A European, Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer.

PURPOSE: The noninterventional, prospective NIMES-ROC phase IV study (NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real-life clinical practice. PATIENTS AND METHODS: Eligible participants included adults with platinum-sensitive recurrent ovarian cancer (PS-ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression-free survival (PFS) according to investigator criteria. RESULTS: Two hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1-24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9-10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1-34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty-four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty-nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment-related AEs or unexpected AEs occurred. CONCLUSION: The combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS-ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials. IMPLICATIONS FOR PRACTICE: This noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum-sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real-life clinical practice.

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin.

Leiomyosarcomas represent the most common variant of uterine sarcomas, and are also considered to be the least chemosensitive. To date, adriamycin and ifosfamide are believed to be the most effective drugs for its treatment, in addition to docetaxel and gemcitabine. Recently, the introduction of trabectedin has provided clinicians with another treatment option, and the drug may have some benefits for patients as it may allow for long-term treatment. We present the case of a patient who previously failed multiple cycles of chemotherapy and who was subsequently treated with 30 cycles of trabectedin as third-line therapy for multiple metastases of uterine leiomyosarcoma. During the treatment period, the dosage and dose interval of trabectedin were optimized because of the appearance of grade 4 hematological and gastrointestinal toxicity. Dose adjustments led to acceptable tolerability. Trabectedin was associated with a very good partial response, especially at the pulmonary and pancreatic levels, and stable disease was achieved at all metastatic sites. The patient is currently continuing treatment with trabectedin and has clinically stable disease after 2 years of therapy. This case report provides further evidence that trabectedin is a valid and well-tolerated therapeutic option that can be used in the long term in uterine leiomyosarcoma.

Laparoscopic Splenectomy as Quaternary Cytoreduction for Isolated Parenchymal Splenic Recurrence of Epitelial Tubo-Ovarian Cancer: Report of a Case and Literature Review.

Isolated parenchymal splenic lesions are very rare and may occur as recurrences in the form of epithelial tubo-ovarian cancer (ETOC). We report a case of solitary parenchymal splenic recurrence of ETOC, which developed 50 months after the initial treatment. A 66-year-old woman underwent laparotomic primary cytoreduction in 2008. After platinum-based chemotherapy, she developed recurrences; thus, she underwent secondary and tertiary cytoreduction in 2011 and 2012 respectively. In April 2013, CT scan documented a solitary parenchymal splenic lesion and it was confirmed by FDG PET/CT. She underwent quaternary cytoreduction by laparoscopic splenectomy. Histopathological evaluation revealed metastatic parenchymal disease consistent with recurrent ETOC. She was alive and disease-free for ten months since splenectomy. In literature there are 35 cases of isolated spleen parenchymal metastasis of ETOC and our report is the first case of laparoscopic splenectomy in the setting of quaternary cytoreduction. Laparoscopic splenectomy as quaternary cytoreduction is safe and feasible and could be congruent to the well-established experiences already reported for the primary, secondary or even tertiary cytoreduction where the absence of residual disease has been translated in a significant survival benefit.

Assessing psychological needs in female cancer patients: a tailored model.

BACKGROUND AND AIM OF THE WORK: Psychosocial needs in cancer patients seem to be underestimated and undertreated. The present research was designed to explore under-considered psychosocial needs (e.g., stressful life events, perceived social support, sense of mastery and depressive/anxious symptoms) of a female cancer group. The aim of the study was to test an assessment psycho-oncological model for female cancer patients. An assessment model of psychosocial needs and Stressful Life Events was operationalized and tests its predictive power. METHODS: We used Discriminant Analysis to test predictive power of the model and of the single variables included in it. 236 oncological patients (mean age 55.50 ± 13.09) were matched with 232 healthy control groups in the study. The following instruments were chosen: the Florence Psychiatric Interview, Hospital Anxiety Depression Scale, Multidimensional Scale of Perceived Social Support, Beck Depression Inventory I, and Sense of Mastery. RESULTS: The model satisfied the assumption criteria and was significant (Ʌ= .680, X2 = 109.73, p< .001). CONCLUSIONS: Stressful events, depression and anxiety were adequate markers of the assessment psycho-oncological model proposed for female cancer patients. The present study provides contributions in a clinical perspective: the results support the relevance of considering an assessment psychosocial model to use in female oncology for an accurate estimation of the women's needs. Women affected by female cancer with an history of Stressful Early and Recent life events and high level of anxiety and depression could positively benefit from a psychotherapy treatment.

