Overestimation of Late Distant Recurrences in High-Risk Patients With ER-Positive Breast Cancer: Validity and Accuracy of the CTS5 Risk Score in the TEAM and IDEAL Trials.

PURPOSE: Most distant recurrences (DRs) in women with hormone receptor-positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS: The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS: A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION: The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

Safety and efficacy of fiducial marker implantation for robotic stereotactic body radiation therapy with fiducial tracking.

PURPOSE: The purpose of this study was to assess the feasibility, efficacy and toxicity of fiducial marker implantation and tracking in CyberKnife® stereotactic radiation therapy (SBRT) applied to extracranial locations. MATERIALS AND METHOD: This is a retrospective, single-centre, observational study to collect the data of all patients treated by stereotactic radiation therapy with fiducial marker tracking at extracranial locations, conducted between June 2014 and November 2017. Information regarding the implantation procedure, the types of toxicity related to marker implantation and the number of markers implanted/tracked during treatment were collected. Complication rates were evaluated using the CTCAE v4 [Common Terminology Criteria for Adverse Events] scale. The technical success rate was based on the ability to optimally track the tumor throughout all treatment fractions. RESULTS: Out of 2505 patients treated by stereotactic radiation therapy, 25% received treatment with fiducial marker tracking. The total number of implantation procedures was 616 and 1543 fiducial markers were implanted. The implantation-related complication rate was 3%, with 16 Grade 1 events and 4 Grade 2 events. The number of treated patients and the number of implanted markers has gradually increased since the technique was first implemented. The median treatment time was 27 min (range 10-76). 1295 fiducials were effectively tracked throughout all treatment fractions, corresponding to a technical success rate of 84%. The difference between the number of fiducials implanted and those tracked during treatment decreased significantly as the site's experience increased. CONCLUSION: Fiducial marker implantation and tracking is feasible, well-tolerated, and technically effective technique in SBRT for extracranial tumors.

Results of PONDx, a prospective multicenter study of the Oncotype DX® breast cancer assay: Real-life utilization and decision impact in French clinical practice.

Adjuvant chemotherapy shows clear benefits in HER2-positive and triple-negative breast cancer (BC). Its benefits are less universal in BCs expressing hormone receptors. The 21-gene Oncotype DX® Breast Recurrence Score test was designed for HR+, HER2- early-stage BC before decision on adjuvant chemotherapy. Its validity and utility was demonstrated prospectively across multiple studies. The observational study PONDx characterized the use of Oncotype DX® Breast in routine practice in France and evaluated its decision impact. Of 882 ER-positive BC patients (67% postmenopausal), most (79%) had N0/Nmic node involvement, grade 2 tumors (68%), tumor size 1-5 cm (88%), and ductal histology (78%). BCs with histopathologically elevated recurrence risk included grade 3: 18%; N1: 21%; Ki67 > 20%: 31%. Recurrence Score results by prognostic category were: <18: 54%, 18-30: 36%; >30: 10%. Compared to recommendations before individual availability of the score, results prompted net absolute reductions in chemotherapy recommendations of 36% (total population), and 29% (grade 3 and/or Ki67 > 20% histologies). Decisions reflected prognostic implications: in the Recurrence Score <18 category, 95% of patients received recommendations of hormonal therapy only, in the >30 category, 97.5% were recommended additional chemotherapy; 95% followed the final recommendations of their physicians. The Recurrence Score provides independent predictive and prognostic information in ER + N0/N1 early BC, including high-risk subgroups. PONDx further characterizes the population where the test is beneficial in real-life use and fits current clinical needs. Oncotype DX® Breast enables relevant net reductions in chemotherapy use, sparing patients from serious toxicities. Its therapeutic implications are highly accepted by physicians and patients.

Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO.

INTRODUCTION: Use of anthracyclines is often limited in older patients due to cardiac and hematologic toxicities. Thanks to its reduced toxicity profile, Pegylated Liposomal Doxorubicin (PLD) allows an extended use of doxorubicin to this population. We aimed at modeling PLD-induced hematotoxicity in patients with metastatic breast cancer ≥70 years old and at finding predictive factors of neutrophil nadir value. METHODS: Sixty patients, enrolled in the DOGMES prospective multicentric phase II trial, were treated with PLD at 40mg/m(2) every 28days during six cycles. Trial design included geriatric covariates assessment at inclusion and monitoring of cells count every week for three cycles. A population model was developed to describe hematopoiesis and hematopoietic reserve in these patients. The effect of co-administered G-CSF (granulocyte colony-stimulating factor) was also examined. RESULTS: A pharmacodynamic model was built using data from 53 patients not receiving G-CSF. This model assumed an instantaneous effect of PLD on the system. Based on this model, exact neutrophil nadir value was computed and ranged between 0.069K/mm(3) and 2.63K/mm(3) confirming the weak hematotoxicity of PLD. The same model was then applied to the 7 patients receiving G-CSF and showed that basal neutrophil count was higher for these patients. No other difference was found between both cohorts. Among the covariates collected, three were predictive of neutrophil nadir value: diabetes, frailty syndrome and assistance at home. CONCLUSION: This developed model allowed the identification of predictive factors of nadir ANC and the identification of patients that are more likely to develop hematotoxicity that should be monitored with attention.

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.

PURPOSE: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODS: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSION: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.

BACKGROUND: Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). METHODS: The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. FINDINGS: 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. INTERPRETATION: Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. FUNDING: Pfizer.

