ABSTRACT
OBJECTIVE: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer. METHODS: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed. RESULTS: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia. CONCLUSIONS: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Bevacizumab , Carboplatin , Carcinoma, Ovarian Epithelial , Folate Receptor 1 , Immunoconjugates , Maytansine , Ovarian Neoplasms , Humans , Female , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Adult , Maytansine/analogs & derivatives , Maytansine/adverse effects , Maytansine/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Carcinoma, Ovarian Epithelial/drug therapy , Progression-Free Survival , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Fallopian Tube Neoplasms/drug therapy , Aged, 80 and over , Peritoneal Neoplasms/drug therapy , Thrombocytopenia/chemically inducedABSTRACT
Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.
Subject(s)
Vulvar Neoplasms , Female , Humans , Adenocarcinoma/pathology , Genital Neoplasms, Female , Paget Disease, Extramammary/diagnosis , Paget Disease, Extramammary/etiology , Paget Disease, Extramammary/therapy , Skin Neoplasms , Vulvar Neoplasms/diagnosis , Vulvar Neoplasms/epidemiology , Vulvar Neoplasms/etiologyABSTRACT
OBJECTIVE: Advanced clear cell gynecologic malignancies remain among the most challenging diseases to manage. We evaluated ovarian and endometrial clear cell carcinoma (OCCC and ECCC) specimens using comprehensive sequencing technology to identify mutational targets and compared their molecular profiles to histologically similar clear cell renal cell carcinoma (ccRCC). METHODS: Using next-generation sequencing (NGS), fragment analysis (FA), and in situ hybridization (ISH), 164 OCCC, 75 ECCC and 234 ccRCC specimens from 2015 to 2018 were evaluated and compared. RESULTS: The highest mutation rates in ECCC and OCCC were noted in: ARID1A (75.0%, 87.5%), TP53 (34.8%, 11.1%), PIK3CA (25.0%, 46.8%), PPP2R1A (8.7%, 16.7%), MSI-high (8.8%, 6.4%) and PTEN (8.3%, 7.1%). Among these mutations, there was no significant difference between OCCC and ECCC mutation prevalence except in TP53, with higher mutation rates in ECCC versus OCCC (34.8 vs. 11.1%, respectively, p < 0.05). ccRCC demonstrated different mutation profiles with higher mutation rates in VHL (80.3%), PBRM1 (43.9%), SETD2 (31.1%), and KDM5C (29.2%). By contrast, VHL, PBRM1, and SETD2 mutations were not found in ECCC and OCCC (0.0%). Compared to ccRCC and ECCC, OCCC was found to have a significantly higher tumor mutation burden (TMB) (19.1%). CONCLUSION: Gynecologic and renal CCC demonstrate separate and disparate somatic profiles. However, OCCC and ECCC are diseases with similar profiles. TMB and MSI analyses indicate that a subset of OCCC may benefit from immunotherapy. Prospective clinical trials are needed and are underway to examine targeted therapies in these gynecologic disease subtypes.
