. Main non-hematologic toxicities were nausea/vomiting, stomatitis and peripheral phlebitis, almost of which were tolerable.
CONCLUSION
NCI chemotherapy seemed to be moderately active and well tolerated in patients with advanced NSCLC.

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A Phase 2 Study with Vinorelbine and Ifosfamide in the Inoperable Non - small Cell Lung Cancer: Moon Hee Lee, Young Jin Yoo, Soo Mi Bang, Gyung Hae Joung, Hyo Jin Kim, Dong Bok Shin, Soon Nam Lee, Seong Rok Kim, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim; J Korean Cancer Assoc. 1999;31(5):972-978.

Abstract PDF: PURPOSE
A phase II study of vinorelbine and ifosfamide combination chemotherapy in patients with advanced or recurrent non-small cell lung cancer (NSCLC) was conducted to assess response rate, response duration, and toxicites.
MATERIALS AND METHODS
Patients with advanced NSCLC who had no prior systemic chemotherapy were eligible. They have no central nervous system metastasis and recurrent or progressive disease after surgery or radiotherapy. Each cycle consisted of vinorelbine 25 mg/m' i.v. days 1 & 8, and ifosfamide 2 g/m i.v. days 1, 2 & 3 with Mesna and treatments were repeated every 21 days.
RESULTS
Forty patients with advanced or recurrent NSCLC were treated at multi center between March, 1997 and March, 1998. Six patients were not evaluable because five patients refused therapy after the first course and one patient was protocol violation. Of 34 evaluable patients, objective responses were seen in 11 (32.4%) patients (CR 0%, PR 32.4%). The median duration of response was 16.4 weeks. The median overall survival was 9.5 months. The toicities of this regimen were acceptable without treatment related toxic death.
CONCLUSION
We concluded that combination regimen of vinorelbine and ifosfamide was effective and tolerable in the treatment of advanced non-small cell lung cancer.

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Combination Chemotherapy with Cisplatin, Ifosfamide, and Etoposide in Small Cell Lung Cancer: In Keun Choi, Byung Soo Kim, Jae Jeong Shim, Sang Won Shin, Yeul Hong Kim, Kyung Ho Kang, Kwang Taek Kim, Jun Suk Kim, Young Ho Choi; J Korean Cancer Assoc. 1999;31(4):692-698.

Abstract PDF: PURPOSE
Although chemotherapy is considered as the mainstay of treatment for small cell lung cancer, long-term survival is not expected in the majority of patients. Until more effective drugs are developed, optimization of available chemotherapeutic regimens and the combination with radiotherapy will be required to improve the survival of small cell lung cancer patients. We conducted a phase II trial to evaluate the effect of a combination chemotherapy of cisplatin, ifosfamide, and etoposide.
MATERIALS AND METHODS
From January 1994 to December 1997, 34 untreated small cell lung cancer patients were enrolled in this study. The treatment schedule included etoposide 80 mg/m/day, ifosfamide 1.5 g/m'/day, cisplatin 20 mg/m/day iv continuous infusion on day 1-3. Cycles were repeated every 4 weeks.
RESULTS
The objective response rate was 58% [localized disease (LD), 100%; extensive disease (ED), 48%]. And complete remission rate was 19% (LD, 38%; ED, 13%). The median survival of all patients was 12 months (LD, 17 months; ED, 12 months). The median duration of response was 7 months. There was one treatment-related death. The hematologic toxicities were tolerable: Leukopenia greater than Grade III was 25%, and thrombocytopenia greater than Grade III was 6%. Nausea and vomiting were seen in most patients, but they were controllable.
CONCLUSION
The combination chemotherapy with cisplatin, ifosfamide, and etoposide as a first line therapy seemed effective with tolerable toxicity in patients with small cell lung cancer.

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Combination Chemotherapy with Etoposide, Ifosfamide, and Cisplatin (VIP) in Small Cell Lung Cancer: Goon Jae Cho, Joo Seop Chung, Ihm Soo Kwak, Ha Yeon Rha; J Korean Cancer Assoc. 1999;31(3):539-547.

