Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe.

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.

Two-month stop in mammographic screening significantly impacts on breast cancer stage at diagnosis and upfront treatment in the COVID era.

INTRODUCTION: The present analysis aims to evaluate the consequences of a 2-month interruption of mammographic screening on breast cancer (BC) stage at diagnosis and upfront treatments in a region of Northern Italy highly affected by the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus. METHODS: This retrospective single-institution analysis compared the clinical pathological characteristics of BC diagnosed between May 2020 and July 2020, after a 2-month screening interruption, with BC diagnosed in the same trimester of 2019 when mammographic screening was regularly carried out. RESULTS: The 2-month stop in mammographic screening produced a significant decrease in in situ BC diagnosis (-10.4%) and an increase in node-positive (+11.2%) and stage III BC (+10.3%). A major impact was on the subgroup of patients with BC at high proliferation rates. Among these, the rate of node-positive BC increased by 18.5% and stage III by 11.4%. In the subgroup of patients with low proliferation rates, a 9.3% increase in stage III tumors was observed, although node-positive tumors remained stable. Despite screening interruption, procedures to establish a definitive diagnosis and treatment start were subsequently carried out without delay. CONCLUSION: Our data showed an increase in node-positive and stage III BC after a 2-month stop in BC screening. These findings support recommendations for a quick restoration of BC screening at full capacity, with adequate prioritization strategies to mitigate harm and meet infection prevention requirements.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: A multicenter Italian experience.

PURPOSE: The everolimus and exemestane combination represents a treatment option for the endocrine sensitive metastatic breast cancer (MBC) patients. The toxicity profile reported in the Bolero 2 trial showed the feasibility in the selected patients. Few data are available for the unselected population. METHODS: In order to evaluate the safety in the unselected population of the clinical practice and to evaluate a possible association of toxicities with previous treatments, clinical data from 181 consecutive patients were retrospectively collected. RESULTS: Due to toxic events, everolimus dosage was reduced to 5 mg in 27% of patients. No association was found in the analysis between toxicity and number of prior therapies, neither between toxicity and response. In the multivariate analysis the previous exposure to anthracyclines for advanced disease represents the only predictive factor of developing grade ≥2 toxicity (OR = 2.85 CI 95% 1.07-7.59, p = 0.036). CONCLUSIONS: The association of everolimus and exemestane has confirmed to be a safe and effective treatment for endocrine sensitive MBC patients even in routine clinical practice. The rate of treatment discontinuation due to toxicity is low and none association between previous number of treatments and response or between toxicity and response was found.

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial.

BACKGROUND: The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line. PATIENTS AND METHODS: NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point. RESULTS: KRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71-1.41, P = 0.977; OS = 1.24, 95% CI 0.87-1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45-1.47; wild-type KRAS 0.79, 95% CI 0.57-1.10). CONCLUSION: In TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients. CLINICAL TRIAL REGISTRATION: NCT00637910.

Optimal tolerability and high efficacy of a modified schedule of lapatinib-capecitabine in advanced breast cancer patients.

PURPOSE: Diarrhea in relation to the lapatinib-capecitabine regimen is a common and debilitating side effect which may interfere with optimal treatment delivery. We performed a post hoc analysis in human epidermal growth factor receptor 2-positive advanced breast cancer patients treated with a modified schedule in its administration, aimed primarily to evaluate grade (G) ≥ 2 diarrhea incidence and, secondarily, treatment efficacy. PATIENTS AND METHODS: Treatment schedule consisted of lapatinib 1,250 mg daily for the first 10 days, then in combination with capecitabine, 2,000 mg/m(2), starting day 11 for the first cycle, and thereafter from day 8, for 14 days of a 21-day cycle, in 3 daily administrations. Lapatinib was dissolved in water, and cholestyramine was continuously given twice a day. RESULTS: Among 38 patients treated and analyzed, the incidence of G ≥ 2 diarrhea was 13.2 %. In 28 patients diarrhea was not observed, while G1-2 diarrhea was reported in 9 (23.7 %) patients; a single episode of G3 diarrhea was observed in 1 (2.6 %) patient. Overall response rate was 34.2 %, clinical benefit 55.3 %, and median progression-free survival 10 months. CONCLUSION: The results of the present post hoc analysis are very encouraging, both in terms of tolerability and treatment efficacy, and all data compare favorably with previous reports of "conventional" administration of the lapatinib-capecitabine regimen.

Recurrence risk in small, node-negative, early breast cancer: a multicenter retrospective analysis.

