Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

doi:10.1016/j.ygyno.2003.10.045

Gynecologic Oncology

Volume 92, Issue 2, February 2004, Pages 639-643

https://doi.org/10.1016/j.ygyno.2003.10.045 Get rights and content

Abstract

Purpose. Vinorelbine is being explored by the Gynecologic Oncology Group (GOG) for its possible use in advanced or recurrent squamous cell carcinoma of the uterine cervix. The objective of this Phase II trial was to evaluate a days 1 and 8 every-21-days schedule and determine its activity in patients who had failed standard chemotherapy.

Patients and methods. Eligible patients with measurable disease and satisfactory baseline bone marrow, liver, and kidney functions were treated with vinorelbine 30 mg/m² given on days 1 and 8 every 21 days. A two-stage sampling design was used, proceeding to a second stage accrual if sufficient activity was documented in the first 25 patients.

Results. The study did proceed to the second stage and accrued 44 patients. There were six objective responses (one complete, five partial) for a response rate of 13.7% (95% confidence interval: 5.2–27.4%). There were three patients with response in extra-pelvic sites (including the complete response) and three with response in the pelvis. The overall frequency of grades 3 and 4 neutropenia was 41%, whereas neuropathy was reported in 27% and was severe in three. Treatment-related pain, very severe in two instances, was also reported in 27%.

Conclusion. Vinorelbine has moderate activity in a pretreated population with squamous cell carcinoma of the cervix. Accordingly, vinorelbine in this days 1 and 8 schedule is being studied further in combination with cisplatin by the GOG.

Introduction

Carcinoma of the uterine cervix continues to present in certain populations at a relatively locally advanced stage in spite of the steady improvements in screening and early detection. Such locally advanced stages are unfortunately associated with recurrences leading to considerable morbidity and mortality after surgery, radiation, or both. Recently, the addition of cisplatin-based chemotherapy given simultaneously with radiation or surgery has led to improved outcome in several studies [1]. This has encouraged further exploration of drugs that might lead to an improved outcome by themselves or combined with cisplatin.

Vinorelbine is a semisynthetic vinca alkaloid initially developed in Europe by Pierre Fabre Pharmaceuticals; eventually, it achieved approval in the United States for the treatment of non-small cell lung cancer in combination with cisplatin [2]. The drug has also shown activity against a number of other solid tumors and lymphomas [3], [4]. As predicted from preclinical studies, it exhibits less neurotoxicity than vincristine and vinblastine, and its dose-limiting toxicity is neutropenia. The parent drug, vinblastine, was studied by the Gynecologic Oncology Group (GOG) in previously treated squamous cervical cancer and was found to have modest activity [5]. Studies performed in Europe have also indicated activity for vinorelbine in metastatic cervical cancer [6] and this drug was selected over the other vinca alkaloids in combination with cisplatin for combined modality studies [7]. In patients with squamous cancer of the cervix, activity has also been shown in a study by M.D. Anderson Cancer Center [8]. Accordingly, trials were begun in patients with both squamous and nonsquamous cervical cancers who had received one prior treatment with cytotoxic chemotherapy, or who were not eligible for higher priority studies of the GOG. This report describes the results of the trial in squamous cervical cancer, utilizing a days 1 and 8 every-21-days schedule of administration. Such a schedule would likely be more suitable than a weekly schedule when given in combination with platinum compounds.

Section snippets

Patients and methods

Eligible patients had histologically proven persistent or recurrent squamous cell carcinoma of the cervix with documented disease progression. Bidimensional measurable disease was required. All patients had been treated with standard local therapy (which could include primary chemoradiation) and were allowed to have received only one prior chemotherapeutic regimen for recurrence; however, prior treatment with vincristine or another vinca alkaloid was not allowed because of likely

Results

Between July 1997 and October 1999, 44 patients with squamous cell cancers were enrolled in two stages. Each stage completed the planned enrollment in less than 4 months. All patients were deemed eligible upon review. Patient characteristics are listed in Table 1. Age, GOG performance status, percentage of pelvic versus extra-pelvic disease, and prior treatment are similar to other Phase II drug studies in previously treated patients with squamous cell cervical cancer conducted by the GOG (J.

