A phase I‐II study of docetaxel‐ifosfamide‐cisplatin (DIP) combination chemotherapy regimen in advanced nonsmall cell lung cancer

Kosmas, Christos; Tsavaris, Nicolas; Makatsoris, Thomas; Onyenadum, A.; Vadiaka, Maria; Stavroyianni, Niki; Sepsas, Evangelos; Dimitropoulos, Dimitris; Rokana, Sofia; Kalofonos, Haralabos P.

doi:10.1002/ijc.10162

Cited by 11 publications

(9 citation statements)

References 47 publications

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“…Based on these preclinical in vitro experimental data, we believe that the sequence and infusion times regarding docetaxel and ifosfamide, as applied in the present study, might lead to potential in vivo synergism between these two drugs (Kearns et al, 1995). Moreover, our prior experience with paclitaxel -ifosfamidecisplatin (Kosmas et al, 2000a, b;2001) or docetaxel -ifosfamide -cisplatin (Kosmas et al, 2002) combinations has demonstrated their feasibility in phase I and phase II studies in advanced solid tumours and lung cancer in particular.…”

Section: Discussionmentioning

confidence: 75%

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Kosmas

Tsavaris²,

Malamos

et al. 2003

Br J Cancer

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Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I -II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel -ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70 -100 mg m À2 over 1 h on day 1 followed by ifosfamide 5 -6 g m À2 divided over days 1 and 2 (2.5 -3.0 g m À2 day À1 over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32 -72) years and performance status (WHO) of 1 (range, 0 -2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3 -68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3 -24 months), median time to progression 6.5 month (0.1 -26 month), and median overall survival 13 months (0.1 -33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients -with 63% developing grade 4 neutropenia (p7 days) and in 12% of these FN, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 12%, grade 1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle. In conclusion, the present phase I -II study determined the feasibility of the docetaxel -ifosfamide combination, defined the MTD and demonstrated the encouraging activity of the regimen in phase II, thus warranting further randomised phase III comparisons to singleagent docetaxel or combinations of the latter with other active agents. ) has demonstrated a broad spectrum of activity against a variety of advanced solid tumours, and breast cancer represents the first in which docetaxel has been successfully tested (Salminen et al, 1999). In particular, for patients with prior anthracycline-based therapy, taxanes represent the treatment of choice in the salvage setting, since previously applied agents have demonstrated infe...

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Section: Discussionmentioning

confidence: 75%

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Kosmas

Tsavaris²,

Malamos

et al. 2003

Br J Cancer

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“…However, with a 12.5% incidence of FN for DICb compared with an average 5–6% for docetaxel-carboplatin in phase II, it appears that DICb is more myelotoxic. However, its bone marrow toxicity is far less than the 20% incidence of FN with our previous phase II study with the DIP regimen [7]. Despite the 30% incidence of grade 4 neutropenia, it can be stated that this was rarely prolonged (>7 days) and therefore, patients were unlikely to be exposed to the rigors of severe FN.…”

Section: Discussionmentioning

confidence: 96%

“…These different types of DNA lesion caused by platinum compounds and oxazaphosphorine cytostatics are repaired by the nucleotide excision repair and the mismatch repair pathways [34]. Over the last 5 years, based on the above theoretical assumptions and experimental data, we developed regimens combining a taxane, ifosfamide, and platinum compounds: initially the paclitaxel-ifosfamide-cisplatin (PIC) [35,36,37], then the DIP [7], and currently the docetaxel-ifosfamide-carboplatin (DICb) regimen.…”

Section: Discussionmentioning

confidence: 99%

“…Combinations of ifosfamide with either carboplatin/cisplatin or gemcitabine were still in use in recent NSCLC EORTC trials [6]. A combination regimen consisting of ifosfamide with docetaxel and cisplatin (DIP) has been tested in a previous phase I/II study by our group in advanced NSCLC, and it has been demonstrated that high individual doses of each drug can be administered with G-CSF, with acceptable toxicity in the outpatient setting [7]. Moreover, we demonstrated an appreciably high activity, prolonged time to progression (TTP) and survival in the phase II part of the above study in advanced NSCLC [7].…”

Section: Introductionmentioning

confidence: 99%

“…A combination regimen consisting of ifosfamide with docetaxel and cisplatin (DIP) has been tested in a previous phase I/II study by our group in advanced NSCLC, and it has been demonstrated that high individual doses of each drug can be administered with G-CSF, with acceptable toxicity in the outpatient setting [7]. Moreover, we demonstrated an appreciably high activity, prolonged time to progression (TTP) and survival in the phase II part of the above study in advanced NSCLC [7]. Similarly, other investigators have demonstrated that a combination of the other taxane, paclitaxel, with ifosfamide and carboplatin (PIC) may yield high activity and acceptable toxicity in advanced NSCLC [8].…”

Section: Introductionmentioning

confidence: 99%

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A Phase II Study of the Docetaxel- Ifosfamide-Carboplatin Combination in Advanced Non-Small-Cell Lung Cancer

et al. 2005

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Purpose: In the present phase II study we evaluated the docetaxel-ifosfamide-carboplatin (DICb) combination in the outpatient setting in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Patients with advanced NSCLC (stages IIIB/IV), WHO performance status (PS) <2, and no prior chemotherapy were eligible. Chemotherapy drug doses were: docetaxel: 80 mg/m², ifosfamide: 3.5 g/m², and carboplatin at a target area under the curve of 5 (based on Calvert’s formula), all on day 1, followed by prophylactic G-CSF. Results: Fourty patients were entered and all are evaluable for response and toxicity: median age: 64 (48–72); PS: 1 (0–1); gender: 29 males/11 females; stages: IIIB: 13 (33%), IV: 27 (67%). Metastatic sites at diagnosis included: lymph nodes: 25; bone: 7; liver: 4; brain: 5; lung nodules: 13; adrenals: 6. Responses were as follows: 22/40 [55%; 95% confidence interval (CI), 54–81%] evaluable patients responded: 4 complete responses, 18 partial responses, 11 had stable disease, and 7 had progressive disease. The median response duration was 7 months (range 2–14 months), median time to progression 9 months (range 2–18 months) and median overall survival 11 months (range 3–46+ months). 1-year survival was 47.5%. Grade 3/4 toxicities included: neutropenia 28/40, with 12 developing grade 4 and 12% febrile neutropenia, thrombocytopenia grade 3: 3/40 and grade 4: 1/40, no grade 3 neuropathy, grade 1 CNS toxicity in 3, no renal toxicity, 8 grade 2 diarrhea and 4 grade 3 vomiting. Conclusion: In the present phase II study the DICb combination yielded important activity and good tolerability in advanced NSCLC.

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A phase I–II study of bi-weekly gemcitabine and irinotecan as second-line chemotherapy in non-small cell lung cancer after prior taxane + platinum-based regimens

Kosmas

Tsavaris

Syrigos

et al. 2006

Cancer Chemother Pharmacol

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A phase I‐II study of docetaxel‐ifosfamide‐cisplatin (DIP) combination chemotherapy regimen in advanced nonsmall cell lung cancer

Cited by 11 publications

References 47 publications

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

A Phase II Study of the Docetaxel- Ifosfamide-Carboplatin Combination in Advanced Non-Small-Cell Lung Cancer

A phase I–II study of bi-weekly gemcitabine and irinotecan as second-line chemotherapy in non-small cell lung cancer after prior taxane + platinum-based regimens

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