Subject(s)
Adenocarcinoma, Clear Cell , Carcinoma, Renal Cell , Endometrial Neoplasms , Kidney Neoplasms , Ovarian Neoplasms , Humans , Female , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Prospective Studies , Endometrial Neoplasms/genetics , Mutation , Kidney Neoplasms/genetics , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathologyABSTRACT
PURPOSE: Evaluate the antitumor activity and safety profile of the combination of mirvetuximab soravtansine and bevacizumab in patients with platinum-resistant ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, whose most recent platinum-free interval was ≤6 months, were administered mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) and bevacizumab (15 mg/kg), intravenously, once every 3 weeks. Eligibility included FRα expression by immunohistochemistry (IHC; ≥25% of cells with ≥2+ intensity). Prior bevacizumab and/or PARP inhibitor (PARPi) treatment were permitted. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: Ninety-four patients received combination treatment with mirvetuximab soravtansine and bevacizumab. Median age was 62 years (range, 39-81). Fifty-two percent had ≥3 prior therapies; 59% had prior bevacizumab; and 27% had prior PARPi. ORR was 44% (95% CI 33, 54) with 5 complete responses, median DOR 9.7 months (95% CI 6.9, 14.1), and median PFS 8.2 months (95% CI 6.8, 10.0). Treatment-related adverse events were consistent with the profiles of each agent, with the most common being blurred vision (all grades 57%; grade 3, 1%), diarrhea (54%; grade 3, 1%), and nausea (51%; grade 3, 1%). CONCLUSION: The mirvetuximab soravtansine plus bevacizumab doublet is an active and well-tolerated regimen in patients with FRα-expressing platinum-resistant ovarian cancer. Promising activity was observed for patients regardless of level of FRα expression or prior bevacizumab. These data underscore the potential for mirvetuximab soravtansine as the combination partner of choice for bevacizumab in this setting.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Ovarian Neoplasms , Humans , Female , Middle Aged , Bevacizumab/therapeutic use , Ovarian Neoplasms/pathology , Folate Receptor 1 , Drug Resistance, Neoplasm , Carcinoma, Ovarian Epithelial/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapyABSTRACT
The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.
Subject(s)
Uterine Cervical Neoplasms , Female , Humans , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/therapy , Uterine Cervical Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
BACKGROUND: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. METHODS: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual. FINDINGS: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group). INTERPRETATION: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. FUNDING: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/analogs & derivatives , Enzyme Inhibitors/therapeutic use , Ovarian Neoplasms/drug therapy , Pyrazoles/therapeutic use , Pyrimidinones/therapeutic use , Canada , Deoxycytidine/therapeutic use , Double-Blind Method , Female , Humans , Middle Aged , Ovarian Neoplasms/pathology , Survival , United States , GemcitabineABSTRACT
OBJECTIVES: Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort. METHODS: Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens. RESULTS: Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent. CONCLUSION: BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents.
Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/therapy , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Neoplasm Grading , Mutation , Cystadenocarcinoma, Serous/diagnosis , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/therapy , Hormones , GenomicsABSTRACT
Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.
Subject(s)
Endometrial Neoplasms/enzymology , Mass Spectrometry , Molecular Targeted Therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proteomics , Apoptosis/drug effects , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/genetics , Endometrial Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Humans , Neoplasms, Cystic, Mucinous, and Serous/pathology , Prognosis , Protein Serine-Threonine Kinases/metabolism , Proteogenomics , RNA Splicing/genetics , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Survival Analysis , Uterine Neoplasms/pathologyABSTRACT
PURPOSE: To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer. METHODS: Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined. RESULTS: Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months). CONCLUSION: The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/administration & dosage , Bevacizumab/adverse effects , Carcinoma, Ovarian Epithelial/immunology , Drug Resistance, Neoplasm , Female , Folate Receptor 1/immunology , Humans , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Maytansine/administration & dosage , Maytansine/adverse effects , Maytansine/analogs & derivatives , Middle Aged , Organoplatinum Compounds/pharmacology , Ovarian Neoplasms/immunology , Progression-Free SurvivalABSTRACT
