Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

BACKGROUND: Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. METHODS: To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. CLINICAL REPORT AND RESULTS: We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. CONCLUSION: uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status. METHODS: Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status. RESULTS: Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk. CONCLUSION: This post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

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.

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.

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.

Adult ovarian granulosa cell tumors: analysis of outcomes and risk factors for recurrence.

OBJECTIVE: Adult granulosa cell tumors represent less than 5% of all ovarian malignancies. The aim of this study was to analyze the clinicopathological parameters and their impact on progression-free and overall survival. METHODS: Patients with primary adult granulosa cell tumors treated in three international referral centers between July 1999 and December 2018 were included. The following data were anonymously exported from the prospective database: age at diagnosis, International Federation of Gynecology and Obstetrics (FIGO) stage, adjuvant therapy, surgical procedures, progression-free survival, and overall survival. Descriptive statistical analysis regarding tumor and treatment characteristics was performed. Survival analyses included Kaplan-Meier functions and Cox proportional hazard ratios (HR). RESULTS: A total of 168 patients with primary adult granulosa cell tumors were included. Median age was 50 years (range 13-82). With regard to stage distribution, 54.2% (n=91) of patients were FIGO stage IA, 1.2% (n=2) were stage IB, 26.8% (n=45) were stage IC, and 17.9% (n=30) were FIGO stage II-IV. 66.7% (n=112) of patients underwent surgical restaging, of whom 17.9% (n=20) were moved to a higher stage. In addition, 36 (21.4%) patients underwent fertility-sparing surgery. After a median follow-up of 61 months (range 0-209), 10.7% of patients (n=18) had recurrent disease and 4.8% (n=8) died of disease. Five-year progression-free survival was 86.1% and estimated overall survival was 95.7%. Five-year progression-free survival was worse for patients with advanced stages (FIGO stage IA/B vs IC: HR 5.09 (95% CI 1.53 to 16.9); FIGO stage IA/B vs II-IV: HR 5.62 (95% CI 1.58 to 19.9)). Nineteen patients receiving adjuvant chemotherapy had lower estimated 5-year progression-free survival compared with patients not receiving chemotherapy (49.7% vs 91.1%, p<0.001; HR 9.15 (95% CI 3.62 to 23.1)). CONCLUSION: The prognosis of patients with primary adult granulosa cell tumors is mainly determined by FIGO stage. The outcome of patients with FIGO stage IC is comparable to those with advanced stages. Fertility-sparing surgery seems to be a safe procedure in stage IA. Our data do not support the use of adjuvant chemotherapy in early and advanced stages of adult granulosa cell tumors.

Hematological disorders after salvage PARPi treatment for ovarian cancer: Cytogenetic and molecular defects and clinical outcomes.

Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/-5 and/or del(7q)/-7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, were found in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome, one had stable disease, eleven underwent induction therapy, followed by allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49) median observation time, 3 out of 16 patients were alive, with one surviving patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant-related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo-panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.

Clinical presentation, diagnosis and management of therapy-related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly-ADP-ribose polymerase inhibitors: A single-center experience.

We investigated the occurrence and management of therapy-related hematological disorders (tr-HDs) in women with epithelial ovarian cancer (EOC) exposed to poly-ADP-ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr-HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr-HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow-up, the actual risk of tr-HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.

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.

An open-label phase 2 study of twice-weekly bortezomib and intermittent pegylated liposomal doxorubicin in patients with ovarian cancer failing platinum-containing regimens.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. METHODS: Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. RESULTS: Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. CONCLUSIONS: The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.

Simple conization and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience.

OBJECTIVES: Simple conization represents a plausible treatment scheme for managing stage IA1-2 tumors conservatively. However its curative potential has not been widely exploited as regards stage IB1 lesions. Recent studies suggest that, in selected circumstances, patients with stage IB1 disease undergoing radical hysterectomy could have been safely cured by simple hysterectomy and even by cervical conization. METHODS: Patients with stage IB1 cervical cancer desiring conservative management underwent simple conization and pelvic lymphadenectomy in three Italian institutes. RESULTS: Thirty-six women received the conservative treatment since 1995 to 2010. Median age was 31 (range 24-40) years and median tumor size was 11.7 mm (range 8-25 mm). Adenocarcinoma was present in 12 cases (33%) and grade 3 neoplasia in 5 (14%). Lymph-vascular space involvement was detected in five patients (14%). Eleven had already a child while two had experienced an early abortion and a fetal loss at second trimester. After a median follow-up of 66 months (range 6-168) only one pelvic lymphnodal relapse was observed. Twenty-one pregnancies occurred in 17 patients and 14 live babies have been born (two preterm at 27 and 32 weeks) while one is ongoing. Three first-trimester miscarriages, one second-trimester fetal loss, an ectopic pregnancy and a termination of pregnancy have been recorded. Five patients decided to undergo hysterectomy after 3-12 years after conservative therapy: in one residual microinvasive adenocarcinoma was found. CONCLUSIONS: Cervical conization represents a feasible conservative management of stage IB1 cervical cancer and shows a low risk of relapse, provided that patients are selected carefully. Conization would be suitable to treat stage IB lesions smaller than 15-20mm. with pathologic negative lymphnodes.

