Role of Diet in the Management of Carcinoid Syndrome: Clinical Recommendations for Nutrition in Patients with Neuroendocrine Tumors.

Nutrition and metabolism are altered in patients with gastroenteropancreatic neuroendocrine tumors, which is related to excessive production of gastrointestinal hormones, peptides, and amines that can cause maldigestion, diarrhea, steatorrhea, and altered gastrointestinal motility. Patients with carcinoid syndrome are at risk of malnutrition due to tryptophan depletion, reduced intake of food, and loss of appetite because of diarrhea and/or flushing. To date, there is limited information on the nutritional issues faced by patients with neuroendocrine tumors, and on what specific recommendations should be made to patients concerning nutrition at various stages of the disease process. Dietary planning should therefore be an integral part of multidisciplinary management for patients with neuroendocrine tumors. Herein, we review current guidance for nutrition in patients with neuroendocrine tumors, focusing on intake of amines and foods to avoid, as well as concurrent medications. We also propose a new and practical food pyramid based on the principles of Mediterranean diet 4.0 that can be easily adapted according to the unmet needs of patients with neuroendocrine tumors at all stages of disease. The overarching goal of the present review is to create greater awareness of nutritional care and considerations that should be given to patients with neuroendocrine tumors.

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.

Atypical Uterine Smooth Muscle Tumors: A Retrospective Evaluation of Clinical and Pathologic Features.

BACKGROUND: Clinical characteristics combined with new biomarkers help discriminate between atypical uterine smooth muscle tumors (AUSMT) and leiomyosarcomas (LMS). PATIENTS AND METHODS: We retrospectively collected a series of leiomyomas (LM), AUSMT, and LMS. Estrogen receptors (ER), progesterone receptors (PR), p16, Ki-67, and p53 expression were assessed by immunohistochemistry. For AUSMT patients, immunohistochemistry evaluations were performed at the time of diagnosis and at recurrences. RESULTS: A total of 27 cases of AUSMT, 22 LM, and 31 LMS were identified. The expression of ER and PR decreased from LM to LMS (ER+: LM 95.5%, AUSMT 88.9%, LMS 41.9%, p < 0.001; PR+: LM 100%, AUSMT 88.9%, LMS 38.2%, p = 0.002). By contrast, p16 and p53 expression increased (p16+: LM 4.5%, AUSMT 40.7%, LMS 45.2%, p = 0.004; p53: LM 9.1%, AUSMT 33.3%, LMS 58.1%, p = 0.001). At a median follow-up of 33.47 months, 40.7% of patients with AUSMT experienced recurrent disease, 6 patients relapsed as AUSMT and 5 as LMS. In univariate analysis was observed that ER status (p = 0.027) and p53 expression (p = 0.015) predicted risk of relapse. CONCLUSIONS: Treatment of AUSMT should be centralized in dedicated centers. International collaborations are needed to optimize research strategy, which may lead to the identification of new useful biomarkers and to improvement in the clinical management of this rare disease.

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.

Surgical Efforts Might Mitigate Difference in Response to Neoadjuvant Chemotherapy in Stage IIIC-IV Unresectable Ovarian Cancer: A Case-Control Multi-institutional Study.