Long-term Results After Neoadjuvant Chemotherapy for Breast Cancer: A Single-center Experience.

BACKGROUND/AIM: We evaluated the efficacy of neoadjuvant chemotherapy (NACT) in reducing locally-advanced breast cancer (LABC) size, thus improving breast-conserving surgery (BCS) rates, as well as its long-term outcome. PATIENTS AND METHODS: We analyzed 59 patients treated between 1999-2017 with NACT and subsequent surgery for LABC. RESULTS: We observed a tumor size reduction in 95% of cases, resulting in downstaging in 62.7%. The average tumor shrinkage was 49%. Women with a reduction in tumor size >50% after NACT had better 10-year OS rates than women with a reduction ≤50% (p=0.025). NACT allowed to perform BCS in 44% cases, whereas the remaining 56% cases underwent mastectomy. Overall, we observed recurrences in 37.2% patients. Recurrence rates after BCS and mastectomy were 30.7% (6 loco-regional and 2 distant cases) and 42.4% (5 loco-regional and 9 distant cases), respectively (p=0.07). CONCLUSION: NACT confirmed its effectiveness in reducing mastectomy rates by approximately 50%, without increasing the risk of local or distant recurrences.

Trabectedin in combination with pegylated liposomal doxorubicin in patients with ovarian tumors.

The majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity.

HER-2/neu and bcl-2 in ovarian carcinoma: clinicopathologic, immunohistochemical, and molecular study in patients with shorter and longer survival.

The bcl-2 protein is a membrane protein involved in prolonging cell survival by inhibiting apoptosis. The HER-2 oncogene, which is located on chromosome 17 and encodes for a tyrosine-kinase growth factor receptor, is amplified and HER-2/neu is overexpressed in 25% to 30% of breast carcinomas. The authors analyzed the bcl-2 expression and the bcl-2 gene and HER-2/neu overexpression and amplification in FIGO stage IIIC, serous, G3, ovarian carcinomas obtained from living patients who had no evident disease 5 years after primary treatment compared with ovarian carcinomas obtained from patients, matched for stage, grade of differentiation, and treatment, who had died of progression of disease no later than 2 years after primary treatment. bcl-2 overexpression was statistically correlated with progression of disease during first-line chemotherapy (P=0.021). The HER-2/neu status was found not to correlate with progression of disease during first-line chemotherapy. Both bcl-2 and HER-2/neu expression were not statistically associated with the clinical outcome of ovarian cancer patients. Gene amplification of the HER-2/neu chromosome 17 was found in all the HER-2/neu, 3+ score, positive-staining ovarian carcinomas. None of the analyzed samples revealed a translocation t(14;18)(q32;q21) in the bcl-2 gene. The knowledge of additional prognostic or even predictive factors, such as bcl-2 expression, in patients with advanced ovarian carcinoma before the primary chemotherapeutic treatment may help in the management of patients who require a more tailored treatment. In addition, the gene amplification of the HER-2/neu suggests that HER-2 is a potential target for treatment in ovarian cancer.

c-Kit expression in patients with uterine leiomyosarcomas: a potential alternative therapeutic treatment.

PURPOSE: Uterine leiomyosarcomas are rare tumors characterized by their resistance to chemotherapy and radiation treatment. Surgery is the primary method of treatment, but for patients with unresectable disease, alternate therapeutic options are clearly warranted. According to initial observations of c-KIT expression, correlation with a bad prognosis, and the successful therapeutic possibility of STI571 in gastrointestinal stromal tumors, the data have encouraged us to study c-KIT expression in these tumors. EXPERIMENTAL DESIGN: We analyzed the expression of c-KIT and genetic assessment of exon 11 of c-kit gene in 32 uterine leiomyosarcomas. RESULTS: In 17 cases (53.1%), we observed a c-KIT expression in tumor cells. Of the 17 patients with distinct c-KIT-positive immunoreactivity, eight had I or II stage disease and nine had III or IV stage disease. Molecular genetic analysis of exon 11, analyzed by direct DNA sequencing, was performed for all of the c-KIT-positive uterine leiomyosarcomas. No mutations were found. CONCLUSION: The conventional chemotherapy in leiomyosarcomas appears to be ineffective for patients with metastatic or unresectable disease, and the management of these patients poses a special problem. In these women, new therapeutic strategies are warranted. The treatment with STI571 in leiomyosarcoma patients might be hypothesized, because uterine leiomyosarcomas also express c-KIT.

