Capecitabine in patients with platinum-pretreated advanced or recurrent cervical carcinoma: a retrospective study.

BACKGROUND: Cervical cancer is a common malignancy among women and, when recurring, presents a dismal prognosis. After platinum failure, second-line treatments report response rates ranging from 3-15%, a median progression-free survival of about 3 months and a median overall survival of about 5.5 months.To retrospectively evaluate the activity and safety of capecitabine in patients with advanced/recurrent cervical carcinoma.MethodsA retrospective review of medical records of recurrent cervical cancer patients, who had failed a previous platinum-paclitaxel treatment and received oral capecitabine 1250 mg/m2 twice daily continuously from day 1 to day 14 every 21 days, was performed from December 2013 to March 2018 at the Gynecologic Oncology Unit of the Fondazione IRCCS National Cancer Institute of Milan, Italy. The response rate was evaluated every three cycles according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria. Common Terminology Criteria for Adverse Events version 4.0 were used to evaluate adverse events. RESULTS: We retrospectively analyzed 35 patients with recurrent cervical carcinoma, treated with oral capecitabine. All patients had previously received and failed a combination of carboplatin plus paclitaxel as first-line therapy for advanced/recurrent disease. Median age at the first capecitabine administration was 53 years (range 27-82). All patients were evaluable for response: the overall response rate was 34.2% (2.8% complete responses and 31.4% partial responses) with a clinical benefit rate of 57% (overall response rate plus 22.8% stabilizations of disease). The most common grade 1-2 adverse events per patient were fatigue (71.3%), hand-foot syndrome (57.0%), diarrhea (31.3%), constipation (17.0%), and nausea (10.4%). Only three patients (8.5%) reported grade 3 adverse events. CONCLUSIONS: Our data suggest that oral capecitabine should be considered an active and safe treatment in patients with recurrent cervical carcinoma after platinum failure. Based on these results, we consider capecitabine as warranting further clinical evaluation.

Locally Advanced Cervical Cancer: Is a Trimodality Treatment a Safe and Effective Approach?

BACKGROUND: Chemoradiotherapy (CRT) is the standard of care for locally advanced cervical cancer (LACC). Pre-treatment lymph nodes (LN) assessment may have an important therapeutic role. CRT followed by adjuvant chemotherapy increased progression free survival (PFS) and overall survival (OS). Our study evaluated the feasibility and the effectiveness of a trimodality strategy in patients with LACC and positive LN. METHODS: Consecutive patients with LACC treated at the National Cancer Institute of Milan were enrolled. All patients underwent pelvic and para-aortic extraperitoneal laparoscopic lymphadenectomy to assess the nodal status. After surgery, patients received radiotherapy followed by chemotherapy according to the stage of disease. RESULTS: Between April 2012 and October 2013, 19 cervical cancer patients were enrolled. Overall, 10 (52.6%) patients presented with positive LN: 6 in the pelvic area and 4 both in the pelvic and para-aortic area. No perioperative major complications occurred. The most common surgical-related adverse events were bleeding (26%), respiratory distress (5%), infection (5%) and the development of lymphoceles (25%). Overall, 15 (78.9%) complete responses and 2 (10.5%) partial responses were registered. After a median follow-up of 43.3 months, 89.5% of patients were alive at the last visit, and 3-year PFS was 63%. CONCLUSIONS: Trimodality treatment appears feasible, well tolerated and promising in terms of oncologic outcome.

Ovarian Cancer in Elderly Patients: Patterns of Care and Treatment Outcomes According to Age and Modified Frailty Index.

