Will the carboplatin-paclitaxel-bevacizumab combination become the preferred option as the first line in advanced cervical cancer? A small experience from a single oncologic Center

Background: Despite the widespread introduction of screening programs, cervical cancer remains an important health problem, particularly in developing countries. Treatment options for patients with metastatic cancer and persistent or recurrent disease after curative therapy are limited and represent an unmet medical need. Patients and Methods: We report three clinical cases of metastatic cervical cancer in women treated with the combination of carboplatin, paclitaxel and bevacizumab. We also discuss current and future therapy for metastatic or recurrent cervical cancer, including ongoing investigations into the addition of bevacizumab to carboplatin/paclitaxel chemotherapy and the role of bevacizumab as maintenance therapy. Results and Conclusion: All three women received clinical benefit from the combination, including one complete and two partial responses. The tolerability of bevacizumab was excellent. Carboplatin/paclitaxel appears to be an acceptable and better tolerated alternative to cisplatin/paclitaxel in advanced or recurrent/persistent disease, and the carboplatin/paclitaxel/bevacizumab combination is under investigation for metastatic, recurrent or persistent cervical cancer in clinical trials such as the CECILIA trial (NCT02467907); the awaited results will add to the evidence for the use of this combination chemotherapy regimen in advanced cervical cancer.

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Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001126 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001126

Author(s):

Claire F Friedman ◽

Alexandra Snyder Charen ◽

Qin Zhou ◽

Michael A Carducci ◽

Alexandre Buckley De Meritens ◽

...

Keyword(s):

Cervical Cancer ◽

Phase Ii ◽

Response Rate ◽

Treatment Options ◽

Objective Response ◽

Primary Objective ◽

Advanced Cervical Cancer ◽

Open Label ◽

Recurrent Cervical Cancer ◽

Platinum Based Chemotherapy

BackgroundThere are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer.MethodsWe report the results from a phase II, open-label, multicenter study (NCT02921269). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsIn the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events.ConclusionsThe combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer.

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SURGERY FOR RESIDUAL DISEASE AFTER RADIOTHERAPY IN LOCALLY ADVANCED CERVICAL CANCER

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-721-725 ◽

2019 ◽

Vol 65 (5) ◽

pp. 721-725

Author(s):

Elmira Shakirova ◽

Andrey Panov ◽

Alevtina Akhmetzyanova ◽

Aliya Gafiullina ◽

L. Ibragimova ◽

...

Keyword(s):

Cervical Cancer ◽

Residual Disease ◽

Locally Advanced ◽

Residual Tumor ◽

Advanced Cervical Cancer ◽

Mri Imaging ◽

Recurrent Cervical Cancer ◽

Locally Advanced Cervical Cancer ◽

Visible Effect ◽

Adjuvant Hysterectomy

Aims: Chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (LACC). However part of the patients develop recurrence during the first year after treatment despite good visible effect at the first follow-up. The role of completion surgery after radiotherapy (RT) is still debated. A number of papers have showed that up to 60% of patients have residual tumor after CRT and RT. But such a surgery is not widely recommended because of increased morbidity of the treatment. The aim of this study was to assess the results of surgery after radiotherapy of LACC. Method: We retrospectively evaluated data on 86 patients with cervical cancer IB - IIIB stages (mostly stage IIB) who underwent surgery in different modalities after CRT and RT with good clinical response in our department in 2015-2018. Results: When small asymptomatic residual disease was detected early after radiotherapy radical hysterectomy was feasible in most of the cases. Patients with clinical manifestation of recurrence had very poor prognosis. Surgery of recurrent cervical cancer sufficiently deteriorates quality of life, even if possible. Conclusion: Thorough examination with adding MRI imaging after initial treatment of cervical cancer needed to identify patients who may benefit from adjuvant hysterectomy.

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Molecular profiles and immune checkpoint inhibitor-related biomarkers analysis in advanced cervical cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18003 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18003-e18003

Author(s):

Qin Xu ◽

Chuanben Chen ◽

Yang Sun ◽

Yibin Lin ◽

Jing Liu ◽

...