Stereotactic Body Radiation Therapy for Oligometastatic Ovarian Cancer: A Step Toward a Drug Holiday.

PURPOSE: To evaluate stereotactic body radiation therapy (SBRT) for metachronous oligometastatic ovarian cancer patients in terms of local control, delay of systemic treatment, survival outcomes, and toxicity. METHODS AND MATERIALS: Retrospective data collection from a single institution was performed. The inclusion criteria were as follows: (1) oligorecurrent or oligoprogressive disease in ovarian cancer patients during or after systemic therapy; (2) surgery or other local therapies not feasible; and (3) relative contraindication to systemic therapy for reasons such as unavailability of additional chemotherapy lines or refusal of the patient. Tumor response and toxicity were evaluated using the Response Evaluation Criteria in Solid Tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. A new systemic therapy regimen was started after an SBRT treatment course in 57 of 109 cases (52.3%). Local progression-free survival, progression-free survival, and overall survival were calculated via the Kaplan-Meier method. The systemic treatment-free interval was calculated in cases without concomitant systemic therapy. RESULTS: Between May 2012 and December 2016, 82 patients (156 lesions) underwent SBRT with a median dose of 24 Gy in 3 fractions. The median follow-up period was 17.4 months. Patients received a median of 3 systemic therapy regimens prior to SBRT. Concomitant systemic therapy was performed for 29 lesions (18.6%). Among 152 evaluable lesions, a complete radiologic response, partial response, stabilization, and progressive disease were observed in 91 (60%), 26 (17%), 24 (16%), and 11 (7%), respectively. No grade 3 or 4 acute or late toxicities were observed. The median systemic treatment-free interval after SBRT was 7.4 months, and 1 of 3 patients was disease free at 1 year after SBRT. The actuarial 2-year local progression-free survival, progression-free survival, and overall survival rates were 68%, 18%, and 71%, respectively. The pattern of failure was predominantly out of field. CONCLUSIONS: SBRT for oligometastatic ovarian cancer showed good local control and a good toxicity profile. It might be an appealing alternative to other invasive local therapies to delay systemic therapy in the case of chemorefractory disease or intolerance to systemic agents.

Risk-reducing Salpingo-Oophorectomy in Women at Higher Risk of Ovarian and Breast Cancer: A Single Institution Prospective Series.

BACKGROUND/AIM: Occult cancers' reported rates vary from 2-12% and serous tubal intraepithelial carcinomas (STICs) have been identified in 3-12% of the prophylactically removed tubes of women carrying a BRCA mutation. The aim of this study was to evaluate the incidence of tubal minor epithelial atypia (STIL), STIC, and occult invasive cancer and to evaluate the cancer-specific mortality in a prospective series of women at higher risk of ovarian and breast cancer undergoing risk-reducing salpingo-oophorectomy (RRSO) n a tertiary cancer center. PATIENTS AND METHODS: A series of RRSO specimens (including endometrial biopsy) from women carrying a BRCA mutation, BRCA-unknown and BRCA-negative were collected between January 1998 and April 2016 at the Division of Gynecology at the European Institute of Oncology. Inclusion criteria were: asymptomatic women who had a negative gynecologic screening within 3 months prior to RRSO. Exclusion criteria were: women with ovarian/tubal cancer prior to RRSO. RESULTS: A total of 411 women underwent RRSO. Median age at RRSO was 47.0 years (range=32-70 years); 75.2% had a history of breast cancer. Fifteen women were diagnosed with an occult cancer (7 STIC, 4 invasive cancers, 2 breast cancers metastatic to the adnexa, 2 endometrial cancer) (3.6%). Sixteen showed a STIL (3.9%). When excluding cases with preoperative positive markers, the occult invasive cancer rate drops to 1.5%. CONCLUSION: Our study, covering an 18-year period, shows a substantial low risk of occult cancer among a high-risk population of women undergoing RRSO. Our data still support the indication for RRSO in higher-risk patients. An endometrial biopsy should also be routinely obtained as it raises the chances of detecting occult endometrial cancers that may be otherwise missed.

Ovarian cancer.

