Real-world data on niraparib maintenance treatment in patients with non-gBRCA mutated platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: The aim of this study was to provide real-world efficacy and safety data on niraparib maintenance treatment in patients with non-germline (gBRCA)1/2 mutated platinum-sensitive recurrent ovarian cancer. METHODS: This retrospective multi-center cohort study included 94 platinum-sensitive recurrent ovarian cancer patients without known gBRCA1/2 mutation treated in an individual patient access program in Norway. The primary outcome was time from start of niraparib treatment to first subsequent treatment. Secondary endpoints included progression-free survival, safety, and tolerability. RESULTS: After median follow-up of 13.4 months (95% confidence interval (CI) 10.0 to 16.8), 68.1% had progressed and 22.3% had died. Of the entire cohort, 61.7% had commenced a new line of treatment, and 24.5% were still receiving niraparib. The median duration of niraparib treatment was 5.0 months (range 0.4 to 27.3), and the median time to first subsequent treatment was 10.7 months (95% CI 8.4 to 13.0). Patients with elevated CA125 prior to start of niraparib had shorter time to first subsequent treatment (7.3 months, 95% CI 4.2 to 10.3) than patients with normalized CA125 (12.2 months, 95% CI 10.9 to 13.7 (p=0.002). Patients who started on individual dose based on weight and platelet counts had fewer dose reductions (p<0.001) and interruptions (p=0.02). CONCLUSION: In a real-world setting, niraparib maintenance treatment in patients with non-gBRCA1/2 mutated recurrent platinum-sensitive ovarian cancer showed effectiveness comparable with published phase III studies and acceptable safety. Individualized dosing is essential to minimize adverse events. CA125 levels at start of niraparib treatment may help to estimate the individual prognosis.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

Cancer Stem Cell Markers Are Differentially Expressed in Malignant Ovarian Germ Cell Tumors.

The objective of this study was to analyze the expression and potential clinical role of cancer stem cell (CSC) markers in malignant ovarian germ cell tumors (MOGCT). CD34, CD44, and SOX2 protein expression by immunohistochemistry was analyzed in 49 MOGCT from patients treated in Norway during the period 1980-2011. Expression was analyzed for association with tumor type and clinicopathologic parameters. Tumors were diagnosed as dysgerminoma (DG; n=15), immature teratoma (IT; n=15), yolk sac tumor (YST; n=12), embryonal carcinoma (n=2), and mixed MOGCT (n=5). Tumor cell CD34 expression was significantly more common in YST, whereas stromal expression was only seen in IT (both P <0.001). CD44 was infrequently expressed, most often focally, in tumor cells, particularly in YST ( P =0.026). CD44 was widely expressed in leukocytes, most prominently in DG. SOX2 was most frequently expressed in IT, with predominantly focal expression in some YST and uniform absence in DG ( P <0.001). Stromal CD34 ( P =0.012) and tumor cell SOX2 expression ( P =0.004) were negatively associated with the involvement of the ovarian surface, presumably due to the low incidence of this event in IT. No significant association was found between CSC marker expression and other clinicopathologic parameters, including age, laterality, tumor diameter, and FIGO stage. In conclusion, CSC markers are differentially expressed in various MOGCT types, suggesting differences in the regulation of cancer-related processes. Expression of CD34, CD44, and SOX2 does not appear to be associated with clinical parameters in this patient group.

Early experiences with PD-1 inhibitor treatment of platinum resistant epithelial ovarian cancer.

OBJECTIVE: In this study, we evaluated the toxicity and clinical efficacy of nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, on patients with platinum resistant ovarian cancer. METHODS: Every second week, 18 patients with platinum resistance ovarian cancer received nivolumab until disease progression occurred. We assessed toxicity, disease control rate, progression free survival (PFS) and overall survival (OS). Radiological response evaluation according to irRECIST was performed every 12th week, while clinical evaluation was done every second week. RESULTS: The disease control rate was 44% (95% confidence interval [CI]=19-87) as 8 showed stable disease, 6 showed progressive disease and 4 died before the first radiological response evaluation. The median OS was 30 weeks (95% CI=14-42; range, 3-95), and PFS was 15 weeks (95% CI=13-17). The median follow-up time was 30 weeks (range, 3-123). The rate of grade 2-5 adverse events was 28% (5 out of 18). Two patients (11%) developed grade 2 and 3 adverse events, respectively, while no grade 4 events were observed. One patient died from intestinal perforation, believed to be caused by concomitant bevacizumab rather than nivolumab. CONCLUSION: This study shows few adverse events, and promising clinical efficacy when using nivolumab for ovarian cancer.

