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OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
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OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Drug Resistance, Neoplasm , Neoplasm Recurrence, Local , Ovarian Neoplasms , Phthalazines , Piperazines , Quinazolines , Humans , Female , Phthalazines/administration & dosage , Piperazines/administration & dosage , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Middle Aged , Drug Resistance, Neoplasm/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Adult , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Quinazolines/administration & dosage , Quinazolines/therapeutic use , Homologous Recombination , Progression-Free Survival , Aged, 80 and over , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/genetics , IndolesABSTRACT
Ovarian cancer is considered the most fatal and costly gynecologic cancer. Although personalized therapies have improved ovarian cancer prognosis, they have resulted in increased financial toxicity concerns among this population. This study evaluated financial toxicity in patients with advanced ovarian cancer. Using secondary data from a study of barriers to palliative care, financial toxicity (FT) was measured through the Comprehensive Score for Financial Toxicity scale. Univariate and bivariate analyses were used to assess the relationship between selected demographic (i.e., age, race, ethnicity, education, place of birth, insurance type, yearly household income, employment status) and treatment-specific variables (i.e., years since diagnosis, surgery, chemotherapy, radiation, hormonal and targeted therapy) with clinically relevant financial toxicity. Characteristics were compared using Fisher's exact or chi squared tests. A total of 38 participants with advanced ovarian cancer were included in this study; 24% (n = 9) reported clinically significant FT. Income (p = .001), place of birth (p = .048) and employment status (p = .001) were related to FT. Study findings highlight that advanced ovarian cancer patients experience high FT, particularly those with low income, who are not able to work and were born outside the US. Further research using larger datasets and more representative samples is needed to inform intervention development and implementation.
Subject(s)
Financial Stress , Income , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/therapy , Ovarian Neoplasms/pathology , Middle Aged , Aged , Financial Stress/psychology , Income/statistics & numerical data , Palliative Care , Socioeconomic Factors , Employment/statistics & numerical data , Adult , Aged, 80 and over , Sociodemographic FactorsABSTRACT
OBJECTIVES: To determine clinical significance of preoperative and pre-chemotherapy CA-125 in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients with stage IA/IB and grade 3, stage IC, clear cell, or completed resected stage II cancer were enrolled in a phase III trial and treated with chemotherapy. Kaplan-Meier method and Cox proportional hazards model were used for statistical analyses. RESULTS: 427 patients with high-risk early-stage ovarian cancer were enrolled. Of 213 patients with preoperative CA-125 data, 79% had elevated CA-125. Median preoperative CA-125 level was 103 U/mL. Patients with ≤10, 11-15, and > 15 cm tumors had median preoperative CA-125 levels of 62, 131 and 158 U/mL, respectively (p = 0.002). For the 350 patients with data for pre-chemotherapy CA-125 level, 69% had elevated pre-chemotherapy CA-125 above 35 U/mL with median value of 65 U/mL. However, age, race, stage, cell type and grade of disease were not correlated with CA-125 levels before and after surgery. On multivariate analysis, elevated pre-chemotherapy CA-125 independently predicted worse recurrence-free survival (HR = 2.13, 95% CI: 1.23-3.69; p = 0.007) and overall survival (HR = 1.99, 95% CI: 1.10-3.59; p = 0.022) after adjusting for age, stage, cell type and grade of disease. Compared to those with normal CA-125, patients with elevated pre-chemotherapy CA-125 had lower recurrence-free survival (RFS, 87% vs. 75%; p = 0.007) and overall survival (OS, 88% vs. 82%; p = 0.02). However, preoperative CA-125 was not prognostic of RFS (p = 0.699) or OS (p = 0.701). CONCLUSIONS: Preoperative CA-125 was elevated in nearly 80% of high-risk early-stage ovarian cancer patients. Pre-chemotherapy CA-125 was associated with recurrence-free and overall survival; however, preoperative CA-125 was not prognostic.
Subject(s)
Ovarian Neoplasms , Female , Humans , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/pathology , Multivariate Analysis , Neoplasm Staging , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Prognosis , Retrospective StudiesABSTRACT
INTRODUCTION: Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. OBJECTIVE: To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. METHODS: Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. RESULTS: Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. CONCLUSIONS: The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.
Subject(s)
Cystadenocarcinoma, Serous , Epstein-Barr Virus Infections , Ovarian Neoplasms , Humans , Female , Infant , Aged , Carcinoma, Ovarian Epithelial/epidemiology , Carcinoma, Ovarian Epithelial/genetics , DNA, Viral/genetics , Prevalence , Herpesvirus 4, Human/genetics , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/genetics , Cystadenocarcinoma, Serous/pathologyABSTRACT
OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.
