MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Combining PARP inhibition and immune checkpoint blockade in ovarian cancer patients: a new perspective on the horizon?

Immune checkpoint inhibitors (ICIs) have completely reshaped the treatment of many malignancies, with remarkable improvements in survival outcomes. In ovarian cancer (OC), however, this emerging class of drugs has not yet found a favorable use due to results from phase I and II studies, which have not suggested a substantial antitumoral activity of these agents when administered as monotherapy. Robust preclinical data seem to suggest that the combination ICIs with poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) may result in a synergistic activity; furthermore, data from phase II clinical studies, evaluating this combination, have shown encouraging outcomes especially for those OC patients not suitable for platinum retreatment. While waiting for ongoing phase III clinical trial results, which will clarify the role of ICIs in combination with PARPis in the newly diagnosed OC, this review aims to summarize the preclinical data and clinical evidence available to date.

Predictors of progression free survival, overall survival and early cessation of chemotherapy in women with potentially platinum sensitive (PPS) recurrent ovarian cancer (ROC) starting third or subsequent line(≥3) chemotherapy - The GCIG symptom benefit study (SBS).

BACKGROUND: Potentially platinum sensitive recurrent ovarian cancer (PPS ROC) is defined by a platinum-free interval of >6 months, and usually treated with platinum-based chemotherapy with variable response and benefit in women who have had 3 or more lines of chemotherapy(≥3). We identified baseline characteristics (health-related quality of life[HRQL] and clinicopathological factors), associated with PFS, OS and early progression (within 8 weeks). The goal is to improve patient selection for chemotherapy based on a nomogram predicting PFS. METHODS: HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with PFS and OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis were included in multivariable analyses using backward elimination to select those significant. Associations with stopping chemotherapy early were assessed with logistic regression. RESULTS: 378 women were enrolled, with median(m)OS and PFS of 16.6 months and 5.3 months, respectively. The majority had ECOGPS 0-1. Chemotherapy was stopped early in 45/378 participants (12%); with mOS 3.4 months (95% CI: 1.7-7.2). Physical function(PF), role function(RF), cognitive function(CF), social function(SF), Global Health Status(GHS) and abdominal/GI symptoms(AGIS) were significant univariable predictors of PFS(p < 0.030). SF remained significant after adjusting for clinicopathological factors; p = 0.03. PF, RF, CF, SF, GHS and AGIS were significant univariable predictors of OS (p < 0.007); PF, RF, SF and GHS remained significant predictors of OS in multivariable models; p < 0.007. Poor baseline PF and GHS were significant univariable predictors of stopping chemotherapy early (p < 0.007) but neither remained significant after adjusting for clinicopathological factors. CONCLUSION: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.

Quality-of-life analysis of the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG study comparing platinum-based versus non-platinum-based 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.

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.

Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results.

OBJECTIVE: We evaluated the rates of response, operability and long term survival and toxicities in a large series of locally advanced cervical cancer (LACC) patients administered neoadjuvant chemotherapy (NACT) with paclitaxel, epirubicin and cisplatin (TEP) followed by radical surgery (RS). Patients and methods The study included 75 consecutive stages IB2-IVA patients administered NACT with paclitaxel (175mg/m(2)), epirubicin (100mg/m(2)) and cisplatin (100mg/m(2)) on day 1 of a 3-weekly cycle for 2-4cycles. Patients were evaluated for objective response by RECIST criteria and triaged to RS. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of diagnosis to recurrence/progression of disease or death, respectively. RESULTS: Complete and partial clinical response was observed in 13 and 28 patients (56.1% objective responses); radical surgery was amenable in 52 patients (71.2%): 14 patients showed complete/microscopic response to treatment. Overall, recurrence/progression of disease was observed in 36 patients, and all of them experienced death of disease. In the whole series median PFS was 48months (5-year PFS=51.0%), and median OS was 72months (5-year OS=53.0%). Overall, 195 courses were administered; treatment was delayed in 6.7% of patients, while dose reduction was required in 36.5% of patients. Grade 3 leukopenia affected 22 patients (29.7%), while Grades 3 and 4 neutropenia was documented in 17 (22.9%) and 6 (8.1%) patients. In the whole series, we recorded 1 death whose relation with treatment-induced toxicity could not be ruled out. CONCLUSIONS: TEP provided favorable rates of response and operability in LACC patients, and allowed the obtainment of encouraging survival data without carrying out an excessive toxicity.