OBJECTIVE: The aim of this study was to identify the rate of 30-day postoperative complications after the use of epidural in women undergoing hysterectomy for gynecologic malignancy. Secondary outcome was the impact of epidural on hospital length of stay. METHODS: A retrospective cohort study was conducted using the American College of Surgeons' National Surgical Quality Improvement Program database. This large dataset includes perioperative risk factors and 30-day post-operative outcomes from more than 680 hospitals. Women who underwent abdominal hysterectomy for a gynecologic malignancy from January 2014 to December 2017 were included. Adult patients (18 years or older) who underwent abdominal hysterectomy were identified using common procedure terminology and international classification of diseases codes. Only laparotomy cases were included, and minimally invasive cases (laparoscopy, transvaginal) were excluded due to the small prevalence of epidural cases in this cohort. All patients received general anesthesia. If patients were noted to have "epidural anesthesia" they were included in the epidural cohort and those receiving other adjuvant techniques (regional blocks or spinal anesthesia) were excluded. The primary outcome of interest was the 30-day occurrence of a pulmonary embolism, deep-vein thrombosis, pneumonia, and urinary tract infection. Those who received epidural analgesia were matched in a 1:1 ratio with a similar group of patients who did not receive epidural analgesia using a calculated propensity score to control for confounding factors. RESULTS: A total of 2035 (13.8%) patients undergoing abdominal hysterectomy for a gynecologic malignancy received epidural analgesia. 1:1 propensity-matched samples included 2035 patients in both epidural and no-epidural groups. Patient characteristics between groups were similar. Overall 30-day complication rates were higher in the epidural group (75.9% vs 62.0%, P<0.01). Specific complications that were higher in the epidural group included: blood transfusion (28.9% vs 22.8%); wound disruption (2.0% vs 1.1%); surgical site infection (10.1% vs 7.2%); and delay in return of bowel function (12.3% vs 9.3%) (all P<0.05). Hospital length of stay was significantly longer in the epidural group as compared with the no-epidural group (5.69 days vs 4.79 days, P<0.01) and readmissions were higher in the epidural group (10.5% vs 9.7%, P<0.01), but there was no difference in 30-day mortality between the groups (P=0.62). DISCUSSION: The rate of 30-day complications and length of stay among women undergoing an abdominal hysterectomy for gynecologic malignancy was higher for those who received epidural analgesia, but there was no difference in 30-day mortality. Although epidural analgesia can provide a number of benefits when used for postoperative pain control, the possible association with increased 30-day morbidity and length of stay needs to be considered.
Subject(s)
Analgesia, Epidural/statistics & numerical data , Genital Neoplasms, Female/surgery , Hysterectomy/statistics & numerical data , Postoperative Complications/epidemiology , Aged , Anesthesia, General , Blood Transfusion/statistics & numerical data , Databases, Factual , Female , Humans , Hysterectomy/adverse effects , Length of Stay/statistics & numerical data , Middle Aged , Patient Readmission/statistics & numerical data , Pneumonia/epidemiology , Postoperative Complications/etiology , Propensity Score , Pulmonary Embolism/epidemiology , Retrospective Studies , Surgical Wound Dehiscence/epidemiology , Surgical Wound Infection/epidemiology , United States/epidemiology , Urinary Tract Infections/epidemiology , Venous Thrombosis/epidemiologyABSTRACT
OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3â¯+â¯3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUCâ¯=â¯5â¯mg/ml·min) and P (175â¯mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPAâ¯ââ¯C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1)â¯ââ¯C/P(D3) (2 & 4â¯mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6â¯mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3â¯months (95% CI 8.5-14.2) and OS 33â¯months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Immunoglobulin Fc Fragments/administration & dosage , Ovarian Neoplasms/drug therapy , Receptors, G-Protein-Coupled/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Aged , Antineoplastic Agents, Phytogenic , Bone and Bones/drug effects , Carboplatin/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Immunoglobulin Fc Fragments/adverse effects , Immunoglobulin Fc Fragments/pharmacology , Maximum Tolerated Dose , Middle Aged , Paclitaxel/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacology , Wnt Signaling Pathway/drug effectsABSTRACT