Correlation of epidermal growth factor receptor expression with tumor microdensity vessels and with vascular endothelial growth factor expression in ovarian carcinoma.

We analyzed in advanced ovarian serous G3 carcinoma the correlation between epidermal growth factor receptor (EGFR) overexpression and tumor angiogenesis and their relation with clinical outcome. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were statistically correlated with disease-free interval and death from disease both in univariate and multivariate analyses while EGFR expression was not correlated with clinical outcome. MVD was significantly associated with progression of disease during chemotherapy while VEGF and EGFR expression were not correlated with responsiveness to chemotherapy (Fisher's exact test). VEGF expression was correlated with MVD (Fisher's exact test). EGFR showed a trend to correlation with MVD. Further studies focusing on the use of angiogenesis inhibitors in addition to EGFR inhibitors on ovarian carcinoma cells may produce therapeutic strategies in the selection of tailored therapies in ovarian cancer patients.

Treatment of uterine sarcoma at the University of Florence from 1980-2001.

PURPOSE: To correlate the treatment used in uterine sarcoma with outcome. The prognostic importance of pathology, clinical parameters and treatment are analyzed. PATIENTS AND METHODS: Forty patients (median age, 59 years; range, 37-85) with histologically verified uterine sarcoma were identified from a database compiled at the University of Florence from 1980 to 2001. Patients were followed for a median of 54 months (range, 3 months to 10 years). Twenty-four patients had leiomyosarcoma, 12 patients had mixed mullerian tumors, and 3 patients had endometrial stromal sarcoma. Stage I, II, III and IV tumors were identified in 22, 2, 9 and 7 patients, respectively. High, intermediate, low and unspecified grade sarcoma occurred in 9, 4, 5 and 22 patients, respectively. RESULTS: At the time of analysis, 58% of patients had died and 42% were alive, with a median survival of 2 years from the initial diagnosis. Cause-specific survival for the entire group was 81%, 41% and 25% at 1, 3 and 5 years, respectively. In our series, univariate analysis for cause-specific survival did not demonstrate statistical significance for histology, grade, stage or age. There appeared to be a significant impact for postoperative radiotherapy in reducing local recurrence with a total dose higher than 50 Gy. CONCLUSIONS: Our data favor treatment for uterine sarcoma with radical surgery plus irradiation, even in elderly patients.

Utility of CDX-2 in distinguishing between primary and secondary (intestinal) mucinous ovarian carcinoma: an immunohistochemical comparison of 43 cases.

Primary and secondary mucinous tumors can involve the ovaries and have similar histologic appearances. The differential diagnosis is important for surgical and chemotherapeutic treatment and for the prognosis, but often it is extremely difficult. This article discusses an immunohistochemical panel that includes carcinoembryonic antigen (CEA), cytokeratin (CK) 7, CK20, CA125, CA19.9, and a new marker, CDX-2, for the distinction between primary ovarian mucinous carcinomas and metastatic (intestinal) ovarian tumors. Forty-three cases representing primary and secondary ovarian tumors were considered and consisted of 14 primary mucinous ovarian carcinomas (PMOCs) and 29 secondary (intestinal) ovarian tumors (SIOTs). Fisher exact test was performed to evaluate the reliability of the respective antibodies to discriminate between PMOCs and SIOTs. CDX-2 was diffusely positive in all SIOTs and was expressed focally in 3 cases (21.42%) of PMOCs. CK7 was diffusely positive in 13 cases (44.82%) of SIOTs and in 13 cases (92.85%) of PMOCs. CK20 was diffusely positive in 17 cases (58.62%) of SIOTs and in 6 cases (42.85%) of PMOCs. CEA was diffusely positive in 28 cases (96.55%) of SlOTs and in 12 cases (85.71%) of PMOCs. CA 19.9 was positive in all SIOTs and in 12 cases (85.71%) of PMOCs. CA125 was positive in 3 cases (10.34%) of SIOTs and in 4 cases (28.57%) of PMOCs. CK7 and especially CDX-2, a specific and sensitive marker, can aid pathologists in making a differential diagnosis (P = 0.003 and P < 0.0005, respectively), whereas CEA, CK20, CA125, and CA 19.9 markers are not high enough to distinguish between primary and secondary mucinous ovarian tumors.

