INTRODUCTION

Cervical cancer (CC) remains a health problem in low- and middle-income countries according to the report issued by GLOBOCAN in 2018¹. In Mexico, 80% of cases are diagnosed at locally advanced stages (IB2 to IVA). The possibility of recurrence is increased according to the initial clinical stage, with recurrence rates in clinical stage IB of 10%, 17% in IIA, 23% in IIB, 42% in IIIC, and 72% in IVA². In addition, between 8% and 17% of cases are initially diagnosed in the metastatic stage. Treatment selection in this group of patients will depend on the site of recurrence, whether local, regional, or distant³.

In metastatic, recurrent, and persistent stages in patients who are not candidates for surgical management and/or radiotherapy, the choice is systemic treatment³ with platinum-based chemotherapy (CT) doublets. The GOG 204 trial assessed the combination of cisplatin with paclitaxel, vinorelbine, gemcitabine, and topotecan and revealed similar efficacy in terms of response rates (29%), progression-free survival (PFS) (5.8 months), and overall survival (OS) (12.9 months), with a tendency for best efficacy in the cisplatin/paclitaxel group⁴.

Five-year survival in the metastatic stage is 16.5% in comparison with 91.5% for localized disease⁵. Therefore, despite the benefits of treatment with CT, there was a need for novel treatments to improve survival and quality of life in this group of patients; among the new biological agents, antiangiogenic therapy has shown the greatest benefits. The aim of this article is to analyze the existing publications on the mechanisms behind this therapeutic approach and the benefits and risks of antiangiogenic therapy in advanced CC patients. To this purpose, the NCBI-PubMed and Medline databases were used to search for original articles that reported the results of studies that assessed the effect of anti-vascular endothelial growth factor (anti-VEGF) antibody therapy on response to treatment, toxicity and side effects, tumor recurrence, and OS in CC patients. Other antiangiogenic therapies were also included in the search. Articles were reviewed by authors and evaluated using the GRADE system. Recommendations on the use of antiangiogenic therapy were established according to the quality of the evidence.

ANTIANGIOGENIC THERAPY IN CERVICAL CANCER

The main cause of CC is human papillomavirus (HPV) latent infection. HPV pathogenic activity hinges on the presence of the E6 and E7 proteins: E6 promotes p53 degradation, while E7 inactivates the retinoblastoma protein. p53 degradation could be responsible for angiogenesis activation through the production of VEGF and downregulation of thrombospondin-1 – a potent angiogenesis inhibitor–⁶. Angiogenesis has a critical function in tumor cell growth and survival, while VEGF plays a highly important role in its control, in tumor growth, and in the development of metastasis⁷.

Some studies have demonstrated the importance of angiogenesis in premalignant lesions of the cervix, with an association between microvessel density and the grade of cervical intraepithelial neoplasia. Cervical samples with high vascularization have been associated with worse survival rates in comparison with poorly vascularized samples (5-year survival of 50% vs. 65%). Furthermore, high levels of VEGF have been associated with CC advanced stages, higher risk of metastasis, and worse PFS and OS data⁸.

BEVACIZUMAB IN CERVICAL CANCER

Bevacizumab is a recombinant humanized monoclonal G1 immunoglobulin antibody targeted against VEGF (anti-VEGF), clinically developed for various oncological entities⁹. A retrospective study of six heavily pretreated CC patients assessed the use of bevacizumab in combination with 5-fluorouracil or capecitabine. Clinical benefit was observed in 67% of patients: one complete response (CR), 17%, one partial response (PR), 17%, and two patients with stable disease (SD), 33%, with a mean time to progression of 4.3 months. In addition, the combination was well tolerated, with anemia being the most common toxic effect. Grade 3 anemia occurred in 17% of patients, Grade 2 in 33%, and Grade 1 in 50%¹⁰.

Bevacizumab has been assessed in Phase II studies. One of them analyzed its efficacy and tolerability in 46 patients with recurrent CC¹¹. PR was achieved in 10.9% of patients and PFS in 23.9%, for a minimum of 6 months. Mean response duration was 6.21 months, PFS was 3.4 months (95% CI: 2.53-4.53), and OS 7.29 months (95% CI: 6.11-10.41 months). Among the main Grade 3 or 4, adverse events (AEs) caused by bevacizumab, hypertension, pain, and thromboembolism, and other events of hematological, gastrointestinal, genitourinary, and renal origin were reported.