Abstract PDF: PURPOSE
Combination chemotherapy has shown promising activity in small cell lung cancer (SCLC). This study was perfonned to determine the efficacy of the combination chemotherapy with etoposide, ifosfamide and cisplatin (VIP) in previously untreated patients with SCLC.
MATERIALS AND METHODS
Patients with SCLC were treated with etoposide (75 mg/m iv. D1-4), ifosfamide (1200 mg/m iv. Dl-4 with mesna) and cisplatin (20 mg/m iv. D1-4). The treatment was repeated every 3 weeks for 6 cycles in principle. Thoracic radiotherapy was administered to patients with limited disease (LD) of SCLC after initial 2 or 3 cycles of chemotherapy subsequently. Praphylactic cranial irradiation (PCI) was given to complete responders of SCLC.
RESULTS
From April 1996 through June 1998, 42 patients were included, but 32 were eligible for the study (4 refused of treatment, 2 lost in follow-up, and 4 combined with other disease). The median age was 62 years (range, 42-74). Twelve patients had LD and 20 patients were with extended disease (ED). Complete response (CR) rate was 34% (LD 58%, ED 20%) and overall response rate was 72% (LD 83%, ED 65%). The median duration of response was 28 weeks (38 weeks in LD, 24 weeks in ED, P=0.016) With the median follow-up period of 65 weeks (6-134 weeks), overall median survival was 43 weeks (56 weeks in LD, 34 weeks in ED, P 0.001), and the median disease free survival (DFS) of eleven CR patients was 16 weeks. Stage, performance, and LDH level were significant prognostic factom (P 0.011, 0.002, 0.043, respectively), but sex and age did not affect the outcome significantly. The hematologic side effects (WHO grade 2) of evaluable 152 cycles of chemotherapy were leukopenia (53%), thrombocytopenia (31%) and anemia (16%); and nonhematologic side effects (WHO grade >2) were alopecia (84%), nausea/vomiting (45%) and stomatitis (19%).
CONCLUSION
It appears that VIP combination chemotherapy is a safe, effective and well tolerated regimen for the patients with SCLC.

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A Phase 2 Study of VP-16 , Ifosfamide , and Cisplatin ( VIP ) Combination Chemotherapy Plus Concurrent Thoracic Irradiation for Limited Small Cell Lung Cancer: Seok Ah Im, Moon Hee Lee, Chul Won Jung, Dae Seog Heo, Yung Jue Bang, Young Soo Shim, Chan Il Park, Noe Kyeong Kim; J Korean Cancer Assoc. 1999;31(2):306-312.

Abstract PDF: PURPOSE
A phase II study of etoposide, ifosfamide, cisplatin combination chemotherapy and concurrent thoracic irradiation in patients with untreated limited small cell lung cancer (SCLC) was conducted to assess toxicities, response rate, response duration, and median survival.
MATERIALS AND METHODS
Patients with histologically confirmed SCLC with a ECOG criteria 2 and adequate renal function and bone marrow reserve were eligible. Each cycle consisted of VP-16 100 mg/m i.v, days 1-3, ifosfamide 1,200 mg/m i.v. days 1-3 with Mesna, and cisplatin 30 mg/m i.v. days 1-3. Cycles were repeated every 21 days. Concutrent thoracic itradiation was given as total 40-45 Gy for 4-5 weeks beginning within 24 hours of the third cycle. Patients with complete remission received prophylactic cranial irradiation after the 6th cycle.
RESULT
Forty two patients with limited SCLC were treated at Seoul National University Hospital between December 1993 and August 1996. Three patients were not evaluable because of lost to follow up (2 patients) and one treatment-related early death. Of 39 evaluable patients, responses were seen in 38 (97%) patients including 22 (56%) complete responses and 16 (41%) partial responses. The median remission duration was 65 wks. The median disease free survival was 60 wks. The median overall survival was not reached and 2-year survival was 69% with median duration of follow up of 63.5 wks. Hematologic side effects (WHO Gr>III/IV) of evaluable 228 cycles of chemotherapy were leukopenia in 34%, thrombocytopenia in 16%. One patient expired after prolonged leukopenia and sepsis. Nonhematologic side effects (WHO Gr>II) included nausea and vomiting (17%) and peripheral neuropathy (2%).
CONCLUSION
VIP combination chemotherapy with concurrent thoracic irradiation is effective and tolerable in limited SCLC.

