Introduction:
Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB–IV ovarian cancer based on results of randomized phase 3 trials. The multicenter ...non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting.
Patients and Methods:
Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease.
Results:
Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0–28, interquartile range 6.9–14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4–19.1) months. The 3-year overall survival rate was 62% (95% CI, 58–67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin.
Discussion:
Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule.
Clinical Trial Registration:
ClinicalTrials.gov
, Identifier NCT01832415.
In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to ...fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.
We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1–21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.
From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2–41·4) from inclusion and 26·0 months (13·8–34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1–13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9–7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43–0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 70·3% of 1017 patients), lymphopenia (66 6·5%), and thrombocytopenia (20 2·0%). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 41·7% of 84 patients in the aromatase inhibitor and palbociclib group vs 39 44·3% of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three 3·6% vs four 4·5%). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.
PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.
Pfizer.
The treatment landscape in metastatic renal cell carcinoma has changed fundamentally over the last decade by the development of antiangiogenic agents, mammalian target of rapamycin inhibitors and ...immunotherapy. Outside of the context of a clinical trial, the treatments are used sequentially. We describe results under real‐life conditions of a sequential treatment strategy, before the era of immunotherapy. All patients were treated according to their prognostic score (either Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium) for advanced renal cell carcinoma. A treatment strategy involving 1 to 4 lines was determined including a rechallenge criterion for the repeat use of a treatment class. Three hundred forty‐four patients were included over 3 years. Overall survival was 57 months in patients with good or intermediate prognosis and 19 months in patients with poor prognosis. In the former group, the proportions of patients treated with 2 to 4 treatment lines were 70%, 38% and 16%, respectively. The best objective response rates for lines 1 to 4 were 46%, 36%, 16% and 17%, respectively. Grade III/IV toxicity did not appear to be cumulative. The recommended strategy was followed in 68% of patients. A large proportion of patients with good or intermediate prognosis who progress after two lines of treatment still have a performance status good enough to receive a systemic treatment, which justifies such a strategy. Overall survival of patients with good and intermediate prognosis was long, suggesting a benefit from the applied approach. These results might be used as selection criterion for the treatment of patients in the era of immune checkpoint inhibitors.
What's new?
Metastatic renal cancer is a notoriously relapsing disease that can be treated with anti‐angiogenic treatments, tyrosine kinase inhibitors, inhibitors of the mammalian Target of Rapamycin or immune checkpoint inhibitors. The authors performed a “real‐life” study testing a sequential strategy of the first three treatments applied to 344 patients with relapsing metastatic renal cancer before the era of immunotherapy. They found that the overall survival of patients with good and intermediate prognosis was long, almost 5 years, and plan a new study including immunotherapy in the future.
Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to ...2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin.
MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months.
From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3–39.7); the median PFS was 10.0 months (95% CI, 8.6–11.0). The median overall survival was 28.1 months (95% CI, 22.3–32.5); and the objective response rate was 58% (95% CI, 47–68). Grade 3–4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia.
Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.
•Carboplatin + non-pegylated liposomal doxorubicin (NPLD) is effective in platinum-sensitive recurrent ovarian cancers.•The disease control rate at 12 months was 30%.•This combination is well tolerated but should be prescribed with G-CSF support.•NPLD could be an alternative to pegylated liposomal doxorubicin in association with carboplatin.
Purpose
Locally advanced head and neck squamous cell carcinoma (HNSCC) has a high rate of recurrence. Induction chemotherapy with DCF (docetaxel, cisplatin, 5-fluorouracil) before chemoradiotherapy ...could lead to the best disease control of inoperable stage III/IV HNSCC but with an increased risk of acute toxicity. Early assessment of therapeutic efficacy is a key issue in considering the benefit of escalation in a poor prognosis population.
