Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable.
To determine whether ...biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen).
A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent.
Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group).
The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications.
Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median IQR, 92.7% 83.7%-98.9% in the triweekly CBZ25 group vs 92.8% 87.0%-98.9% in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 62.5% vs 5 of 98 5.1%; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 72.9%) vs biweekly CBZ16 (55 of 98 56.1%). One patient (triweekly CBZ25 group) died of a neutropenic complication.
In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable.
ClinicalTrials.gov Identifier: NCT02961257.
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.
Alzheimer's disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport ...of Aβ across the blood-brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.
Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer ...setting.
To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease.
This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used.
Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks 6 cycles), or ADT alone (1 year).
The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life.
Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio HR, 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients 48.0%), febrile neutropenia (10 8.0%), and thrombocytopenia (4 3.0%). There was no significant between-arm difference in overall quality of life.
Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease.
French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.
Anti-angiogenic therapies may induce sexual disorders. This longitudinal study evaluated the impact of anti-angiogenic agents on the sexual life of 75 patients with metastatic renal cancer. After 3 ...months of treatment, 69% of patients reported changes in their sexual life (mainly decrease of pleasure, interest) independently of the other side effects. Sexual disorders should be taken into account in oncology supportive care departments.
Targeted therapies, in particular antiangiogenic therapies (AATs), have become the standard of treatment for metastatic renal cell carcinoma (mRCC). Although common adverse effects like fatigue have been well-established, sexual disorders induced by these treatments, although often reported, have been poorly evaluated. The aim of this study was to evaluate the impact of AATs on the sexual life of patients with mRCC and the relationships with quality of life (QoL), fatigue, and biologic parameters.
This longitudinal study included patients with mRCC on first- or second-line AATs. Sexuality was evaluated by the French version of Changes in Sexual Functioning Questionnaire short-Form (CSFQ); QoL and fatigue were measured by the Functional Assessment of Cancer Therapy General (FACT-G) and the Multidimensional Fatigue Inventory (MFI-20), respectively. Biologic parameters were also assessed.
Among 75 patients included in the study, 39 agreed to respond to the sexual functioning questionnaire (CSFQ). At baseline, all patients had at least 1 sexual dysfunction. No relationship with QoL, fatigue, and biologic parameters was shown. After 3 months of treatment, a decrease in at least 1 sexual dimension was observed in 69% of patients. The most affected sexual dimensions were pleasure (34%) and desire/interest (38%). No significant relationship between sexual dysfunctions and biologic parameters was found. The percentage of non-participants (50%) and the absence of a control arm are the main limitations.
Patients with mRCC exhibit sexual dysfunction that could be increased by AATs independently of the impact on fatigue and QoL. Further studies aiming to define the role of biologic parameters like inflammatory markers and thyroid parameters are warranted.
Sexual disorders induced or degraded by AAT are an independent side effect that should be taken into account in oncology supportive care departments.
This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific ...antigen and known or suspected second malignancy.
F-FCH and F-FDG PET/CT were performed 15±9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean±SD: 15±9 months).
Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P<0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively).
We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied.
Context:
Treatment modalities for progressive iodine-refractory poorly differentiated thyroid carcinomas are not yet well defined. Molecular targeted therapy with multikinase inhibitors has recently ...shown promising results, and cytotoxic chemotherapy is generally considered of low efficacy.
Objective:
We report the case of a 57-yr-old woman with an advanced iodine-refractory poorly differentiated thyroid cancer who was treated sequentially between October 2006 and March 2011 with two different regimens of cytotoxic chemotherapy and three lines of multikinase inhibitors.
Methods:
Efficacy and adverse effects of the consecutive treatment modalities, i.e. vandetanib, doxorubicin-cisplatin combination, sorafenib, paclitaxel-carboplatin combination, and sunitinib, are reported.
Results:
The patient presented a complete tumor response to a doxorubicin-cisplatin combination lasting 10 months and to a paclitaxel-carboplatin regimen lasting 5 months and had no or limited response to kinase inhibitors, i.e. progression after 3 months of vandetanib, progression after 4 months of sorafenib, and stable disease for 8 months with sunitinib treatment.
Conclusions:
When tumor progresses with kinase inhibitors, cytotoxic chemotherapy may be an alternative in selected cases of advanced iodine-refractory poorly differentiated thyroid cancer. For those rare cases, clinical management should benefit from a multidisciplinary team approach through specialized networks.
Abstract Background Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue. Objective To evaluate the ...impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC. Design, setting, and participants This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo ( n = 58) and 6 mo ( n = 50). Outcome measurements and statistical analysis We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient. Results and limitations A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed ( p < 0.05) but not with objective cognitive decline. Cognitive complaints and fatigue had a significant impact on most of the domains of QoL ( p < 0.01). A positive correlation was found between fatigue and inflammatory markers but not with cognition. The main limitation of this study is the absence of a control group. Conclusions AAT induced cognitive decline in patients with mRCC independently of fatigue. These side effects affecting QoL should be better assessed in clinical trials and taken into account in routine practice. Patient summary Fatigue is a well-known effect of antiangiogenic therapies (AATs) of cancer. The study performed in patients with treated metastatic renal cancer shows a decline of cognitive functions induced by AATs, such as information-processing speed or working memory, in a third of patients, independently of fatigue. Patients on AATs should be informed of these possible adverse effects.
The brain vascular endothelium operates as a dynamic regulatory interface to maintain the cell environment of the nervous system. In the vicinity of astrocytes, brain endothelial cells develop ...characteristic features conferring a strong cellular impermeability which limits the penetration of various compounds. The aim of our study was to determine by differential proteomic analysis the changes occurring in bovine brain capillary endothelial cells (BBCEC) differentiated in co-culture with astrocytes compared with endothelial cells cultured alone. In order to obtain reproducible and meaningful protein profiles of in vitro blood-brain barrier models, three sample preparation procedures were carried out to provide the first 2-D comparative proteomic study of BBCEC. Our study highlights advantages and drawbacks of each procedure. The cellular proteins prepared from mechanical scraping of collagen-seeded BBCEC were strongly contaminated by serum proteins. Enzymatic dissociation of BBCEC by trypsin or collagenase solved this problem. A comparative 2-DE profile study of collagenase-harvested BBCEC revealed that cytoskeleton-related proteins (actin, gelsolin and filamin-A) show the most significant quantitative changes in the Triton soluble protein fraction from BBCEC that exhibit characteristics closest to the in vivo situation.
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