Discussion

The chemotherapy of cervical cancer has assumed greater importance with the demonstration of an impact of chemoradiation regimens on the survival of patients with locally advanced disease [1]. Until recently, the GOG has continued to retain as the standard treatment for future comparisons cisplatin as a single agent at a dose of 50 mg/m². Higher doses of this agent in the past were associated with higher response rates than with this lower dose, but at a cost of greater toxicity and no

Acknowledgements

This study was supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517).

The following Gynecologic Oncology Group institutions participated in this study: Walter Reed Army Medical Center, University of Mississippi Medical Center, Hospital of the University of Pennsylvania, The Milton S. Hershey School of Medicine of the Pennsylvania State University, Cincinnati College of

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J.A. Blessing

Design, analysis and interpretation of chemotherapy trials in gynecologic cancer

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Cervical cancer treatment update: A Society of Gynecologic Oncology clinical practice statement
2023, Gynecologic Oncology
Cervical cancer is the most commonly diagnosed gynecologic cancer worldwide. Although the incidence has declined with increased screening and higher uptake of human papillomavirus (HPV) vaccination in high-income countries, this disease remains the second highest cause of cancer mortality among women in low- and middle-income countries. In this clinical practice statement, we describe therapies for cervical cancer by treatment setting, as well as quality of life, financial toxicity, and disparities associated with this disease. In addition to chemotherapy and radiation, therapeutic strategies for cervical cancer include immune checkpoint blockade, antiangiogenics, and antibody-drug conjugates. Optimal treatment for recurrent cervical cancer remains an area of unmet need, necessitating further exploration of rational and innovative treatment approaches, including cell and immune-based therapies. Importantly, development of effective therapies for cervical cancer must incorporate strategies to ensure universal equitable access to HPV vaccination, screening, and treatment. Important consequences of the disease and treatment that impact quality of life must also be addressed. Patients with cervical cancer are at increased risk for financial toxicity, which can lead to downstream detrimental effects on physical, financial, and career outcomes. Underrepresentation of racial and ethnic minorities in gynecologic oncology clinical trials highlights the urgent need for collaborative and focused initiatives to bridge the significant divide and alleviate inequalities in the prevention and treatment of cervical cancer.
Two staged phase II clinical trial of Eribulin monotherapy in advanced or recurrent cervical cancer
2023, Gynecologic Oncology
Eribulin a microtubule targeting agent and analog of Halichondrin B, a natural product isolated from marine sponge H. okadai, has proven clinical efficacy in metastatic pretreated breast cancer and liposarcoma. We conducted a 2-stage Phase II study of eribulin in patients with advanced/recurrent cervical cancer to examine its clinical activity and evaluate biomarkers for predictors of response.
Women with advanced/recurrent cervical cancer after ≤1 prior chemotherapy regimen, measurable disease and ECOG performance status ≤2 were treated with eribulin (1.4 mg/m² IV day 1 and 8, every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression-free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03) and overall survival (OS). Exploratory endpoints were associations of biomarkers with clinical activity. Immunohistochemistry was performed on archival tumor samples. Overexpression was defined when both intensity and distribution scores were ≥ 2.
32 patients enrolled from 11/2012–5/2017. 29/32 patients had prior chemotherapy with cisplatin/paclitaxel/bevacizumab (n = 12) or cisplatin/gemcitabine (n = 12) as the most common regimens. 14 patients received prior paclitaxel. 1 (3%) had a complete response, 5 (16%) had a partial response and 13 (41%) had stable disease for ORR of 19% (95% CI 8, 37). Those who are paclitaxel naïve experienced the greatest benefit with a 29% ORR (95% CI 12, 54). Patients who received prior paclitaxel responded less favorably than those who did not (p = .002) and had a shorter PFS and OS. Grade 3/4 adverse events occurring in >10% of patients were anemia (n = 12, 38%), neutropenia (n = 7, 22%) and leukopenia (n = 6, 19%). Analysis of correlative predictors of response revealed that patients who did not overexpress βII and BAX were significantly more likely to respond to e`ribulin. PFS was significantly shorter in patients with βII and BAX overexpression, OS was significantly shorter in those with βIII and BAX overexpression. These associations remained after multivariate analysis.
