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Clinical Trial
. 2020 Aug 1;107(5):964-973.
doi: 10.1016/j.ijrobp.2020.04.019. Epub 2020 Apr 22.

Phase 1 Trial of Concurrent Gemcitabine and Cisplatin with Image Guided Intensity Modulated Radiation Therapy for Locoregionally Advanced Cervical Carcinoma

Loren K Mell  1 , Ronghui Xu  2 , Catheryn M Yashar  3 , Michael T McHale  4 , John P Einck  3 , Jyoti Mayadev  5 , Euyhyun Lee  6 , Pratibha Binder  4 , Dominique Rash  3 , Ramez Eskander  4 , Elena S Heide  7 , Steven C Plaxe  4 , Arno J Mundt  5 , Cheryl C Saenz  4
Affiliations
Clinical Trial

Phase 1 Trial of Concurrent Gemcitabine and Cisplatin with Image Guided Intensity Modulated Radiation Therapy for Locoregionally Advanced Cervical Carcinoma

Loren K Mell et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: The use of concurrent doublet chemotherapy with radiation for locoregionally advanced cervical cancer (LACC) is limited by gastrointestinal and hematologic toxicity. By reducing radiation dose to bowel and bone marrow, image guided intensity modulated radiation therapy (IG-IMRT) may improve chemotherapy tolerance. The goal of this study was to determine whether IG-IMRT could lead to improved tolerance to concurrent cisplatin and gemcitabine for LACC.

Methods and materials: We conducted an open-label, nonrandomized, prospective phase 1 dose escalation trial at a tertiary academic cancer center (ClinicalTrials.gov identifier: NCT01554410). We enrolled patients with stage IB-IVA cervical cancer, with either an intact cervix or posthysterectomy with residual/recurrent pelvic or paraortic nodal involvement, undergoing radical pelvic or extended field chemoradiation therapy. Treatment consisted of chemoradiation with IG-IMRT (45-47.6 Gy, 25-28 fractions to the pelvis ± paraortic nodes with simultaneous nodal boost to 53.2-59.4 Gy, 28 fractions) plus 5 cycles of concurrent weekly cisplatin 40 mg/m2 with escalating doses of gemcitabine (50, 75, 100, or 125 mg/m2). Cohorts were separated preregistration according to whether the patient received pelvic or extended field IG-IMRT and whether gemcitabine followed (CG) or preceded (GC) cisplatin delivery. Dose-limiting toxicity (DLT) events were monitored up to 30 days after chemoradiation therapy. The primary endpoint was maximum tolerated dose (MTD) resulting in DLT probability ≤20%.

Results: Between February 2011 and June 2019, 35 patients were registered. Overall, 7 patients (20.0%) experienced DLTs. For the pelvic field cohort, the estimated MTD was 100 mg/m2 with GC sequencing, which is higher than the previously reported MTD for this regimen. The extended field cohort was closed after 2 of 3 patients experienced a DLT at the first dose level.

Conclusions: IG-IMRT can permit higher doses of concurrent gemcitabine with cisplatin and pelvic radiation for LACC. However, acute toxicity remains a factor with this regimen, depending on radiation volume and chemotherapy sequencing.

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Figures

Fig. 1.
Fig. 1.
CONSORT diagram and cohort distribution.
Fig. 2.
Fig. 2.
Outcomes for patients with cervical cancer treated with image guided intensity modulated radiation therapy with concurrent cisplatin and gemcitabine. (A) Overall survival. (B) Disease-free survival. (C) Locoregional failure.
Fig. 3.
Fig. 3.
Longitudinal changes in acute blood counts according to chemotherapy sequencing in patients receiving pelvic irradiation with cisplatin 40 mg/m2 weekly and gemcitabine ≥75 mg/m2 weekly. (A) Absolute neutrophil counts, k/μL. (B) lymphocyte counts, k/μL. (C) Hemoglobin levels, g/dL. (D) Platelet counts, k/μL. Follow-up values were obtained 1 to 3 months after completion of therapy. Abbreviations: CG = cisplatin followed by gemcitabine; GC = gemcitabine followed by cisplatin.
See this image and copyright information in PMC

Comment in

  • In Regard to Mell et al.
    Yuce Sari S, Gultekin M, Yildiz F. Yuce Sari S, et al. Int J Radiat Oncol Biol Phys. 2020 Nov 15;108(4):1115-1116. doi: 10.1016/j.ijrobp.2020.05.045. Int J Radiat Oncol Biol Phys. 2020. PMID: 33069340 No abstract available.
  • In Reply to Sari et al.
    Mell LK, Xu R, Saenz CC. Mell LK, et al. Int J Radiat Oncol Biol Phys. 2020 Nov 15;108(4):1116-1117. doi: 10.1016/j.ijrobp.2020.05.044. Int J Radiat Oncol Biol Phys. 2020. PMID: 33069341 No abstract available.

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