OBJECTIVE: The present study assessed the predictive value of age and Modified Frailty Index (mFI) on the management of primary epithelial ovarian cancer (EOC) patients aged 70 years or older (elderly). METHODS: A retrospective multicenter study selected elderly EOC patients treated between 2006 and 2014. Treatments were analyzed according to the following age group categories: (1) 70 to 75 years versus (2) older than 75 years, and mFI of less than 4 (low frailty) versus greater than or equal to 4 (high frailty). RESULTS: Seventy-eight patients were identified (40 in age group 1 and 38 in age group 2). The mFI was greater than or equal to 4 in 23 women. Median age of low frailty and high frailty was not significantly different (75.6 vs 75.3). Comorbidities were equally distributed according to age, whereas diabetes, hypertension, obesity, and chronic renal failure were more frequent in the high-frailty group. Performance status was different only according to mFI. Twenty percent of age group 1 versus 55.3% of age group 2 underwent none or only explorative surgical approach (P = 0.003), whereas surgical approaches were similar in the 2 frailty groups. The rate of postoperative complications was higher in high-frailty patients compared with low-frailty patients (23.5% vs 4.3%; P = 0.03). Chemotherapy was administered to all the patients, a monotherapy regimen to 50% of them. No differences in toxicity were registered, except more hospital recovery in the high-frailty cohort. Median survival time was in favor of younger patients (98 versus 30 months) and less-frailty patients (56 vs 27 months). CONCLUSIONS: Elderly EOC patients can receive an adequate treatment, but patients who are older than 75 years can be undertreated, if not adequately selected. The pretreatment assessment of frailty through mFI could be suggested in the surgical and medical management.

Is Ovarian Cancer Being Managed According to Clinical Guidelines? Evidence From a Population-Based Clinical Audit.

BACKGROUND: In the northwestern Italian region of Piedmont, current statistics on hospitalizations show that surgical treatment for ovarian cancer (OC) is taking place in many small hospitals, as opposed to a more centralized approach. A population-based clinical audit was promoted to investigate whether OC is being managed according to clinical guidelines, identify determinants of lack of adherence to guidelines, and evaluate the association between adherence to guidelines and survival. PATIENTS AND METHODS: Residents diagnosed with OC in 2009 were identified in the regional hospital discharge records database. All hospitalizations within 2 years from diagnosis were reviewed. Patients were classified according to their initial pattern of care, defined as "with curative intent" (CIPC) if including debulking surgery aimed at maximal cytoreduction. Adherence to guidelines for surgery and chemotherapy and the effects of this adherence on OC survival were investigated with logistic regression and Cox models. RESULTS: The final study sample consisted of 344 patients with OC, 215 (62.5%) of whom received CIPC. Increasing age, comorbidities, and metastases were negatively associated with receiving CIPC. In the CIPC group, surgical treatment was adherent to guidelines in 35.2%, whereas chemotherapy was adherent in 87.8%. Surgical treatment that was adherent to guidelines [hazard ratio (HR), 0.72; 95% confidence interval (CI), 0.45-1.15] and absence of residual tumor (HR, 0.55; 95% CI, 0.32-0.94) were associated with better survival in the CIPC group, and chemotherapy that was adherent to guidelines was associated with a significant reduction in the risk of death (HR, 0.49; 95% CI, 0.28-0.87). CONCLUSIONS: Results support the need to reorganize the clinical pathway of patients with OC in the Piedmont Region and the need for better adherence to current guidelines.

Complications after the treatment of endometrial cancer: a prospective study using the French-Italian glossary.

