Gemcitabine and oxaliplatin (GEMOX) in patients withcisplatin-refractory germ cell tumors: a phase II study

Pectasides, D.; Pectasides, Melina; Farmakis, Dimitrios; Aravantinos, G.; Nikolaou, Maria; Koumpou, Maria; Gaglia, A.; Kostopoulou, V.; Mylonakis, N.; Skarlos, D.

doi:10.1093/annonc/mdh103

Cited by 99 publications

(50 citation statements)

References 13 publications

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“…Finally, our multicentre experience of the OXA -GE combination in patients with resistant ovarian cancer is close to that reported in other types of platinum-refractory tumours Franciosi et al, 2003;Pectasides et al, 2004). Despite experimental (Bergman et al, 1996) and clinical evidence of synergism between these two drugs, their optimal administration, either sequential or concurrent, remains to be determined in resistant ovarian cancer patients.…”

Section: Discussionsupporting

confidence: 72%

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group

Ray‐Coquard

Weber

Crétin³

et al. 2009

Br J Cancer

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Advanced ovarian carcinoma in early progression (o6 months) (AOCEP) is considered resistant to most cytotoxic drugs. Gemcitabine (GE) and oxaliplatin (OXA) have shown single-agent activity in relapsed ovarian cancer. Their combination was tested in patients with AOCEP in phase II study. Fifty patients pre-treated with platinum -taxane received q3w administration of OXA (100 mg m -2 , d1) and GE (1000 mg m -2 , d1, d8, 100-min infusion). Patient characteristics were a : median age 64 years (range 46 -79),and 1 (84%) or 2 (16%) earlier lines of treatment. Haematological toxicity included grade 3 -4 neutropaenia (33%), anaemia (8%), and thrombocytopaenia (19%). Febrile neutropaenia occurred in 3%. Non-haematological toxicity included grade 2 -3 nausea or vomiting (34%), grade 3 fatigue (25%),and grade 2 alopecia (24%). Eighteen (37%) patients experienced response. Median progression-free (PF) and overall survivals (OS) were 4.6 and 11.4 months, respectively. The OXA -GE combination has high activity and acceptable toxicity in AOCEP patients. A comparison of the doublet OXA -GE with single-agent treatment is warranted.

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Section: Discussionsupporting

confidence: 72%

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group

Ray‐Coquard

Weber

Crétin³

et al. 2009

Br J Cancer

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“…There is evidence to suggest that oxaliplatin is active against cisplatin-resistant cancers and cells [8,9,[12][13][14]. This has also been reported in SCLC, in one study the 16-fold cisplatin-resistant SR2 SCLC subline was sensitive to oxaliplatin [33] while another variant of this subline that was 3.3-fold resistant to cisplatin, was 1.4-fold resistant to oxaliplatin [47].…”

Section: Discussionmentioning

confidence: 85%

“…The clinical evidence that oxaliplatin is active against cisplatin resistant cancers involves reports of oxaliplatin having greater activity against platinum pre-treated testicular cancer when combined with other chemotherapeutics such as gemcitabine [12,13] or irrinotecan [14] rather than oxaliplatin as a single agent [15]. In these studies it is difficult to determine whether it is the oxaliplatin or the combination of drugs that produces a response in cisplatin pre-treated patients.…”

Section: Introductionmentioning

confidence: 99%

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Stordal

Davey

2005

Cancer Chemother Pharmacol

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Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines.Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models 3 of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC.

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“…However, clinical trials demonstrating a response using oxaliplatin combination therapy in platinum-resistant patients often credit oxaliplatin's lack of cross resistance for the success of treatment 59,61 . The observed benefit from oxaliplatin combination regimens may well be due to the activity of the other agent or synergy between the two agents, rather than any innate ability for oxaliplatin to overcome cisplatin resistance.…”

Section: Oxaliplatin In the Treatment Of Patients With Cisplatin-resimentioning

confidence: 99%

Oxaliplatin for the treatment of cisplatin-resistant cancer: A systematic review

Stordal

Pavlakis

Davey

2007

Cancer Treatment Reviews

145

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Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. We undertook a systematic review of the literature to identify, describe and critique the clinical and pre-clinical evidence for the use of oxaliplatin in patients with "cisplatinresistant" cancer. We identified 25 pre-clinical cell models of platinum resistance and 24 clinical trials reporting oxaliplatin based salvage therapy for cisplatin-resistant cancer. The pre-clinical data suggests that there is cross-resistance between cisplatin and oxaliplatin in low-level resistance models. In models with high level resistance (>10 fold) there is less cross resistance between cisplatin and oxaliplatin, which may be a reason why oxaliplatin is thought to be active in cisplatin-resistant cancer. In clinical trials where oxaliplatin has been used as part of salvage therapy for patients who have failed cisplatin or carboplatin combination chemotherapy, there was a much lower response rate in patients with platinum-refractory or resistant cancers compared to platinum-sensitive cancers. This suggests that there may be cross-resistance between cisplatin and oxaliplatin in the clinic. Oxaliplatin as a single agent had a poor response rate in cisplatin refractory and resistant cancer. Oxaliplatin performed better in combination with other agents for the treatment of platinum resistant/refractory cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer.3

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Gemcitabine and oxaliplatin (GEMOX) in patients withcisplatin-refractory germ cell tumors: a phase II study

Abstract: The combination of GEMOX is an active, moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT. The 14% long-term disease-free status accomplished in this heavily pretreated patient population is quite encouraging.

Cited by 99 publications

References 13 publications

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Oxaliplatin for the treatment of cisplatin-resistant cancer: A systematic review

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