Eribulin shows modest activity in patients with recurrent/advanced cervical cancer with a favorable toxicity profile. Prior paclitaxel exposure is associated with decreased eribulin response. βII, βIII tubulin subtypes and BAX are predictors of response and survival. Eribulin may be an option for women with paclitaxel-naïve recurrent/advanced cervical cancer.
Systemic therapy for advanced cervical cancer: Leveraging the historical threshold of overall survival
2023, Critical Reviews in Oncology/Hematology
Cervical cancer (CC) is a worldwide problem, especially in low- and middle-income countries, where patients are often diagnosed with locally advanced disease. Until recently, all chemotherapy drugs achieved low ORR and 12-month overall survival (12- month OS) for advanced CC after failure for platinum compounds. Advances in systemic therapy with immunotherapy, targeted therapy, and antibody-drug conjugates (ADC) have leveraged the 12-month OS limit. Recently, immunotherapy (pembrolizumab) has become the standard of care in first-line advanced CC combined with platinum and taxane and in second-line after platinum doublet failure.
Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study
2021, The Lancet Oncology
Citation Excerpt :
Furthermore, the objective response rate of 24% in this study was higher than the 11% previously reported with single-agent chemotherapy in this setting (unpublished). The lower bound of the 95% CI for the confirmed objective response rate in our study (16%) is higher than those reported for other therapies in this setting (eg, 15% for pemetrexed,14 14% for vinorelbine,29 5% for gemcitabine,30 and 11% for bevacizumab11), including pembrolizumab (14·3%).16 A phase 2 trial done in China (the CLAP trial) evaluating combination treatment with the PD-1 inhibitor camrelizumab and the VEGFR2 inhibitor apatinib reported an investigator-assessed objective response rate (per RECIST [version 1.1]) of 55·6% (95% CI 40·0–70·4) in patients with metastatic, recurrent, or persistent cervical cancer.31
Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody–drug conjugate, in this patient population.
This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.
102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.
Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.
Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.
Phase II study of axalimogene filolisbac (ADXS-HPV) for platinum-refractory cervical carcinoma: An NRG oncology/gynecologic oncology group study
2020, Gynecologic Oncology
Women with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460).
Volunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 10⁹ colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS).
Among 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3–12.1) and median PFS was 2.8 months (95% CI: 2.6–3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment.
At the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma.
Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review
2016, Critical Reviews in Oncology/Hematology
Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed.
We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease.
Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC).
Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration.
Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer.
Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.

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¹: Reprint Address: GOG Administrative Office, Four Penn Center,1600 John F. Kennedy Blvd., Suite 1020, Philadelphia, PA 19103.USA

²: Present address: St. Joseph's Regional Medical Center, 801 E. LaSalle Ave., Pavillion 2, Suite 150, South Bend, IN 46617.

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Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Eur. J. Cancer

Gynecol. Oncol.

Am. J. Obstet. Gynecol.

Chemoradiation for patients with cervical cancer

Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multicenter trial including 612 patients

J. Clin. Oncol.

Navelbine in advanced epithelial ovarian cancer: a study of the French Oncology Centers

Semin. Oncol.

The current status of vinorelbine (Navelbine) in breast cancer

Semin. Oncol.

Phase II study of vinblastine in previously treated squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study

Am. J. Clin. Oncol.

Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix

J. Clin. Oncol.

Phase II study of vinorelbine in advanced squamous carcinoma of the cervix (SCC)

J. Clin. Oncol.

Design, analysis and interpretation of chemotherapy trials in gynecologic cancer