Subject(s)
Endometrial Neoplasms , Paclitaxel , Humans , Female , Paclitaxel/adverse effects , Treatment Outcome , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/etiology , Progression-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1ß, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.
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Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.
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PURPOSE: Palliative care aims to provide symptom relief and general support for patients with serious illness. Despite experiencing significant treatment side effects, specialty palliative care is under-utilized by patients with advanced ovarian cancer. We explored barriers to palliative care in this population. METHODS: We conducted a sequential mixed-methods study. Qualitative: we interviewed patients with advanced ovarian cancer (N = 7). Guided by the Social Ecological Model (SEM), interviews assessed intrapersonal, interpersonal, organizational, and policy-level barriers to receipt of specialty palliative care. Interviews were audio-recorded, transcribed, and analyzed with directed content analysis. Quantitative: patients with advanced ovarian cancer (N = 38) completed self-report surveys assessing knowledge about, attitudes towards, and prior experiences with specialty palliative care. Descriptive statistics were used to characterize survey responses. RESULTS: Qualitative analysis identified barriers to specialty palliative care at each SEM level. Intrapersonal factors (e.g., knowledge, attitudes) were most frequently discussed. Other common barriers included insurance coverage and distance/travel time. Survey responses indicated most participants were aware of palliative care (74%) but had mixed attitudes towards palliative care and did not feel they needed for palliative care. No survey respondents had received a physician recommendation for palliative care, and a sizable minority (29%) thought palliative care referral should only take place when patients have no remaining treatment options. CONCLUSION: Among patients with advanced ovarian cancer, barriers to specialty palliative care exist at multiple levels. Our results underscore the potential value of a multilevel intervention to support receipt of palliative care in this population.
Subject(s)
Hospice and Palliative Care Nursing , Ovarian Neoplasms , Physicians , Humans , Female , Palliative Care/methods , Patients , Ovarian Neoplasms/therapyABSTRACT
OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.
Subject(s)
Ovarian Neoplasms , Female , Humans , Carboplatin , Creatinine , Glomerular Filtration Rate , Kidney Function Tests , Ovarian Neoplasms/drug therapy , Retrospective StudiesABSTRACT
OBJECTIVE: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction. METHODS: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared. RESULTS: We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups. CONCLUSIONS: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.
Subject(s)
Neoplasms, Glandular and Epithelial , Ovarian Neoplasms , Female , Humans , Aged , Carcinoma, Ovarian Epithelial/drug therapy , Carboplatin , Ovarian Neoplasms/pathology , Disease-Free Survival , Neoplasms, Glandular and Epithelial/drug therapy , Paclitaxel , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm StagingABSTRACT
OBJECTIVE: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. METHODS: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. RESULTS: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy. CONCLUSIONS: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950).
Subject(s)
Neoplasms, Glandular and Epithelial , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , CA-125 Antigen , Neoplasms, Glandular and Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/drug therapy , Carboplatin , Paclitaxel , Doxorubicin , Polyethylene Glycols , Recurrence , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapyABSTRACT
PURPOSE: The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor-positive ovarian cancer. METHODS: This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS: From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor-positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P < .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P < .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION: This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.
Subject(s)
Folate Receptor 1 , Ovarian Neoplasms , Humans , Female , Folate Receptor 1/analysis , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Folic Acid , Molecular Imaging/methodsABSTRACT
OBJECTIVES: To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4). CONCLUSIONS: Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.
Subject(s)
Ovarian Neoplasms , Humans , Female , Prognosis , Carcinoma, Ovarian Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Disease-Free Survival , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Staging , CA-125 Antigen , Carboplatin , PaclitaxelABSTRACT
OBJECTIVES: Central nervous system metastases (CNSm) secondary to endometrial cancer (EC) are rare. As a result, prognostic factors for this patient population are not well described. METHODS: EC patients with CNSm were identified retrospectively from two academic centers. EC patients without CNSm (non-CNSm) were used as controls. Chi-square and Fisher's exact tests were used for analysis of categorial variables. Wilcoxon tests were used for quantitative measures. Overall survival (OS) was compared with Log-rank test. Cox proportional hazard models were used to estimate hazard ratios for OS. RESULTS: 22 EC patients with CNSm and 354 non-CNSm patients were included. Compared to non-CNSm EC, the CNSm cohort was younger (58.5 vs 62.0 years, p = 0.018) with lower BMI (27.7 vs. 33.7 kg/m2, p = 0.005), and had more advanced stages (p = ≤ 0.001), grade 3 tumors (81.8% CNSm vs 25.1% non CNSm, p≤0.001) and serous histology (22.7% vs 8.5%, p = 0.010). Median survival after CNSm diagnosis was 9 months (95% CI 4, NA). CNSm was a strong poor prognostic factor (HR death 4.96, p = 0.022). Improved OS was seen with CNS as the only disease site (83m CNSm only vs 30m additional sites, p = 0.007) and less than five CNSm (49m <5 vs. 23m ≥5, p = 0.004). Surgical resection of CNSm (OS 83m surgery vs 33m no surgery, p = 0.003) or multimodal therapy (83m multimodal vs 33m single therapy, p = 0.027) resulted in longer OS. CONCLUSIONS: CNSm is a poor prognostic factor in EC, however, low volume disease with aggressive treatment may result in more favorable survival outcomes.
