Giulia Amadio

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

Background:The NGR-hTNF (asparagine–glycine–arginine–human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels.Methods:Patients progressing after ⩾1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m−2 and doxorubicin 60 mg m−2 every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients.Results:A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6–12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2–2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12–39%) had partial response (2 with PFI<6; 6 with PFI=6–12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6–12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6–12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001).Conclusion:Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.

Targeting the hallmarks of ovarian cancer: The big picture

OBJECTIVE As a result of relevant achievements in the field of translational research, several active drugs and multiple biological targets are available in ovarian cancer (OC). In this complex scenario, there is an urgent need to effectively summarize the available data in order to update conclusions, and outline perspectives. METHODS The results in terms of target identification and drug development have been summarized using the well-known hallmarks of cancer firstly described, and recently modified by Hanahan and Weinberg [1-2]. Published data from clinical trials have been retrieved from PubMed, Embase, CINAHL and Cochrane database. Ongoing clinical trials were searched using clinicaltrials.gov web platform, and identified using NCT number. RESULTS Genomic instability and angiogenesis are the most actively investigated hallmarks in high-grade serous OC, and the inhibition of tumor immune evasion appears as the emerging strategy for molecularly-driven therapy. Targeting sustained proliferative signaling through MEK and mTOR inhibitors seems the most promising approach in clear cell, and low-grade serous OC. CONCLUSIONS This substantial amount of data suggests that targeted therapies are already part of the clinical and therapeutic management of OC patients. The expectations of getting from translational research a better knowledge of tumor biology and therefore personalized drugs are high and worthy of maximum effort from referral centers.

Trabectedin as single agent in the salvage treatment of heavily treated ovarian cancer patients: A retrospective, multicenter study

OBJECTIVE The aim of this multicenter, retrospective study was to evaluate the efficacy and the safety of single agent Trabectedin (ET-743, Yondelis) in very heavily treated, relapsed ovarian cancer (ROC) patients. PATIENTS AND METHODS Response to treatment was classified according to RECIST criteria. Progression-free (PFS), and overall survival (OS) were also assessed. RESULTS 98 patients were analyzed (originally 67 platinum sensitive, and 31 platinum refractory/resistant). Median number of previous regimens was 4 (range: 1-6). In the whole population, overall response rate (ORR) was 27.5%; stable disease (SD) was observed in 33 patients (33.6%), and clinical benefit was achieved in 60 cases (61.2%). ORR was 38.6% in fully platinum sensitive population, and 26.1% in partially platinum sensitive patients. In platinum refractory/resistant disease, ORR was 12.9%. Overall, median PFS and OS were 5, and 13 months, respectively. Patients responding to Trabectedin showed a more favorable PFS (median = 9 months) than patients with SD (median = 6 months), or progression (median = 2 months). Median OS of responding patients was 18 months compared to 14 months in SD patients, and 9 months in progressing patients. Grade 3-4 neutropenia was observed in 17 (17.3%) patients. Transient and non-cumulative Grade 3-4 AST and ALT level elevation was found in 7 (7.1%), and 13 (13.3%) cases, respectively. There was 1 case of Grade 3, and 1 case of Grade 4 cardiac toxicity. CONCLUSIONS Trabectedin, as a single agent, retains its efficacy in terms of rate of ORR and clinical benefit in heavily treated ROC patients, especially in the group of platinum sensitive disease.

Treatment of cervical cancer in Italy: Strategies and their impact on the women

Treatment of cervical cancer greatly varies according to the stage of the disease. Laparoscopic surgical staging is emerging as a valid approach, compared to clinical and imaging staging, to better identify the treatment plan. Minimally invasive surgery plays the greatest role in the treatment of early cervical carcinoma (ECC). Laparoscopically assisted radical vaginal hysterectomy (LARVH) is an alternative surgical strategy in this subset of patients. Interest has been increasing in using conservative fertility-sparing surgery such as laparoscopic vaginal radical trachelectomy (LVRT) or chemo-conization, options to be preferred in selected patients, with early-stage disease and asking for future fertility. Chemoradiotherapy currently represents the gold standard in the treatment of patient with locally advanced cervical cancer (LACC). In Italy, neoadjuvant chemotherapy (NACT) followed by radical surgery is today emerging as a valid alternative to the standard chemoradiation and the paclitaxel, ifosfamide and cisplatin (TIP) regimen is one of the most active neoadjuvant chemotherapeutic treatments. Moreover, the combination of different strategies to maximize local control should be considered. Among different approaches to this issue the use of a three-modality treatment, including radiotherapy, chemotherapy and surgery has been investigated. Our data on a large single-institutional series of LACC patients treated with chemoradiation followed by radical surgery confirm that this three-modality treatment can achieve overall survival (OS) and Disease Free Survival (DFS) rates at least comparable to chemoradiation alone, with an acceptable rate of complications. Tailoring of radical surgery, on the basis of intraoperative findings, such as lympho-nodes status, might play an important role in diminishing the overall rate of complications and eventually improve quality of life (QoL) of these patients. Cervical cancer generally has an aggressive impact on relatively young women and, as we experienced, the relevance of psychosocial aspects in gynaecologic oncology has become a main issue.