PURPOSE: Recurrences and deaths are known to occur, even if less frequently, in small, node-negative breast cancer patients, and decision on adjuvant treatments remains controversial. In the present analysis, we evaluate recurrence risk in patients with pT1 a, b, c, node-negative, breast cancer, accordingly with some prognostic biological factors. METHODS: We retrospectively evaluated 900 node-negative patients (pT1a, b, c) surgery treated between 2000 and 2009 in four Italian oncologic centers. We defined 3 different cohorts: ER positive (ER+); Her-2 positive (Her-2+); and triple negative (TN). RESULTS: pT1a was seen in 7.6% of patients, 37.7 % pT1b, 54.8 % pT1c. Concerning the 3 different cohorts, 58.2 % were ER+; 10.8 % were Her-2+; 8.2 % were TN. Overall, chemotherapy was given to 3.0 %, 27.2 %, 69.8 % of pT1a, b, c, respectively, and to 22.7 %, 58.8 %, 68.9 % of ER+, Her-2+, TN subgroups. At a median follow-up of 67 months, 5-year DFS was 96.3 %, 89.2 %, 89.4 % in pT1a, b, c, respectively (100 %, 93.6 %, 89.8 % in ER+; 100 %, 78.7 %, 85.0 % in Her-2+; 100 %, 76.8 %, 85.2 % in TN) (p = ns). At multivariate analysis, histologic grade and Ki-67 resulted independent prognostic factors. Overall, 5-year OS was 98 %, without differences among pT1a, b, c, or among the 3 cohorts. CONCLUSIONS: Overall, 5-year DFS was very favorable in this series of small, node-negative breast cancers, but Her-2+ and TN cohorts have a higher recurrence rate than ER+ cohort (p < 0.0001); pT1c, but also pT1b, in Her-2+ and TN subgroups, have a worse outcome, and effective chemotherapy treatment should be considered in these unfavorable subgroups.

Weekly epirubicin plus docetaxel as first-line treatment in metastatic breast cancer.

This study was designed to evaluate the efficacy and tolerability of a weekly schedule of epirubicin in combination with docetaxel in the first-line treatment of patients with metastatic breast cancer (MBC). A total of 43 women with MBC not previously treated with chemotherapy for metastatic disease received weekly epirubicin 25 mg m(-2) and docetaxel 25 mg m(-2) for a maximum of five cycles (total cumulative epirubicin dose of < or =900 mg m(-2)). Dose reduction was not permitted. Objective response and evaluation of toxicity profile were the primary study end points; time to progression and overall survival were secondary end points. Patients were followed for a median of 21 (4-38) months. Analysis was by intent to treat; 33 patients completed five cycles of therapy, and the median dose of epirubicin administered to the 43 patients was 23 mg m(-2). Twenty-five patients (58%) achieved a partial response and one (2%) achieved a complete response. An additional 12 patients (28%) had stable disease. The median time to progression was 11 months (95% confidence intervals (CI) 7-14) overall, and 13 months (95% CI 12-14) in the 26 patients who responded to treatment. Median overall survival was 25 months for responders and 14 months for nonresponders. Grade 3/4 neutropenia occurred in 16% of patients and in 6% of cycles. One patient developed cardiac toxicity (20% reduction in left ventricular ejection fraction). The combination of epirubicin plus docetaxel is highly active in MBC, with a manageable toxicity profile. Such a weekly schedule might provide a valuable treatment option for MBC.

Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC).

This study was performed to determine the activity of adding continuous infusion (CI) of 5-fluorouracil (5-FU) to gemcitabine (GEM) vs GEM alone in advanced pancreatic cancer (APC). In all, 94 chemo-naïve patients with APC were randomised to receive GEM alone (arm A: 1000 mg m(-2) per week for 7 weeks followed by a 2 week rest period, then weekly for 3 consecutive weeks out of every 4 weeks) or in combination with CI 5-FU (arm B: CI 5-FU 200 mg m(-2) day(-1) for 6 weeks followed by a 2 week rest period, then for 3 weeks every 4 weeks). Overall response rate (RR) was the primary end point and criteria for decision were planned according to the Simon's optimal two-stage design. The overall RR was 8% (arm A) and 11% (arm B) (95% confidence interval: 0.5-16% and 2-22%), respectively, and stable disease was 29 and 28%. The median duration of RR was 34 weeks (range 25-101 weeks) for GEM and 26 weeks (range 16-46 weeks) for the combination. The median progression-free survival (PFS) was 14 weeks (range 2-65 weeks) and 18 weeks (range 4-51 weeks), respectively. The median overall survival (OS) was 31 weeks (range 1-101 weeks) and 30 weeks (1-101 weeks). Toxicity was mild in both arms. This study does not show promising activity in terms of RR, PFS and OS for the double combination arm in APC.

