Objective The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial ...cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. Study Design Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. Results Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients ( P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients ( P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. Conclusion Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of this study was to analyze the oncological outcome of stage I malignant ovarian germ cell tumors patients included in the MITO-9 study to identify those who might be recommended routine ...surveillance alone after complete surgical staging.
MITO-9 was a prospective observational study analyzing data collected between January 2013 and December 2019. Three groups were identified: group A included 13 patients stage IA dysgerminoma and IAG1 immature teratoma; group B included 29 patients with stage IB-C dysgerminomas, IA-C G2-G3 immature teratomas and stage IA mixed malignant ovarian germ cell tumors and yolk sac tumors; and group C included five patients (two patients with stage IC1 and one patient with stage IC2 yolk sac tumors and two patients with mixed-stage IC2 malignant ovarian germ cell tumors).
A total of 47 patients with stage I conservatively treated malignant ovarian germ cell tumors were analyzed. Two patients in group B were excluded from the routine surveillance alone group due to positive surgical restaging. Therefore, a total of 45 patients were included in the study. Median follow-up was 46.2 months (range; 6-83). In total, 14 of 45 patients (31.1%) received chemotherapy, while 31 (68.9%%) underwent surveillance alone. One patient in group A, with stage IA dysgerminoma had a relapse, successfully managed with conservative surgery and chemotherapy. None of the patients in group B and C relapsed. All patients were alive at completion of the study. Overall, among 31 patients (68.9%) who underwent surveillance alone, only one patient relapsed but was treated successfully.
Our data showed that close surveillance alone could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C dysgerminomas, IA-IC G2-G3 immature teratomas, and IA mixed malignant ovarian germ cell tumors with yolk sac tumor component.
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Background: The standard of treatment of stage I MOGCTs is surgery followed by BEP (bleomycin + etoposide + cisplatin) chemotherapy, except for stage IA dysgerminoma (D) and IAG1 ...immature teratoma (IT). Surveillance has emerged as a possible option to avoid adjuvant chemotherapy in IB-C1 D, IA-C G2 – G3 IT, and in stage IA mixed and yolk sac tumors (YST), after comprehensive surgical staging (CSS) with negative postoperative markers. The aim of this study was to analyze oncological outcome of stage I MOGCT patients included in the MITO9 study. Methods: MITO9 was a prospective observational study analyzing data collected between 2013 and 2018. 41 patients with stage I conservatively treated MOGCTs were included. Three groups were identified: group A. IA D and IAG1 IT candidate to surveillance according to guidelines; group B. stages IB-C1 D, stage IA-C G2-G3 IT, stage IA mixed and YST were consulted about the option of close surveillance vs adjuvant chemotherapy in case of CSS; group C. all other patients receiving BEP. Results: Median age was 25.6 years (range 14-40). Median follow up was 36,4 months. Group A included 12 patients, 5 IA G1 IT and 7 IA D. Group B included 24 patients. Of these, 2 out of 5 patients (40%) were positive at restaging and were excluded from surveillance protocol. Seven of the 22 remaining patients (31.8%) received chemotherapy, while 15 (68.1%) were enrolled in the surveillance protocol. Out of these 15 patients, 4 were stage IC D (one IC1, one IC2 and two IC3), 2 were mixed stage IA with YST tumor, 9 were G3 IT (four IA, three IC2, one IC3 and one IB). The 7 patients receiving chemotherapy were: 1 dysgerminoma IC2, 2 YST IA, 3 IT G3 (one IA and one IC2) and 1 mixed IA tumour. Group C included 5 patients, three IC YST and two mixed IC2 with YST. Survival of these patients was 100%, while disease free survival was 97.5%. Only one patient in C Group, a stage IA G3 IT treated with adjuvant BEP, relapsed as mature teratoma. None of the patients in the surveillance protocol experienced relapse. Conclusions: These data suggest that close surveillance could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C1 D, stage IA G2 – G3 IT, stage IA mixed and YST. These findings deserve further confirmation in an international cooperative setting.
Mucinous ovarian carcinoma have a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of chemotherapy in patients with ...platinum sensitive recurrent mucinous ovarian cancer.
The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005. Patients with recurrent ovarian cancer with > 6 months of platinum free interval were considered eligible.
Twenty patients with mucinous histotype and 388 patients with other histotypes were analyzed. At baseline, mucinous tumours differed from the others for an higher number of patients with lower tumor grading (p = 0.0056) and less advanced FIGO stage (p = 0.025). At time of recurrence, a statistically significant difference was found in performance status (worse in mucinous, p = 0.024). About 20% of patients underwent secondary cytoreduction in both groups, but a lower number of patients were optimally debulked in the mucinous group (p = 0.03). Patients with mucinous cancer received more frequently single agent platinum than platinum based-combination therapy or other non-platinum schedules as second line therapy (p = 0.026), with a response rate lower than in non-mucinous group (36.4% vs 62.6%, respectively, p = 0.04). Median time to progression and overall survival were worse for mucinous ovarian cancer. Finally, mucinous cancer received a lower number of chemotherapy lines (p = 0.0023).
This analysis shows that platinum sensitive mucinous ovarian cancer has a poor response to chemotherapy. Studies dedicated to this histological subgroup are needed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
PI3K-AKT-mTOR inhibitors have been proposed as alternative therapeutic strategy for tumors resistant to conventional drugs. The mammalian target of rapamycin (mTOR) inhibitor everolimus has ...been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumors (PitNETs) cell growth and vitality in a subset of patients. Sensitivity to everolimus has been demonstrated to be reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. This limited efficacy of everolimus due to AKT re-activation could be overtaken by upstream AKT phosphorylation inhibition. Given it was recently demonstrated that DRD2 mediates a reduction of p-AKT in a subset of NF-PitNETs and in rat prolactin-secreting tumor cells MMQ through a β-arrestin 2-dependent mechanism, the aim of the present work was to test the efficacy of adjuvant treatment with cabergoline in increasing sensitivity of human primary cultured NF-PitNET cells to antiproliferative effects of everolimus. In addition, to test a possible role of β-arrestin2.
We found that 9 out of 14 NF-PitNETs were resistant to everolimus 1 nM, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs basal), increased p27 and reduced cyclin D3 expression. In everolimus unresponsive NF-PitNETs group, 3 h everolimus treatment determined a significant increase of p-AKT/total-AKT ratio (+2.1-fold, p < 0.01, vs basal), and this effect was reverted by cabergoline cotreatment in all tested samples.
To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed, 1nM everolimus did not affect MMQ cells proliferation due to an increase of p- AKT/total-AKT ratio (+1.53 ± 24%, p<0.001 vs basal), whereas cabergoline reduced cell proliferation (-22.8 ± 6.8%, p<0.001 vs basal) and AKT phosphorylation. The combined treatment of everolimus and cabergoline induced a significant reduction of both cell proliferation (-34.8 ± 18%, p<0.001 vs basal) and p-AKT/total-AKT ratio (-34.5 ± 14%, p<0.001 vs basal). To test a possible involvement of β-arrestin 2, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented everolimus and cabergoline co-treatment inhibitory effects on both p-AKT and cells proliferation.
In conclusion, these data revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs, by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitors antitumoural activity, paving the way for a potential combined therapy in β-arrestin 2 expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
Bilaterality is rare in malignant ovarian germ cell tumors (MOGTs). The bilateral ovarian involvement represents a critical issue when diagnosed in young women desiring to preserve fertility. The aim ...of this study was to evaluate clinical characteristic and management of patients bilateral MOGTs.
Patients affected by bilateral MOGT and treated at MITO group centers were reviewed.
In 145 patients with MOGTs, 5.5% were bilateral. Three patients were affected by dysgerminoma (associated with bilateral gonadoblastoma in 1), 2 by immature teratoma, 2 by mixed germ cell tumors, and 1 by embryonal carcinoma. International Federation of Gynecology and Obstetrics stage was 3 IB, 1 IC, 3 IIIC, and 1 IV. Three patients received radical surgery, and the patient with dysgerminoma associated with gonadoblastoma received bilateral adnexectomy. Four patients received fertility-sparing surgery; 2 patients received unilateral salpingo-oophorectomy and contralateral cystectomy; in 2 patients, the ovaries were completely transformed in neoplastic tissue; suspecting a contralateral dysgerminoma histology, a unilateral salpingo-oophorectomy and contralateral biopsy were performed, and the contralateral neoplastic ovary was left unresected. Six patients received adjuvant chemotherapy. Seven patients are disease free after a median follow-up of 54 months. The patient affected by embryonal carcinoma died of disease. Two patients resumed menstruation, and one had a pregnancy. A compromised ovarian function was found in 2 patients, and they were addressed to oocyte cryopreservation.
Bilateral MOGTs have a good prognosis. In dysgerminoma histology, residual disease could be left to spare fertility. An oncological and reproductive function follow-up is recommended.
Abstract Objective The objective of this prospective randomized phase III trial was to compare paclitaxel plus carboplatin (PC) versus topotecan plus carboplatin and paclitaxel (TPC) in women with ...suboptimal stage III (residual tumour >1 cm) or stage IV ovarian cancer to evaluate the survival rate and toxicities. Methods Eligible for the study were patients aged at least 18 years old with histological/cytological diagnosis of FIGO stages III (residual tumour ⩾1 cm after primary surgery) – IV epithelial ovarian cancer. Patients were randomized to iv PC on day 1, every 21 days or iv topotecan daily for three days and PC on day 3, every 21 days. Results The intention to treat population was made of 326 patients in total, 170 in the PC group and 156 in the TPC group. The life table estimates of survival probabilities at one, three and five years were, respectively, 0.94 (95% CI: 0.88–0.97), 0.53 (95% CI: 0.44–0.62) and 0.32 (95%CI: 0.23–0.42) in the PC group, and 0.92 (95% CI: 0.86–0.95), 0.52 (95% CI: 0.42–0.61), and 0.32(95%CI: 0.22–0.43) in the TPC group (log-rank test at 5 years: ns). The results of the survival analysis based on Cox regression model showed no statistically significant differences between groups ( p -value: ns). The number of subjects with at least one event with possible relationship to study medication was 151 (88.8%) in the PC group and 139 (89.1%) in the TPC group ( p = ns). In the PC group, 79 patients (23.6%) experienced at least one Adverse Event (AE) graded as severe and 16 patients (4.8%) at least one life-threatening AE, whilst in the TPC group, the number of patients who presented at least one severe or life-threatening AE was 86 (24%) and 37 (10.3%), respectively. Conclusion The results of the present study show that the addition of topotecan to a standard paclitaxel/carboplatin regimen in the treatment of advanced epithelial ovarian cancer did not result in significant advantages in terms of survival rate. A slightly worse toxicity profile for TPC was observed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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