Despite availability of primary and secondary prevention measures, cervical cancer persists as one of the most common cancers among women around the world. Although early-stage disease can be cured ...with radical and even fertility-sparing surgery, patients with metastatic and recurrent cervical cancer have poor prognosis with historically limited treatment options and incurable disease. Significant advances in cervical cancer treatment have emerged as the result of clinical trials that have sought to determine the best therapy to prolong overall and progression-free survival. Most recently, trials that have involved angiogenesis blockade in addition to standard chemotherapy have demonstrated improved overall and progression-free survival. This review serves to highlight pivotal trials in chemotherapy development for advanced, metastatic, and recurrent cervical cancer that includes the paradigm-shifting work that demonstrates increased overall survival with angiogenesis blockade.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•All women with ovarian cancer should be offered germline testing for BRCA mutations and other cancer susceptibility genes•Patients with deleterious BRCA mutations should be offered frontline ...maintenance therapy with a PARP inhibitor•Assays for homologous recombination deficiency may guide treatment options in patients without a deleterious BRCA mutation•Tumor molecular profiling may identify targeted therapies for off-label use in patients with limited treatment options
Advances in next generation sequencing have allowed for rapid and economical germline and tumor genomic profiling. Targeted therapies based on molecular tumor profiling are now integrated into treatment guidelines for many solid tumors. In epithelial ovarian cancer, 50% of tumors possess damaging mutations in homologous recombination repair genes (aka homologous recombination deficiency or HRD) which includes the BRCA genes. Deleterious BRCA mutations and HRD have recently emerged as predictive biomarkers for the use of PARP inhibitors in ovarian cancer. Every patient with ovarian cancer must be referred for genetic counseling and germline testing for BRCA mutations. Multigene panel genetic testing may be more informative and cost-effective than limited testing of cancer susceptibility genes. Patients without a germline deleterious BRCA mutation must be assessed for a somatic BRCA mutation. Assays for HRD may help guide treatment options in women who do not have a BRCA mutation. Currently, all patients with a germline or somatic BRCA mutation should be offered upfront maintenance therapy with a PARP inhibitor. During May 2020, options for maintenance therapy with a PARP inhibitor were expanded to patients with HRD and HR-proficient tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal ...antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54–0.95; p = .004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3 months; HR 0.77; 95% CI, 0.62–9.95; p = .007. Post-progression survival was not significantly different between the arms in GOG 240.
Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies.
•The rationale to support the study of anti-angiogenesis therapy is described.•The results of GOG protocol 240 are presented along with global aftermath.•The thesis of immunologic tolerance manifestation in cervical cancer is developed.•Studies of checkpoint inhibition in advanced cervical cancer are highlighted.
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Journal
Journal of Clinical Oncology,
A 36-year-old white married mother of two small children presented with intermenstrual bleeding, dyspareunia, and pelvic pain. Because of significant lapses in ...health care coverage, she had had only sporadic screening for cervical cancer over the past 15 years. On evaluation with a vaginal speculum, her cervix was found to have been replaced by a friable lesion 5 cm in diameter. Biopsy revealed poorly differentiated, squamous cell carcinoma. Bimanual pelvic and rectovaginal examination, as well as radiographic imaging studies, were consistent with an International Federation of Gynecology and Obstetrics (FIGO) stage IB3 squamous cell carcinoma of the cervix. She was treated with cisplatin-based chemoradiation (40 mg/m
body surface area once per week with a planned total dose of 50 Gy using intensity modulated radiotherapy) plus high-dose-rate intracavitary brachytherapy (to bring the total dose to point A to 80 to 85 Gy). Despite missing eight radiotherapy sessions because of transportation issues, she had a complete clinical response. Fourteen months later, she developed severe pelvic and right flank pain. In the clinic, she was cachectic and reported significant abdominal discomfort that kept her from eating well over the past several months. She was no longer able to work as a medical assistant and spent most of her time confined to her apartment. Physical examination demonstrated a fixed, firm pelvic mass; a computed tomography-guided biopsy confirmed recurrent carcinoma, and staging scans disclosed a pulmonary metastasis.
We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary ...peritoneal carcinoma.