Radiosurgery with or without A 2-mm margin for 93 single brain metastases.

PURPOSE: Retrospective comparison of Linac radiosurgery (RS) in 93 single brain metastases with or without a 2-mm margin. PATIENTS AND METHODS: A total of 153 patients had Linac RS (between April 1992 and June 2004), with 139 patients (90.8%) evaluable in June 2005. Sixty-one patients (44%) had extracranial lesions and 65 patients had neurologic symptoms (47%). RS alone: 105 patients (66%); RS +whole brain radiotherapy: 34 patients (24%). Single metastasis: 93/139 patients; classic RS: 42/93 patients; 2-mm margin: 51/93 patients; 30 multiple lesions patients were excluded. TREATMENT: 15 Mv X-ray Linac, circular minibeams, 8-30 mm, four to six noncoplanar coronal arcs. Isodose was 60-80%; doses were 10-20 Gy. FOLLOW-UP: 12 months-13 years; median, 14 months. RESULTS: Local control (LC) was not improved in 51 margin patients vs. 42 classic RS patients: 1 year: 69.1% and 72.4%. Two-year LC rate: 64% and 54.7%, respectively. Survival: median classic RS: 11.3 months; margin RS, 19 months (p = 0.34) and 1 year, 41.6% and 60.2%, respectively. Margin RS patients had a significantly higher rate of severe parenchymal complications: 19.6% vs. 7.1% (p = 0.02); surgery was necessary in 4 of 51 cases vs. 1 of 42 classic RS cases. CONCLUSION: No increase of 1- and 2-year LC rate in margin RS or survival and median survival: 11.3 vs. 19 months (NS) 2-mm margin associated with more severe parenchymal complications (p = 0.02). This procedure is therefore not recommended. Late CT images and 1-mm margin as recommended by pathologists, use of three-dimensional magnetic resonance imaging and fuzzy method to calculate volumes may yield better results. Stereotactic hypofractionation requires further studies.

A phase II study of an oxaliplatin/vinorelbine/5-fluorouracil combination in patients with anthracycline-pretreated and taxane-pretreated metastatic breast cancer.

The aim of this phase II study was to evaluate safety and efficacy of an oxaliplatin/vinorelbine/5-fluorouracil (FON) combination in anthracycline and taxane-pretreated metastatic breast cancer patients. The following treatment was given: on day 1 of a 21-day cycle, oxaliplatin 130 mg/m (2-h intravenous infusion); on days 1 and 5, vinorelbine [dose level (DL) 1: 17.5 mg/m; DL2: 22 mg/m]; on days 1-5, continuous infusion 5-fluorouracil (DL1: 600 mg/m/day; DL2: 750 mg/m/day). Forty-seven patients were treated (DL1: 43; DL2: 4). Median age was 54 years; 68% had liver metastases, 53% were taxane refractory/resistant and 38% were anthracycline refractory/resistant. Patients received a median of six treatment cycles. Of 46 eligible patients, 16 had partial response; the overall response rate was 34.8% (95% confidence interval 21.3-50.3%), 11 had stable disease lasting more than 4 months. Median follow-up was 13.0 months, median time to progression 5.7 months and estimated overall survival 18.8 months. DL2 was too toxic with three patients having grade 3-4 toxicity, including one death. At DL1, 26 patients (60%) experienced grade 3-4 neutropenia (six febrile neutropenia) and eight had grade 3 oxaliplatin-specific peripheral neuropathy after a median of 646.4 mg/m oxaliplatin (range 124-1619 mg/m). Oxaliplatin (130 mg/m, day 1)/vinorelbine (17.5 mg/m, days 1,5)/5-fluorouracil (600 mg/m/day, days 1-5) demonstrate encouraging activity and a manageable safety profile in anthracycline- and taxane-pretreated metastatic breast cancer patients.

Sequential administration of docetaxel followed by cisplatin-vindesine: a pilot study in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

In this phase II study, the feasibility and efficacy of sequential chemotherapy were tested with agents shown to be active as monotherapy. Patients with chemotherapy-naive, locally advanced or metastatic non-small cell lung cancer were selected for the study. Treatment involved four cycles of docetaxel (100 mg/m(2) on day 1, every 3 weeks) (sequence A), followed by four cycles of cisplatin-vindesine (cisplatin 120 mg/m(2) on day 1 and vindesine 3 mg/m(2) on days 1, 8, 15, and 22, every 4 weeks) (sequence B). Responding patients received 3 cycles of docetaxel 100 mg/m(2) (day 1, every 3 weeks) as consolidation (sequence C). Thirty-two patients entered the study with thirty being evaluable for efficacy. Four patients showed a partial response and one patient a complete response, resulting in an objective response rate of 16.7 %. The median survival time (intent-to-treat) was 11 months (95 %CI = 8.0-15.4 months) with an estimated 1-year survival rate of 47%. The median time to progression was 17.6 weeks in the evaluable population. Main grade 4 toxicity was neutropenia (21.8 % and 68.2 % of patients in sequence A and B, respectively) while grade 3 peripheral neuropathy was documented in five patients during sequence B. There were no treatment-related deaths. Sequential chemotherapy may show promise for the treatment of advanced non-small cell lung cancer. Given the feasibility of this pilot study, sequential chemotherapy concept should be investigated with newer cisplatin-based regimens using this approach in larger prospective studies.