Another Phase II trial evaluated the combination of CT with topotecan and cisplatin plus bevacizumab in the treatment of recurrent or persistent carcinoma of the cervix¹². Twenty-six patients were evaluated, one of whom achieved CR and 8 PR, with a mean response duration of 4.4 months, and 10 patients had SD with a duration of 2.2 months. The probability of PFS at 6 months was 59% (80% CI: 46-70%), and for the set of patients, mean PFS was 7.1 months (80% CI: 4.7-10.1 months) and mean OS was 13.2 months (80% IC: 8.0-15.4 months). Treatment delay of at least one cycle due to toxicity was recorded in 59% of patients, while 78% had to be hospitalized to manage toxicity. Reported hematologic AEs (Grades 3-4) included thrombocytopenia (82%), leukopenia (74%), anemia (63%), and neutropenia (56%). Red blood cell transfusion was required by 78% of patients and platelet transfusion by 30%. Other non-hematologic Grades 3-4 toxicities were metabolic abnormalities (44%), pain (33%), and genitourinary or renal complications (30%). This study showed that the combination of topotecan plus cisplatin with bevacizumab is active but highly toxic.

These studies set the standard for conducting the GOG 240 Phase III trial that, in 2014, led to the approval of bevacizumab by the U.S. Food and Drug Administration for the treatment of advanced CC. The study assessed bevacizumab effectiveness with a combination of CT in patients with recurrent, persistent, or metastatic CC. Four-hundred and fifty-two patients were randomized to receive CT with or without bevacizumab (15 mg/kg day 1). CT consisted of 21-day cycles with cisplatin (50 mg/m² day 1) plus paclitaxel (135 or 175 mg/m² day 1) or topotecan (0.75 mg/m² days 1-3) plus paclitaxel (175 mg/m² day 1). The study data showed that the addition of bevacizumab to CT was associated with an increase in OS (17.0 vs. 13.3 months; HR: 0.71; 95% CI: 0.54-0.95; p = 0.004) and in response rates (48% vs. 36%; p = 0.008) in comparison with CT alone. Bevacizumab was also associated with an increased incidence of AEs, which included Grade ≥2 hypertension (25% vs. 2%), Grade ≥3 thromboembolic events (8% vs. 1%), and Grade ≥3 gastrointestinal fistulae (3% vs. 0%). There was no quality of life deterioration according to the Functional Assessment of Cancer Therapy-Trial Outcome Index questionnaire for CC, which was applied to patients from cycle 1 through cycle 9 (98.75% CI: −4.1-1.7; p = 0.30)¹³.

In the GOG 240 final analysis, the benefit was still a greater OS in patients treated with CT plus bevacizumab in comparison with CT alone (16.8 vs. 13.3 months; HR: 0.77; 95% CI: 0.62-0.95; p = 0.0068). When analyzing by CT, bevacizumab was observed to be able to increase OS only when added to cisplatin plus paclitaxel (17.5 vs. 15.0 months), while there was no difference when added to topotecan plus paclitaxel (16.2 vs. 12.0 months). OS in patients who had not previously received pelvic radiotherapy was higher in the group treated with bevacizumab in comparison with the group treated with CT alone (24.5 vs. 16.8 months), although the differences were not significant (HR: 0.64; 95% CI: 0.37-1.10; p = 0.11). Post-progression OS also did not show significant differences between treatments (8.4 vs. 7.1 months; HR: 0.83; 95% CI: 0.66-1.05; p = 0.06). PFS final data also revealed that adding bevacizumab to CT decreased the risk of progression by approximately 32% in comparison with CT alone (8.2 vs. 6.0 months; HR: 0.68; 95% CI: 0.56-0.84; p = 0.0002). The overall response rate (ORR) was 49% in patients treated with CT plus bevacizumab and 36% for CT alone (p = 0.003), 50% and 46% in patients treated with cisplatin plus paclitaxel with and without bevacizumab, respectively, and 48% and 25% for those who received topotecan plus paclitaxel with and without bevacizumab (p = 0.0004). The most commonly reported AEs were the development of fistulas. The incidence of fistulas of any grade was 15% in patients treated with CT plus bevacizumab versus 1% in those treated with CT alone and Grade 3 fistulas, 6% and <1%, respectively¹⁴.

The incorporation of bevacizumab to the treatment of recurrent, persistent, or metastatic CC represents a huge advance since it shows a survival benefit; however, we lack a biomarker to define which group of patients are candidates for treatment with bevacizumab.

The original impetus to study poor prognosis markers in advanced CC was to identify a priori patients who were unlikely to respond to conventional cytotoxic therapy in an effort to avoid the administration of futile treatment¹⁵. The Moore criteria were identified in the platinum or cytotoxic era when antiangiogenic agents were not yet used in randomized clinical trials in patients with CC¹⁶-¹⁸.