INTRODUCTION: The evaluation of treatment complications is crucial in modern oncology because they heavily influence the every day life of patients. Several authors confirmed the reproducibility of the French-Italian glossary to score the complications in patients with endometrial cancer after radiotherapy (RT), but the treatment of endometrial carcinoma is primarily surgical and chemotherapy is often used for high-risk disease. OBJECTIVES: This study aimed to analyze the incidence of complications in our patients treated for endometrial cancer and to verify whether the glossary is a suitable instrument in the description of complications after surgery, RT, and chemotherapy. METHODS: The data of patients affected by endometrial cancer treated in the Gynecology and Obstetrics Academic Department, Azienda Ospedaliera Mauriziano Umberto I in Turin from 2000 to 2009 (with surgery alone or integrated treatments) were prospectively collected, and complications were described using the glossary. Every patient included in the analyses had a minimum of 18 months follow-up. RESULTS: Of the 271 patients, 68 (25%) experienced at least 1 complication with 87 overall complications. Most of the complications were mild (63%) and were found in the urinary (30%) or cutaneous systems (30%). Forty-four (50%) complications appeared within 1 year after treatment, but 9 (10%) complications appeared after 60 months of follow-up. Patients who were submitted to both surgery and RT showed a trend of higher rate of at least 1 complication (19/58 [32.7%]) if compared with surgery alone (36/135 [26.6%]), even if the difference was not statistically significant (P = 0.09). The incidence of complications in patients treated or not with lymphadenectomy was not statistically different (P = 0.088), whereas patients treated with laparotomy had a higher rate of cutaneous complications if compared with the laparoscopic approach (P = 0.018). The glossary included all observed complications. CONCLUSIONS: One every 4 women treated for endometrial cancer develops a complication. Clinicians should check for complications especially after integrated treatments maintaining surveillance even in the long term. The glossary is a comprehensive instrument to describe the complications of endometrial cancer, regardless of the type of treatment delivered.

Neoadjuvant Chemotherapy Prior Fertility-Sparing Surgery in Women with FIGO 2018 Stage IB2 Cervical Cancer: A Systematic Review.

Nowadays, the optimal management of patients with cervical cancers measuring 2-4 cm desiring to maintain fertility is still uncertain. In this systematic review, we assessed the reliability of neoadjuvant chemotherapy (NACT) prior to fertility-sparing (FS) surgery in International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB2 cervical cancer, in terms of pathologic response, oncological and obstetric outcomes. The review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data, using MEDLINE and PubMed, were searched for from 1 January 2005 up to 1 December 2020. We identified 20 articles and 114 women with IB2 disease, possible candidates for NACT prior to FS surgery. However, uterine conservation was achieved only in 76.7% of them. Patients reached optimal pathological response to NACT in 60.9% of cases and a TIP (cisplatin, ifosfamide and paclitaxel) regime was related to the best response. Suboptimal response to NACT appeared to be an independent negative prognostic factor. Up to 9.2% of patients recurred with a median 7.4-months DFS, and 4.6% of patients died of disease. Fifty percent of women tried to conceive after treatment and NACT prior to conization appeared to be the most promising alternative to upfront radical trachelectomy in terms of obstetric outcomes. In conclusion, NACT prior to FS surgery is an option, but the literature about this issue is still weak and FS should be carefully discussed with patients.

Angiogenesis and molecular markers in advanced epithelial ovarian cancer: a retrospective study.

OBJECTIVE: The role of molecular markers in ovarian cancer is still a matter of debate. Angiogenesis is a necessary condition for tumor growth. Hypoxia induces angiogenesis, and cyclooxygenase-2 (COX-2), p53 and HER2 are involved in cancer proliferation and angiogenesis regulation. The aims of this study were to evaluate the relationship between intratumoral microvessel density (IMD) and the expression of molecular markers that affect angiogenesis (COX-2, p53 and HER2) in advanced epithelial ovarian cancer (EOC), to analyze their prognostic and predictive value and their association with clinicopathological features, such as serum hemoglobin level at diagnosis (Hb). METHODS: Immunohistochemical staining with CD34 (for IMD), COX-2, p53 and HER2 antibodies was performed in 113 patients with advanced EOC who had undergone primary surgery. Clinicopathological data were collected and statistical analyses were performed. RESULTS: Neither IMD, COX-2 nor HER2 had any predictive or prognostic value in EOC. A relationship that approached statistical significance was found between p53 expression and a complete response to treatment (p=0.05). p53 expression and tumor grade were inversely associated (p=0.012). Hb<12g/dl had predictive value (p=0.02). CONCLUSIONS: In our series IMD, COX-2 and HER2 had neither prognostic nor predictive value in advanced EOC. p53 and Hb may be predictive factors. The results and clinical usefulness of immunohistochemistry are controversial. Further evaluations are required to determine whether the serum levels of molecular markers correlate with the results of immunohistochemical assays and whether they offer any prognostic and/or predictive value. Targeted therapy remains the ultimate goal of these studies.

