Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

PURPOSE: Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS: A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS: Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION: Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Real world data of niraparib in platinum sensitive relapsed ovarian cancer: A multicenter experience of the MITO group.

OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.

Long-Term Outcomes With Pharmacological Ovarian Suppression During Chemotherapy in Premenopausal Early Breast Cancer Patients.

BACKGROUND: Although use of gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is an established strategy to protect ovarian function in premenopausal breast cancer patients, no long-term safety data are available, raising some concerns in women with hormone receptor-positive disease. There are controversial data on its fertility preservation potential. METHODS: The Prevention of Menopause Induced by Chemotherapy: a Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6 (PROMISE-GIM6) trial is a multicenter, randomized, open-label, phase III superiority trial conducted at 16 Italian centers from October 2003 to January 2008. Eligible patients were randomly assigned to (neo)adjuvant chemotherapy alone (control arm) or combined with the GnRHa triptorelin (GnRHa arm). The primary planned endpoint was incidence of chemotherapy-induced premature ovarian insufficiency. Post hoc endpoints were disease-free survival (DFS), overall survival (OS), and post-treatment pregnancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Of 281 randomly assigned patients, 80.4% had hormone receptor-positive breast cancer. Median follow-up was 12.4 years (interquartile range = 11.3-13.2 years). No differences in 12-year DFS (65.7% [95% CI = 57.0% to 73.1%] in the GnRHa arm vs 69.2% [95% CI = 60.3% to 76.5%] in the control arm; HR = 1.16, 95% CI = 0.76 to 1.77) or in 12-year OS (81.2% [95% CI = 73.6% to 86.8%] in the GnRHa arm vs 81.3% [95% CI = 73.1% to 87.2%] in the control arm; HR = 1.17, 95% CI = 0.67 to 2.03) were observed. In patients with hormone receptor-positive disease, the hazard ratio was 1.02 (95% CI = 0.63 to 1.63) for DFS and 1.12 (95% CI = 0.59 to 2.11) for OS. In the GnRHa and control arms, 9 and 4 patients had a posttreatment pregnancy, respectively (HR = 2.14, 95% CI = 0.66 to 6.92). CONCLUSIONS: Final analysis of the PROMISE-GIM6 trial provides reassuring results on the safety of GnRHa use during chemotherapy as a strategy to preserve ovarian function in premenopausal patients with early breast cancer, including those with hormone receptor-positive disease.

Olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer: Japan subset from the PAOLA-1/ENGOT-ov25 trial.

OBJECTIVE: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1. METHODS: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint). RESULTS: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11-1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16-2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab. CONCLUSION: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02477644.

Characteristics and outcome of BRCA mutated epithelial ovarian cancer patients in Italy: A retrospective multicenter study (MITO 21).

OBJECTIVE: Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. METHODS: We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. RESULTS: Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2-80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. CONCLUSIONS: This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.

Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial.

AIM: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours. PATIENTS AND METHODS: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. RESULTS: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. CONCLUSION: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

The MITO CERV-2 trial: A randomized phase II study of cetuximab plus carboplatin and paclitaxel, in advanced or recurrent cervical cancer.

BACKGROUND: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients. PATIENTS AND METHODS: ARCC patients, ECOG PS ≤ 1, were randomized to CP for 6 cycles with or without CET (400 mg/m2 one week before starting CP, then 250 mg/m2 weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5 months expected median EFS and a 6.4 months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis. RESULTS: 108 patients were assigned to CP (n = 53) or CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23 months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 months (one-tail P = 0.43), median PFS was 5.2 and 7.6 months (one-tail P = 0.20) and median OS was 17.7 and 17 months (one-tail P = 0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance. CONCLUSION: CP-CET was not more active than CP alone in unselected ARCC patients.

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.

Safety of epirubicin adjuvant chemotherapy in a breast cancer patient with chronic renal failure undergoing hemodialytic treatment.

Anthracycline-based adjuvant chemotherapy is very effective in early breast cancer, but there are limited data on the use of epirubicin in patients with chronic renal failure undergoing hemodialytic treatment. We report the case of a patient with early breast cancer and chronic renal failure who was treated with adjuvant weekly epirubicin. Treatment was well tolerated. The patient is still alive and relapse free 58 months after surgery. If the patient will be disease free after 5 years, she will be reconsidered for renal transplantation. In conclusion, weekly epirubicin appears to be a safe adjuvant chemotherapy option for early breast cancer patients with chronic renal failure undergoing hemodialytic treatment.

HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.

BACKGROUND: HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. PATIENTS AND METHODS: HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest. RESULTS: Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. CONCLUSION: HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

Cancer of the penis.

Cancer of the penis is rare in Europe, accounting for less than 0.5% of all cancers. Phimosis and poor hygiene are strong risk factors whereas neonatal circumcision is a contributing factor in the prevention of this disease. More than 95% of penile carcinomas are squamous cell carcinomas. Early disease (stage I-II) is curable in most patients, who can be treated by conventional penile amputation or, in selected cases, by organ preserving techniques, including Moh's micrographic surgery, laser ablation or radiation therapy (external-beam, brachytherapy). For more advanced primary tumours, penile amputation is required. Survival of patients with penile cancer is strongly related to the presence and extent of nodal metastases. Bilateral inguinal lymphadenectomy is recommended for palpable lymph nodes that persist 3 or more weeks after removal of the primary tumour and a course of antibiotic therapy. In patients with proven inguinal lymph node metastases, bilateral ileoinguinal dissection should be performed. When the nodes are clinically negative, "prophylactic" inguinal lymphadenectomy may be a reasonable approach in patients with invasive tumours (T2 or greater), high grade tumours, or tumours exhibiting vascular invasion. The role of chemotherapy, as adjuvant and neoadjuvant or primary treatment in metastatic disease, needs to be further explored in prospective clinical trials.

Weekly paclitaxel in metastatic breast cancer patients: a phase II study.

UNLABELLED: AIMS ANID BACKGROUND: Paclitaxel, a microtubule inhibitor, is one of the most active drugs in metastatic breast cancer. A weekly schedule, at a median dose-intensity of 91 mg/m2, is effective and has less side effects than a 3-week schedule. In this phase II study, we evaluated the toxicity and the activity of weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. STUDY DESIGN: Between February 1999 and February 2001, 26 patients with metastatic breast cancer were treated with weekly paclitaxel (60-90 mg/m2/1 hour iv infusion/weekly). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, paclitaxel was stopped after 6 months of therapy. RESULTS: At a median follow-up of 18.7 months (range, 6.8-30.8), all patients are assessable for response and toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and 10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1-48.5). The median duration of response was 7.6 months (range, 1.8-12.4); median time to progression was 4.86 months (range, 1.4-12.4); median overall survival was 9.9 months (range, 1.7-29.2+). Treatment was well tolerated. Hematological toxicity was mild and only one patient developed grade 3 anemia. Two patients experienced grade 3 cardiovascular toxicity; both had received anthracycline-based regimens. CONCLUSIONS: In our experience, weekly administration of paclitaxel shows a substantial degree of activity even in pretreated metastatic breast cancer patients. The toxicity profile is favorable.