BACKGROUND: Most women with advanced epithelial ovarian cancer develop recurrent disease, despite maximal surgical cytoreduction and adjuvant platinum-based chemotherapy. In observational studies, secondary cytoreductive surgery has been associated with improved survival; however its use is controversial, because there are concerns that the improved outcomes may reflect selection bias rather than the superiority of secondary surgery. OBJECTIVE: To compare the overall survival of women with platinum-sensitive recurrent ovarian cancer treated at National Cancer Institute-designated cancer centers who receive secondary surgery vs chemotherapy. STUDY DESIGN: This retrospective cohort study included women from 6 National Cancer Institute-designated cancer centers diagnosed with platinum-sensitive recurrent ovarian cancer between January 1, 2004, and December 31, 2011. The primary outcome was overall survival. Propensity score matching was used to compare similar women who received secondary surgery vs chemotherapy. Additional analyses examined how these findings may be influenced by the prevalence of unobserved confounders at the time of recurrence. RESULTS: Among 626 women, 146 (23%) received secondary surgery and 480 (77%) received chemotherapy. In adjusted analyses, patients who received secondary surgery were younger (P = 0.001), had earlier-stage disease at diagnosis (P = 0.002), and had longer disease-free intervals (P < 0.001) compared with those receiving chemotherapy. In the propensity score-matched groups (n = 244 patients), the median overall survival was 54 months in patients who received secondary surgery and 33 months in those treated with chemotherapy (P < 0.001). Among patients who received secondary surgery, 102 (70%) achieved optimal secondary cytoreduction. There were no significant differences in complication rates between the 2 groups. In sensitivity analyses, the survival advantage associated with secondary surgery could be explained by the presence of more multifocal recurrences (if 4.3 times more common), ascites (if 2.7 times more common), or carcinomatosis (if 2.1 times more common) among patients who received chemotherapy instead of secondary surgery. CONCLUSION: Patients with platinum-sensitive recurrent ovarian cancer who received secondary surgery had favorable surgical characteristics and were likely to have minimal residual disease following secondary surgery. These patients had a superior median overall survival compared with patients who received chemotherapy, although unmeasured confounders may explain this observed difference.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial/therapy , Cytoreduction Surgical Procedures/methods , Neoplasm Recurrence, Local/therapy , Ovarian Neoplasms/therapy , Platinum Compounds/therapeutic use , Reoperation/methods , Adolescent , Adult , Aged , Carcinoma, Ovarian Epithelial/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/pathology , Propensity Score , Retrospective Studies , Survival Rate , Young AdultABSTRACT
BACKGROUND: Patients with ovarian cancer experience a high rate of anemia throughout their treatment course, with rates that range from 19-95%. Blood transfusions offer symptom relief but may be costly, are limited in supply, and have been associated with worse 30-day surgical morbidity and mortality rates. OBJECTIVE: The purpose of this study was to identify risk factors for blood transfusion with packed red blood cell and to develop a transfusion risk score to identify patients who undergo surgery for ovarian cancer and who are at lowest risk for a blood transfusion. Our aim was to help clinicians identify those patients who may not require a crossmatch to encourage resource use and cost-savings. STUDY DESIGN: This is a retrospective database cohort study of 3470 patients who underwent hysterectomy for ovarian cancer with the use the National Surgical Quality Improvement Program database from 2014-2016. The association between risk factors with respect to 30-day postoperative blood transfusion was modeled with the use of logistic regression. A risk score to predict blood transfusion was created. RESULTS: Eight hundred ninety-one (25.7%) patients received a blood transfusion. In multivariate analysis, blood transfusion was associated independently with age (odds ratio, 1.90, P<.01), African American race (odds ratio, 2.30; P<.01), ascites (odds ratio, 1.89; P=.02), preoperative hematocrit level <30% (odds ratio, 10.70; P<.01), preoperative platelet count >400×109/L (odds ratio, 1.75; P<.01), occurrence of disseminated cancer (odds ratio, 1.71; P<.01), open surgical approach (odds ratio, 7.88; P<.01), operative time >3 hours (odds ratio, 2.19; P<.01), and additional surgical procedures that included large bowel resection (odds ratio, 4.23; P<.01), bladder/ureter resection (odds ratio, 1.69; P=.02), and pelvic exenteration (P=.02). A preoperative risk score that used age, race, ascites, preoperative hematocrit level, platelets, presence of disseminated cancer, planned hysterectomy approach, and procedures accurately predicted blood transfusion with good discriminatory ability (C-statistic=0.80 [P<.001]; C-statistic=0.69 [P<.001] for derivation and validation datasets, respectively) and calibration (Hosmer-Lemeshow goodness-of-fit, P=.081; P=.56 for derivation and validation datasets, respectively). CONCLUSION: Patients who undergo hysterectomy for ovarian cancer experience a high incidence of blood transfusions in the perioperative period. Preoperative risk factors and planned surgical procedures can be used in our transfusion risk score to help predict anticipated blood requirements.