Impact of bevacizumab containing first line chemotherapy on recurrent disease in epithelial ovarian cancer: A case-control study

OBJECTIVE To evaluate the timing and pattern of relapse, and duration of response to second line chemotherapy in advanced ovarian cancer (AOC) patients treated with first line carboplatin-paclitaxel chemotherapy with or without bevacizumab. PATIENTS AND METHODS This is a case-control study including 222 AOC patients. Seventy-four women treated with first line carboplatin-paclitaxel-bevacizumab chemotherapy (Cases) were matched based on laparoscopic predictive index value, and residual tumor at first surgery with 148 AOC patients treated with carboplatin-paclitaxel. Distribution of pattern of relapse, and response to second line chemotherapy was compared between the two groups. Time to Progression (TTP) for second line chemotherapy was also analyzed for study purpose. RESULTS Median platinum-free interval (PFI) was 16months (range 2-65) in Cases, compared with 9months (1-83) in Controls (p-value=0.001). Twenty patients (51.3%) among Cases showed recurrence in multiple anatomic sites, compared with 31 (31.9%) in the Control group (p-value=0.035). Peritoneal recurrence occurred as diffuse in 30 Cases (96.8%), and 60 Controls (82.2%; p-value=0.046). Secondary cytoreductive surgery (SCS) was successfully completed in 53.5% of Controls compared to 10.0% of Cases (p-value=0.016). In women with fully platinum-sensitive relapse, response rate to second line chemotherapy was 85.2% in Controls, compared to 38.4% in Cases (p-value=0.002). Finally, Cases showed a shorter TTP, compared to Controls (5months vs 8months; p-value=0.041). CONCLUSIONS Incorporation of bevacizumab into upfront regimens prolongs PFI in AOC patients, but is associated with wider presentation of relapse, lower rate of complete SCS, and shorter TTP to second line chemotherapy in women with platinum-sensitive disease.

Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence.

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented.

Real-world management of trabectedin/pegylated liposomal doxorubicin in platinum-sensitive recurrent ovarian cancer patients: A national survey

Background Trabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients. Methods We carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians’ approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions. Results Fifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients’ choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%. Conclusions This survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.

Emerging drugs for endometrial cancer.

Introduction: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings. Areas covered: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials. Expert opinion: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.

Trabectidin as single-agent in heavily pretreated patients with relapsed ovarian cancer (ROC): results from a retrospective study

Cancer and its treatment tend to destroy both sexual function and sexual performance. In gynaecological oncology that applies even more because the sexual machinery is directly involved. As a result, sex for fun and sex for procreation will disappear from the couples menu. Bothering about possible sexual side effects seems not very relevant. That makes discussing this topic also absent from the menu of the oncology professionals, causing unnecessary additional sadness to the woman and her partner and potentially causing additional damage to their relationship.

8030 POSTER Phase II Study of NGR-hTNF Plus Doxorubicin in Relapsed Ovarian Cancer (OC)

5022 Background: NGR-hTNF consists of tumor necrosis factor fused with the peptide NGR, which selectively binds to a CD13 overexpressed on tumor blood vessels. NGR-hTNF is able to increase the intratumoral doxorubicin distribution by altering tumor vasculature. METHODS OC patients failing at least one prior platinum-taxane line and with platinum-free interval either lower than 6 months (PFI<6) or between 6 to 12 months (PFI<12) received NGR-hTNF 0.8 µg/m2 and doxorubicin 60 mg/m2on day 1 every 3 weeks. Doxorubicin was maintained up to 8 cycles and NGR-hTNF until disease progression. Primary endpoint was response rate. A 2-stage study design assumed that ≥2/17 and ≥6/37 patients with objective response would warrant further testing. RESULTS Thirty-seven patients (25 with PFI<6; 12 with PFI<12) pretreated with 1 to 5 chemotherapy lines (median 1) were enrolled. Median age was 57 years (range 35-72) and 32 patients presented with a PS of 0. Median PFI was 4.6 months (95% CI 3.4-5.8). Baseline CA125 ranged from 6 to 5,787 U/mL (median 549). Median baseline neutrophil-to-lymphocyte ratio (NLR), an index of systemic host immune response to tumor, was 2 (range 1-17). In total, 172 cycles were given (median 4; range 1-8). Neither increase of doxorubicin-related toxicities nor grade 3-4 NGR-hTNF related toxicity were registered. Common grade 1-2 toxicity were transient chills (58%). After first study stage (n=17), 6 patients showed partial response (2 with PFI<6; 4 with PFI<12) and the trial met its primary endpoint. After study completion (n=37), a total of 17 patients had experienced stable disease (10 with PFI<6; 7 with PFI<12), yielding an overall disease control rate of 66% (92% in PFI<6; 48% in PFI<12). Median progression-free survival (PFS) was 5.0 months (95% CI 4.4-5.6) in overall population, 3.7 months in patients with PFI<6, and 8.2 months in patients with PFI<12. Moreover, median PFS was 7.8 vs 3.4 months (HR=0.37; p=0.01) in patients with baseline NLR lower or higher than the median value, respectively. After a median follow-up of 5.1 months, 31 patients (84%) were still alive. CONCLUSIONS Tolerability and activity of NGR-hTNF plus doxorubicin deserve further randomized testing versus doxorubicin alone in platinum-resistant/refractory OC.