Long-term neurotoxicity and Raynaud's phenomenon in patients treated with cisplatin-based chemotherapy for malignant ovarian germ cell tumor.

INTRODUCTION: The aim was to evaluate "overall neuropathy", defined as peripheral paresthesia and Raynaud's phenomenon, in long-term survivors of malignant ovarian germ cell tumors (MOGCTs) treated with cisplatin-based chemotherapy (CBCT). MATERIAL AND METHODS: Ninety-three MOGCT survivors recorded in Norway in 1980-2009 (median follow up: 15 years) were included in this analysis. Forty-nine received CBCT (CBCT group) and 44 received other or no chemotherapy (non-CBCT group). Applying the scale for chemotherapy-induced neurotoxicity, the prevalence of overall neuropathy (ie score >1 on a 0-3 scale) was compared between the two groups. Forty women from the CBCT group also underwent neurophysiological and neurological examinations; results from the neurological examination were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Effects version 4 (NCI-CTCAE scale v4). These women were then categorized into subgroups of low (≤3 cycles of CBCT, n = 23) and high CBCT (≥4 cycles of CBCT, n = 17). RESULTS: Twenty-eight (57%) women from the CBCT group reported overall neuropathy, compared with 20 (45%) in the non-CBCT group (P = .06). Of the 40 MOGCT survivors in the CBCT group who underwent neurophysiological and neurological examinations, 14 (35%) showed NCI-CTCAE grade ≥1 signs or symptoms of peripheral neuropathy. Pathological findings of NCI-CTCAE grade 2 or 3 signs or symptoms were found in four survivors (10%) from the high CBCT subgroup, all of whom also showed objective signs of neuropathy. CONCLUSIONS: Though about half of our MOGCT survivors reported overall neuropathy after CBCT, more severe pathological neurological/neurophysiological findings that impacted daily living were recorded in only 10% of them. Our observations of a similar prevalence of self-reported overall neuropathy in the CBCT and non-CBCT group, combined with limited objective neurological findings, warrant further study to increase the understanding of the specific pathophysiological pathways of long-term CBCT-induced neuropathy.

A national, prospective observational study of first recurrence after primary treatment for gynecological cancer in Norway.

INTRODUCTION: Gynecological cancer patients are routinely followed up for five years after primary treatment. However, the value of such follow up has been debated, as retrospective studies indicate that first recurrence is often symptomatic and occurs within two to three years of primary treatment. We prospectively investigated time to first recurrence, symptoms at recurrence, diagnostic procedures, and recurrence treatment in gynecological cancer patients after primary curative treatment. MATERIAL AND METHODS: Clinicians from 21 hospitals in Norway interviewed 680 patients with first recurrence of gynecological cancer (409 ovarian, 213 uterine, and 58 cervical cancer patients) between 2012 and 2016. A standardized questionnaire was used to collect information on self-reported and clinical variables. RESULTS: Within two years of primary treatment, 72% of ovarian, 64% of uterine, and 66% of cervical cancer patients were diagnosed with first recurrence, and 54, 67, and 72%, respectively, had symptomatic recurrence. Of symptomatic patients, 25-50% failed to make an appointment before their next scheduled follow-up visit. Computer tomography was the most common diagnostic procedure (89% of ovarian, 76% of uterine, and 62% of cervical cancer patients), and recurrence treatment in terms of chemotherapy was most frequently planned (86% of ovarian, 46% of uterine, and 62% of cervical cancer patients). CONCLUSIONS: A majority of patients experienced symptomatic recurrence, but many patients failed to make an appointment earlier than scheduled. Most first recurrences occurred within two years of primary treatment; the mean annual incidence rate for years 3-5 after primary treatment was <7%. New models for follow up of gynecological cancer patients could be considered.

Epithelial-mesenchymal transition markers in malignant ovarian germ cell tumors.