Surgery on breast cancer in pregnancy.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer develops either during or within 1 year after pregnancy, it is a rare disease arising in 1:3,000 to 1:10,000 pregnant women. Prognosis of this tumor is influenced by local or systemic treatment, which might be conditioned by gestational age and limited by the concern on potential adverse impact on fetus. The aim of this literature review is to analyze the main topics regarding surgical treatment of patients diagnosed with breast cancer in pregnancy: anesthesia and maternal-fetal monitoring, type of breast surgery, immediate breast reconstruction after radical surgery and management of the axilla. Some important topics remain controversial since the relative rarity of PABC precludes the feasibility of large studies leading to a lack of literature data. Multi-institutional collaboration is warranted to collect women with PABC, in order to best define surgical treatment in view of associated maternal and fetal risks.

Treatment of recurrent ovarian cancer with pegylated liposomal doxorubicin: a reappraisal and critical analysis.

The vast majority of ovarian cancer relapses on front-line therapy and the optimal treatment of recurrent ovarian cancer remains controversial. This review is based on the relevant published literature indexed in PubMed on pegylated liposomal doxorubicin (PLD), either alone or in combination with other drugs, as one option in relapsed disease. PLD showed an improved pharmacokinetic profile, with a slower plasma clearance and a longer circulation time, compared to other conventional doxorubicin formulations. PLD is considered to have little potential for cardiotoxicity, even at prolonged and high cumulative doses, although there appears to be room for improvement in terms of maximal dose allowed. Notwithstanding, there remain some concerns about cardiac safety, and patient monitoring is generally advocated. No data are available on the possibility to rechallenge PLD treatment in recurrent ovarian cancer, as already known for other drugs. Optimization of treatment regimens with PLD will allow a more rational treatment in advanced ovarian cancers for which few therapeutic options are available.

Can Vulnerable Elders Survey-13 predict the impact of frailty on chemotherapy in elderly patients with gynaecological malignancies?

The management of gynaecological cancers in elderly women and high-risk patients is an even more relevant issue, because the increase in longevity and comorbidities. The assumption of frailty based on age alone may lead to inadequate and inappropriate treatment and frailty assessment is recommended. The aim of this study was to assess if Vulnerable Elders Survey-13 (VES-13), as indicator of frailty, can predict the toxicity of chemotherapy in gynaecological cancers.VES-13 was administered to patients aged ≥ 70 years with ovarian, endometrial and cervical cancers who underwent chemotherapy from 2010 to 2016.Eighty-four patients aged ≥ 70 years (mean age 74.6) were included, 36 patients (42.9%) resulted vulnerable (score ≥ 3). Thrombocytopenia and anaemia were more prevalent in the vulnerable subjects (81.3% versus 18.7%, P = .0005, and 81.8% versus 18.2%, P = .005, respectively), while neutropenia was similar between the 2 groups. Vulnerable women had higher risk of non-haematological toxicities. Most of the patients (77.4%) completed chemotherapy, but dose reductions and discontinuations were more common in the vulnerable group (66.7% versus 33.3%, P = .07 and 68.4% versus 31.6%, P = .01, respectively).To our knowledge, this is the first study to evaluate VES-13 exclusively in elderly women with gynaecological cancers. VES-13 may be useful to stratify this category of patients according to vulnerability in order to identify women at risk of toxicity and to prevent complications induced by chemotherapy.

Rucaparib: a new treatment option for ovarian cancer.