Subject(s)
Central Nervous System Neoplasms , Endometrial Neoplasms , Neoplasms, Second Primary , Central Nervous System , Female , Humans , Prognosis , Retrospective StudiesABSTRACT
Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non-small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.
Subject(s)
Lung Neoplasms , Neoplasms, Glandular and Epithelial , Ovarian Neoplasms , Receptors, Odorant , Female , Humans , Cell Line, Tumor , Immunotherapy, Adoptive , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Neoplasms, Glandular and Epithelial/metabolism , Ovarian Neoplasms/metabolism , Receptors, Odorant/metabolism , T-LymphocytesABSTRACT
PURPOSE: This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer. PATIENTS AND METHODS: This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response. RESULTS: The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable). CONCLUSION: Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Fallopian Tube Neoplasms , Ovarian Neoplasms , Antibodies, Bispecific , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Fallopian Tube Neoplasms/drug therapy , Female , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Paclitaxel , Platinum/therapeutic use , RNA/therapeutic use , Retrospective Studies , Tumor Microenvironment , Vascular Endothelial Growth Factor AABSTRACT
OBJECTIVE: To determine the effect of distance to closest negative margin on survival after pelvic exenteration (PE). METHODS: In this retrospective analysis of PE at Moffitt Cancer Center from 2000 to 2019, baseline characteristics, clinical details, and outcomes were ascertained. Distance to closest negative margin was measured. Close and distant negative margins were defined as <3 mm and ≥3 mm from malignancy to nearest surgical margin, respectively. Overall survival (OS) and progression-free survival (PFS) were determined, and Kaplan-Meier curves were compared. Cox proportional hazards regression was used to examine the association of margin status with OS and PFS. RESULTS: Of 124 PEs with malignancy, 80 (64.5%) had negative margins. Median survival was 62 (95% confidence interval [CI] 27-70) months for negative and 21 (95% CI 15-29) months for positive margins. Of 76 with negative margins and documented margin length, 26 had close and 50 had distant margins. Median survival was 32 (95% CI 14-62) months for close and 111 (95% CI 42-166) months for distant margins. Distant margins were associated with improved OS (p = 0.0054) and PFS (p = 0.0099) compared to close margins. After adjusting for other prognostic factors, patients with distant margins had significantly decreased risk of all-cause mortality (HR 0.39, 95% CI 0.19-0.78; p = 0.008) and progression (HR 0.48, 95% CI 0.23-0.99; p = 0.04) compared to positive margins. No significant differences in OS or PFS were observed between close and positive margins. This survival benefit remained among those with cervical cancer. Median survival in this cohort was 34.1 (95% CI 2.0-69.8) months for close and 165.7 (95% CI 24.5-165.7) for distant margins. CONCLUSIONS: Distant margins following PE are associated with improved OS and PFS compared to close margins.
Subject(s)
Pelvic Exenteration , Uterine Cervical Neoplasms , Female , Humans , Margins of Excision , Neoplasm Recurrence, Local/surgery , Progression-Free Survival , Retrospective Studies , Uterine Cervical Neoplasms/surgeryABSTRACT
Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1low) tissue-resident T cells (TRMstem cells), but not recirculating TCF1+ T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on â¼13% of CD8+ tumor-infiltrating T cells (â¼3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.
Subject(s)
Immunologic Memory , Ovarian Neoplasms , CD8-Positive T-Lymphocytes , Female , Humans , Lymphocytes, Tumor-Infiltrating , Memory T CellsABSTRACT
OBJECTIVE: To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer. METHODS: A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA-IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses. RESULTS: Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival. CONCLUSION: More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size.