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Clinical Efficacy of Combination Chemotherapy with Cisplatin , Ifosfamide , and Oral Etoposide ( PIE ) in Advanced Non - Small Cell Lung Cancer: Yeul Hong Kim, Jae Hong Seo, Byung Soo Kim, Sang Won Shin, Jae Jung Shin, Kyung Ho Kang, Young Ho Choi, Kwang Tak Kim, Jun Suk Kim; J Korean Cancer Assoc. 1999;31(2):297-305.

Abstract PDF: PURPOSE
A prolonged administration of etoposide increases its effectiveness on the suggestion that pralonged maintenance of low levels is an important factor in determining its activity. Many studies have been tried to define the efficacy of combination of oral etoposide with other chemotherapeutic drugs such as cisplatin, 5-FU, and ifosfamide in patients with advanced non-small cell lung cancer (NSCLC). In this study, we evaluated the effectiveness and toxicities of combination chemotherapy of oral etoposide with intravenous cisplatin and ifosfamide in advanced NSCLC patients.
MATERIALS AND METHODS
Thirty-three patients with inoperable NSCLC who had measurable diseases and had not been treated with chemotherapeutic drug, were enrolled in this study (from May 1995 to April 1998). Treatment consisted of intravenous cisplatin (20 mg/m(2)/day, Day 1-3) and ifosfamide (1,800 mg/m(2)/day, Days 1-3) with Mesna (1,100 mg/m(2)/day, Days 1-3), and oral etoposide (50 mg/m(2)/day, Days 4-17). This treatment was repeated every 4 weeks. Patients showing stable disease or a better response were continued on treatment with the range of one to nine cycles (medium: 3 cycles). All patients were evaluated for the response, survival, and toxicity of this combination chemotherapy.
RESULTS
Eleven patients showed either complete responses [CR, 3 (9%)] or partial responses [PR, 8 (24%)]. The median number of treatment cycles were 5 (range, 3-9) for responders and 2 (range, 1-7) for non-responders. The responders had median response duration of 10 months and the overall survival of 12 months. The overall survival of responders were longer than that of non-responders (median 19 vs 5 months, p 0.0232). The toxicities of this treatment were tolerable without treatment related death. Limiting toxicities were myelosuppression and oral mucbsities, Grade 3 or 4 leukopenia and oral mucosities were observed in 34% and 9%, respectively.
CONCLUSION
The combination of cisplatin, ifosfamide, and oral etoposide produced encouraging response rates and median survival duration in patients with response. Further study of this combination is warranted in comparison with standard cisplatin+etoposide regimen or intravenous etoposide, cisplatin and ifosfamide regimen.

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Phase II Study of Ifosfamide, Epirubicin and Cisplatin(IEP) in Patients with Small Cell Lung Cancer: Hwi Joong Yoon, Hyun Joo Park, Si Young Kim, Kyung Sam Cho, Jung Hee Kim, Sung Eon Hong; J Korean Cancer Assoc. 1998;30(4):728-736.

Abstract PDF: PURPOSE
Although it is well recognized that SCLC is a chemo and radiosensitive tumor, only fraction of treated patients have a complete remission, fewer still have durable remissions. This study was performed to evaluate the clinical effects of IEP chemotherapy in patients with SCLC.
MATERIALS AND METHODS
Patients with histologically proven SCLC who has measurable disease and previously untreated, were eligible. Treatment consisted of ifosfamide 1000 mg/m2 iv infusion for 1 hour on days 1~5 with mesna uroprotection; epirubicin 60 mg/m2 iv on day 1; and cisplatin 20 mg/m2 iv infusion on days 1~5 with hydration; repeated treatment every 4 weeks RESULTS: Twenty four patients(20 males, 4 females) were eligible for response to IEP chemotherapy. The two patients were excluded because one died before evaluating response to chemotherapy and the other had brain metastasis. The median age was 61(range 34-74). Fifteen patients had a limited disease(LD), nine patients had a extensive disease(ED). The overall response rate was 86.4%(CR 36.4%, PR 50%). In LD, response rate was 86.7%(CR 46.7%) and in ED, response rate was 85.7%(CR 14.3%). The median overall survival time was 43.5 weeks. The median survival time of LD and ED was 46.5 weeks and 43.5 weeks respectively. The median time to progression was 20 weeks in responders. The toxicity was moderate. One toxic death was observed. Grade 1 or 2 non-hematologic toxicities consisted of alopecia, nausea and vomiting in all cases, peripheral neuropathy in 3, hematuria in 2, mucositis in 11, and fever/infection in 6. Hematologic toxic effects included leukopenia(> or =grade.3, 16.5%), anemia(> or =grade 3, 1%), and thrombocytopenia(> or =grade 3, 6.8%).
CONCLUSIONS
These results suggest that IEP chemotherapy may be useful as a treatment strategy in small cell lung cancer, but its efficacy is equivalent. The phase III study should be needed.

