Sunday, July 1, 2007
Saturday, June 30, 2007
The MITO-2 (Multicentre Italian Trials in Ovarian cancer)
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 5532
Author(s):S. Pignata, G. Scambia, A. Savarese, E. Breda, R. Sorio, A. Vernaglia Lombardi, V. Gebbia, P. Scollo, D. Lorusso, A. Morabito
Abstract:
Background: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III study comparing the effect on progression-free survival of carboplatin/paclitaxel versus carboplatin/stealth liposomal doxorubicin (CLD) in 1st-line AOC patients. Due to the lack of published phase II data on the CLD schedule, safety and activity analyses were planned within the trial. The former, previously reported for the first 50 patients treated with CLD, showed mild haematological toxicity, while non-hematological events seldom were higher than grade 2. Methods: AOC patients with AOC (stage IC-IV), aged =75, ECOG PS =2, are randomized to CP (carboplatin AUC 5 / paclitaxel 175 mg/m2, d1q21) or to CLD (carboplatin AUC 5 + Stealth liposomal doxorubicin 30 mg/m2, d1q21), both treatments for 6 cycles. According to a phase 2 design with p0=30%, p1=50%, alfa=0.10, 50 patients with measurable target lesions as defined by RECIST criteria were required and >20 responses had to be observed in order to define that the experimental schedule was sufficiently active to warrant phase III continuation. Results: Out of the first 137 patients randomly assigned to CLD, 87 were not eligible for response assessment by RECIST (35 had only non target lesions; 28 had only Ca 125 increased; 23 had no lesion and normal Ca 125; 1 never started treatment). Out the 50 patients eligible for response assessment, overall 34 responses were recorded (14 complete, 20 partial) for a response rate of 68% (95% CI: 53.3-80.5). In addition, among 35 patients with all non-target lesions 9 (26%) complete responses and 18 (51%) nonCR- nonPD were observed. In the remaining 28 patients evaluable only for Ca 125, this normalized in 96% of the cases at the end of the 6 cycles. Conclusions: An a priori planned activity analysis showed that CLD every 3 weeks is feasible and active in AOC patients suboptimally debulked and with measurable lesions. The trial is ongoing; as of December 28th, 2006, 615 patients have been enrolled out of 810 planned.
Author(s):S. Pignata, G. Scambia, A. Savarese, E. Breda, R. Sorio, A. Vernaglia Lombardi, V. Gebbia, P. Scollo, D. Lorusso, A. Morabito
Abstract:
Background: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III study comparing the effect on progression-free survival of carboplatin/paclitaxel versus carboplatin/stealth liposomal doxorubicin (CLD) in 1st-line AOC patients. Due to the lack of published phase II data on the CLD schedule, safety and activity analyses were planned within the trial. The former, previously reported for the first 50 patients treated with CLD, showed mild haematological toxicity, while non-hematological events seldom were higher than grade 2. Methods: AOC patients with AOC (stage IC-IV), aged =75, ECOG PS =2, are randomized to CP (carboplatin AUC 5 / paclitaxel 175 mg/m2, d1q21) or to CLD (carboplatin AUC 5 + Stealth liposomal doxorubicin 30 mg/m2, d1q21), both treatments for 6 cycles. According to a phase 2 design with p0=30%, p1=50%, alfa=0.10, 50 patients with measurable target lesions as defined by RECIST criteria were required and >20 responses had to be observed in order to define that the experimental schedule was sufficiently active to warrant phase III continuation. Results: Out of the first 137 patients randomly assigned to CLD, 87 were not eligible for response assessment by RECIST (35 had only non target lesions; 28 had only Ca 125 increased; 23 had no lesion and normal Ca 125; 1 never started treatment). Out the 50 patients eligible for response assessment, overall 34 responses were recorded (14 complete, 20 partial) for a response rate of 68% (95% CI: 53.3-80.5). In addition, among 35 patients with all non-target lesions 9 (26%) complete responses and 18 (51%) nonCR- nonPD were observed. In the remaining 28 patients evaluable only for Ca 125, this normalized in 96% of the cases at the end of the 6 cycles. Conclusions: An a priori planned activity analysis showed that CLD every 3 weeks is feasible and active in AOC patients suboptimally debulked and with measurable lesions. The trial is ongoing; as of December 28th, 2006, 615 patients have been enrolled out of 810 planned.