INTRODUCTION: Approximately 50% of high-grade serous ovarian cancers present a deficiency in the pathways involved in homologous recombination (HR). PARP inhibitors prevent single-strand DNA damage repair and determine a progression of the defect towards double-strand breaks, which results in a process known as 'synthetic lethality'. Areas covered: In this review, the authors discuss the efficacy and toxicity of rucaparib either as a single agent or as a maintenance treatment for ovarian cancer. This includes the NGS Foundation Medicine evaluation of the role of this drug in the treatment algorithm of ovarian cancer. Moreover, perspectives on the future development of this drug are presented. Expert opinion: The FDA has approved this drug for the treatment of recurrent BRCA-mutated ovarian cancers, which were previously treated with at least two chemotherapies and has accepted the supplemental new drug application for maintenance use in patients who respond to platinum-based chemotherapy via the Prescription Drug User Fee Act (PDUFA) on 6 April 2018. European Medicines Agency (EMA) approval in the same setting is awaited. The possibility of using PARP inhibitors as a maintenance therapy, as a front-line therapy to combat recurrence, and in combination with anti-angiogenic agents and immune-therapies appears to be of particular interest.

Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: design, development and place in therapy.

Epithelial ovarian cancer is the sixth most common cancer among women worldwide and the first cause of death among gynecological malignancies. Most of the patients present recurrent disease and unfortunately cannot be cured. The unsatisfactory results obtained with salvage chemotherapy have elicited investigators to search for novel biological agents capable of achieving a better control of the disease. In the setting of homologous recombination deficiency, the DNA errors that occur cannot be accurately repaired, and the treatment with poly(ADP-ribose) polymerase (PARP) inhibition results in definitive cell death in a process called synthetic lethality. As a result of two positive clinical trials, Olaparib was approved in 2014 by U.S. Food and Drug Administration and European Medicines Agency as the first-in-class PARP inhibitor. Olaparib is effective and well tolerated in homologous recombination deficient patients. Several studies with Olaparib have been conducted in the recurrent setting either as maintenance in platinum-responsive patients or as a single agent. Ongoing trials are focused on the use of olaparib as maintenance in the first-line ovarian cancer setting alone or in combination with antiangiogenic agents. Future perspectives will probably investigate the association of olaparib with novel agents as check-point inhibitors and PI3K-AKT inhibitors. The PARP inhibitor era is just at the beginning.

The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer.

INTRODUCTION: Recurrence is a common event in endothelial ovarian cancer (EOC) patients, and the choice of the most appropriate treatment is driven by the platinum-free interval, molecular characteristics of the disease such as BRCA mutational status, previous treatments and toxicity. Areas covered: This review focuses on the main hematologic and non-hematologic toxicities correlated with the use of licensed antiangiogenic agents and PARP inhibitors in recurrent platinum-sensitive EOC, providing recommendations for their management. Expert opinion: The clinical research over the next years will be focused on a more precise characterization of molecular pathways underlying tumorigenesis of the five ovarian tumors, to improve the decision-making process in these rare diseases. For this purpose, new study designs and international collaborations will become mandatory. Immunotherapy, antiangiogenic agents and PARP inhibitors will be combined to build a treatment strategy algorithm which will allow patients to receive all the available treatment option, in the more appropriate sequence.

Aggressive clinical course of primary invasive vaginal carcinoma associated with type 61 HPV: a case report.

Primary invasive vaginal cancer is one of the rarest malignant processes in the female genital tract. The etiology has not been identified, but the strongest association is with HPV infection and subtypes 16 and 18 have the highest oncogenic potential. We present the case of a young woman diagnosed with metastatic squamous cell carcinoma of the vagina associated with HPV type 61, a non-oncogenic HPV type. We report the propensity of a primary vaginal neoplasm to spread to lymphatic vessels early and the unresponsive aggressive behavior to multimodal therapy.