Keyword(s):

Cervical Cancer ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Figo Stage ◽

Advanced Cervical Cancer ◽

Single Nucleotide Variants ◽

Paired Samples ◽

Target Capture ◽

Pathological Subtype ◽

Molecular Profiles

e18003 Background: Treatment options for advanced cervical cancer (ACC) are limited and patients experiencing recurrence after first-line chemotherapy and bevacizumab have a poor prognosis. Checkpoint inhibitors targeting the PD-1/PD-L1 are promising treatment option. However, related genomic biomarker study is rare reported in ACC. Methods: We prospectively enrolled 102 pts with ACC. Tumor and plasma samples were obtained to analysis genomic profiles. DNA was sequenced by target-capture deep sequencing with the pan-cancer panel. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1. Results: The median age of enrolled pts was 63 yrs, and most (84.3 %, 86/102 pts) weresquamous carcinoma. A total of 93 tissues and 96 plasma were collected from 102 pts. The most frequently mutated genes were PIK3CA (40.9%, 38/93 pts), KMT2D (35.5%, 33/93 pts), and KMT2C (28.0%, 26/93 pts) in tissues. 80% (77/96 pts) of plasma was detected positive, with PIK3CA (23.4%, 18/77 pts), KMT2D (20.8%, 16/77 pts), KMT2C (20.8%, 17/77 pts) mutant frequently. Among 87 pts with paired samples, at least a tumor-derived mutation was detected in 35 (40.2%)plasma. Median of tTMB was 11.9 mut/Mb, and 45% pts were TMB-H. Significant correlation was found between tTMB and bTMB (Pearson r = 0.39, P = 0.001). Higher tTMB was identified in KMT2D- or KMT2C-mut pts (P = 0.002 or P = 0.01, respectively). tTMB showed no relation with clinic characteristics, including pathological subtype, FIGO stage, and status of distant metastasis. PD-L1 expression (CPS≥1) was identified in 53 pts (93 %, 53/57) and mutually independent with TMB status. Conclusions: Molecular profiles and TMB in plama showed high consistence with that in tissue. Prospective clinical trial is ongoing to determine the genomic biomarkers and the PD-L1 expression as predictive factors for the ICI efficacy in ACC (ChiCTR1900023015).

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Screening for Cervical Cancer in Low-Resource Settings in 2011

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2011-0695-ra ◽

2013 ◽

Vol 137 (6) ◽

pp. 782-790 ◽

Cited By ~ 5

Author(s):

Rosemary Tambouret

Keyword(s):

Cervical Cancer ◽

Health Care Organizations ◽

Treatment Options ◽

Personal Communication ◽

Cervical Cytology ◽

Middle Income ◽

Screening Programs ◽

Low Resource ◽

Middle Income Countries ◽

Cytology Screening

Context.—Cervical cancer remains the most common malignancy in women living in low- and middle-income countries, despite the decline of the disease in countries where cervical cytology screening programs have been implemented. Objectives.—To review the current incidence of cervical cancer in low-resource countries, the availability and types of screening programs, and the treatment options. Data Sources.—Literature review through PubMed, Internet search, and personal communication. Conclusions.—Although data are incomplete, available figures confirm that the rate of cervical cancer deaths and the availability of cervical cancer screening programs are inversely proportional and vary, in general, by the wealth of the nation. Despite the success of cervical cytology screening, many major health care organizations have abandoned screening by cytology in favor of direct visualization methods with immediate treatment of lesions by cryotherapy provided by trained, nonmedical personnel.

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Molecular-guided therapy for disseminated cervical cancer: present and future

Medical Council ◽

10.21518/2079-701x-2020-9-121-126 ◽

2020 ◽

pp. 121-126

Author(s):

A. А. Rumyantsev

Keyword(s):

Cervical Cancer ◽

Metastatic Cancer ◽

Antiangiogenic Therapy ◽

Phase Iii ◽

Cervix Uteri ◽

Term Survival ◽

Recurrent Cervical Cancer ◽

Number Of Patients ◽

Incidence And Mortality ◽

High Level

Сervical cancer is recognized as one of the leaders in mortality from gynecological oncological diseases. The incidence and mortality from cervical cancer over the past 10 years remained at a consistently high level. For a long time, the only treatment option for metastatic and/or recurrent cervical cancer was cytotoxic chemotherapy, but its results remained extremely unsatisfactory: the 5-year overall survival rate was about 12%. This article is devoted to a review of the current possibilities of targeted and immunotherapy of metastatic and/or recurrent cervical cancer. We reviewed the most recent studies in the field of the effectiveness of antiangiogenic therapy including a critical and detailed analysis of the results of the GOG-240 phase III study. The data of modern literature in the field of immunotherapy using PD-1 / PD-L1 signaling pathway inhibitors in metastatic cervical cancer has been studied. It was found that a significant number of patients (34-95%) showed increased expression of PD-L1 in the tumor tissue, and 3-6% of patients showed a high level of microsatellite instability (MSI) in the tumor, which reveals the possibility of immunotherapy for this disease. We also conducted a review of ongoing clinical studies on the use of targeted and immunotherapy of advanced cervical cancer and the prospects for changing the “landscape” of treatment for this disease were assessed. On the example of a clinical case of treatment of a real patient, the possibilities of modern targeted and immunotherapy of metastatic cancer of the cervix uteri were analyzed, which gave a possibility to ensure long-term survival for the patient with an initially poor prognosis.