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Combination Chemotherapy with Cisplatin , Etoposide , and Ifosfamide ( PIE ) in the Advanced Non - Small Cell Lung Cancer: Sang Won Shin, Byung Soo Kim, Jae Jung Shin, Yeul Hong Kim, Kyung Ho Kang, Young Ho Choi, Kwang Tak Kim, Jun Suk Kim; J Korean Cancer Assoc. 1998;30(2):225-230.

Abstract PDF: PURPOSE
Combination chemotherapy with cisplatin and etoposide have been considered as one of the chemotherpy regimen for non small cell lung cacer(NSCLC) with the response rate of 20~40%. Ifosfamide is one of the most active agent against NSCLC. And so, we initiated a phase II trial for advanced NSCLC to determine the effect of PIE(cisplatin, ifosfamide, etoposide) regimen.
MATERIALS AND METHODS
36 patients with inoperable non-small cell lung cancer who had no prior systemic chemotherapy were treated with combined ifosfamide (1,800 mg/m2 plus mesna 1,100 mg/m2 by intravenous continuous infusion daily for 3 days) with cisplatin (20 mg/m2 intravenous for 3 days) and etoposide (80 mg/m2 intravenous for 3 days). We evaluated the response rate, survival and toxicities of these patients.
RESULTS
The objective response rate was 28%(CR; 2/36, 6%, PR; 8/36, 22%). Among 10 responders, 7 patients were in good ECOG performance status(0~1). The mean survival of all these patients were 43 weeks(8~141 weeks); the responding patients survived longer than the non-responders(median survival; 59 weeks vs 28 weeks, p<0.05). The toxicities of this regimen were acceptable without treatment related toxic death.
CONCLUSION
We concluded that PIE regimen is effective in the treatment of advanced non-small cell lung cancer with acceptable toxicities and long-term follow up is warranted.

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Combination Chemotherapy with Etoposide, Ifosfamide, and Cisplatin (VIP) in Small Cell Lung Cancer: Mi Young Park, Joon Yeon Won, Kyung Tae Park; J Korean Cancer Assoc. 1997;29(6):1011-1021.

Abstract PDF: PURPOSE
A prospective phase II trial was conducted in patients with small cell lung cancer (SCLC) to determine whether the response rate, duration of response, and overall survival can be improved by a combination chemotherapy with etoposide, ifosfamide, and cisplatin (VIP).
MATERIALS AND METHODS
From May 1994 to April 1997, thirty-three previously untreated patients with SCLC received individualized treatment tailored to disease extent. Twenty-one patients with limited disease (LD) received six cycles of chemotherapy consisting of etoposide 120 mg/m2, ifosfamide 1,500 mg/m2, and cisplatin 25 mg/m2 all given intravenously on days 1, 3 and 5. Cycles were repeated every 3 weeks for six cycles. Thoracic radiotherapy was administered to 15 patients with LD of SCLC subsequently after initial two or three cycles of chemotherapy. Prophylactic cranial irradiation was given to complete responders of SCLC. Chemotherapy alone was administered to 12 patients with extensive disease (ED) of SCLC.
RESULTS
Complete response (CR) rate was 51% (LD 67%, ED 25%) and overall response rate was 94% (LD 95%, ED 92, p=0.022). And the median duration of response of all patients was 8 months (11 months in LD, 6.5 months in ED, p=0.042). With a median follow-up period of 13 months (3+~36), the median survival of all patients was 12 months (16 months in LD, 9.5 months in ED, p=0.006), and the median disease-free survival (DFS) of 17 CR patients was 12 months. Stage and performance status score were important prognostic factor, but sex, age, and LDH level did not affect the outcome significantly. Among 21 patients with LD, 15 patients received radiotherapy and 6 did not. The overall response rate of patients who received radiotherapy was significantly higher than that of patients who did not (p=0.045). But there were no significant differences in duration of response and OS between them (p=0.055, p=0.068, respectively). The major side effects (greater than grade 2 of WHO criteria) of evaluable 154 cycles of chemotherapy were alopecia (76%), nausea/vomiting (54%), leukopenia (27%), anemia (19%), and thrombocytopenia (15%).
CONCLUSION
VIP chemotherapy has produced a high complete remission rate and it is a safe and well-tolerated regimen in SCLC. However, compared to previous reports, it has not improved overall survival significantly. Further phase II and III studies are warranted to confirm the efficacy of VIP chemotherapy.