The application of the Moore criteria to the entire GOG-240 study population had the purpose of prospectively analyze previously identified clinical prognostic factors, to validate a score using said criteria: performance status, pelvic disease, ethnicity, disease-free interval <1 year, and previous exposure to cisplatin. Risk categories included low risk (0-1 factor), intermediate risk (2-3 factors), and high risk (4-5 factors). The benefit of receiving bevacizumab was observed to be superior in moderate– and high-risk patients, with an increase in OS of up to 5.8 months¹⁹,²⁰. A retrospective study assessed the eligibility of patients with recurrent and metastatic CC with a follow-up of more than 10 years and found that the main reasons for exclusion from treatment were transvaginal active bleeding and poor renal function²¹.

The combination of carboplatin and paclitaxel plus bevacizumab in metastatic disease can be considered an alternative treatment option in patients who are not candidates for cisplatin, which is evidence provided by the Japanese study that assessed carboplatin non-inferiority versus cisplatin²².

The preliminary report of the CECILIA open-label Phase II study, which is assessing the efficacy and safety of the combination with carboplatin area under the curve 5 every 3 weeks and paclitaxel at 175 mg/m² plus bevacizumab 15 mg/kg every 3 weeks in 150 patients with metastatic, recurrent, or persistent CC, suggests that the combination is safe, with a similar risk of fistulae to that in the GOG 240 trial²³.

With these data, the National Comprehensive Cancer Network, the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) guidelines recommend the use of bevacizumab combined with CT in patients with CC, in metastatic or recurrent disease with a high degree of recommendation and high quality of evidence²⁴-²⁶.

OTHER ANTIANGIOGENIC AGENTS AND TARGETED THERAPIES IN THE TREATMENT OF CERVICAL CANCER

Additional targeted strategies include other antiangiogenic agents (pazopanib, lapatinib, sunitinib, or cediranib), which have not been approved for standard management.

Pazopanib is a tyrosine kinase inhibitor (TKI) that inhibits the signal transduction of multiple VEGF receptors, platelet-derived growth factor receptors (PDGFR), and stem cell receptor (c-KIT). Lapatinib is a TKI that inhibits epidermal growth factor receptor (EGFR) and HER2/neu. One study assessed 230 patients with advanced CC, who were randomized to receive pazopanib or lapatinib monotherapy. Pazopanib showed better PFS (18.1 vs. 17.1 weeks; HR: 0.66; 90% CI: 0.45-0.91; p < 0.013) and OS (50.7 vs. 39.1 weeks; HR: 0.67; 90% CI: 0.46-0.99; p = 0.045) than lapatinib²⁷.

Sunitinib is a TKI that inhibits several VEGF receptors, the PDGFR receptor, and c-kit. A Phase II trial with 19 patients showed a 3.5-month PFS (95% CI: 2.6-7 months) with no documented treatment response and high morbidity with 26.3% of cases developing fistulae, which led to rule out sunitinib monotherapy in CC (19). Cediranib is a TKI that inhibits several VEGF receptors. A Phase II study compared cediranib treatment versus placebo in 69 patients with recurrent or metastatic CC. PFS was 35 weeks for cediranib and 30 weeks for placebo (HR: 0.61; 80% CI: 0.41-0.89; p = 0.046), and ORR was 66% and 42%. Cediranib was associated with a higher incidence of Grade 3 or 4 neutropenia than placebo (31% vs. 9%, p = 0.019); in addition, 50% and 34% of patients experienced Grades 2-4 diarrhea and hypertension, respectively, with no impact on OS²⁸.

Another pathway implicated in CC is that of EGFR which, like angiogenesis, plays an important role in CC pathogenesis. EGFR overexpression in CC is considered a factor of poor prognosis in terms of survival and response to CT²⁹. With the above evidence, EGFR blockade was considered to be a potential approach that could be used in the treatment of CC. Pilot and Phase II trials were conducted with EGF pathway TKI such as erlotinib and gefitinib. As a single agent, erlotinib was shown to be inefficient, while gefitinib, as second- or third-line treatment, showed no objective response in patients with metastatic disease³⁰,³¹.

Cetuximab and nimotuzumab, which are anti-EGFR antibodies, either alone or in combination with CT, showed discrete activity in small pilot studies or Phase II clinical trials and although these agents were well tolerated, there was no clinical response³²,³³.

CONCLUSIONS

Angiogenesis is a process proven to be determinant for tumor growth and invasion. Therefore, antiangiogenic therapy with bevacizumab, targeted against VEGF, shows promise to prevent tumor recurrence and the development of advanced disease. The combination of CT and bevacizumab is the best approach in advanced CC patients, with a demonstrated increase in OS as well as in PFS and response rates.

RECOMMENDATIONS