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High-Grade Cervical Dysplasia following Radiation Therapy for Invasive Cervical Cancer: A Report of Four Cases

Case Reports in Oncology ◽

10.1159/000382117 ◽

2015 ◽

Vol 8 (2) ◽

pp. 217-221 ◽

Cited By ~ 2

Author(s):

Mila Pontremoli Salcedo ◽

Andrea M. Milbourne ◽

Anuja Jhingran ◽

Patricia J. Eifel ◽

Pedro T. Ramirez ◽

...

Keyword(s):

Cervical Cancer ◽

Radiation Therapy ◽

Gynecologic Oncology ◽

Invasive Cervical Cancer ◽

Locally Advanced ◽

Cervical Dysplasia ◽

High Grade ◽

Advanced Cervical Cancer ◽

Recurrent Cervical Cancer ◽

Locally Advanced Cervical Cancer

Introduction: The standard treatment for locally advanced cervical cancer is chemoradiation, with the majority of patients having a complete response to the therapy. The current surveillance recommendations from the Society of Gynecologic Oncology include annual cytology, with a small proportion of patients subsequently diagnosed with high-grade cervical dysplasia (CIN 2/3). To date, there is limited information regarding the optimal treatment and outcome for patients diagnosed with CIN 2/3. The current report describes the diagnosis, management and outcome of 4 patients diagnosed with CIN 2/3 following chemoradiation. Case Description: We describe 4 patients who developed CIN 2/3 seven months to 8 years following radiation therapy for locally advanced cervical cancer. All 4 patients were asymptomatic and the abnormalities were first detected by a Pap test. Three of the patients were managed conservatively with observation, and the CIN 2/3 resolved without intervention. One patient underwent 2 cervical conizations followed by a hysterectomy with no residual dysplasia noted on the hysterectomy specimen. Conclusion: The majority of patients with recurrent cervical cancer after chemoradiation are symptomatic, and most cases are detected by a physical examination. The role of cytology, colposcopy and biopsies may be of limited value. Furthermore, the significance of the diagnosis of CIN 2/3 in patients previously treated with radiation therapy was not associated with recurrent disease in the 4 patients described. Our results suggest that cytology may be of limited value in detecting recurrence in patients following radiation therapy, even when CIN 2/3 is detected.

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Pattern of disease in recurrent cervical cancer associated with response to pembrolizumab.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18006 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18006-e18006

Author(s):

Kathryn Miller ◽

Olga T. Filippova ◽

Sara A. Hayes ◽

Nadeem Abu-Rustum ◽

Carol Aghajanian ◽

...

Keyword(s):