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Chemotherapy of Advanced Soft Tissue Sarcoma with Etoposide, Ifosfamide, and Cisplatin (VIP): Won Seog Kim, Kyung Hae Jung, Hyun Ah Kim, Sung Hyun Yang, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim; J Korean Cancer Assoc. 1997;29(1):128-135.

Abstract PDF: PURPOSE
Soft tissue sarcomas are uncommon primary malignancies. So studies on the effective chemotherapy for soft tissue sarcomas are limited. We started this study to evaluate the effectiveness of VIP (etoposide, ifosfamide, cisplatin) combination chemotherapy for advanced soft tissue sarcomas.
MATERIALS AND METHODS
Thirty patients with recurrent or metastatic soft tissue sarcoma were treated with VIP combination chemotherapy between December 1989 and June 1996. Each patient was given etoposide 75 mg/m2, ifosfamide 1000 mg/m2, cisplatin 20 mg/m2 intravenously for five consecutive days every three weeks. Mesna (sodium-2-mercaptoethansulfonate) was given to avoid the urologic toxicity.
RESULTS
Twenty-eight of 30 patients were evaluable for response, and among the 28 evaluable patients, there were 9 partial response (32%). Duration of response in 9 responders ranged from 4.1 to 16.2 months (median 8.8 months). Overall survival ranged from 1.7 to 41.5 months (median 11 months) and survival was better for patients with partial response (median survival 14.8 months vs. 9.7 months with stable disease vs. 5.1 months with progressive disease p=0.0006). Nausea and vomiting was noted in more than 90% of cycles, but was markedly severe in only 4%. Leukopenia was noted in 60% of cycles, including 11% of cycles with counts <2,000/mm3. There was no treatment related death, but we had to stop chemotherapy in 2 patients due to leukopenia (1 patient) and neurotoxicity (1 patient).
CONCLUSION
Combination of etoposide, ifosfamide, and cisplatin was fairly active for advanced soft tissue sarcoma, with myelosuppresion and peripheral neuropathy being the most serious toxicities.

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5-Fluorouracil, Leucovorin, Ifosfamide and Cisplatin (FLIP) Combination Chemotherapy for Adevanced Non-Small Cell Lung Cancer: Hyun Sik Jeong, Keunchil Park, Jung Ae Lee, Young Iee Park, In Sook Woo, Ki Suk Jung, Young Suk Park, Duk Jhe Shun, Won Seog Kim, Jeong A Kim, Sung Soo Yoon, Won Ki Kang, Hong Ghi Lee, Chan Hyung Park; J Korean Cancer Assoc. 1997;29(1):46-52.