A partial response in anaplastic carcinoma of the thyroid with liposomal doxorubicin.

Anaplastic thyroid carcinoma is a rare disease with a poor prognosis. Surgery represents the curative treatment for limiting the disease. In the presence of locoregional disease, not suitable for surgery, and for metastastic disease, chemotherapy represents the treatment option. Single agents chemotherapy can produce some responses; doxorubicin is an active drug with a rate of partial response lower than 20%. Association with cisplatin seems to be more active producing a higher rate of complete responses. Liposomal doxorubicin is a new class of anthracyclines, derived from a structural modification of doxorubicin, representing a new form of an old drug with pharmacological characteristics that facilitate a more easy elusion from immune system, a longer half-life, an increased tumor cell uptake and a reduced toxicity if compared with parental drug. Herein we report the first case of an anaplastic thyroid carcinoma treated with the use of liposomal doxorubicin. The encouraging response observed with single agent liposomal doxorubicin (70% according to RECIST criteria) deserves further investigations.

Gemcitabine and cisplatin in the treatment of elderly patients with advanced non-small cell lung cancer: impact of comorbidities on safety and efficacy outcome.

The aim of the study was to describe in detail the impact of aging and comorbidities on safety and efficacy of gemcitabine-cisplatin in the subset of elderly with advanced NSCLC. We report the results of our study which enrolled patients aged over 65 years or older. This study included 46 patients consecutively admitted to our Department. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 2, of a 21-day cycle. The Charlson score method was chosen to evaluate the conditions of comorbidity. All patients were evaluable for toxicity and 44 for activity. A total of 128 courses were administered, with a median of 3 courses per patient and a dose-intensity of 93% and 88% for gemcitabine and cisplatin, respectively. Grade 3-4 neutropenia (22% of patients) and grade 3 asthenia (4.5%), emesis (4.5%) and nephrotoxicity (4.5%) were the most severe adverse events. Univariate analysis of toxicity did not show any significant difference among all groups. The overall response rate was 45.6% (95% CI, 31.3-60). At a median follow up of 13 months, the median and progression-free survival were 15 and 8 months, respectively. The multivariate analysis resulted in objective response and disease control being predictive of longer survival. The combination of gemcitabine and cisplatin appears to be an effective and tolerated regimen for elderly patients with advanced NSCLC, regardless of aging and condition of comorbidities. Prospective randomized trials based on specific geriatric assessment are required to obtain compelling information for the optimal management of elderly patients with advanced NSCLC.

Weekly vinorelbine and docetaxel as second-line chemotherapy for pretreated non-small cell lung cancer patients: a phase I-II trial.

Docetaxel was proven to be effective as second-line therapy for patients with advanced NSCLC after failure of platinum-based front-line chemotherapy. We designed this phase I/II study to define the Maximum Tolerated Dose of weekly docetaxel combined with weekly vinorelbine, and subsequently evaluate tolerability and activity of this schedule in NSCLC patients who were progressive after treatment with either cisplatin and gemcitabine or carboplatin and paclitaxel regimens. To be eligible for the study, patients were required to have a WHO performance status < or =2, failure after at least two cycles of first platinum-based chemotherapy, and no prior treatment with docetaxel and vinorelbine. A total of 27 patients were enrolled in this phase I/II study. A weekly docetaxel dose of 25 mg/m2 was recommended in combination with fixed vinorelbine dose of 20 mg/m2, and 24 patients were treated at this dose level. Severe neutropenia (62%) and febrile neutropenia (29%) were the most frequent toxicities, with 83% of patients requiring dose modification or delay. In the phase II study, 5 (21%) patients obtained a partial response, 8 (33%) patients had stable disease, whereas 10 (42%) patients progressed. After a median follow-up of 18.7 months, median survival was 8 months, with 30% surviving at 1 year. Regardless of the use of weekly docetaxel schedule, this regimen was highly myelosuppressive, and did not seem to improve response rate and survival compared to single-agent docetaxel. No further developments of this schedule are warranted.

Response of metastatic epidermoid anal cancer to single agent irinotecan: a case report.

We report a case of a patient affected by epidermoid anal cancer who had hepatic progression after standard therapy with the Nigro regimen (fluorouracil and mitomycin C plus radiotherapy). This is an uncommon neoplasm against which only few chemotherapeutic agents have been tested. In our patient salvage treatment with low dose irinotecan resulted in a partial response.