Subject(s)
Erythrocyte Transfusion , Hysterectomy/adverse effects , Ovarian Neoplasms/surgery , Postoperative Hemorrhage/epidemiology , Age Factors , Aged , Cohort Studies , Databases, Factual , Ethnicity , Female , Humans , Middle Aged , Postoperative Hemorrhage/diagnosis , Postoperative Hemorrhage/ethnology , Postoperative Hemorrhage/prevention & control , Predictive Value of Tests , Preoperative Period , Retrospective Studies , Risk Factors , United States/epidemiologyABSTRACT
OBJECTIVES: Lymph node involvement has a significant impact on prognosis that may direct adjuvant therapy. The role of routine lymph node staging (LNS) is controversial given conflicting results in multiple studies. Our aims are to describe treatment patterns of LNS, identify factors impacting LNS, and quantify the contemporary trends. METHODS/MATERIALS: The National Cancer Data Base was queried for patients undergoing hysterectomy for endometrioid and serous uterine carcinomas from 2003 to 2012. For endometrioid tumors, LNS was considered indicated if at least 1 of 4 criteria was met. Multivariate logistic regression and Cox proportional hazards model were used. RESULTS: A total of 161,683 patients were identified who received hysterectomy for 155,893 (96.4%) endometrioid and 5790 (3.6%) serous carcinomas. Receipt of LNS was significantly associated with greater than 50% myometrial invasion (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.55-1.73), grades 3 to 4 (OR, 3.03; 95% CI, 2.83-3.25), and tumor size greater than 2 cm (OR, 1.17; 95% CI, 1.28-1.26). Of the 97,152 patients with endometrioid carcinoma who met criteria for comprehensive staging, 73,268 (75.4%) underwent LNS. Patients with endometrioid carcinoma meeting criteria for LNS were less likely to receive LNS if they were of African American race (OR, 0.92; 95% CI, 0.86-0.98), had Medicaid insurance status (OR, 0.75; 95% CI, 0.69-0.81), had Medicare insurance (OR, 0.82; 95% CI, 0.79-0.86), or received care at a community program (OR, 0.39; 95% CI, 0.33-0.46). CONCLUSIONS: Nationally, most patients with greater than 50% myometrial invasion, grades 3 to 4, and/or tumor size greater than 2 cm receive LNS, but this was significantly impacted by insurance status, demographic characteristics, and facility location/type.