Abstract PDF: PURPOSE
To evaluate the response rate and toxicity of combination chemotherapy including 5-fluorouracil (F), leucovorin (L), ifosfamide (I) and cisplatin (P) for the previously untreated patients with unresectable stage IIIB or IV non-small cell lung cancer.
MATERIALS AND METHOD
The doses of FLIP were 5-fluorouracil 800 mg/m2 CI days 1-5, leucovorin 20 mg/m2 IV days 1-5, ifosfamide 1000 mg/m2 CI days 1-3, cisplatin 100 mg/m2 IV day 1 respectively. Cycles were repeated every 3 weeks until disease progression. Seventy-three previously untreated patients were enrolled. Age ranged from 30 to 73 (median 56 years); 43 were male, 30 female. Fifty-three patients had performance status (ECOG) 0-1 and 19 performance status 2. Twenty-two patients had stage IIIB and 51 stage IV. Follow-up ranged from 7+ to 160weeks (median 57 weeks).
RESULTS
The overall response rate was 46.7% for 62 evaluable patients. (CR 1 patient, PR 28 patients) Median response duration was 24 weeks (range 1+ to 36+ weeks). Toxicity > Grade II (WHO) included: granulocytopenia 19.8%, anemia 13.5%, nausea and vomiting 31.5% stomatitis 46.5%, neuropathy 24.6%.
CONCLUSION
FLIP chemotherapy was comparable to other combination chemotherapy for advanced non-small cell lung cancer with moderate toxicities.

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5-Fluorouracil , Ifosfamide and Cisplatin ( FIP ) Combination Chemotherapy for Advanced Non - Small Cell Lung Cancer: Young II Seo, Yougn Suk Park, Jae Myung Lee, Jo Young Choi, Hyun Soo Kim, Byung Dong Cho, Yu Mi Seo, Yun Chang Han, Ho joong Kim, In Gyu Hyun, Ki Suk Shun, Keun Chil Park, Duk Jhe Shun; J Korean Cancer Assoc. 1995;27(2):284-292.

Abstract PDF: We conducted a phase II trial of combining 5-fluorouracil(5-FU), ifosfamide(IFM), and cisplating(DDP) in previously untreated patients with advanced, unresectable, non-small cell lung cancer(NSCLC). Each cycle consisted of 5-FU 100 mg/m i. v. days 1-5, IFM 1000 mg/m i. v. days 1-3 with mesna, and DDP 100 mg/m i. v. day 1. Cycles were repeated at 3 week intervals. Twenty eight patients were enralled. Age ranged from 36 to 73(median 57 yearsk 24 were male, 4 female. Eleven patients had stage IIIb disease and 17 stage IV. Two patients were not evaluable because of lost to follow up. None had a complete response, 13 patients(50%) had par- tial responses, 8(31%) had stable diseases, and 5(19%) had progressive disesses. The median response duration was 11.2 weeks; the median time to progression was l2 weeks. The overall median survival was 19 weeks(27.5 weeks for responders, 12.8 weeks for non-responders). Majar side effects were alopecia, nausea/vomiting and stomatitis, all of which were we11 tolerated and reversible. By univariate analysis, stage and performance status correlated with time to progression and overall survival time. In conclusion, FIP combination chemotherapy for patients with advanced, unresectable non- small cell lung cancer seems to be an effective and well-tolerated regimen.

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A Phase 2 Study of VP-16 , Ifosfamide Cisplatin ( VIP ) Combination Chemotherapy for Small Cell Lung Cancer: Rok Yun Lee, Young Suk Park, Yun Chang Han, Ho Joong Kim, In Gyu Hyun, Ki Suk Jung, Jung Ae Rhee, In Sook Woo, Young Iee Park, Keun Chil Park, Duk Jhe Shun, Sang Gyu Choi, Do Hoon Oh, Hoon Sik Bae; J Korean Cancer Assoc. 1995;27(4):620-630.

