Neoadjuvant Chemotherapy With Cisplatin and Gemcitabine Followed by Chemoradiation Versus Chemoradiation for Locally Advanced Cervical Cancer: A Randomized Phase II Trial

Costa, Sirlene Maria da; Bonadio, Renata Colombo; Gabrielli, Flávia Carolina Grosso; Aranha, Andrea; Genta, Maria Luiza Nogueira Dias; Miranda, Vanessa da Costa; Freitas, Daniel Salvatore de; Filho, Elias Abdo; Ferreira, Patrícia A.O.; Machado, Karime Kalil; Scaranti, Mariana; Carvalho, Heloísa de Andrade; Estevez-Diz, Maria Del Pilar

doi:10.1200/jco.19.00674

Cited by 70 publications

(54 citation statements)

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“…Cervical cancer closely correlates with high rates of infection with human papillomavirus (HPV), especially HPV16 and HPV18, and is the fourth most common gynecological malignancy and second leading cause of cancer-associated female mortality globally (da Costa et al, 2019). According to new statistics, that there are 528,000 new diagnoses and 266,000 deaths annually.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

Zhu

Tian

et al. 2020

Front. Genet.

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Recent discoveries have led to the development of novel ideas and techniques that have helped elucidate the correlation between epigenetics and tumor biology. Nowadays, the field of tumor genetics has evolved to include a new type of regulation by epigenetics. An increasing number of studies have demonstrated the importance of DNA methylation and hydroxymethylation in specific genes in the progression of cervical cancer. Determining the methylation and hydroxymethylation profiles of these genes will help in the early prevention and diagnosis, monitoring recurrence, prognosis, and treatment of patients with cervical cancer. In this review, we focus on the significance of aberrant DNA methylation and hydroxymethylation in cervical cancer and the use of these epigenetic signatures in clinical settings.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

Zhu

Tian

et al. 2020

Front. Genet.

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“…This study was conducted as a secondary analysis of the CIRCE trial to evaluate quality of life outcomes (NCT 01973101). 15 The CIRCE trial is a randomized, phase II trial, assessing the efficacy and safety of neoadjuvant chemotherapy with cisplatin and gemcitabine followed by chemoradiation with cisplatin for patients with locally advanced cervical cancer. Patients were allocated, by a simple 1:1 randomization using a computer generated random list, to three cycles of neoadjuvant chemotherapy with cisplatin and gemcitabine followed by standard chemoradiation followed by brachytherapy or standard chemoradiation and brachytherapy alone ( Figure 1).…”

Section: Methodsmentioning

confidence: 99%

“…The primary endpoint was 3 year progression free survival and the secondary endpoints were complete response rate, overall survival, toxicity, and quality of life. 15 Quality of life questionnaires were applied at baseline and after completion of treatment at 3, 6, 9, and 12 months. The baseline assessment was performed following diagnosis but prior to treatment initiation and prior to the medical consultation.…”

Section: Methodsmentioning

confidence: 99%

“…Additional eligibility criteria for the CIRCE trial are described elsewhere. 15 All patients provided written informed consent before randomization.…”

Section: Patientsmentioning

confidence: 99%

“…15 The neoadjuvant chemotherapy group was associated with decreased 3 year progression free survival, with 3 year progression free survival rates of 40.9% compared with 60.4% in the chemoradiation arm (hazard ratio (HR) 1.84 (95% confidence interval (CI) 1.04 to 3.26); p=0.03), lower overall survival (3 year overall survival 60.7% vs 86.8%; HR 2.79 (95% CI 1.29 to 6.01); p=0.006), and lower complete response rates (56.3% vs 80.3%; p=0.008). 15 Toxicities were similar between arms, except for a higher frequency of hypomagnesemia and neuropathy in the neoadjuvant chemotherapy arm. The study concluded that the addition of neoadjuvant chemotherapy to chemoradiation is not superior and is possibly inferior to chemoradiation alone in the treatment of locally advanced cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

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Quality of life of locally advanced cervical cancer patients after neoadjuvant chemotherapy followed by chemoradiation versus chemoradiation alone (CIRCE trial): a randomized phase II trial