Subject(s)
Endometrial Neoplasms/surgery , Lymph Node Excision/statistics & numerical data , Lymph Nodes/pathology , Lymph Nodes/surgery , Aged , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/epidemiology , Carcinoma, Endometrioid/radiotherapy , Carcinoma, Endometrioid/surgery , Chemoradiotherapy, Adjuvant , Chemotherapy, Adjuvant , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/epidemiology , Cystadenocarcinoma, Serous/radiotherapy , Cystadenocarcinoma, Serous/surgery , Databases, Factual , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/radiotherapy , Female , Humans , Lymph Node Excision/trends , Middle Aged , Neoplasm Staging , Prognosis , Radiotherapy, Adjuvant , United States/epidemiologyABSTRACT
OBJECTIVES: The purpose of this study was to examine the impact of adjuvant radiation on overall survival (OS) and cancer specific survival (CSS) in patients with lymph node (LN) positive endometrial cancer. METHODS: We analyzed all women diagnosed with FIGO stage IIIC endometrial adenocarcinoma in the Surveillance, Epidemiology, and End Results database from 2004 to 2012 (n=2177). Patients not undergoing surgery or with missing treatment information were excluded. Chi-squared tests were used to compare predictors of treatment received. Cox proportional hazards model and Kaplan-Meier method were used to assess OS and CSS. RESULTS: The median age was 60 (27-84) and the median follow-up was 31months (2-107). Adjuvant radiation was administered to 1248 (60.3%) patients. A total of 1363 (65.9%) patients had pelvic LN involvement while 658 (31.8%) had para-aortic involvement. The 3-year actuarial OS for patients with and without radiation was 80.5% and 67.6%, respectively (p<0.001). The 3-year actuarial CSS for patients with and without radiation was 83.4% and 73%, respectively (p<0.001). On multivariable analysis, receipt of radiotherapy remained associated with OS (HR 0.61 95% CI 0.51-0.74) and CSS (HR 0.65, 95% CI 0.53-0.80). After propensity matching, radiotherapy continued to be associated with an improved OS (HR 0.65 95% CI 0.54-0.78) and CSS (HR 0.65 95% CI 0.53-0.81). The addition of brachytherapy was not associated with OS or CSS. CONCLUSIONS: In this large population registry analysis, adjuvant radiation was associated with improved OS and CSS in patients with LN positive endometrial cancer. Prospective data is needed to confirm these findings.
Subject(s)
Adenocarcinoma/mortality , Adenocarcinoma/radiotherapy , Endometrial Neoplasms/mortality , Endometrial Neoplasms/radiotherapy , Lymph Nodes/pathology , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Cohort Studies , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Female , Humans , Logistic Models , Lymphatic Metastasis , Middle Aged , Neoplasm Staging , Radiotherapy, Adjuvant , SEER Program , United States/epidemiologyABSTRACT
INTRODUCTION: Our study sought to characterize the presentation, local management and outcomes of invasive cervical cancer with regard to patient insurance status. METHODS: We queried the NCI-SEER database for invasive cervical cancer cases in patients aged 18-64 from 2007 to 2011. We analyzed clinical and socioeconomic data with regard insurance status (insured, Medicaid, or uninsured). We tested for associations between patient insurance status and treatment with definitive surgery for FIGO IA2-IB1 patients, and treatment with suboptimal radiation therapy (RT) for FIGO IB2-IVA patients (other than combination external beam and brachytherapy). We evaluated overall and cause specific survival according to insurance status. RESULTS: 11,714 cases were analyzed: 60% insured, 31% Medicaid, and 9% uninsured. FIGO III/IV stage at presentation was more frequent with Medicaid (40%) and uninsured (42%) compared to insured patients (28%) (p<0.001). For FIGO IA2-IB1 patients, receipt of definitive surgery was inversely associated with uninsured status (OR [95%CI]=0.65 [0.47-0.90], p<0.001) in univariable analysis; however the relationship lost significance after multivariable adjustment. For FIGO IB2-IVA patients, the use of suboptimal RT was associated with uninsured status (OR [95%CI]=1.33 [1.07-1.65], p=0.011) in adjusted analyses. Among all patients, overall mortality was increased with Medicaid (HR [95%CI]=1.16 [1.05-1.28], p=0.003) and uninsured status (HR [95%CI]=1.17 [1.01-1.34], p=0.031) in multivariable analysis. Cancer specific mortality survival trended towards significance in multivariable analyses for both Medicaid (HR [95%CI]=1.11 [1.00-1.24] and uninsured status (HR [95%CI]=1.14 [0.98-1.33]). CONCLUSIONS: Disparities in cervical cancer treatment with regard to insurance status are apparent in a recent cohort of American patients. Later stage at presentation and differences in management partially account for the inferior prognostic outcomes associated with Medicaid and uninsured status.