Methods
Patients with stage III/IV HNSCC, in whom DCF induction chemotherapy followed by concurrent chemoradiotherapy had been validated by a multidisciplinary team, were prospectively included in the study. FDG PET/CT scans were performed in all patients before and after two of the three cycles of DCF. EORTC99 criteria were used to evaluate PET responses as follows: group 1 (metabolic responders) showing a complete response (CR) or partial response (PR), and subgroup 0 (metabolic nonresponders) showing stable disease (SD) or progressive disease (PD). The primary endpoint for monitoring patients was event-free survival (EFS). EFS probabilities between the two groups were estimated by the Kaplan-Meier method and statistically compared using the log-rank test.
Results
Fifteen consecutive patients (14 men, 1 woman; age 57.5 ± 6.2 years, mean ± SD) were analysed. Therapeutic assessment by PET/CT demonstrated CR in four patients, PR in six, SD in four and PD in one. Among the ten patients with a metabolic response (group 1), none had relapsed at the time of this report, while four of five patients with no metabolic response (group 0) showed recurrence within an average of 9.0 ± 1.6 months. Median EFS was, respectively, 18.9 months (3.8–25.3 months) and 10.2 months (7.5–12.7 months) in group 1 and group 0. The corresponding 1-year EFS rates were 100 % and 20 %, respectively. The difference in EFS between the two groups was statistically significant (
p
= 0.0014).
Conclusion
Early therapeutic response demonstrated on FDG PET/CT after two cycles of induction chemotherapy with DCF in patients with inoperable stage III/IV HNSCC seems to be a predictive factor for EFS.
Older patients with ovarian cancer represent a heterogeneous population. The French National Group of Investigators for the Study of Ovarian and Breast Cancer developed the geriatric vulnerability ...score (GVS) to identify geriatric parameters predictive of poor outcomes. A prospective validation of the GVS was needed.
The EWOC-1 study (NCT02001272) was an international, open-label, phase 2, three-arm trial designed according to a two-step process. Patients aged 70 years or older with newly diagnosed stage III or IV ovarian cancer were identified and the GVS determined. Those with a GVS of 3 or greater were randomly assigned to the EWOC-1 trial, stratified by country and surgical outcome, to receive three different carboplatin with or without paclitaxel regimens; those not included in the EWOC-1 trial were followed up in the EWOC-1 registry. External validation of the GVS was a secondary endpoint of the trial. Three validation cohorts were identified: the total population (validation cohort 1 V1, n=447), the registry-only population (validation cohort 2 V2, n=327), and the carboplatin–paclitaxel-treated population (validation cohort 3 V3, n=320).
From Dec 11, 2013, to Nov 16, 2018, 447 patients were included in 48 academic centres in six countries; 120 in the EWOC-1 trial and 327 in the EWOC-1 registry. Median follow-up was 19·7 (95% CI 8·5–29·7) months for the total cohort; missing values were low (<2%). According to the maximum likelihood analysis, the hazard ratio (HR) of death in V1 was 1·8 (95% CI 1·1–3·1, p=0·029) for those with a GVS of 1; 2·4 (1·4–4·0, p=0·0009) with a GVS of 2; 4·1 (2·5–7·0, p<0·0001) for a GVS of 3; 5·5 (3·3–9·3, p<0·0001) for a GVS of 4; and 9·1 (4·7–17·5, p<0·0001) for a GVS of 5 compared with a score of 0. Whatever the validation cohort, GVS of 3 or more significantly segregated two groups with different overall survival: V1 (median 13·2 95% CI: 10·8–18·7 vs 40·8 32·0–45·6 months; HR 2·8 95% CI 2·2–3·7; p<0·0001); V2 (11·9 95% CI 8·8–18·1 vs 40·8 32·0–45·6 months, HR 3·5 2·5–4·9; p<0·0001); and V3 (18·1 95% CI 15·8–31·8 vs 43·0 40·6–49·7 months, HR 2·6 1·9 to 3·7; p<0·0001).
The GVS has high prognostic performance for overall survival in patients with advanced ovarian cancer, independently of geographic and historic effect (V1), as well as treatment patterns (V3), validated in an international population. Even though the GVS is time consuming it will allow the stratification of populations for clinical research and might permit the orientation of the geriatric intervention to specific domains.
French National Cancer Institute.
For the French translation of the abstract see Supplementary Materials section.
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