Arruda

Costa

Bonadio

et al. 2020

Int J Gynecol Cancer

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ObjectiveThe CIRCE trial (NCT 01973101) investigated the efficacy, safety, and quality of life of the addition of neoadjuvant chemotherapy with cisplatin and gemcitabine to standard chemoradiation for locally advanced cervical cancer (stages IIB–IVA). The impact of both treatment arms on quality of life is reported in the present study.MethodsPatients completed the European Organization of Research and Treatment of Cancer questionnaire QLQ-C30 and CX24 before treatment and at 3, 6, 9, and 12 months after treatment. Linear mixed models were fitted to analyze differences in quality of life over time and between groups. Differences in mean quality of life scales >10 points and p<0.05 were considered clinically relevant and statistically significant, respectively. Inclusion criteria were: (1) histological diagnosis of locally advanced invasive carcinoma of the uterine cervix, International Federation of Gynecology and Obstetrics stages IIB–IVA; (2) signed informed consent to participate in the CIRCE trial; and (3) answered at least one quality of life questionnaire. Excluded were patients who did not complete any quality of life questionnaire. Relevant exclusion criteria for the CIRCE trial included Eastern Cooperative Oncology Group performance status >2 and peripheral neuropathy >2. Mann–Whitney U tests were performed to assess differences between groups in quality of life at baseline. To evaluate differences between treatment arms, linear mixed models were fitted using the transformed quality of life scores as a dependent variable and time of follow-up and study arm as factors.ResultsA total of 107 patients were enrolled (n=55 neoadjuvant chemotherapy arm; n=52 chemoradiation arm). Quality of life compliance rates were higher for the chemoradiation group at every assessment time (ranging from 75–86.5% in the chemoradiation arm vs 55–81.8% in the neoadjuvant chemotherapy arm). For quality of life results at baseline, no statistically significant difference between the groups was seen. For both groups, most scales showed improvements over time, except for worsening of the summary score, sexual enjoyment, peripheral neuropathy, and menopausal symptoms. For chemoradiation, body image was lower (p<0.001) and patients presented more lymphedema (p<0.001) and sexual worry (p<0.001) at 12 months compared with baseline. Comparing study arms, neoadjuvant chemotherapy showed significantly lower scores in the menopausal symptoms scale (p=0.03) and higher scores for sexual/vaginal functioning (p=0.01). At 12 months, clinical differences were seen only for body image and menopausal symptoms scale, with neoadjuvant chemotherapy presenting better body image scores and a lower burden of menopausal symptoms.ConclusionAfter treatment for locally advanced cervical cancer, patients improved in most quality of life aspects. However, worsening was observed in sexual enjoyment, peripheral neuropathy, and menopausal symptoms. To improve patients’ quality of life, efforts should be made to prevent and treat these long term effects of locally advanced cervical cancer treatment.

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Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin

et al. 2023

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ImportancePatients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography–based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors.ObjectiveTo compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors.Design, Setting, and ParticipantsThis comparative effectiveness study comprised all 7 consecutive patients with gynecologic tumors who were treated with ART with artificial intelligence segmentation from January to May 2022 at the West German Cancer Center. All adapted treatment plans were reviewed for the new scenario of organs at risk and target volume. Dose distributions of adapted and scheduled plans optimized on the initial planning computed tomography scan were compared.ExposureOnline ART for gynecologic tumors.Main Outcomes and MeasuresTarget dose coverage with ART compared with IGRT for PTV margins of 5 mm or less in terms of the generalized equivalent uniform dose (gEUD) without increasing the gEUD for the organs at risk (bladder and rectum).ResultsThe first 10 treatment series among 7 patients (mean [SD] age, 65.7 [16.5] years) with gynecologic tumors from a prospective observational trial performed with ART were compared with IGRT. For a clinical PTV margin of 5 mm, IGRT was associated with a median gEUD decrease in the interfractional clinical target volume of −1.5% (90% CI, −31.8% to 2.9%) for all fractions in comparison with the planned dose distribution. Online ART was associated with a decrease of −0.02% (90% CI, −3.2% to 1.5%), which was less than the decrease with IGRT (P &lt; .001). This was not associated with an increase in the gEUD for the bladder or rectum. For a PTV margin of 0 mm, the median gEUD deviation with IGRT was −13.1% (90% CI, −47.9% to 1.6%) compared with 0.1% (90% CI, −2.3% to 6.6%) with ART (P &lt; .001). The benefit associated with ART was larger for a PTV margin of 0 mm than of 5 mm (P = .004) due to spreading of the cold spot at the clinical target volume margin from fraction to fraction with a median SD of 2.4 cm (90% CI, 1.9-3.4 cm) for all patients.Conclusions and RelevanceThis study suggests that ART is associated with an improvement in the percentage deviation of gEUD for the interfractional clinical target volume compared with IGRT. As the gain of ART depends on fractionation and PTV margin, a strategy is proposed here to switch from IGRT to ART, if the delivered gEUD distribution becomes unfavorable in comparison with the expected distribution during the course of treatment.

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Neoadjuvant Chemotherapy With Cisplatin and Gemcitabine Followed by Chemoradiation Versus Chemoradiation for Locally Advanced Cervical Cancer: A Randomized Phase II Trial

Cited by 70 publications

References 22 publications

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

Quality of life of locally advanced cervical cancer patients after neoadjuvant chemotherapy followed by chemoradiation versus chemoradiation alone (CIRCE trial): a randomized phase II trial

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin

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