Cervical Cancer ◽

Survival Analysis ◽

Lymph Node ◽

Progression Free Survival ◽

Complete Response ◽

Advanced Cervical Cancer ◽

Duration Of Treatment ◽

Recurrent Cervical Cancer ◽

Kaplan Meier ◽

Mesonephric Adenocarcinoma

e18006 Background: Pembrolizumab received accelerated FDA approval for treatment of metastatic or recurrent PD-L1 positive cervical cancer in 6/2018. Since then, the clinical characteristics of patients who best respond to this immunotherapy have remained undefined. We sought to describe patients with advanced cervical cancer who derived durable clinical benefit (DCB) from pembrolizumab therapy. Methods: Patients with advanced or recurrent cervical cancer who received pembrolizumab from 8/2017-12/2019 at our institution were assessed. Reviewed data included patient demographics, treatment history, baseline pattern of metastatic disease at initiation of anti-PD-1 treatment, and outcomes. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS). Treatment response was evaluated by computed tomography using RECIST 1.1 criteria. Results: 14 patients with recurrent cervical cancer received pembrolizumab. Median age was 55 years (range, 21-76); 79% (n = 11) had squamous cell carcinoma (SCC). The 3 non-SCC histologies included endocervical adenocarcinoma, high-grade endometroid adenocarcinoma, and mesonephric adenocarcinoma. 93% (n = 13) expressed PD-L1; 1 patient whose tumor was MSI-H did not undergo PD-L1 testing. 93% (n = 13) had received prior radiation, and 86% (n = 12) had received 1 or more prior lines of chemotherapy. Median duration of treatment was 4.9 months (range, 1.4-15.2), and median follow-up was 7.9 months (range, 2.1-29.9). On RECIST review, the overall response rate was 21% (n = 3), including 2 partial responses and 1 complete response. Two patients (14%) had stable disease of ≥6 months for an observed DCB of 36%. Of the 5 patients with DCB, 4 remain on pembrolizumab, with observed antitumor activity of up to 15.4 months. On univariable analysis, a lymph node and/or lung only baseline pattern of metastasis was associated with improved response to pembrolizumab (n = 7, P= 0.02). On survival analysis, patients with lymph node and/or lung pattern of disease had a 6-month PFS rate of 86%, compared to a 6-month PFS rate of 0% in patients with visceral or multi-site disease ( P< 0.001). Conclusions: Pembrolizumab showed promising activity in our patient cohort, with a DCB rate of 33%. Patients with lymph node and/or lung only patterns of metastasis at baseline had the greatest radiologic response compared to patients with visceral or multi-site disease. Our results suggest that there may be an underlying pathophysiology of metastatic patterns that confer improved response to anti-PD-1 therapy in advanced cervical cancer.

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A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyw143 ◽

2016 ◽

Vol 47 (1) ◽

pp. 39-46 ◽

Cited By ~ 9

Author(s):

Toru Sugiyama ◽

Mika Mizuno ◽

Yoichi Aoki ◽

Manabu Sakurai ◽

Tadaaki Nishikawa ◽

...

Keyword(s):

Cervical Cancer ◽

Adverse Events ◽

Overall Response Rate ◽

Response Rate ◽

Japanese Patients ◽

Primary Objective ◽

Phase Iii ◽

Advanced Cervical Cancer ◽

Recurrent Cervical Cancer ◽

Overall Response

Background Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. Methods The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h), cisplatin (50 mg/m2) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. Results The seven treated patients received a median of nine (range 7–12) bevacizumab cycles and six (range 4–12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42–100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. Conclusions According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.

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Identifying Molecular Changes in Early Cervical Cancer Samples of Patients That Developed Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2021.715077 ◽

2022 ◽

Vol 11 ◽

Author(s):

Vera de Geus ◽

Patricia C. Ewing-Graham ◽

Willem de Koning ◽

Maurits N. C. de Koning ◽

Thierry P. P. van den Bosch ◽

...

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

T Cells ◽

Recurrent Disease ◽

Early Stage ◽

Treatment Options ◽

Molecular Signature ◽

Recurrent Cervical Cancer ◽

Increased Risk ◽

Early Stage Cervical Cancer

Cervical cancer is one of the most common cancers in women worldwide. Patients diagnosed with early-stage cervical cancer have a good prognosis, however, 10-20% suffer from local or distant recurrent disease after primary treatment. Treatment options for recurrent cervical cancer are limited. Therefore, it is crucial to identify factors that can predict patients with an increased risk of recurrence to optimize treatment to prevent the recurrence of cervical cancer. We aimed to identify biomarkers in early-stage primary cervical cancer which recurred after surgery. Formalin-Fixed, Paraffin-Embedded surgical specimens of 34 patients with early-stage cervical cancer (FIGO 2009 stage 1B1) and 7 healthy controls were analyzed. Targeted gene expression profiling using the PanCancer IO 360 panel of NanoString Technology was performed. The findings were confirmed by performing immunohistochemistry stainings. Various genes, namely GLS, CD36, WNT5a, HRAS, DDB2, PIK3R2, and CDH2 were found to be differentially highly expressed in primary cervical cancer samples of patients who developed distant recurrence. In addition, The relative infiltration score of CD8+ T cells, CD80+CD86+ macrophages, CD163+MRC1+ macrophages, and FOXP3+IL2RA+ regulatory T cells were significantly higher in this group of samples. In contrast, no significant differences in gene expression and relative immune infiltration were found in samples of patients who developed local recurrence. The infiltration of CD8 and FOXP3 cells were validated by immunohistochemistry using all samples included in the study. We identified molecular alterations in primary cervical cancer samples from patients who developed recurrent disease. These findings can be utilized towards developing a molecular signature for the early detection of patients with a high risk to develop metastasis.

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