Abstract
Background
Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The ...randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surgery. We report a nintedanib exposure-response relationship in the nintedanib arm.
Methods
Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar model-building strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings.
Results
The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found.
Conclusions
An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM.
Clinical trial identification
2011-006288-23.
Legal entity responsible for the study
ARCAGY-GINECO.
Funding
Boehringer Ingelheim.
Disclosure
N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.
Abstract
Background
Long term information on the risk/benefit ratio of currently available therapies remains crucial for treatment decisions. In the PACS04 phase III trial, patients (pts) with ...node-positive (N+) breast cancer (BC) were double-randomized to concomitant taxane-anthracycline versus standard FEC, as well as 1-year trastuzumab versus nill in the HER2+ subpopulation.
Methods
3009 pts (20% HER2+, 12% triple negative (TNBC) BC) were randomly assigned to receive 6 cycles of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) or epirubicin 75mg/m2 and docetaxel 75 mg/m2 (ED). Pts with HER2+ tumors were randomized to either trastuzumab (TRA) for one year, or observation (OBS). The primary endpoint was disease-free survival (DFS).
Results
After a median 115-month follow-up, DFS was not different in the ED compared to the FEC arm (70% vs 68% respectively, HR = 0.88 95% CI: 0.77-1.01; p = 0.064), nor was OS: 80% with FEC and 81% with ED (HR = 0.97 95% CI: 0.81-1.16; p = 0.729). Subgroup analysis suggested better DFS with ED in non-TNBC pts HR = 0.82 (0.71-9.96) p = 0.02. In the 528 pts with HER2+ BC, there was trend for a higher DFS in the TRA arm (68%; 95% CI: 61-74) versus the OBS arm (60%; 95% CI: 54-66); HR = 0.77 95% CI:0.57-1.03; p = 0.079 (intent to treat population). In the per protocol population, DFS, but not OS, was significantly higher in the TRA arm (HR: 0.69 95%CI: 0.51-0.94; p = 0.0156). ED led to more neurological and hematological toxicities (31% vs 11% febrile neutropenia) and led to 5 versus 1 treatment-related deaths. During follow-up, 75 pts developed a second non-breast primary cancer (43 with FEC and 32 with ED); 12 were hematologic malignancies (7 with FEC and 5 with ED). Long term cardiac deaths were rare (3 with FEC and 1 with ED).
Conclusions
This study did not show superiority of the concomitant anthracycline-taxane arm, which was more toxic in high-risk N+ BC pts. Long-term results of the HER2+ subpopulation are in line with the other adjuvant TRA trials but less striking probably due to lack of power. Long term cardiac toxicity and second primary cancer rate are similar to what has been reported by others.
Clinical trial identification
NCT00054587.
Legal entity responsible for the study
UNICANCER. 101 rue Tolbiac, 75013 Paris, France.
Funding
Roche, Ligue Nationale Contre le Cancer.
Disclosure
All authors have declared no conflicts of interest.
Abstract
Aim: Society now makes it easier for women with breast cancer to make important decisions about their disease management. The likelihood of long survival makes the issue of pursuing work ...during treatment a genuine reality for women and their physicians.
Methods: In 2012, we conducted a survey of 97 physicians involved in breast cancer treatment (medical oncologists, radiotherapists, surgeons) and 216 women who declared their intention to pursue their professional activity despite the diagnosis and treatment of breast cancer.
Results: Thirty one percent (N = 68) achieved their objective and 61% (N = 132), with at least one day off work, did not (no answers for 7%, N = 16). Comparison of these two groups reveals many factors associated with an increased success rate: job satisfaction (77.9% vs. 56.8%; p ≤ 0.05), a higher perceived benefit of work on both psychological well-being (average 8.60/10 vs. 7.69/10; p ≤ 0.05) and social life (average 8.36/10 vs.7.59/10; p ≤ 0.05), flexibility of medical encounters (80.9% vs. 65.9%; p ≤ 0.05) and information received from the physician (85.3% vs. 70.5%; p ≤ 0.05). Interestingly, women who achieved their objective were likely to have more people under their supervision (mean = 26.9 versus 7.3; p ≤ 0.05) suggesting that social responsibility may be an impetus for working during treatment. The type of treatment also had an impact on the rate of success: positive impact for radiotherapy alone (35.3% vs. 19.7%; p ≤ 0.05) and negative for chemotherapy (30.9% vs. 47.0%; p ≤ 0.05). Positions with a high level of perceived psychological stress were associated with a lower success rate (20.6% vs. 36.4%; p ≤ 0.05). Interestingly, with no clear, direct causal link, women who achieved their objective were more likely, at the end of their treatment, to still be in the same job (69.1% versus 37.9 % p ≤ 0.05). The declared motivations for maintaining a professional activity (personal, social, financial) had no significant impact on the success rate.
Conclusions: With the anticipated improvement in the benefit/adverse effects ratio of therapy and the increasing move towards therapeutic de-escalation, the question of working during treatment is likely to become more widespread and physicians should be more aware of this aspiration.
Disclosure: E. Antoine: Consultant fees from Roche. All other authors have declared no conflicts of interest.