Abstract PDF: We conducted a phase II trial combining etoposide(VP-16), ifosfamide(IFM), and cisplatin (DDP) in previously untreated patients with histologicaliy confirmed small cell lung cancer (SCLC). Each cycle consisted of VP-16 100mg/m(2) i.v. days 1-3, IFM 1,000mg/m i.v. days 1-2 with mesna, and DDP 100mg/m(2) i.v. day 1. Cycles were repeated at 3 week intervals. Patients of limited SCLC received chest irradiation concurrently with the third cycle of VIP chemotherapy. Patients with complete remission received prophylactic cranial irradiation after the 6th cycle of chemotherapy. Thirty-seven patients were enrolled. Ages ranged from 34 to 76(median 61 years); 32 were male, and 5 female. Nineteen patients had limited disease(LD) and 18 extensive disease(ED). Three patients were not evaluable because of lost to follow up(2 patients) and early death(l patient). Of 34 evaluable patients, 13 patients(LD; 12, ED; I) had complete re- missions, 19 patients(LD: 6,ED; 13) had partial remissions and overall remission rate was 94 %. The median remission duration was 8.6 months(LD; 12.5months, D; 5.1months)..Disease free survival was 14.5 months in patients achieved complete remission. The median dura- tion of follow-up was 21 months (1 to 39 months), and overall median survival was 12.8 months(16.1 months for LD, 8.2 months for ED). Hematologic side effects(WHO Gr>=2) of evaluable 168 cycles of chemotherapy were anemia in 10 occassions(6%), leukopenia in 35 occassions(21%), thrombocytopenia in 27 occassions(16%). Nonhematologic side effects(WHO Gr>=2) included alopecia(91%), nausea and vomiting (80%), peripheral neuropathies (31%), and stomatitis (11%). In conclusion, VIP combination chemotherapy seems to be a safe, effective, and well-tolerated regimen in SCLC.

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Phase 2 study of Ifosfamide Single and Ifosfamide and Doxorubicin Combination Chemotherapy for Hepatocellular Carcinoma: Soo Jeong Park, Hyeoung Joon Kim, Chul Won Jung, Sang Jae Lee; J Korean Cancer Assoc. 1996;28(4):718-726.

Abstract PDF: Though hepatocellular carcinoma(HCC) is one of the ten most common cancers in the world, the prognosis is dismal because most tumors are not suitable for surgical resection at the time of diagnosis. Doxorubicin is the only chemotherapeutic agent generally accepted to be of some use in its treatment. Doxorubicin is first described by Olweny et al in 1975 to cause regression in all ll HCC subjects evaluated, later trials showed response rate varying from 0% to 44%. However, the median survival was not increased. In 1988, intravenous ifosfamide has also been reported in unresectable HCC to induce partial remission and more longer survival duration than previous study. Therefore, we conducted a phase II trial ifosfamide, and combining ifosfamide and doxorubicin in previously untreated patients with histologically confirmed HCC and evaluate the efficacy and combining effect of ifosfamide. Each cycle consisted of ifosfamide 1.5gm/§³ i.v. days 1~5 with mesna in single therapy and ifosfamide 1.3gm/§³ i.v. days 1~5 with mesna and doxorubicin 40mg/§³ i.v. day 1 in combination chemotherapy, repeated every 4 weeks. Thirty-three patients were enrolled (ifosfamide: 16, ifosfamide and doxorubicin: 17). Five patients were not evaluated beacause of lost to follow-up and refusal to further therapy. Of twenty-eight evaluable patients, four patients achieved partial remissions, one in ifosfamide and three in combination chemotherapy and overall remission rate was 14%(8% in ifosfamide and 19% in combination chemotherapy). The median remission duration of ifosfamide and combining ifosfamide and doxorubicin were 5 and 4.5 months, respectively. The median follow-up duration were 2.5 months(0.5~8.5 months) in ifosfamide and 4 months(0.5~10 months) in combination chemotherapy. The median survivals in ifosfamide and combination chemotherapy were 2.5 months and 4.5 months, respectively(p=0.16 for survival curves by log rank test). Hematologic side effects(WHO Gr¡A2) of evaluable 92 cycles of chemotherapy (ifoefamide: 33, ifosfamide and doxorubicin: 59) were anemia in 5 occassions (ifosfamide: 1, ifosfamide and doxorubicin: 4), leukopenia in 10 occasions(ifosfamide: 2, ifosfamide and doxorubicin: 8), and 1 occassion thrombocytopenia in combination chemotherapy. Non-hematologic side effects(WHO Gr¡A2) included alopecia(7%), nausea and vomiting(21%), without hemorrhagic cystitis and other toxicities. In conclusion, ifosfamide, and ifosfamide and doxorubicin combination chemotherepy seems to be similar effect for far advanced hepatocellular carcinoma and can not be prolongation of patients survival. Since those responses seen were generally incomplete and transient, further clinical trials of this agent used in combination or sequentially with other agents are indicated.

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