C. Pisano

Carboplatin and Pegylated Liposomal Doxorubicin for Advanced Ovarian Cancer: Preliminary Activity Results of the MITO-2 Phase III Trial

Background: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. Patients and Methods: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m2 or PLD 30 mg/m2 every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). Results: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). Conclusions: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group

Anthracyclines and platinum derivates are active drugs for advanced endometrial carcinoma (AEC), but new schedules with higher efficacy and better tolerability are needed. A phase II study was conducted to describe activity and tolerability of carboplatin (C)+pegylated liposomal doxorubicin (PLD) in patients with AEC. Patients with chemonaive AEC, PS ⩽2, aged <75 years, with at least one measurable lesion were eligible. Treatment was C (area under curve 5)+PLD (40 mg m−2) on day 1 every 4 weeks, up to six cycles. Forty-two patients were needed in a single-stage design, with at least 13 objective responses to define the treatment active. Forty-two patients were enrolled. Median age was 64 years (31–74). A total of 64% of patients were recurrent while 36% were advanced. Three complete (7%) and 22 partial responses (52%) were observed, for an overall response rate of 59.5% (95% exact CI: 43.3–74.3). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of patients) were grade 3/4 neutropaenia 33%/14%, febrile neutropaenia 5%, grade 3/4 thrombocytopaenia 17%/5%, grade 3/4 anaemia 31%/2%. Skin toxicity was mild: grade 1 14%, grade 2 10%, grade 3 5%. Hair loss: complete 5%, partial 12%. The combination of carboplatin and PLD shows good activity and favourable toxicity as first-line chemotherapy of patients with AEC, deserving further studies in this setting.

Prognostic impact of pretreatment neutrophil-to-lymphocyte ratio in castration-resistant prostate cancer patients treated with first-line docetaxel

Abstract Background: The neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, has been associated with poor outcome in several solid tumors, including prostate cancer. We retrospectively investigated the prognostic role of pretreatment NLR in metastatic castration-resistant prostate cancer (mCRPC) patients treated with first-line docetaxel. Methods: All CRPC patients treated with first-line docetaxel at two Italian institutions, with available data about baseline neutrophil and lymphocyte values, were included in this retrospective analysis. Patients were divided in two groups according to NLR ratio (low NLR: ≤3; high NLR: >3). Outcome measures were progression-free (PFS) and overall survival (OS), measured from the start of docetaxel treatment. Univariate and multivariate analysis (adjusting for baseline prostate-specific antigen, alkaline phosphatase, lactate dehydrogenase, hemoglobin, albumin, performance status, use of opioids and presence of visceral disease) were performed. Results: One hundred and seventy-nine patients treated between 2004 and 2016 were analyzed and 110 had information about pretreatment NLR. Forty-six patients (42%) had low NLR and 64 (58%) had high NLR. Median PFS was 8.8 months in patients with low NLR versus 7.3 months in those with high NLR [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.75–1.69, p = .58]. Median OS was 34.9 months in patients with low NLR versus 20.2 months in those with high NLR (HR 1.85, 95% CI 1.07–3.19, p = .02). At multivariate analysis, NLR confirmed an independent impact on OS (HR 3.16, 95% CI 1.50–6.65, p = .002). Conclusion: In this retrospective series, metastatic CRPC patients who started first-line docetaxel with a low pretreatment NLR had a significantly better survival. In addition to known prognostic factors, NLR can be useful to improve prognostic evaluation of patients in this setting.

Multidisciplinary treatment of early stage endometrial cancer.

Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.

Trabectedin in Ovarian Cancer: Is it now a Standard of Care?

In patients with recurrent ovarian cancer, the choice of second-line therapy is complex. Several factors have to be considered, such as platinum-free interval (PFI), residual toxicity from the previous treatments, BRCA1/2 gene mutation status. Trebectedin is a minor groove DNA binder derived from a marine organism that has shown efficacy in different settings in ovarian cancer therapy. It has been approved in the treatment of partially platinum sensitive (PPS) (PFI between 6 and 12 months) relapsed ovarian cancer according to the statistically significant progression-free survival (7.3 versus 5.8 months) and overall survival (22.2 versus 18.9 months) benefit compared with single-agent pegylated liposomal doxorubicin (PLD) in the OVA 301 phase III trial. This drug has been shown to prolong the time to first subsequent treatment and improve the efficacy of further platinum-based chemotherapy. The role of trabectedin/PLD followed by platinum combination compared with the reverse sequence in PPS is actually in evaluation in the INOVATYON phase III study, which will clarify the best sequence to be adopted in this setting. Trabectedin has been shown to be active in patient carriers of BRCA mutations, probably for its mechanism of action directly affecting DNA and it is actually tested as a single agent in some phase III trials in BRCA mutated and BRCAness ovarian cancer patients. Trabectedin is also active on the immune system. There is, therefore, the rational for new trials of a combination with immune checkpoint inhibitors.

Metastatic Renal Medullary Carcinoma Treated With Immune Checkpoint Inhibitor: Case Report and Literature Review

Renal medullary carcinoma (RMC) is an uncommon type of kidney cancer. Most patients present with advanced disease at diagnosis, and the prognosis is extremely poor, with a median overall survival of 4 months. RMC is refractory to common target therapies used to treat renal-cell carcinoma. Vascular endothelial growth factor or mammalian target of rapamycin inhibitors demonstrate poor activity. Platinum-based combination chemotherapy provides the best palliative clinical benefit. There is no accepted standard second-line treatment. Greater understanding of the molecular mechanisms of malignancies have led to the development of immunotherapy. In renal-cell carcinoma, nivolumab, an antieprogrammed cell death 1 monoclonal antibody, showed an improvement in median overall survival and overall response rate compared to everolimus as second-line therapy. Because of RMC’s rarity, no prospective studies or large retrospective series are currently available. Only few case reports have reported responses with antieprogrammed cell death 1 immune checkpoint therapy in patients with RMC. This case report describes a clinical and radiologic response in a RMC patient treated with second-line nivolumab.

Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinumbased chemotherapy in patients with partially platinum-sensitive recurrent ovarian cancer

Background MITO-8 showed that prolonging platinum-free interval by introducing non-platinum-based chemotherapy (NPBC) does not improve prognosis of patients with partially platinum-sensitive recurrent ovarian cancer. Quality of life (QoL) was a secondary outcome. Patients and methods Ovarian cancer patients recurring or progressing 6-12 months after previous platinum-based chemotherapy (PBC) were randomized to receive PBC or NPBC as first treatment. QoL was assessed at baseline, third and sixth cycles, with the EORTC C-30 and OV-28 questionnaires. Mean changes and best response were analysed. Progression-free survival, response rate, and toxicity are also reported for proper interpretation of data. All analyses were based on intention-to-treat. Results Out of the 215 patients, 151 (70.2%) completed baseline questionnaire, balanced between the arms; thereafter, missing rate was higher in the NPBC arm. At mean change analysis, C30 scores were prevalently worse in the NPBC than PBC arm, statistical significance being attained for emotional functioning, global health status/QoL, fatigue, and dyspnoea (effect sizes ranging from 0.30 to 0.51). Conversely, as for OV28 scale, the other chemotherapy side-effects item was significantly worse with PBC at three and six cycles, with a larger effect size (0.70 and 0.54, respectively). At best response analysis, improvement of emotional functioning and pain and worsening of peripheral neuropathy and other chemotherapy side-effects were significantly more frequent in the PBC arm. Progression-free survival (median 9 versus 5 months, P = 0.001) and objective response rate (51.6% versus 19.4%, P = 0.0001) were significantly better with PBC. Allergy, blood cell count, alopecia, nausea, musculoskeletal, and neurological side-effects were more frequent and severe with PBC; hand-foot skin reaction, rash/desquamation, mucositis, and vascular events were more frequent with NPBC. Conclusion MITO-8 QoL analysis shows that deterioration of some functioning and symptom scales is lower with PBC, with improvement of emotional functioning and pain, despite worsening of toxicity-related items. ClinicalTrials.gov NCT00657878.

886PDTRABECTEDIN IN PATIENTS WITH BRCA MUTATED AND BRCANESS PHENOTYPE ADVANCED OVARIAN CANCER (AOC): PHASE II PROSPECTIVE MITO-15 STUDY

ABSTRACT Background: Trabectedin (Yondelis®) is a minor groove DNA binding agent with suggested activity in patients with defective homologous recombinant DNA repair. This prospective phase II study was designed to evaluate activity of trabectedin in patients with BRCA mutated and BRCAness phenotype AOC (EudraCT N: 2011-001298-17). Methods: AOC patients with documented BRCA mutation or BRCAness phenotype, defined as having had at least 2 previous responses to platinum therapy, were treated with trabectedin 1.3 mg/m2 as a 3-hour i.v. infusion every 3 weeks until disease progression. According to the platinum sensitivity at the time of enrollment, patients were stratified in platinum resistant (PR, Results: A total of 100 patients were enrolled and 88 were evaluable for response (46 PR, 42 PS) after a median follow up of 6 months (range: 1.5-20). Patients had a median age of 59 years (range 49-73); most had serous-papillary histology (86%) and 60% were grade 3. Patients were pretreated with a median of 4 (range 2-14) prior chemotherapy lines and received a median of 6 (range 1-15) trabectedin cycles with a median cumulative dose of 11.0 mg/m2 (range 1.9-30). In the whole population ORR was 41%, median PFS 4.5 months, while median OS was not reached (NR). Patients with BRCA mutations (n = 7), achieved 4 PR (57.1%), 1 SD and 2 PD. Among 518 administered cycles the most frequent grade 3/4 toxicities were neutropenia 17.3%, leukopenia 7.7% and elevation of liver aminotransferases 5.2%. Evaluation of responses according to BRCA mutational status, expression profiling and DNA polymorphisms of genes involved in DNA repair is still ongoing. Conclusion: Trabectedin represents a valid treatment option in patients with platinum-sensitive AOC and documented BRCA mutation or BRCAness phenotype after multiple platinum lines. n (%) ORR CR PR SD DCR (ORR +SD PD Median PFS (months) Median OS (months) PR n = 46 (%) 15 (32.6) 0 15 (32.6) 12 (26.1) 27 (58.7%) 19 (41.3) 2.7 10 PS n = 42 (%) 21 (50) 4 (9.5) 17 (40.5) 10 (23.8) 31 (73.8%) 11 (26.2) 6 NR ORR, overall response rate; CR, complete response; PR, partial response; SD, stabilization of disease; DRC, disease control rate; PD, progression of disease; PFS, progression-free survival; OS, overall survival; NR, not reached. Disclosure: C. Rigamonti: I am an employee of PharmaMar, S.A (Grupo Zeltia). All other authors have declared no conflicts of interest.