COX-2 status in relation to tumor microvessel density and VEGF expression: analysis in ovarian carcinoma patients with low versus high survival rates.

Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and microvessel density (MVD) have been reported to be significantly related to carcinogenesis and to tumoral progression. The aim of the study was to analyse immunohistochemically the overexpression of COX-2 and VEGF, and the MVD between one another, and also in relation with clinical outcome in ovarian carcinoma. We selected 52 patients with ovarian carcinoma homogeneous by stage, type and histological grade, surgical and chemotherapeutic treatment. Of these, 28 patients had died of progression of their disease within 2 years of their primary surgical treatment, while 24 patients were alive with no evident disease at 5 years from the primary surgical treatment. The differences of the COX-2 status, the MVD and the VEGF expression in the two groups of ovarian carcinoma patients with low and high survival rate, respectively, were calculated according to the Fisher's exact test and the logistic regression. The shift in location of MVD in the two groups of patients was calculated according to the Wilcoxon Mann-Whitney test. MVD was correlated with COX-2 and VEGF overexpression (P=0.009 and P=0.003, respectively), COX-2 and VEGF were correlated to one another (P=0.044). In logistic regression analysis, COX-2, VEGF, and MVD were significant (P=0.017, P=0.008, P<0.0005, respectively). In the cases with low survival rate, the average MVD was 102, while in the cases with high survival rate the average MVD was 40.5 (P<0.0005). The evaluation of the COX-2, the VEGF and the MVD may give additional prognostic information for first-line chemotherapy and clinical outcome of patients with ovarian carcinoma and may encourage selection of more tailored therapies. Angiogenesis inhibitors or COX-inhibitors probably can have synergistic effects with chemotherapy.

COX-2 and preoperative CA-125 level are strongly correlated with survival and clinical responsiveness to chemotherapy in ovarian cancer.

BACKGROUND: CA-125 is elevated in the serum of the majority of ovarian carcinoma patients. Cyclooxygenase-2 is an enzyme whose synthesis is upgraded by several cytokines, growth factors, and tumor promoters. METHODS: We analyzed cyclooxygenase-2, preoperative CA-125 levels, and CA-125 levels during chemotherapy in 41 FIGO stage III, grade 3, ovarian serous carcinoma patients in relation to survival with a logistic regression. The correlation of cyclooxygenase-2 expression and CA-125 preoperative level with clinical responsiveness to chemotherapy was studied according to Fisher's exact test. We compared 23 patients living with no evident disease five years after primary treatment to 18 patients who had died of progression of disease no later than two years after primary treatment. RESULTS: Cyclooxygenase-2 overexpression (p = 0.014 and p = 0.036) and preoperative CA-125 level (p = 0.012 and p = 0.029) were found to be independent predictors of survival in univariate and multivariate analyses. Cyclooxygenase-2 and CA-125 level were correlated to responsiveness to chemotherapy (p = 0.003 and p = 0.036, respectively; Fisher's exact test). The patients with a CA-125 level <35 U/ml after two cycles of chemotherapy showed a longer survival (p = 0.008). The median preoperative CA-125 was 195 in high survival patients and 650 in low survival patients (p= 0.004, Wilcoxon Mann-Whitney test). CONCLUSIONS: Cyclooxygenase-2 overexpression and CA-125 levels may help the management of ovarian cancer patients, permitting the selection of more aggressive and tailored first-line therapy.