Successful multimodal treatment of a breast cancer patient with a recurrence invading the chest wall.

We describe successful operative management of a solitary breast cancer metastasis in the chest wall after complete response with concomitant non-pegylated liposomal doxorubicin (NPLD) and docetaxel followed by sternal rib resection with prosthetic reconstruction. We report a case of a 41-year-old woman who had a breast cancer recurrence infiltrating neighboring osteo-cartilage of the left sternal body, the cartilaginous portion of the third and fourth ipsilateral ribs and was inseparable from the rear side pectoral reaching deep into contiguity with the pericardium. After 6 cycles of chemotherapy with NPLD plus docetaxel, sternal rib resection with prosthetic reconstruction was performed. Histological examination did not show any evidence of residual tumor. At 9 months of follow-up, the patient appears free of disease. Our case demonstrates that a multimodal approach in patients with chest wall recurrence of breast cancer without distant metastasis, may be safe and effective for maintaining a good quality of life.

The 'lead vessel': a vascular ultrasound feature of metastasis in the ovaries.

OBJECTIVE: To investigate, in a series of metastatic and primary invasive ovarian lesions examined by color Doppler, the prevalence of a main peripheral vessel penetrating into the central part of the ovarian mass with a tree-shaped morphology, defined as the 'lead vessel'. METHODS: This was a retrospective study of 31 patients with histopathologically confirmed metastatic involvement of the ovary and 106 patients with confirmed primary invasive ovarian carcinoma, who had undergone standardized ultrasound examination, with established definitions of ultrasound characteristics. We retrieved sonographic images and videoclips, focusing on the detection of the lead vessel. RESULTS: The presence of the lead vessel was detected in 11/31 (35.4%) metastatic ovarian tumors, and in only two (0.01%) cases of primary ovarian carcinoma (P = 0.0001). At color Doppler analysis, metastatic ovarian lesions were characterized by significantly lower pulsatility index (P = 0.0001) and resistance index (P = 0.0001) values, and significantly higher peak systolic velocity (P = 0.0002) and time-averaged maximum velocity (P = 0.04) values, when compared with primary ovarian carcinomas. The lead vessel was detected in 11/21 (52%) solid metastatic lesions and in no cases of multilocular or multilocular-solid lesions (P = 0.008). CONCLUSION: The lead vessel is a novel sonographic feature of vascular morphology in solid ovarian metastases. The more frequent observation of this feature in metastatic ovarian tumors compared with primary invasive ovarian carcinomas warrants further investigation in order to explore its potential role in the diagnosis of metastatic ovarian masses.

Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study.

BACKGROUND: A prospective phase II study was conducted to evaluate the efficacy and toxicity of the combination docetaxel (Taxotere) (DTX) and oxaliplatin (OXA) in ovarian cancer patients recurring after a platinum-free interval (PFI) >12 months. PATIENTS AND METHODS: DTX, 75 mg/m(2), was administered by 60 min i.v. infusion, followed by OXA, 100 mg/m(2), given by a 2 h i.v., on day 1 every 21 days. RESULTS: From October 2003 to June 2006, 43 ovarian cancer patients were enrolled. Median PFI was 26 months. All patients were available for response evaluation: 17 complete responses and 12 partial responses were registered, for an overall response rate of 67.4%. The median response duration was 10 months. Stable disease was documented in 11 patients (median duration = 5.5 months). The median time to progression and overall survival were 14 and 28 months. A total of 259 courses were administered. Grade 3-4 leukopenia was documented in 32.5% of the patients, while no case of severe anemia and thrombocytopenia was observed. Grade 3-4 neurotoxicity and grade 2 alopecia were observed in 9.3% and 34.9% of cases, respectively. CONCLUSION: DTX/OXA combination is an active regimen with a favorable toxicity profile, for treatment of recurrent platinum-sensitive ovarian cancer patients.