A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration
time curve 6) and paclitaxel (175 mg/m
) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for
and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.
Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8
32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for
mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-
HRR, the HR was 0.65 (95% CI, 0.51 to 0.85).
, HRR, and CD31 were not predictive of bevacizumab activity.
No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for
mutations and homologous recombination deficiency is essential.
Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling. The Gynecologic Oncology Group studied ...carboplatin plus paclitaxel (TC) as a noninferior alternative to TAP.
GOG0209 was a phase III, randomized, noninferiority, open-label trial. Inclusion criteria were stage III, stage IV, and recurrent endometrial cancers; performance status 0-2; and adequate renal, hepatic, and marrow function. Prior radiotherapy and/or hormonal therapy were permitted, but chemotherapy, including radiosensitization, was not. Patients were treated with doxorubicin 45 mg/m
and cisplatin 50 mg/m
(day 1), followed by paclitaxel 160 mg/m
(day 2) with granulocyte colony-stimulating factor or paclitaxel 175 mg/m
and carboplatin area under the curve 6 (day 1) every 21 days for seven cycles. The primary endpoint was overall survival (OS; modified intention to treat). Progression-free survival (PFS), health-related quality of life (HRQoL), and toxicity were secondary endpoints.
From 2003 to 2009, 1,381 women were enrolled. Noninferiority of TC to TAP was concluded for OS (median, 37
41 months, respectively; hazard ratio HR, 1.002; 90% CI, 0.9 to 1.12), and PFS (median, 13
14 months; HR, 1.032; 90% CI, 0.93 to 1.15). Neutropenic fever was reported in 7% of patients receiving TAP and 6% of those receiving TC. Grade > 2 sensory neuropathy was recorded in 26% of patients receiving TAP and 20% receiving TC (
= .40). More grade ≥ 3 thrombocytopenia (23%
12%), vomiting (7%
4%), diarrhea (6%
2%), and metabolic (14%
8%) toxicities were reported with TAP. Neutropenia (52%
80%) was more common with TC. Small HRQoL differences favored TC.
With demonstrated noninferiority to TAP, TC is the global first-line standard for advanced endometrial cancer.
To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma.
Eligible patients ...were randomly assigned to six cycles of IV paclitaxel 80 mg/m
once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m
once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m
over 3 hours day 1, IP cisplatin 75 mg/m
day 2, and IP paclitaxel 60 mg/m
day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22.
A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm.
Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.
Summary Background Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore ...the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. Methods The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel 175 mg/m2 of body surface area and carboplatin area under the curve 5) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00565851. Findings Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5–62·2 for chemotherapy plus bevacizumab; IQR 40·8–59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7–46·2) versus 37·3 months (32·6–39·7) in the chemotherapy group (hazard ratio HR 0·829; 95% CI 0·683–1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680–0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 12% vs two 1%), fatigue (27 8% vs eight 2%), and proteinuria (27 8% vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection n=1 and myelodysplastic syndrome n=1) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection n=1, febrile neutropenia n=1, myelodysplastic syndrome n=1, secondary malignancy n=1; deaths not classified with CTCAE terms: disease progression n=3, sudden death n=1, and not specified n=1). Interpretation The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. Funding National Cancer Institute and Genentech.
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Ovarian cancer ranks fifth in mortality among women with cancer and accounts for more death compared to any other gynecological cancers. This review summarizes the most recent literature on ...disparities in ovarian cancer as well as within recent clinical trials.
Recent studies have identified a notable disparity in genetic testing utilization, disease stage at the time of diagnosis, and adherence to treatment guidelines between Black women and their White counterparts, ultimately leading to increased mortality rates among Black women from ovarian cancer. Additionally, there is an underreporting of race in clinical trials and those that do report race demonstrate significant racial disparities within trial participants with the majority of participants being White.
It is imperative that we address the significant racial disparities within ovarian cancer and clinical trials to establish a framework of equitable healthcare provision. Multiple determinants, such as implicit bias, provider mistrust, accessibility hurdles, and socioeconomic influences, appear to contribute to the current disparities faced by women of color. Further investigation is warranted, encompassing a deeper understanding of diverse patient perspectives and identifying barriers to receiving optimal care and participating in clinical trials.
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