A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer

Gonçalvès, Anthony; Fabbro, Michel; Lhommé, C.; Gladieff, L.; Extra, Jean-Marc; Floquet, Anne; Chaigneau, L.; Carrasco, A. Tisseron; Viens, Patrice

doi:10.1016/j.ygyno.2007.07.057

Cited by 124 publications

(77 citation statements)

References 27 publications

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“…[23][24][25] Lack of activity in advanced disease as monotherapy has also being reported for the small molecule inhibitors of the EGFR erlotinib and gefitinib. 26,27 The finding on this study that nimotuzumab seems to increase stabilization of disease merits further study, nevertheless, our results should be taken with caution because the design of this study which included administration of chemotherapy for 6 cycles concurrent with weekly nimotuzumab does not allow us to conclude on the activity of nimotuzumab as single agent. In addition, the paucity of studies with either targeted therapy of cytotoxic chemotherapy in third or more lines of palliative treatment makes difficult to establish valid comparisons, thus, our results can only be considered as hypothesis-generating.…”

Section: Discussionmentioning

confidence: 75%

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer

Cetina¹,

Crombet

Jiménez-Lima

et al. 2015

Cancer Biology & Therapy

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Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second-or thirdline chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m 2 as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m 2 ) or cisplatin (50 mg/m 2 ) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.

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Section: Discussionmentioning

confidence: 75%

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer

Cetina¹,

Crombet

Jiménez-Lima

et al. 2015

Cancer Biology & Therapy

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“…These data combined with the relation that we find for EGFR and pEGFR immunostaining and poor response to (chemo)radiation suggest that the addition of EGFR inhibitors to standard chemoradiation should be evaluated in advanced-stage cervical cancer patients. Up to now, in cervical cancer, only a single phase II study using gefitinib, an EGFR tyrosine kinase inhibitor, as monotherapy for recurrent cervical cancer was reported recently with modest response rates (40). Clinical trials with cetuximab in addition to (chemo) radiation in the treatment of locally advanced cervical cancer are ongoing.…”

Section: Discussionmentioning

confidence: 99%

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Noordhuis

Eijsink

Hoor

et al. 2009

Clinical Cancer Research

102

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Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. Results: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). Conclusions: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials. (Clin Cancer Res 2009;15(23):7389-97) Standard treatment of locally advanced cervical cancer has changed from radiotherapy alone to concurrent platinum-based chemoradiation. Despite this change, the 5-year survival in patients with locally advanced cervical cancer is still ∼52% (1). Currently, there are no (biological) markers available that accurately predict response to (chemo)radiation.Epidermal growth factor receptor (EGFR) is involved in the ErbB signaling pathway, which is often dysregulated in cancer. Autophosphorylation of EGFR to phosphorylated EGFR (pEGFR) leads to activation of two downstream pathways: the Ras/Raf/ mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK pathway and the phosphatidylinositol 3-kinase/ AKT pathway. PTEN (phosphatase and tensin homologue deleted on

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“…The EGFR tyrosine kinase inhibitor, gefitinib, was ineffective in patients with refractory cervical cancer, although 87% of tumors expressed high levels of EGFR. 70 A phase 2 study of combined erlotinib, cisplatin, and radiation therapy 71 in 23 patients with untreated stage IIB to IIIB squamous cell carcinoma induced a complete remission rate of 91.3%, which was higher than the rates produced in trials of cisplatin and radiation alone. Additional studies of EGFR kinase domain inhibition with lapatinib, an EGFR and HER2 dual inhibitor, with or without pazopanib, a tyrosine kinase small molecule inhibitor against the VEGF receptor (VEGFR), has accrued, but the results are pending.…”

Section: Review Article 3172mentioning

confidence: 95%

Novel chemotherapy approaches for cervical cancer

Movva

Rodriguez

Arias-Pulido

et al. 2009

Cancer

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Cancer of the cervix is the second most common malignancy among women worldwide. The last 20 years have lead to numerous advances in the medical management of locally advanced cervical cancer, including preventive vaccination, chemoradiation, and neoadjuvant chemotherapy. The treatment of metastatic disease is palliative at best. Platinum‐based chemotherapy remains the standard of care for inoperable patients who have recurrent disease. However, because most patients initially receive concomitant platinum‐based therapy with radiation, many recurrent tumors are refractory to platinum. The use of novel therapeutic approaches targeted to the carcinogenic processes that leads to the ontogenesis of cervical cancer should be promoted in clinical studies to improve patient outcomes. Cancer 2009; 115:3166–80. © 2009 American Cancer Society.

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A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer

Cited by 124 publications

References 27 publications

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Novel chemotherapy approaches for cervical cancer

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