Subject(s)
Healthcare Disparities/statistics & numerical data , Insurance, Health/statistics & numerical data , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/therapy , Adolescent , Adult , Female , Humans , Medicaid/statistics & numerical data , Middle Aged , Neoplasm Staging , SEER Program , Treatment Outcome , United States/epidemiology , Uterine Cervical Neoplasms/economics , Uterine Cervical Neoplasms/pathology , Young AdultABSTRACT
OBJECTIVE: Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. METHODS: The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. RESULTS: The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice. CONCLUSION: Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Doxorubicin/analogs & derivatives , Genes, BRCA1 , Immunomodulation/drug effects , Lymphocytes, Tumor-Infiltrating/drug effects , Ovarian Neoplasms/genetics , T-Lymphocytes/drug effects , Animals , Antibiotics, Antineoplastic/immunology , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Doxorubicin/immunology , Doxorubicin/pharmacology , Female , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Mice , Ovarian Neoplasms/immunology , Polyethylene Glycols/pharmacology , T-Lymphocytes/immunology , Xenograft Model Antitumor AssaysABSTRACT
Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy.
Subject(s)
Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/secondary , Ovarian Neoplasms/secondary , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic/surgery , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/surgery , Combined Modality Therapy , Female , Humans , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Ovary/pathology , Ovary/surgery , Treatment OutcomeABSTRACT
Objective: Type 1 endometrial cancer (EC) survivors who are overweight or obese are at increased risk of comorbidities and reduced quality of life. Lifestyle modification interventions (e.g., healthy eating, exercise) may help these women reduce excess weight and improve their quality of life. However, existing interventions have shown limited success. Guided by Self-Determination Theory, the proposed study sought to identify factors associated with perceived importance of weight loss and exercise as well as interest in lifestyle modification interventions (components of extrinsic and intrinsic motivation) among EC survivors with overweight or obesity to inform future intervention development. Methods: One hundred type 1 EC survivors [body mass index (BMI) ≥ 25 kg/m2] completed a cross-sectional survey assessing sociodemographics, medical factors, exercise, risk perceptions and provider communication, quality of life, barriers to dieting and exercise, perceived importance of healthy lifestyles, and desired intervention content. Results: EC survivors who were aware obesity is a risk factor for EC were significantly more likely to perceive weight loss as important and were interested in weight loss programs and receiving information about exercise (ps < 0.05). Additionally, EC survivors who reported their provider discussed the importance of a healthy weight after their diagnosis were significantly more likely to perceive exercise as important and were interested in receiving dieting information. Conclusions: EC survivors expressed interest in lifestyle modification interventions. Increasing awareness about the risk of obesity and provider discussions about healthy weight during routine appointments may motivate EC survivors to engage in lifestyle modification interventions.
ABSTRACT
Non-Gestational Ovarian Choriocarcinoma (NGOC) is an extremely rare ovarian tumor, with an incidence of less than 0.6% of malignant ovarian germ cell tumors. Its close pathologic resemblance to Gestational Ovarian Choriocarcinoma (GOC), however, requires special attention as the treatments differ greatly. NGOC typically affects patients in late adolescence or early reproductive years. As a result, NGOCs are often misdiagnosed as ectopic pregnancies due to their common presentation of bleeding, abdominal pain, adnexal mass, and positive serum beta-HCG. On pathologic examination, the tumor is indistinguishable from GOC, and only after review of tissue for paternal genetic components can the diagnosis of NGOC be made. Imaging studies often show highly vascular lesions with further investigation with computer topography (CT) sometimes showing metastatic lesions in the lungs, pelvis, vagina, and liver. These lesions are often hemorrhagic and can lead to catastrophic bleeding. Treatment is vastly different from GOC; NGOC requires treatment with both surgical resection and chemotherapy, with Bleomycin, Etoposide, and Cisplatin (BEP) being the most used regimen. With correct diagnosis and treatment, patients can often receive fertility sparing treatment with long term survival.