A randomized trial comparing concurrent chemoradiotherapy with single-agent cisplatin versus cisplatin plus gemcitabine in patients with advanced cervical cancer: An Asian Gynecologic Oncology Group study☆
Introduction
Cervical cancer is the third most common cancer and the fourth leading cause of cancer mortality among women worldwide [1]. Since 1999, several randomized trials have shown that patients with cervical cancer when treated concurrently with cisplatin-based chemotherapy and radiotherapy (CCRT) had a significant survival advantage when compared with those treated with radiotherapy alone [2]. The magnitude of the observed survival benefits quickly made CCRT the standard-of-care in patients with cervical cancer. While these studies differed in regimens (e.g. single cisplatin or cisplatin plus 5-fluorouracil), there was no suggestion that the combination cisplatin-based chemotherapy programs were superior to simpler and less toxic single-agent cisplatin [3]. From the available data, it is reasonable to conclude that single-agent cisplatin in combination with radiation would be the preferred treatment. However, patients with advanced cervical cancer treated with concurrent CCRT still have 20–30% chance of local failure [4], [5] and 18–25% of distant failure [5], [6]. How to improve the control of both locoregional and distant sites is still an important issue for the treatment of advanced cervical cancer.
Gemcitabine (2′,2′-difluorodeoxycytidine) is a nucleoside analog which replaces deoxycytidine during DNA replication and inhibits the activity of ribonucleotide reductase [7]. In addition to its established uses in pancreatic and non-small cell lung cancer, this drug has been shown in clinical trials to be active against a wide variety of solid tumors [8]. As a single agent, gemcitabine has little activity as first- or second-line therapy for cervical cancer [9]. However, when gemcitabine is combined with cisplatin, the combination achieves 75% partial or complete response rates in patients with metastatic cervical cancer [10]. Since gemcitabine is also a potent radiosensitizer [7], several studies have been undertaken to clarify the use of cisplatin and gemcitabine in combination with radiotherapy for patients with cervical cancer. For example, in a phase II trial for 23 patients with stage IIA through IIIB cervical cancer, Umanzor et al. reported a 90% complete response rate and 80% 2-year disease-free survival when using standard radiotherapy with weekly cisplatin 40 mg/m2 and gemcitabine 125 mg/m2 [11]. Toxicity was moderate: only one patient developed grade 3 neutropenia and there were no grade 4 hematological toxicities.
A recent randomized phase III trial by Dueñas-González et al. showed improved survival for the treatment of stage IIB–IVA cervical cancer by the addition of weekly concurrent gemcitabine and 2 cycles of adjuvant gemcitabine and cisplatin to standard single-agent CCRT [12]. The 3-year progression-free survival (PFS) rates were significantly improved from 65% in the standard chemoradiotherapy arm to 74.4% in the cisplatin and gemcitabine arm. This is the first phase III trial showing advancement in the treatment of locally advanced cervix cancer in the past decade. However, it remains uncertain to what extent the survival benefit observed is attributable to the addition of gemcitabine in the chemoradiation phase or of an adjuvant chemotherapy phase.
An Asian Gynecologic Oncology Group (AGOG) study was designed to determine whether the addition of gemcitabine in the chemoradiation phase, without the adjuvant chemotherapy, can improve survival in locally advanced cervical cancer, two years before the Dueñas-González's trial results were known.
Section snippets
Eligibility criteria
The study was approved by the Institutional Review Board of the participating hospitals and abided with the ethical standards of the Helsinki Declaration on good clinical practice. All patients signed informed consent. Eligibility criteria for this AGOG 09-001 trial were as listed on the ClinicalTrials.gov with an Identifier: NCT00842660. Eligible patients were between 35 and 70 years old with a new pathological diagnosis of cervical cancer with squamous cell carcinoma. They were International
Results
Between March 2009 and March 2013, 89 candidates, after MRI examination, were reviewed at a combined conference. Fifteen patients were excluded during screening, mainly because of additional findings by PET or poor renal/liver function. The study CONSORT diagram is presented in Fig. 1. Thirty-seven patients were randomized to arm C and the other 37 patients were randomized to arm CG. Six eligible patients were excluded before the beginning of treatment, five in arm C and one in arm CG. Three
Discussion
Despite theoretical advantages of adding gemcitabine to CCRT, this trial did not demonstrate the superiority of multi-agent compared with single-agent CCRT for patients with locally-advanced cervical cancer. The OS and PFS rates were similar in both arms (OS: HR 0.93, 95% CI = 0.35–2.49, p = 0.89; PFS: HR 0.86, 95% CI = 0.39–1.91, p = 0.71). The combination regimen was tolerable, but the addition of gemcitabine increased grade 2–4 hematological toxicities, including neutropenia and thrombocytopenia.
The
Grant supports
This study was supported by grants from the Chang Gung Medical Foundation (CMRPG380471, CMRPG380671 and OMRPG3A0011) and the Ministry of Health and Welfare — Taiwan (DOH101-TD-B-111-005, DOH102-TD-B-111-005 and DOHW103-TDU-B-212-113003).
Role of funding source
Chang Gung Medical Foundation, the Ministry of Health and Welfare — Taiwan or Eli Lilly and Company were not involved in the design of the study, collection, management, analysis or interpretation of the data, preparation, review or approval of the manuscript.
The following are the supplementary data related to this article.
Conflict of interest statement
We declared that none of the above will cause conflicts of interest.
Acknowledgments
We want to thank Eli Lilly and Company who supplied free gemcitabine for this trial.
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2019, International Journal of Radiation Oncology Biology PhysicsCitation Excerpt :Therapeutic challenges in the management of locally advanced cervix cancer (LACC; International Federation of Gynecology and Obstetrics stages IIB-IVA) have led to the pursuit of strategies to optimize the efficacy of radiation therapy (RT), the mainstay of treatment in LACC. Of these, most approaches have been undertaken with chemotherapy (CT) as neoadjuvant CT (NACT),1-10 concurrent chemoradiation therapy (CTRT),11-37 adjuvant CT (ACT),31,38,39 or various combinations of these.38,40 Apart from CT, other interventions with RT include hypoxic cell sensitizers (HypCS) (RT + HypCS; chemical radiosensitizers or hyperbaric oxygen),41-48 immunomodulators (Imm) (RT + Imm),49-54 hyperthermia (HT) with RT (HTRT),55-60 or HT with CTRT (HTCTRT).61
Impact of para-aortic recurrence risk-guided intensity-modulated radiotherapy in locally advanced cervical cancer with positive pelvic lymph nodes
2018, Gynecologic OncologyCitation Excerpt :Previous studies had demonstrated the conflicting results regarding the potential benefit of a combination of gemcitabine and cisplatin during CCRT and adjuvant chemotherapy. However, these trials consistently revealed significantly more grade 3–4 toxicities [26–28]. Mabuchi et al. revealed the safety and efficacy of paclitaxel plus carboplatin-based CCRT followed by consolidation chemotherapy [29].
Pelvic Radiation and Normal Tissue Toxicity
2017, Seminars in Radiation OncologyCitation Excerpt :Extended-field radiation to treat para-aortic or common iliac nodes in this setting causes high rates of acute hematologic toxicity in gynecologic patients.135 Patients with advanced cervical cancer are still at risk for local failure, and investigation of intensified treatment with gemcitabine and cisplatin increased grade 3-4 neutropenia and thrombocytopenia.136,137 Many studies show a decrease in bone marrow dose and hematologic toxicity with IMRT instead of 3D radiation.138-141
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This trial is registered as NCT00842660 on https://clinicaltrials.gov/ct2/show/NCT00842660.