Decreased myelotoxicity of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC) with cisplatin infusion on day 15.

In a multicenter phase II Italian trial that used a 28-day dosing schedule of gemcitabine on days 1, 8, and 15 and cisplatin on day 2, thrombocytopenia and neutropenia were the main dose-limiting toxicities observed. The aim of the present study was to determine whether using 15-day cisplatin in lieu of the standard 2-day schedule in combination with weekly gemcitabine would decrease expected myelotoxicities, particularly thrombocytopenia. Fifty-one patients with advanced non-small cell lung cancer (NSCLC), a median age of 62 years (range 31-76) and baseline Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1, were enrolled. Twenty-four patients had stage IIIA-B disease and 27 had stage IV. Patients received gemcitabine 1000 mg/m(2) on days 1, 8, 15, and cisplatin 100 mg/m(2) on day-15, every 28 days for a total of 151 cycles. All patients were evaluable for toxicity. Grades 3 and 4 thrombocytopenia was observed in 16% of patients, grades 3 and 4 neutropenia in 35% of patients, and grade 3 anemia in 4% of patients (no grade 4 anemia). Nonhematologic toxicity was mild. Two patients had grade 3 vomiting, and another had grade 4 hepatic toxicity only after gemcitabine administration. The dose intensity of gemcitabine and cisplatin was well maintained. Of the 45 patients evaluable for response, there were 22 (49%) partial responders, 7 (15.5%) minimal responders, 9 (20%) with stable disease, and 7 (15.5%) progressions. Compared with the schedule used in a multicenter phase II Italian trial (day 2 cisplatin), day-15 cisplatin decreases incidences of thrombocytopenia (16 vs. 52%) and anemia (4 vs. 25%); the occurrence of neutropenia is similar (35 vs. 36%). Response rates are also similar (49 vs. 54%).

Capecitabine and oxaliplatin in advanced colorectal cancer: a dose-finding study.

PURPOSE: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer (ACRC). The aim of this dose-finding trial was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the activity of the combination in patients with advanced colorectal cancer. PATIENTS AND METHODS: Twenty-five chemotherapy-pretreated patients received the combination of capecitabine and oxaliplatin. Capecitabine was administered orally twice a day continuously for 14 days in doses ranging from 1,650 to 2,500 mg/m2/d, and oxaliplatin was administered as a two-hour infusion on day 1 using dose, ranges from 100 to 130 mg/m2 repeated every three weeks. RESULTS: Twenty-five patients were assessable for toxicity, and DLTs were diarrhea (grade > or = 3: 27%) and stomatitis (grade > or = 3: 9%) at dose level VI. Dose level V (capecitabine 2500 mg/m2 and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal, overall neurotoxicity (grade 1-4) was 27% with 1% grade 3-4. A global response rate was 17% (95% confidence interval (95% CI): 2%-32%) and the median overall survival was 12 months. CONCLUSION: The recommended dose for further phase II studies is capecitabine 2,500 mg/m2/d with intermittent schedule and oxaliplatin 120 mg/m2 every three weeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitis and vomiting. This combination should be studied in phase II trials in advanced colorectal.

Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature.

BACKGROUND: Malignant insulinoma is a rare tumor. Metastatic disease confined to the liver can be treated with various locoregional treatments. CASE REPORT: We report a case of a young woman who developed liver metastases twelve years following resection of a pancreatic insulinoma positive to anti-insulin antibodies. With five cycles of intra-arterial locoregional chemotherapy (fluorouracil and epirubicin) to the liver and monthly hormone therapy (octreotide) the patient obtained a clinical complete response. After twelve months she is still disease free. CONCLUSION: Locoregional therapy for insulinoma metastatic to the liver might represent the treatment of choice; hepatic intra-arterial chemotherapy is an interesting therapeutic approach which deserves attention. The role of somatostatin analogs is limited to symptom control.

[Atrial fibrillation in a patient with non-small-cell carcinoma of the lung in the course of paclitaxel therapy]. / Fibrillazione atriale in un paziente affetto da Non Small Cell Lung Cancer in corso di chemioterapia con paclitaxel.

We report a clinical case of a patient with NSCLC who experienced an atrial fibrillation during paclitaxel infusion. Before chemotherapy, his cardiological function was normal. No cardiovascular and/or thyroid associated disease were previously reported. The patient did not receive any drugs with pro-arrhythmic effects. Incidence of cardiovascular toxicity in patients treated with paclitaxel is low, and does not justify strict cardiological monitoring otherwise deserved to patients with preexistent risk factors.