Evaluation of paclitaxel/carboplatin in a dose dense or weekly regimen in 66 patients with recurrent or primary metastatic cervical cancer

doi:10.1016/j.ejca.2012.01.006

European Journal of Cancer

Volume 48, Issue 9, June 2012, Pages 1332-1340

https://doi.org/10.1016/j.ejca.2012.01.006 Get rights and content

Abstract

Background and aims

To evaluate paclitaxel/carboplatin in a dose dense (TCdd) and weekly (TCw) regimen in recurrent or primary metastatic cervical cancer.

Methods

Six courses of paclitaxel (90 mg/m²) and carboplatin (area under the curve (AUC) 4) were administered on d1, d8 q3 wks in TCdd. Eighteen courses of paclitaxel (60 mg/m²) and carboplatin (AUC 2.7) were administered weekly in TCw. Response rates were determined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Criteria.

Results

Sixty-six patients were included (44 TCdd and 22 TCw). TCdd and TCw were administered as first-line chemotherapy in 48% and 41%, second-line in 43% and 18%, and third/fourth-line in 9% and 41%, respectively. Response (confirmed or unconfirmed) was observed in 58% and 36% for TCdd and TCw, respectively. As first-line, the response rates for TCdd and TCw were the same (55%). As second or more line, the response rates for TCdd and TCw were 61% and 29%, respectively. In patients, receiving TCdd as first-line systemic treatment, median overall survival (OS) and progression-free survival (PFS) was 10 and 5 months. As first-line, the median OS for TCw also was 10 months (median PFS not reached). There was no statistical difference in PFS or OS between patients treated with TCw or TCdd. Grade 3–4 toxicity was mostly bone-marrow related and was more common with TCdd. Febrile neutropenia was observed in 0% and 12% of the patients treated with TCw and TCdd, respectively.

Conclusions

Combination of paclitaxel and carboplatin in a dose dense regimen or weekly regimen resulted in favourable response rate and toxicity profile compared with cisplatin-based combination regimens. TCdd appears to be more toxic than TCw, but resulted in higher response rates than TCw in patients with recurrent metastatic cervical cancer who received prior chemotherapy.

Introduction

In Europe, 55000 women are diagnosed with cervical cancer per year, and 25,000 women die of this disease per year.¹ For patients with recurrent or primary metastatic disease, prognosis is poor with a 1-year survival rate between 15% and 20%.2, 3 Systemic chemotherapy is often the only possible treatment option with cisplatin, paclitaxel and topotecan as the most commonly used drugs.4, 5

Historically, cisplatin remains the most extensively studied agent in cervical cancer. Initial gynecologic oncology group (GOG) data reported response rates (RR) of 44% in chemo-naive patients with cisplatin 50 mg/m².⁶ Several studies7, 8, 9, 10 showed that, although response rates were higher, toxicities, caused by single-agent cisplatin regimen also increased substantially when dose intensity increases to more than 50 mg/m² every 3 weeks. Different from cisplatin, carboplatin has a more favourable non-haematologic toxicity profile. Two studies conducted in ovarian cancer11, 12 demonstrated that the combination of carboplatin and paclitaxel was less toxic and had a similar effectiveness compared to cisplatin and paclitaxel in the treatment of ovarian cancer. However, experience with substituting carboplatin for cisplatin is limited in recurrent or metastatic cervical cancer. The GOG and the Southwest Oncology Group have studied carboplatin as a single agent in recurrent or metastatic squamous carcinoma of the cervix. The overall RRs were 15% and 11%, respectively, in these two trials with a substantially better toxicity profile when compared with cisplatin.13, 14

In 1996 a study of the GOG documented that single-agent paclitaxel at a dose of 170 mg/m² resulted in a 17% objective response rate in advanced squamous cell carcinoma of the cervix.¹⁵ Two studies published in 2009 found that the addition of paclitaxel to the cisplatin/ifosfamide combination leads to a significant improvement in response rate and PFS in patients with recurrent or metastatic cancer, but with a significant increase in toxicity.16, 17

A phase III trial by the GOG demonstrated that cisplatin/paclitaxel not only improves response rate over single agent cisplatin, but also progression-free survival in patients with fédération internationale de gynécologie et d’Obstétrique (FIGO) stage IV b, recurrent or persistent squamous cell carcinoma of the cervix. Nevertheless, this regimen needed to be given over 24 h to reduce neurologic toxicity and required either an inpatient hospital stay or an outpatient infusion pump for each cycle.⁵ Recently, the GOG group assessed the toxicity and efficacy of cisplatin doublet combinations in advanced and recurrent cervical cancer. They concluded that neither vinorelbine plus ciplatin, nor gemcitabine plus cisplatin, nor topotecan plus cisplatin is superior to paclitaxel plus cisplatin in terms of RR, overall survival (OS) and PFS. Given the difference in OS between paclitaxel plus cisplatin (PC) and the other regimens (12.9 versus 10–10.3 months), PC is worth considering in treatment planning taking into account the multiple days of therapy required per cycle.⁴

The use of paclitaxel/carboplatin (TC) in patients with cervical cancer was first reported in a case report in 1996 by Termrungruanglert et al.¹⁸ Till recently, several retrospective studies on the value of TC 3-weekly with 3–51 recurrent or advanced cervical cancer patients have been reported, and they described response rates of 20–68%.19, 20, 21, 22, 23, 24, 25 However, no controlled clinical trial has been published evaluating the efficacy of 3-weekly TC in patients with recurrent cervical cancer. Nevertheless, 3-weekly TC showed an improvement toxicity profile compared with paclitaxel/cisplatin (TP) and in addition, because of its ease of administration, 3-weekly TC is not only a feasible alternative for TP, but may be in the patients’ best interest in the treatment of recurrent and metastatic cervical cancer. From this belief, a Japanese group recently started a randomised control trial to evaluate the non-inferiority of paclitaxel/carboplatin 3-weekly compared with paclitaxel/cisplatin combination therapy in patients with stage IV b, persistent or recurrent cervical cancer.²⁶ In some countries, the combination of cisplatin and topotecan is preferred since this is the only multiagent regimen which was able to show a statistically significant improvement of OS. However, this combination therapy had significantly higher toxicity, with 70% experiencing grade 3–4 neutropenia, 18% with febrile neutropenia, and 31% with grade 3–4 thrombocytopenia.⁵

Studies performed in patients with recurrent ovarian, endometrial, and breast carcinoma showed that using a weekly regimen could improve response rates with a favourable toxicity profile.22, 27, 28 In non-small cell lung cancer weekly administered paclitaxel and carboplatin are well tolerated and have efficacy and survival comparable to those with standard dosing.²⁹

In a recent study weekly paclitaxel–carboplatin was tested as neoadjuvant chemotherapy prior to surgery in stage I b2–III b cancer and resulted in a response rate of 87%.³⁰ Therefore we compared in a single-centre, retrospective, non-randomised study the dose dense combination of paclitaxel and carboplatin with the weekly combination of paclitaxel and carboplatin in patients with recurrent or metastatic cervical cancer.

Section snippets

Eligibility

Eligible patients had recurrent or metastatic cervical cancer that was histologically proven at primary diagnosis. Furthermore, their disease was not amenable to curative treatment with surgery or radiation therapy. At initial diagnosis, staging had been performed according to the FIGO classification system. Patients were required to have tumour measurable by computed tomography (CT), or magnetic resonance imaging (MRI). Measurable disease by CT or MRI was accepted without biopsy confirmation

Results

A total of 66 patients with recurrent or metastatic cervical cancer were enrolled in this study from August 2005 till February 2011. Forty-four of them received TCdd therapy and 22 of them received TCw therapy. One patient, who developed an extreme allergic reaction after the administration of first cycle of TCdd, was not included in the evaluation of response, PFS and OS. All 22 patients receiving TCw were evaluable for response, PFS and OS. Two patients, who received part of their TCdd and

Discussion

Median survival for patients with advanced or recurrent cervical cancer who cannot be treated with surgery or radiation therapy is poor, and fewer than 20% of these patients survive 1 year.

Many factors complicate the administration of conventional chemotherapeutic agents in this patient population, including the following. First, the majority of patients who experience relapse will have received prior radiation therapy, limiting bone marrow function. Second, compromised blood supply to tumour

Conflict of interest statement

None declared.

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Two-dimensional gel electrophoresis (2-DE) accompanied by matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS) was used to analyze and identify differentially expressed proteins in ten cases of advanced cervical cancer patients receiving cisplatin-based NAC. Each of these patients received more than two cycles of NAC. Cell proliferation rate in cisplatin resistant human cervical cancer cell Hela/DDP and its parent cell Hela after treatment with Hsp70 inhibitor and/or cisplatin were tested by MTT assay.
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Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection.
In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel–ifosfamide–carboplatin or a combination of paclitaxel–carboplatin was used as neoadjuvant chemotherapy.
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Although no study has demonstrated, the addition of G-CSF may also be important to preclude dose reductions and decrease the incidence of dose delays. Dose reductions were needed in the earlier retrospective studies in ovarian [12], endometrial [17] and cervical cancer [18] in 24%, 42% and 12% of the patients respectively, and delays in 62%, 43% and 75% respectively. In the current study reduction of carboplatin was needed in 47% and of paclitaxel in 18% of the patients, not unexpectedly mainly due to thrombocytopenia.
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We performed a systematic review of the literature comparing CDDP and CBDCA based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled.
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