OBJECTIVE: The aim of the study was to evaluate outcomes of patients with unresectable advanced ovarian cancer experiencing complete response (CR) to neoadjuvant chemotherapy. METHODS: Data of consecutive patients undergoing neoadjuvant chemotherapy plus interval debulking surgery (IDS) were retrospectively reviewed in 4 Italian centers. Using a propensity-matching algorithm, we compared data of patients achieving CR with neoadjuvant chemotherapy (no macroscopic either microscopic residual disease (RD) at the time of IDS) with patients achieving partial response (PR). This latter group was stratified by the presence of RD (RD = 0 vs RD > 0). RESULTS: Overall, 193 had IDS after neoadjuvant chemotherapy: 25 (13%), 81 (41.9%), and 74 (38.3%) patients had CR, PR with RD of 0, and PR with RD of more than 0, respectively. In addition, 13 (6.7%) patients had no macroscopic disease detected at DS but just microscopic disease at pathological examination. For the study purpose, 25 patients achieving CR were matched (1:2) with 50 patients having PR and RD of 0 and 50 patients having PR and RD of more than 0. As the result of propensity matching, baseline characteristics were similar between groups. Comparing survival outcomes of patients having CR and PR with RD of 0, we observed that type of response to chemotherapy did not influence disease-free (hazard ratio = 1.53 [95% confidence interval = 0.88-2.66], P = 0.127) and overall (hazard ratio = 1.74 [95% confidence interval = 0.76-4.01], P = 0.189) survivals. Patients achieving CR experienced significantly better disease-free survival (P = 0.004) and a trend toward better overall survival (P = 0.06) than patients achieving PR with RD of more than 0 at IDS. CONCLUSIONS: Complete cytoreduction might mitigate the difference in response to neoadjuvant chemotherapy. The presence of RD at IDS is associated with worse survival outcomes.

Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: A retrospective MITO group study.

OBJECTIVE: To investigate the impact of morcellation on survival outcomes of patients affected by undiagnosed uterine sarcoma. METHODS: This is a retrospective study performed in 8 referral centers of MITO group. Data of women undergoing morcellation for apparent benign uterine myomas who were ultimately diagnosed with stage I uterine sarcoma on final pathology were compared with data of women who did not undergo morcellation. Uterine sarcoma included: leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), low-grade endometrial stromal sarcomas (LG-ESS) and undifferentiated uterine sarcomas (UUS). Two-year survival outcomes were evaluated using Kaplan-Meir and Cox models. RESULTS: Overall 125 patients were identified: 31(24.8%), 21(16.8%) and 73(58.4%) patients had power morcellation during laparoscopy, non power morcellation during open surgery and non morcellation during open procedures, respectively. Considering patients affected by LMS, morcellation did not correlated with disease-free survival. However, patients undergoing either morcellation or power morcellation experienced a 3-fold increase risk of death in comparison to patients who had not morcellation (p=0.02). A trend towards an increase of recurrence was observed for patients undergoing morcellation for STUMP (HR 7.7, p=0.09); while no differences in survival outcomes were observed for patients with LG-ESS and UUS. CONCLUSIONS: Our data suggest that morcellation increase the risk of death in patients affected by undiagnosed LMS. Further prospective studies are warranted in order to assess the risk to benefit ratio of power morcellator utilization in patients with apparent benign uterine myomas.

Emesis and nausea related to single agent trabectedin in ovarian cancer patients: a sub-study of the MITO15 project.

The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation-carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them. We thought to carry on a sub-study in the MITO 15 context focused on chemotherapy-induced nausea and vomiting (CINV) associated with trabectedin single agent. For all patients enrolled in the trial, we evaluated the antiemetic regimen at the first cycle, acute and delayed CINV, any rescue therapy, any change in the prophylactic antiemetic regimen, and the potential relationship between dexamethasone dosage and incidence of CINV. Overall, our findings were consistent with literature and confirmed that trabectedin can be classified as moderately emetogenic. We observed slightly higher rates of both nausea and vomiting compared to previous experiences with trabectedin monotherapy, probably due to intrinsic features of our population: all females and suffering from ovarian cancer. It seems that in preventing acute CINV, the combination of three drugs was more effective than the doublet; however, the difference did not reach statistical significance; further studies are required to verify such hypothesis. Given the extreme heterogeneity of the antiemetic regimens used, it appears that a standard antiemetic protocol does not exist and more specific guidelines for clinicians are needed.

A Nutritional Approach for the Management of Chemotherapy-Induced Diarrhea in Patients with Colorectal Cancer.