Long-Term Follow-Up of a Randomized Trial Comparing Concurrent Single Agent Cisplatin or Cisplatin-Based Combination Chemotherapy or Hydroxyurea
Long-Term Follow-Up of a Randomized Trial Comparing Concurrent Single Agent Cisplatin or Cisplatin-Based Combination Chemotherapy or Hydroxyurea During Pelvic Irradiation for Locally Advanced Cervical Cancer:
A Gynecologic Oncology Group Study Peter G. Rose,* Shamshad Ali, Edwin Watkins, J. Tate Thigpen, Gunter Deppe, Daniel L. Clarke-Pearson, and Samuel Insalaco
From Case Western Reserve University and Cleveland Clinic Foundation, Cleveland, OH; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY; Columbus Regional Hospital, Columbus, IN; University of Mississippi Medical Center, Jackson, MS; Wayne State University/Karmanos Cancer Institute, Detroit, MI; University of North Carolina, Chapel Hill, NC; and the Tacoma General Hospital, Tacoma, WA.
* To whom correspondence should be addressed. E-mail: rosep@ccf.org
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Purpose: We report the long-term survival and toxicity of a randomized phase III study comparing cisplatin alone with cisplatin, flurouracil, and hydroxyurea versus hydroxyurea concurrent with pelvic irradiation for patients with locally advanced cervical cancer with pathologically negative para-aortic nodes.
Patients and Methods: Comparisons of progression-free (PFS) and overall survival (OS) between treatment arms utilized Kaplan-Meier and log-rank statistics. Relative risk estimates adjusting for prognostic factors were determined using the Cox proportional hazards regression model. Pearson's 2 test was used to assess differences in adverse events.
Results: The analysis included 526 patients. The median follow-up among surviving patients was 106 months. Consistent with the original report, improvement in PFS and OS was evident for both cisplatin-containing arms compared with hydroxyurea (P < .001). Analogous results were seen for stage IIB and for stage III disease (each P < .025). The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) with cisplatin and 0.51 (95% CI, 0.38 to 0.67) with cisplatin-based combination chemotherapy compared with hydroxyurea.
Among 518 patients who received radiation, acute (grade 3 or 4) gastrointestinal or urologic toxicities occurred in 66 with cisplatin (19.1%) and 29 with hydroxyurea (16.8%). Delayed radiation toxicity occurred in six patients who received cisplatin (1.7%) and two who received hydroxyurea (1.2%; P = .680).
Conclusion: Cisplatin-based chemotherapy during pelvic radiation therapy improves long-term PFS and OS among locally advanced cervical cancer patients collectively and for stage IIB and III disease, individually. There was no observed increase in late toxicity with cisplatin-based chemoradiotherapy.
A Gynecologic Oncology Group Study Peter G. Rose,* Shamshad Ali, Edwin Watkins, J. Tate Thigpen, Gunter Deppe, Daniel L. Clarke-Pearson, and Samuel Insalaco
From Case Western Reserve University and Cleveland Clinic Foundation, Cleveland, OH; Gynecologic Oncology Group Statistical & Data Center, Roswell Park Cancer Institute, Buffalo, NY; Columbus Regional Hospital, Columbus, IN; University of Mississippi Medical Center, Jackson, MS; Wayne State University/Karmanos Cancer Institute, Detroit, MI; University of North Carolina, Chapel Hill, NC; and the Tacoma General Hospital, Tacoma, WA.
* To whom correspondence should be addressed. E-mail: rosep@ccf.org
'//-->
Purpose: We report the long-term survival and toxicity of a randomized phase III study comparing cisplatin alone with cisplatin, flurouracil, and hydroxyurea versus hydroxyurea concurrent with pelvic irradiation for patients with locally advanced cervical cancer with pathologically negative para-aortic nodes.
Patients and Methods: Comparisons of progression-free (PFS) and overall survival (OS) between treatment arms utilized Kaplan-Meier and log-rank statistics. Relative risk estimates adjusting for prognostic factors were determined using the Cox proportional hazards regression model. Pearson's 2 test was used to assess differences in adverse events.
Results: The analysis included 526 patients. The median follow-up among surviving patients was 106 months. Consistent with the original report, improvement in PFS and OS was evident for both cisplatin-containing arms compared with hydroxyurea (P < .001). Analogous results were seen for stage IIB and for stage III disease (each P < .025). The relative risk of progression of disease or death was 0.57 (95% CI, 0.43 to 0.75) with cisplatin and 0.51 (95% CI, 0.38 to 0.67) with cisplatin-based combination chemotherapy compared with hydroxyurea.
Among 518 patients who received radiation, acute (grade 3 or 4) gastrointestinal or urologic toxicities occurred in 66 with cisplatin (19.1%) and 29 with hydroxyurea (16.8%). Delayed radiation toxicity occurred in six patients who received cisplatin (1.7%) and two who received hydroxyurea (1.2%; P = .680).
Conclusion: Cisplatin-based chemotherapy during pelvic radiation therapy improves long-term PFS and OS among locally advanced cervical cancer patients collectively and for stage IIB and III disease, individually. There was no observed increase in late toxicity with cisplatin-based chemoradiotherapy.
Doxorubicin encapsulated in phospholipid copolymer penetrates solid tumors
NEW YORK (Reuters Health) - A novel drug delivery system devised by scientists in China improves the penetration of doxorubicin into solid tumors while reducing its systemic toxicity, according to their article in the Journal of the National Cancer Institute for July 4.
The drug carrier consisted of hydrophilic polyethylene glycol (PEG) and hydrophobic phosphatidylethanolamine (PE), Dr. Wei Liang and colleagues at the Chinese Academy of Sciences in Beijing report in their paper. They state that the copolymer forms micelles about 10 to 20 nm in size.
Compared with "naked" doxorubicin, the "nanoassemblies" containing the drug were more rapidly internalized by cultured non-small-cell lung carcinoma cells. Lower concentrations were required for cytotoxic effects.
The researchers' in vivo studies involved mice inoculated subcutaneously with Lewis lung carcinoma cells. After 5 days, they were treated intravenously with free doxorubicin or doxorubicin in micelles.
Subsequent tumor growth rates and metastasis were "dramatically decreased," and survival was substantially increased. Dr. Liang's team also observed that encapsulated doxorubicin was associated with increased penetration into tumor cells.
The encapsulated doxorubicin was significantly less toxic than free doxorubicin, causing weight gain instead of weight loss, maintaining white blood cell counts, and minimizing the extent of myocarditis.
"The tightly packed structure of (PEG-PE encapsulated doxorubicin) may be the source of its high antitumor activity and low systemic toxicity," Dr. Liang and colleagues indicate. "This property should be considered in the construction of nanoassemblies as delivery systems for other chemotherapeutic models."
In an editorial, Dr. Matthew R. Dreher from the National Institutes of Health in Bethesda, Maryland, and Dr. Ashutosh Chilkoti from Duke University in Durham, North Carolina, applaud the "impressive preclinical results" attained by Dr. Liang's group.
At the same time, they maintain, more answers regarding their methodology and a lot more research to establish the behavior of encapsulated doxorubicin will be required before the nanoassemblies can be considered for clinical use.
The drug carrier consisted of hydrophilic polyethylene glycol (PEG) and hydrophobic phosphatidylethanolamine (PE), Dr. Wei Liang and colleagues at the Chinese Academy of Sciences in Beijing report in their paper. They state that the copolymer forms micelles about 10 to 20 nm in size.
Compared with "naked" doxorubicin, the "nanoassemblies" containing the drug were more rapidly internalized by cultured non-small-cell lung carcinoma cells. Lower concentrations were required for cytotoxic effects.
The researchers' in vivo studies involved mice inoculated subcutaneously with Lewis lung carcinoma cells. After 5 days, they were treated intravenously with free doxorubicin or doxorubicin in micelles.
Subsequent tumor growth rates and metastasis were "dramatically decreased," and survival was substantially increased. Dr. Liang's team also observed that encapsulated doxorubicin was associated with increased penetration into tumor cells.
The encapsulated doxorubicin was significantly less toxic than free doxorubicin, causing weight gain instead of weight loss, maintaining white blood cell counts, and minimizing the extent of myocarditis.
"The tightly packed structure of (PEG-PE encapsulated doxorubicin) may be the source of its high antitumor activity and low systemic toxicity," Dr. Liang and colleagues indicate. "This property should be considered in the construction of nanoassemblies as delivery systems for other chemotherapeutic models."
In an editorial, Dr. Matthew R. Dreher from the National Institutes of Health in Bethesda, Maryland, and Dr. Ashutosh Chilkoti from Duke University in Durham, North Carolina, applaud the "impressive preclinical results" attained by Dr. Liang's group.
At the same time, they maintain, more answers regarding their methodology and a lot more research to establish the behavior of encapsulated doxorubicin will be required before the nanoassemblies can be considered for clinical use.
Wednesday, June 6, 2007
Docetaxel
Docetaxel is of the chemotherapy drug class; taxane, and is a semi-synthetic analogue of paclitaxel (Taxol®), an extract from the rare Pacific yew tree Taxus brevifolia.[2] Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel – an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and readily available European yew tree.
Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester and a tert-butyl substitution exists on the phenylpropionate side chain. The carbon 10 functional group change causes docetaxel to be more lipid soluble than paclitaxel
Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester and a tert-butyl substitution exists on the phenylpropionate side chain. The carbon 10 functional group change causes docetaxel to be more lipid soluble than paclitaxel
Sunday, April 1, 2007
Wednesday, February 21, 2007
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