The purpose of this study was to determine the expression and potential clinical role of epithelial-to-mesenchymal transition (EMT)-related factors in malignant ovarian germ cell tumors (MOGCT). Protein expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, and vimentin by immunohistochemistry was analyzed in 42 MOGCT from patients treated in Norway during the period 1981-2001. Expression was analyzed for association with clinicopathologic parameters. E-cadherin (p = 0.016) and HMGA2 (p = 0.002) expression was significantly higher in immature teratomas and yolk sac tumors compared with dysgerminomas. Vimentin (p < 0.001) and Zeb1 (p = 0.029) staining was significantly higher in immature teratomas compared with yolk sac tumors and dysgerminomas, whereas no significant differences were observed for N-cadherin and P-cadherin. EMT-associated markers were not significantly related to clinicopathologic parameters including age, tumor diameter, and FIGO stage. In conclusion, based on this limited series, EMT-associated markers are not associated with clinical parameters in MOGCT, in contrast to ovarian carcinoma. EMT-related proteins are differentially expressed among various MOGCT subtypes, suggesting differences in biological characteristics associated with invasion and metastasis.

Long-term ototoxicity in women after cisplatin treatment for ovarian germ cell cancer.

OBJECTIVE: Evaluate long-term cisplatin-induced ototoxicity in women treated for malignant ovarian germ cell tumors (MOGCT). METHODS: Seventy-four women treated for MOGCT in Norway (1980-2009) were analyzed: 41 had received cisplatin-based chemotherapy (CBCT) ("Cases") and 33 had no CBCT ("Controls"). Median follow-up was 15years. Hearing was assessed by pure tone audiometry and by the SCIN questionnaire. Air conduction thresholds were reported as absolute hearing thresholds and age-adjusted thresholds. Absolute and age-adjusted hearing loss were defined as thresholds of >20dB at any frequency. Tinnitus was evaluated using the Tinnitus Handicap Inventory. Serum Platinum Concentration (SPC) was determined. RESULTS: Absolute hearing loss was identified in 21 Cases (51%) and 24 Controls (73%). After adjusting for age, only 9 Cases (22%) and 5 Controls (15%) remained. Age-adjusted hearing thresholds at 4, 6 and 8kHz were slightly but significantly higher in Cases compared to Controls. Subjective hearing loss was reported by 27% of Cases and 21% of Controls, who were significantly older. Elevated SPC values were detected up to 20years after CBCT, but SPC did not correlate significantly with age-adjusted hearing loss. The rate of tinnitus was similar in Cases and Controls. CONCLUSION: Long-term MOGCT survivors treated with CBCT have small but significant reductions in age-adjusted hearing thresholds at 4, 6 and 8kHz versus Controls. Approximately one in four women experienced subjective hearing loss. To avoid overestimation of clinically relevant cisplatin-induced ototoxicity, absolute hearing thresholds should be age-adjusted and compared to an age-matched control group.

The impact of cisplatinum-based chemotherapy on ventricular function and cardiovascular risk factors in female survivors after malignant germ cell cancer.

AIMS: Among male cancer survivors, cisplatinum-based chemotherapy (CBCT) is associated with impaired left ventricle (LV) diastolic function, increased risk of metabolic syndrome, and increased cardiovascular morbidity and mortality. Comparable data in females are limited. The long-term effects of cisplatin on right ventricle (RV) function are unknown in both genders. We aimed to investigate the impact of CBCT on cardiovascular risk factors and cardiac function in female survivors after malignant ovarian germ cell tumour (MOGCT). METHODS AND RESULTS: This national cross-sectional follow-up study recruited MOGCT survivors, diagnosed from 1980-09 (n = 153). Seventy-four (48%) participated in out-patient visit, of whom 41 had received CBCT (62% of all CBCT): median age, 35 years (range, 18-64 years); median time since CBCT, 14 years (range, 5-31 years). Participants were categorized into high-CBCT (n = 19) and low-CBCT (n = 22) groups and compared with age-matched healthy females. All participants underwent laboratory tests and echocardiography to determine cardiac function. Compared with low-CBCT participants, the high-CBCT group showed significantly impaired RV function, as evaluated by tricuspid annular plane systolic excursion (22.6 ± 2.4 mm vs. 26.3 ± 3.6 mm; P < 0.001); RV S' (10.7 ± 1.9 cm/s vs. 12.4 ± 2.3 cm/s; P = 0.01); RV global longitudinal strain (-23.4 ± 2.4% vs. -25.7 ± 3.7%; P = 0.02), and tricuspid annular displacement (21 ± 2 mm vs. 24 ± 3 mm; P = 0.001). LV diastolic function was impaired in the high-CBCT group compared with controls. Patients and controls exhibited similar metabolic syndrome prevalences. CONCLUSIONS: Among long-term survivors of MOGCT, CBCT was associated with impaired RV function and LV diastolic function. Unlike men, women do not appear to have an elevated risk of metabolic syndrome after CBCT.