Color Doppler velocimetry and three-dimensional color power angiography of cervical carcinoma.

OBJECTIVES: To investigate the blood flow within invasive cervical carcinoma by transvaginal two-dimensional (2D) color spectral Doppler and three-dimensional (3D) color power angiography and to correlate these parameters with the clinicopathological characteristics. METHODS: Seventy-four patients with invasive cervical carcinoma were enrolled for the analysis. Squamous cell carcinoma serum antigen levels (SCC) were obtained for all the patients. Sections of all malignant tissues were analyzed for tumor expression of cyclooxygenase-2 (COX-2). All patients underwent color and spectral Doppler examination and 44 patients had 3D color power angiography. Color spectral Doppler parameters (color score, lowest resistance index (RI), highest peak systolic velocity (PSV)) and 3D color power angiography indices (relative color, average color, flow measure) of FIGO I/II cervical cancers were compared with those obtained in a control group of 24 patients with a normal uterine cervix. Pulsed Doppler parameters and the 3D vascular indices were compared with clinicopathological parameters, SCC serum antigen levels and tumor COX-2 expression. RESULTS: At color Doppler analysis 72 patients (97%) showed intralesional detectable vessels. Color spectral Doppler and 3D-derived parameters were significantly different in FIGO I/II cervical cancers compared with those in women with a normal cervix. A significantly higher color score (P = 0.0008), lower RI (P = 0.032) and higher PSV (P = 0.004) were associated with a tumor diameter > or =4 cm compared with smaller tumors. The highest PSV was significantly higher in patients with FIGO stage III/IV compared with FIGO stage I/II (P = 0.0069). There was a direct correlation between PSV and SCC (r = +0.44, P = 0.003). The median relative color was significantly higher in patients with a higher color score (P = 0.0006). No statistically significant correlations were found between 3D color power angiography parameters and the clinicopathological characteristics or between the 3D vascular parameters and biological factors. CONCLUSIONS: Alterations of 3D ultrasound-derived vascular indices were found in patients with cervical cancer compared with those with a normal cervix. Moreover, some vascular indices proved to be associated with tumor size. The assessment of a possible clinical role of 2D and 3D ultrasound-derived vascular indices in cervical cancer deserves further investigation.

Expression of cyclooxygenase-2 (COX-2) in tumour and stroma compartments in cervical cancer: clinical implications.

This study aims at investigating the relationship between cyclooxygenase-2 expression in tumour vs stroma inflammatory compartment and its possible clinical role. The study included 99 stage IB-IV cervical cancer patients: immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase-2. CD3, CD4, CD8, CD25, Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours. An inverse relation was found between cyclooxygenase-2 levels (cyclooxygenase-2 IDV) of tumour vs stroma compartment (r=-0.44, P<0.0001). The percentage of cases showing high tumour/stromal cyclooxygenase-2 IDV ratio was significantly higher in patients who did not respond to treatment (93.3%) with respect to patients with partial (60.5%), and complete (43.7%) response (P= 0.009). Cases with a high tumour/stroma cyclooxygenase-2 IDV ratio had a shorter overall survival rate than cases with a low tumour/stroma cyclooxygenase-2 IDV (P<0.0001). In the multivariate analysis advanced stage and the status of tumour/stroma cyclooxygenase-2 IDV ratio retained an independent negative prognostic role. The proportion of CD3(+), CD4(+), and CD25(+) cells was significantly lower in tumours with high tumour/stroma cyclooxygenase-2 IDV ratio, while a higher percentage of mast cells was detected in tumours showing high tumour/stroma cyclooxygenase-2 IDV ratio. Our study showed the usefulness of assessing cyclooxygenase-2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis.