Dose-dense neoadjuvant chemotherapy before radical surgery in cervical cancer: a retrospective cohort study and systematic literature review.

OBJECTIVE: To evaluate the role of dose-dense neoadjuvant chemotherapy followed by radical hysterectomy in reducing adjuvant radiotherapy in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB1-IB2/IIA1 cervical cancer with disrupted stromal ring and as an alternative to concurrent chemoradiotherapy in FIGO 2018 stages IB3/IIA2. METHODS: This was a retrospective cohort study including patients with FIGO 2018 stage IB1-IIA2 cervical cancer undergoing dose-dense neoadjuvant chemotherapy at the European Institute of Oncology in Milan, Italy between July 2014 and December 2022. Weekly carboplatin (AUC2 or AUC2.7) plus paclitaxel (80 or 60 mg/m2, respectively) was administered for six to nine cycles. Radiological response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria. The optimal pathological response was defined as residual tumor ≤3 mm. Kaplan-Meier curves were used to estimate survival rates. A systematic literature review on dose-dense neoadjuvant chemotherapy before surgery for cervical cancer was also performed. RESULTS: A total of 63 patients with a median age of 42.8 years (IQR 35.3-47.9) were included: 39.7% stage IB-IB2/IIA1 and 60.3% stage IB3/IIA2. The radiological response was as follows: 81% objective response rate (17.5% complete and 63.5% partial), 17.5% stable disease, and 1.6% progressive disease. The operability rate was 92.1%. The optimal pathological response rate was 27.6%. Adjuvant radiotherapy was administered in 25.8% of cases. The median follow-up for patients who underwent radical hysterectomy was 49.7 months (IQR 16.8-67.7). The 5-year progression-free survival and overall survival were 79% (95% CI 0.63 to 0.88) and 92% (95% CI 0.80 to 0.97), respectively. Fifteen studies including 697 patients met the eligibility criteria for the systematic review. The objective response rate, operability rate, and adjuvant radiotherapy rate across studies ranged between 52.6% and 100%, 64% and 100%, and 4% and 70.6%, respectively. CONCLUSIONS: Dose-dense neoadjuvant chemotherapy before radical surgery could be a valid strategy to avoid radiotherapy in stage IB1-IIA2 cervical cancer, especially in young patients desiring to preserve overall quality of life. Prospective research is warranted to provide robust, high-quality evidence.

Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer: lessons learned and future directions.

Poly (ADP-ribose) polymerase inhibitors (PARPi) represent a new standard of care in the upfront treatment of advanced epithelial ovarian cancer to the point that the vast majority of patients now receive a PARPi, alone or in combination with the anti-angiogenic bevacizumab, as part of their first-line maintenance therapy. The clinical benefit of PARPi is well established; however, much has changed since their introduction and several relevant questions have been raised and remain unresolved in the post-PARPi era. The decision-making process regarding the most appropriate first-line maintenance therapy could be challenging in clinical practice, especially in the homologous recombination-proficient setting, and several other factors need to be considered apart from the mutational status. Concerns regarding post-PARPi progression treatment have emerged, highlighting an unmet need to define a valid algorithm strategy. PARPi may not only compromise the response to further platinum due to cross-resistance mechanisms but the impact on subsequent non-platinum chemotherapy and surgery also remains unclear. Definitive results on the role of PARPi rechallenge are awaited, especially in the case of oligoprogression managed with locoregional treatment. Moreover, the updated overall survival data from the recurrent setting warrant caution in using PARPi as single agents for unselected patients. Several PARPi combination regimens are emerging for overcoming PARPi resistance and may become our new therapeutic armamentarium. This review discusses a set of clinically relevant issues in the PARPi era and provides a glimpse of future challenges and opportunities in ovarian cancer treatment.

Myeloid neoplasms post PARP inhibitors for ovarian cancer.

The incidence of myeloid neoplasms following treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with ovarian cancer has been gradually increasing over the last few years. The cumulative exposure to PARPi and the improved overall survival of patients with ovarian cancer may represent key underlying explanations behind such trend. Fortunately, the earlier introduction of PARPi in the frontline setting reduces the risk of developing secondary myeloid neoplasms. The etiopathogenesis is still unclear but is likely to be multifactorial. The first 2 years of PARPi exposure seem to be the critical window for the onset of myeloid neoplasms post PARPi, with persistent cytopenia recognized as an early warning sign. Despite intensive treatment strategies, the outcome remains poor. There is an unmet clinical need to learn how to minimize risk, make an early diagnosis, and manage myeloid neoplasms post PARPi. First, decision making regarding the optimal maintenance treatment should avoid a 'PARPi-for-all' strategy. PARPi should be used cautiously in cases of high baseline risk for myeloid neoplasms and/or patients who are less likely to have a benefit. Active surveillance, accurate differential diagnosis, and prompt hematological referral are key management pillars. This review discusses what is known on this emerging issue as well as unresolved questions.

A Ten-Year Real-Life Experience with Pazopanib in Uterine Leyomiosarcoma in Two High-Specialized Centers in Italy: Effectiveness and Safety.

BACKGROUND: Uterine leiomyosarcoma (uLMS) is characterized by aggressive behavior associated with a high risk of relapse and mortality. Several therapeutic agents have been employed in the treatment of metastatic disease, with a poor objective response rate. Pazopanib, approved in 2012, is a multi-targeted, orally active small molecule that exerts its effects by inhibiting several tyrosine kinases. To date, poor research on real-life data has been conducted. We aimed to assess the effectiveness and safety of the drug in everyday clinical practice. METHODS: We present results of multicenter retrospective data on 38 patients with heavily pretreated metastatic uLMS who underwent oral pazopanib during their therapeutic journey. RESULTS: At a median follow-up of 8.6 months, the disease control rate was 55.2%, with 17% partial responses and 15 patients (39.5%) with stable disease. At a median follow-up of 8.6 months, median progression-free survival was 4 months, and median overall survival was 19.8 months. The most common grade 3 adverse events (AEs) drug-related were hepatic toxicities, diarrhea, hypertension, nausea, and vomiting (all of them with an incidence of 5% considering the whole study cohort). No grade 4 AEs occurred. CONCLUSIONS: Pazopanib in everyday clinical practice is safe and shows a good disease control rate with prolonged survival.

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer.

BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

INTRODUCTION: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER: NCT01706120.

Neoadjuvant chemotherapy in cervical cancer: an update.

The role of neoadjuvant chemotherapy (NACT) has been investigated in order to improve prognosis of patients with locally advanced cervical cancer. According to a meta-analysis, NACT followed by radiotherapy may be detrimental with a low dose of cisplatin and longer cycle intervals. Some meta-analyses showed NACT followed by surgery resulted in a reduction in the risk of death by 35% with a gain of 14% in the 5-year survival compared with radiotherapy. In a Cochrane meta-analysis, overall survival and progression-free survival were significantly improved with NACT followed by surgery versus surgery alone (23% reduction in the risk of death). The platinum/paclitaxel combination is now the preferred regimen in the neoadjuvant setting and preliminary data indicate that dose-dense regimens are feasible and effective (overall response rate: 67.8-87%). A weekly regimen with carboplatin/paclitaxel before chemoradiation showed promising results and the INTERLACE ongoing trial will help to confirm whether additional short-course chemotherapy given weekly before chemoradiation will lead to an improvement in overall survival.

Pre-chemotherapy hemoglobin levels and survival in patients with advanced epithelial ovarian cancer who received a first-line taxane/platinum-based regimen: results of a multicenter retrospective Italian study.

OBJECTIVE: The aim of this retrospective multicenter study was to assess whether the pre-chemotherapy hemoglobin levels have any impact on the clinical outcome of patients with advanced epithelial ovarian cancer who received a first-line taxane/platinum-based regimen. METHODS: The study was conducted on 315 patients who underwent initial surgery followed by taxane/platinum-based chemotherapy for FIGO stage IIc-IV epithelial ovarian cancer. All the patients had ECOG performance status 0-1 at presentation. The median follow-up of survivors was 36 months (range, 6-120 months). RESULTS: The 25%, 50%, and 75% quantiles of hemoglobin levels before starting first-line chemotherapy were 10.2, 11.4, and 12.3 g/dl, respectively. Residual disease after initial surgery (>1 cm versus 12.3 g/dl) were inversely related to overall survival at univariate (P = 0.03) but not at multivariate analysis. CONCLUSIONS: This investigation showed that hemoglobin levels before starting first-line taxane/platinum-based chemotherapy are not an independent prognostic factor for overall survival in patients with advanced epithelial ovarian cancer.