Phase I Trial of Erlotinib Combined with Cisplatin and Radiotherapy for Patients with Locally Advanced Cervical Squamous Cell Cancer

Abstract

Purpose: This phase I trial was aimed to determine the maximum tolerated dose and related toxicity of erlotinib (E) when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Experimental Design: In a modified Fibonacci design, the study aimed to study three cohorts of at least three patients receiving escalating doses of erlotinib (50/100/150 mg) combined with cisplatin (40 mg/m 2 , weekly, 5 cycles) and radiotherapy (external beam 4,500 cGy in 25 fractions, followed by 4 fractions/600 cGy/weekly of brachytherapy) in squamous cell cervical carcinoma patients, stage IIB to IIIB. Results: Fifteen patients were enrolled, 3 at dose level (DL) 50 mg, 4 at DL100 mg, and 8 at DL 150 mg. Patients presented median age 47 (36-59), stage IIB (46.2%) and IIIB (53.8%). Overall, E+CRT was well-tolerated. Three patients did not complete the planned schedule. One patient at DL 100 mg withdrew informed consent due to grade 2 rash; at DL 150 mg, 1 patient presented Raynaud's Syndrome and had C interrupted, and another patient presented grade 4 hepatotoxicity. The latter was interpreted as dose limiting toxicity and a new cohort of 150 mg was started. No further grade 4 toxicity occurred. Grade 3 toxicity occurred in 6 cases: diarrhea in 3 patients, rash in 2 patients, and leukopenia in 1 patient. E+CRT did not lead to limiting in-field toxicity. Conclusions: E+CRT is feasible to locally advanced squamous cell cervical cancer and is well tolerated.The maximum tolerated dose has been defined as150 mg.To the best of our knowledge, this is the first report of a combination of erlotinib, cisplatin, and pelvic radiotherapy.

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

“…Among the selective agents targeting the EGFR cascade are the anti-EGFR antibodies (mAb-C225 and ICM-C225, also designated cetuximab and erbitux, respectively), antisense oligonucleotide directed against EGFR or its ligands EGF and TGF-␣, and the selective inhibitors of EGFR tyrosine kinase activity such as 4-(3Ј-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478), N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (gefitinib; Iressa; ZD1839) N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib; Tarceva; OSI-774) (Table 1) (Chung and Saltz, 2005;Haruki et al, 2005;Hynes and Lane, 2005;Shelton et al, 2005;Shepherd et al, 2005;del Carmen et al, 2005;Bonner et al, 2006;Citri and Yarden, 2006;Hanna et al, 2006;Khambata-Ford et al, 2007;Nogueira-Rodrigues et al, 2008;Shaw and Prowse, 2008;Yonesaka et al, 2008;Griffero et al, 2009;Montagut and Settleman, 2009). Alternatively, the molecular targeting of EGFR downstream signaling elements, including RAS/ RAF/MEK, PI 3 K/Akt/mTOR, NF-B, cyclooxygnase-2, and vascular endothelial growth factor/vascular endothelial growth factor receptor might represent another effective therapeutic approach (Table 1) (Chung and Saltz, 2005;Haruki et al, 2005;Hynes and Lane, 2005;Shelton et al, 2005;del Carmen et al, 2005;Citri and Yarden, 2006;Xu et al, 2008;Montagut and Settleman, 2009).…”

Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

“…Our group has previously reported an institutional study with erlotinib in cervical cancer, in which this combination was also safe and well tolerated (35).…”

“…Although the doses and RT plans are different, we cannot discard the relationship of this event with acneiform rash, which is more prevalent in the face and neck than in the pelvis (35).…”

18F-FDG-PET-based tumor delineation in cervical cancer: Threshold contouring and lesion volumes

“…This cohort was part of a phase I/II trial of erlotinib combined to cisplatin and radiation. 15,16 Staging was performed with clinical examination and all of the patients had CT, MR and 18 F-FDG PET/CT scans before treatment, as well as cistoscopy and rectosigmodoscopy. Locally advanced disease was defined as FIGO stage greater than IB2 and lesser than IVB.…”