Abstract
Background: The molecular apocrine breast cancer subset has recently been identified. These tumours are estrogen receptor (ER) negative but are characterised by the expression of many genes ...expressed by ER-positive luminal tumours and, interestingly, are androgen receptor (AR) positive. One third of these tumours are HER2-negative. Abiraterone acetate (AA) is a novel, selective, irreversible, and potent inhibitor of CYP17 enzymatic activity that reduces testosterone levels in the blood to undetectable range.
Trial design: We are conducting an uncontrolled, open-label, prospective, multicentric, phase II trial to evaluate the clinical activity of AA in patients with molecular apocrine inoperable locally advanced or metastatic breast cancer. Before inclusion, tumour samples (primary or metastatic) from patients presenting with a triple negative cancer are screened centrally for confirmation of ER/PgR/HER2 negativity and assessment of AR positivity. Additionally patients could be chemotherapy naïve or have received any number of lines of chemotherapy with measurable or non-measurable disease. Patients receive AA 1,000 mg and prednisone 10 mg daily until progression or unacceptable toxicity. The primary endpoint is the clinical benefit rate (CR + PR + SD ≥ 24 weeks). Secondary objectives include objective response rate, duration of response, overall survival, progression-free survival and safety. The translational research study focuses on identifying AA response biomarkers as well as improving the molecular definition of apocrine breast cancer, and describing the variation of circulating tumour cells levels. The target accrual is 31 patients. This is a single stage design to discriminate between a 15% and 35% clinical benefit (power 80%, Alpha 5%). As of April 2014, 28 French centers are open for enrolment (first site opened since June 2013). 18 centers have registered 59 patients. Of 55 centrally reviewed tumours, 25 (45%) were tested as ER/PgR/HER2 negative and AR positive leading to the inclusion of 19 patients for now.
Disclosure: All authors have declared no conflicts of interest.
The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the French Federation of Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, ...and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients.
To update clinical practice guidelines for first line medical treatment of patients with ovarian neoplasms in collaboration with the French Society for Gynaecologica Oncology.
The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts. The CPGs are defined following the definitions of the Standards, Options and Recommendations project. Once the guideline has been developed, the document is submitted for review by independent reviewers.
This article is a summary version of the full document presenting the clinical practice guidelines with algorithms. After surgery, most patients with ovarian neoplasms need adjuvant medical treatment. These guidelines concern the initial medical treatment (chemotherapy, hormone treatment and immunotherapy) and potential consolidation treatment. To complete the indications, two alternative treatment strategies are taken into account: no treatment and radiotherapy. This updated version concerns the indications and the modalities of chemotherapy. The main modifications are: 1) first-line chemotherapy for ovarian neoplasm can be taxane-platinum or carboplatine alone; 2) poly-chemotherapy is no longer a standard; 3) for early stages, except for stage IA grade I non-clear-cell tumours, adjuvant chemotherapy should be preferred to no treatment; 4) chemotherapy is standard for all stage III tumours, irrespective of the surgical result; 5) for stage IA G2-3 to IIA tumours, complete surgical staging and determination of the histological grade are standards.
From 1982 to 1992,146 adults with Ewing's sarcoma, have been treated for their first tumoral event in 3 french cancer centres. There were 91 maies and 56 females. The médian âge was 20.2 (16–55) ...years. As regards site, 62 pts (42.5%) had extremity lésions, 57 pts (39%) had axial tumor (vertebra 8%, pelvic 31%), 13 pts (9%) had rib primary lésion, and 14 pts (9.5%) had extraskeletal disease. 41
pts (28%) were metastatic at diagnosis. Chemotherapy was the first treatment in 90% of the no metastatic patients and 88% of the metastatic patients were treated with curative intent. All patients could receive more than 90% of the previous dose of chemotherapy, although 53 pts received a regimen initially designed also for pediatrie pts. In 66 pts (45%) surgery was done as part of local treatment, of those 45 pts were given post operative radiotherapy. Radiotherapy was performed in 119 pts with a médian dose of 45
Gy; 23% of the patients received less than 50
Gy. With a médian follow-up of 5 years, overall survival (OS), metastatic free survival (MFS) and local récurrence free survival (LRFS) were and for the no metastatic and the metastatic pts: 50.3%/7% (
P
<
0.0001);47.8%/5% (
P
<
0.0001); 66.3%/46.3% (
P
<
0.0001) respectively. The analysis for prognostic variables in 105 M-pts is presented below:
OS
DFS
MFS
LRFS
Histologie responso
36.5/85.5
30.4/43.4
36.2/52.8
0, 1,2/3,4
p
=
0.003
p
=
0.02
p
=
0.03
&x f;m
44.6/65.3
37.5/44.8
40.4/53.7
p
=
0.04
Sites extremity
61.3
p
=
0.05
47.4
p
=
0.02
47.97
p
=
0.06
74.3
pelvic
38.2
28.3
33.1
52.6
vertebra
0
p
<
0.001
0
p
<
0.001
40
0
central
26.2
17.4
39.9
56.4
chest
85.7
51.4
68.6
80
extraskeletal
88.9
62.2
62.2
89.9
Prognostics factors correlated with a poor overall survival were female gender, axial tumor localization and poor histologie response to initial chemotherapy. In conclusion, from this series, naturai history and évolution did not show out to be différent for Ewing sarcoma occurring in children. Moreover pediatrie chemotherapy protocols appeared to be correctly tolerated. As in pediatrie pts, novel approached had to be designed for M+ and poor responders to initial chemotherapy.
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