Antonio Frassoldati

Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results

BACKGROUND Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. PATIENTS AND METHODS Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. RESULTS At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). CONCLUSIONS Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. CLINICAL TRIALS REGISTRATION NO NCT00171340.BACKGROUND Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. PATIENTS AND METHODS Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. RESULTS At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). CONCLUSIONS Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

Observational study on quality of life, safety, and effectiveness of first‐line cetuximab plus chemotherapy in KRAS wild‐type metastatic colorectal cancer patients: the ObservEr Study

Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real‐world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first‐line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ‐C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression‐free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab‐specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan—Incidence rate ratio [IRR] 1.72, P < 0.0001) and gender (male vs. female—IRR 1.38, P = 0.0008). Compliance at first postbaseline evaluation was 97.75%. Median overall survival was 23.6 months, median progression‐free survival 8.3 months. Cetuximab plus chemotherapy did not compromise QoL in the routine clinical setting when patients receive close monitoring plus prophylactic or reactive management of skin reactions. We observed the same correlation between overall survival (OS) and skin reactions reported in controlled clinical trials, also in this setting.

The management of skin toxicity during cetuximab treatment in advanced colorectal cancer: how much does it cost? A retrospecive economic assessment from a single-center experience

AIMS AND BACKGROUND Skin rash is a predictable and manageable side effect of anti-EGFR therapy such as cetuximab. The aim of this study is to estimate the costs for the foreseeable management of skin toxicity in patients treated with cetuximab in our institute in order to assess the direct medical economic impact. METHODS AND STUDY DESIGN We retrospectively analyzed all consecutive patients with advanced colorectal cancer treated with cetuximab at our institute from June 2006 to May 2011. We evaluated the severity and mean duration of skin rash for each grade and we identified the costs for the different therapeutic interventions. Patients were treated according to the general consensus management of skin toxicity associated with cetuximab treatment. RESULTS We evaluated 31 patients. The median follow-up was 28.95 months (range, 1.84-75.49). At last follow-up 10 patients (32.3%) were alive with metastases, 18 patients (58.1%) had died, 1 patient (3.2%) was alive without evidence of disease, and 2 patients (6.5%) were lost to follow-up. The median progression-free survival was 8.26 months and the median overall survival 32.89 months. Nineteen patients (61.3%) developed skin toxicities: 7 patients (22.6%) grade 1, 9 patients (29.0%) grade 2, 3 patients (9.7%) grade 3; no grade 4 skin toxicity was observed. The median duration of grade 1 toxicity was 79 days (no specific treatments were started), of grade 2 toxicity 95 days (cost range, € 199.50-294.50) and of grade 3 toxicity 64 days (cost range, € 159.42-233.90). CONCLUSIONS Our experience, through the analysis of nonselected cases, showed that the management of skin toxicities related to cetuximab is not so expensive. We recommend proper care of low-grade toxicities in order to reduce progression to high-grade toxicities and the resulting risk of hospitalization, which really impacts on costs.

Abstract P4-21-39: Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study

Background: In metastatic breast cancer, the CDK4,6 inhibitor palbociclib associated with fulvestrant proved superior to fulvestrant alone in HER2-negative breast cancer (NEJM 2015). In HER2-positive tumors, the dual blockade of the receptor plus an aromatase inhibitor led to a 21% rate of pCR in a neoadjuvant setting in ER+ cancers (J Clin Oncol 2013). In preclinical studies concomitant inhibition of CDK4,6 and trastuzumab led to synergistic antitumor activity (Cancer Cell 2016). The extent of early change and the persistence of Ki67 down-regulation are robust markers of the effects of endocrine treatments in hormone receptors positive breast carcinomas in the setting of neoadjuvant endocrine therapy (Ann Oncol 2012). Methods: In this exploratory Phase II trial (NCT02530424), women with invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy were treated with every 3 wks trastuzumab and pertuzumab for 6 cycles combined with palbociclib 125 mg po q.d. x 21 q. 4 wks and fulvestrant i.m. 500 mg, both given for 5 cycles (HPPF). The primary endpoint was characterization of Ki67 changes from baseline before therapy, at 2 weeks and at surgery. Results: A total of 23 patients with centrally confirmed HER2 and ER positive breast cancer were recruited for this study. Ki67 was also assessed centrally. At baseline 30% of cases were classified as locally advanced, 43% as cN0 and 78% had Ki67 values > 20%. Objective clinical response was documented in 96% of patients and pCR (absence of invasive cells in breast and axillary nodes) was documented in 22% (pCR in breast only was 26%). The geometric means of Ki67 expression assessed at baseline, after 2 weeks of treatment and at surgery were 30.8 (SD 15.1), 3.9 (SD 15.9) and 9.2 (SD 16.6) respectively. The mean change in Ki67 values from baseline to after 2 weeks was -24.5 (paired t-test: P grade 3 were reported. The most frequent G 3 adverse events were neutropenia (26% of patients) and gastrointestinal disorders (17%). Conclusions: Neoadjuvant triple targeting of ER, HER2 and Rb in HER2+/ER+ breast cancer treatment caused a significant and rapid decrease of Ki67 that was of larger magnitude after 2 weeks than at surgery irrespective of the recorded objective clinical response. The good tolerability, the rapid effect on Ki67, the consistent clinical response, and the rate of pCR with this chemotherapy-free approach support further clinical testing and additional molecular characterization. Supported in part by an unrestricted grant from Pfizer Italia S.r.l. and from Roche S.p.a. Italia Citation Format: Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-39.

Adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive early breast cancer: Evidence evaluation and GRADE recommendations by the Italian Association of Medical Oncology (AIOM)

Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice.

9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.

Background Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

[Oncological quality indicators and Colorectal Cancer Program: data from 2009-2010 of University Hospital in Ferrara, Italy].

The aim of this study is to analyse the oncological quality indicators on our Colorectal Cancer Program, that are reflective of the scope of care, feasible to implement and supported by evidence. We compared two different populations during the same period: patients referring to our Clinical Oncology Unit coming from Regional Colorectal Cancer Screening Program and the other population that was not in any Colorectal Cancer Program. On the basis of our experience, we concluded for high-quality care for both population. Any critical point should be carefully analysed in order to implement quality of care.