Ovarian cancer accounts for 4% of all cancers in women and is the leading cause of death from gynaecologic malignancies. Because early-stage ovarian cancer is generally asymptomatic, approximately 75% of women present with advanced disease at diagnosis. Survival is highly dependent on stage of disease: 5-year survival in patients with early-stage is 80-90% compared to 25% for patients with advanced-stage disease. For all patients, a comprehensive surgical staging should be performed to obtain the histological confirmation of diagnosis and to evaluate the extent of disease. Patients with early-stage should both be optimally staged and be treated with adjuvant platinum-based chemotherapy if they have a medium or high-risk tumour. For advanced disease the currently recommended management is primary cytoreductive surgery followed by platinum-paclitaxel combination chemotherapy. Appropriate salvage therapy is based on the timing and nature of recurrence and the extent of prior chemotherapy. Surgical resection should be considered in patients with long-term remission, especially in those with isolated recurrences and good performance status. Platinum-based combination represents the standard second-line chemotherapy in patients with platinum-sensitive relapsed ovarian cancer. Salvage chemotherapy in platinum-refractory patients usually results in low response rates and short survival.

A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer.

PURPOSE: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. METHODS: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. RESULTS: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 micromol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 micromol/L 4-HPR. CONCLUSIONS: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention.

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.

Randomized phase III clinical trial evaluating weekly cisplatin for advanced epithelial ovarian cancer.

This randomized, open label, phase III clinical trial (1988-1992) compared the efficacy and safety of a dose-dense regimen of single-agent cisplatin with a standard 3-weekly schedule in first-line chemotherapy for advanced epithelial ovarian cancer. Two hundred eighty-five patients were randomly assigned to the experimental dose-dense arm (cisplatin 50 mg/m(2) weekly × nine cycles) or to the control (standard treatment) arm (cisplatin 75 mg/m(2), administered on day 1 every 21 days × six cycles). The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall response to chemotherapy, and toxicity. Toxicity and response to treatment were compared with the χ(2) test using trend or exact correction. PFS and OS were estimated by Kaplan-Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 16.8 years, no differences were observed between the two treatments in PFS (experimental arm: 17.2 months; control arm: 18.1 months; HR = 1.08, 95% confidence interval [CI] = 0.83 to 1.40; P = .57) and in OS (experimental arm: 35 months; control arm: 32 months; HR = 0.97, 95% CI = 0.75 to 1.26; P = .97). Thus, increasing dose intensity of cisplatin does not improve PFS or OS compared with standard chemotherapy.

Management of ovarian stromal cell tumors.

PURPOSE: To describe the clinical management of ovarian stromal cell tumors, which are a heterogeneous group of neoplasms that develop from the sex cords and the ovarian stroma. DESIGN: We reviewed the current evidence on the clinical management of these relatively rare ovarian malignancies, which are typically detected at an early stage and may recur as late as 30 years following the initial treatment. The overall prognosis is favorable with a long-term survival ranging from 75% to 90% for all stages. Adult granulosa cell tumor (GCT) is the most common malignancy among these tumors. RESULTS: Surgery is the cornerstone of initial treatment. In women of childbearing age and with disease limited to one ovary, a fertility-sparing surgery can be a reasonable approach. Tumor stage represents the most important clinical parameter of prognostic relevance. The value of postoperative adjuvant therapy for high-risk patients has not been proven by prospective randomized studies. Platinum-based chemotherapy is used currently for patients with advanced stages or recurrent disease, with an overall response rate of 63% to 80%. Taxane and platinum combination chemotherapy seems to be a reasonable candidate for future trials. Little evidence exists for the use of radiation or hormonal therapy, and these modalities should be restricted to selected cases. Given the propensity of GCT for late relapse, prolonged follow-up is required. CONCLUSION: Surgery remains the most effective treatment for ovarian stromal tumors and, whenever feasible, for relapsing disease. Platinum-based chemotherapy is currently used in metastatic or recurrent tumors.

Chemo-conization in early cervical cancer.

OBJECTIVES: The aim of the present study is to support the safety and feasibility of chemo-conization for early-stage cervical tumor in young patients wishing to preserve their fertility. METHODS: Between October 2004 and November 2006, eleven patients were scheduled for conservative treatment. Subjects were selected for this treatment on the basis of favorable cervical tumors (<3 cm) and a desire to maintain fertility. All patients underwent neoadjuvant chemotherapy followed by conization or conization alone with pelvic lymphadenectomy. Obstetrical and oncologic outcomes were evaluated. RESULTS AND CONCLUSIONS: The mean age of the eleven patients was 32 (range: 24-41), Figo Stage was IB1 in 8 cases and 3 cases were Stage IA2. Histological findings were squamous cell carcinoma in 5 patients and adenocarcinoma in 6 patients. Two patients were treated with TEP regimen every 3 weeks for three courses, while one patient had adjuvant chemotherapy with TEP. No recurrences were observed after a median follow-up of 20 months (range 7-29 months). Three pregnancies occurred during the follow-up period. Although the number is small, in selected patients this conservative approach seems to be feasible to cure early-stage cervical cancer therefore maintaining fertility.