This study aimed to determine if dietary modifications using a nutritional regimen could prevent or reduce the incidence of cancer therapy-induced diarrhea in patients with metastatic colorectal cancer and to evaluate the relationship of Vitamin D blood levels with diarrhea severity. Patients with metastatic colorectal cancer were enrolled. A Mediterranean diet, containing some special limitations aiming to reduce the risk of diarrhea, was administered before and during the entire chemotherapy program. Enrolled patients numbering 60/137 (44%) had diarrhea during chemotherapy. Adherence to the diet was high in 36 (26.3%) patients, medium in 94 (68.6%), and low in 7 (5.1%). Mean adherence to the diet was significantly lower in patients who experienced diarrhea with maximum grade 2−3 compared to those who had no diarrhea or grade 1 diarrhea (score = 5.4 ± 1.9 vs. 7.1 ± 1.5, p < 0.001). Patients with higher adherence to the diet had a lower risk of grade 2−3 diarrhea (odds ratio: 0.5 (95% CI: 0.3−0.7, p < 0.001)). In addition, patients who completed a higher number of chemotherapy cycles had an increased risk of grade 2−3 diarrhea (odds ratio: 1.2 (95% CI: 1.0−1.5, p = 0.02)). Of note, a lower level of Vitamin D correlated with an increased risk of G2-G3 diarrhea (p = 0.03). A diet based on vegetables with a controlled fiber content, Mediterranean Modified Healthy Diet (MMHD), is useful to control the incidence of cancer therapy-induced diarrhea.

Short-course olanzapine to prevent delayed emesis following carboplatin/paclitaxel for gynecologic cancer: a randomised study.

PURPOSE: To explore efficacy of short-course olanzapine with or without low-dose dexamethasone for prevention of delayed emesis in gynecologic cancer patients receiving carboplatin/paclitaxel. METHODS: This was a prospective study in 81 chemo-naive patients receiving 0.25 mg intravenous palonosetron, 16 mg dexamethasone, and 10 mg oral olanzapine before chemotherapy. On days 2 and 3, patients randomly received 10 mg olanzapine (arm A; n=27), 10 mg olanzapine plus 4 mg dexamethasone (arm B; n=27), or 8 mg dexamethasone (reference arm C; n=27). The primary endpoint was total control (TC; no vomiting, no rescue antiemetics, and no nausea) on days 2-5, using a diary. Secondary endpoints included proportion of patients with no emesis impact on daily life using the Functional Living Index-Emesis (FLIE) questionnaire, and patient's satisfaction with antiemetic coverage. RESULTS: Fifty-two percent of patients in arm A (P=0.406), 59% in arm B (P=0.779), and 67% in arm C had a delayed TC. Secondary analyses showed no significant difference across arms in any efficacy endpoint. FLIE scores as well as mean satisfaction scores were similar across arms. CONCLUSIONS: In this exploratory study with a small sample size, we did not find any clue about better control of delayed emesis with either olanzapine regimen in gynecologic cancer patients treated with carboplatin/paclitaxel and receiving the same prophylaxis for acute emesis.

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.

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.

Palonosetron plus dexamethasone effectively prevents acute and delayed chemotherapy-induced nausea and vomiting following highly or moderately emetogenic chemotherapy in pre-treated patients who have failed to respond to a previous antiemetic treatment: comparison between elderly and non-elderly patient response.

Aim of the present phase II non-randomized study was to verify whether palonosetron might be able to prevent acute and especially delayed CINV for either HEC or MEC, starting from the second chemotherapy cycle, in patients who had failed to respond to a different antiemetic 5-HT(3) antagonist during the first cycle. Stratification factor was age <65 years vs. > or =65 years of patients included. Forty-seven cancer patients (23 elderly and 24 non-elderly) scheduled to receive HEC or MEC regimens who had experienced CINV grade 3-4 during the first chemotherapy course and for whom the same course of chemotherapy regimen was further scheduled were enrolled. Complete response (CR) and complete control (CC) rates for the acute, delayed and overall phases of CINV were not significantly different between elderly and non-elderly patients. Palonosetron was safe: only grade 1-2 toxicities were observed with a peak of 12.9% for asthenia with no significant difference between elderly and non-elderly patients. In conclusion, single dose palonosetron (250 microg) should be considered a safe and effective second generation 5-HT(3) antagonist in the prevention of nausea and vomiting induced by HEC or MEC, irrespective of patients' age.