Cabazitaxel (CBZ), a novel tubulin-binding taxane, improves overall survival in metastatic castration-resistant prostate cancer (mCRPC) that progresses during or after docetaxel treatment. We have ...designed a phase II study to evaluate the efficacy and safety of CBZ as a weekly schedule for ‘unfit’ mCRPC patients after docetaxel failure.
In this single arm phase II study. CBZ was weekly administered in 1-hour infusion on days 1, 8, 15 and 22, every 5 weeks at 10 mg/m2 to eligible ‘unfit’ patients; oral prednisone (5 mg) was administered twice a day. Circulating tumour cells (CTCs) were also collected. New treatment scheme was considered effective if at least 65% of patients met a clinical benefit criteria based on prostate-specific antigen (PSA)-progression-free survival (PFS) values at week 12.
Seventy patients (median age: 73.9 years) were enrolled; overall, 71.4% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2; and 84%, 16% and 11% had bone, liver and lung metastases, respectively. Objective partial response or stable disease was achieved in 61% of patients, while PSA responses of ≥50% and ≥80% were observed in 34.8% and 10.6%, respectively. The median PSA-PFS was 4.8 months; and 68.6% of patients had no progression at week 12. The most frequent grade 3/4 toxicities were neutropenia (2.8%), leukopenia (5.7%) and thrombocytopaenia (9%); no cases of febrile neutropenia were reported. Early CTC response was significantly correlated with PSA-PFS.
CBZ/prednisone administered weekly to ‘unfit’ mCRPC patients appears to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance. Early CTC response appears to be valuable as an early end-point of therapeutic efficacy.
•Weekly cabazitaxel instead of every 3 weeks has been tested.•Circulating tumour cells (CTCs) have been assessed.•‘Unfit’ patients could benefit with the proposed regimen.•Changes in CTCs could be useful in these cases as an early response marker.
The advent of immunotherapy has revolutionized cancer treatment. Unfortunately, this has not been the case for metastatic castration-resistant prostate cancer (mCRPC), likely due to the heterogeneous ...and immune-suppressive microenvironment present in prostate cancer. The identification of molecular biomarkers that could predict response to immunotherapy represents one of the current challenges in this clinical scenario. The management of advanced castration-resistant prostate cancer is rapidly evolving and immunotherapy treatments, mostly consisting of immune checkpoint inhibitors combinations, BiTE
(bispecific T-cell engager) immune therapies, and chimeric antigen receptors (CAR) are in development with promising results. This review analyses the current evidence of immunotherapy treatments for mCRPC, evaluating past failures and promising approaches and discussing the directions for future research.
Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian ...cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial.
TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete.
Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 60% of 678 in the trebananib group and 221 66% of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months 15·0–17·6) and the placebo group (15·0 months 12·6–16·1) groups (hazard ratio 0·93 95% CI 0·79–1·09; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 35% vs placebo 126 38%) anaemia (76 11% vs 40 12%), and leucopenia (81 12% vs 35 10%). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group.
Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population.
Amgen.
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some ...biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20-25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.
Background Breast cancer is one of the most prevalent diseases in women. Prevention and treatments have lowered mortality; nevertheless, the impact of the diagnosis and treatment continue to impact ...all aspects of patients' lives (physical, emotional, cognitive, social, and spiritual). Objective This study seeks to explore the experiences of the different stages women with breast cancer go through by means of a patient journey. Methods This is a qualitative study in which 21 women with breast cancer or survivors were interviewed. Participants were recruited at 9 large hospitals in Spain and intentional sampling methods were applied. Data were collected using a semi-structured interview that was elaborated with the help of medical oncologists, nurses, and psycho-oncologists. Data were processed by adopting a thematic analysis approach. Results The diagnosis and treatment of breast cancer entails a radical change in patients' day-to-day that linger in the mid-term. Seven stages have been defined that correspond to the different medical processes: diagnosis/unmasking stage, surgery/cleaning out, chemotherapy/loss of identity, radiotherapy/transition to normality, follow-up care/the "new" day-to-day, relapse/starting over, and metastatic/time-limited chronic breast cancer. The most relevant aspects of each are highlighted, as are the various cross-sectional aspects that manifest throughout the entire patient journey. Conclusions Comprehending patients' experiences in depth facilitates the detection of situations of risk and helps to identify key moments when more precise information should be offered. Similarly, preparing the women for the process they must confront and for the sequelae of medical treatments would contribute to decreasing their uncertainty and concern, and to improving their quality-of-life.
The current cancer care system must be improved if we are to have in-depth knowledge about breast cancer patients' experiences throughout all the stages of their disease.
This study seeks to describe ...breast cancer patients' experience over the course of the various stages of illness by means of a journey model.
This is a qualitative descriptive study. Individual, semi-structured interviews will be administered to women with breast cancer and breast cancer survivors. Patients will be recruited from nine large hospitals in Spain and intentional sampling will be used. Data will be collected by means of a semi-structured interview that was elaborated with the help of medical oncologists, nurses, and psycho-oncologists. Data will be processed adopting a thematic analysis approach.
The outcomes of this study will afford new insights into breast cancer patients' experiences, providing guidance to improve the care given to these individuals. This protocol aims to describe the journey of patients with breast cancer through the healthcare system to establish baseline data that will serve as the basis for the development and implementation of a patient-centered, evidence-based clinical pathway.
Abstract
Background
The purpose of this study was to investigate the sociodemographic factors related to psychological distress, spirituality, and resilience, and to examine the mediating role of ...spirituality with respect to psychological distress and resilience in patients with advanced, unresectable cancer during the Covid-19 pandemic.
Methods
A prospective, cross-sectional design was adopted. Data were collected from 636 participants with advanced cancer at 15 tertiary hospitals in Spain between February 2019 and December 2021. Participants completed self-report measures: Brief Resilient Coping Scale (BRCS), Brief Symptom Inventory (BSI-18), and Spiritual well-being (FACIT-Sp). Hierarchical linear regression models were used to explore the mediating role of spirituality.
Results
Spirituality was significantly different according to the person’s age and marital status. Psychological distress accounted for 12% of the variance in resilience (β = − 0.32,
p
< 0.001) and spirituality, another 15% (β =0.48,
p
< 0.001). Spirituality acted as a partial mediator in the relationship between psychological distress and resilience in individuals with advanced cancer.
Conclusions
Both psychological distress and spirituality played a role in resilience in cases of advanced cancer. Spirituality can help promote subjective well-being and increased resilience in these subjects.
Abstract
Background and Aims
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin is increasingly used for the treatment of ovarian and peritoneal ...cancer. Acute kidney injury (AKI) is a frequent complication after cisplatin containing HIPEC therapy. The aim of this study was to compare the incidence and severity of AKI and renal survival after HIPEC compared to repeated cycles of conventional high-dose intraperitoneal cisplatin in patients with ovarian and malignant peritoneal cancer.
Method
We conducted a retrospective study that included patients with ovarian cancer that received repeated cycles of high-dose intraperitoneal cisplatin and patients with ovarian and primary malignant peritoneal cancer that received HIPEC with cisplatin in our center between August 2006 and September 2022. Demographic and perioperative data were compared between both groups. We compared the incidence of AKI defined as a rise in serum creatinine by ≥ 0.3 mg/dL within 48 hours (KDIGO criteria), the severity of AKI defined as stages I, II and III using the KDIGO staging, the rate of kidney function recovery and need for renal replacement therapy in both groups. We performed logistic regression analysis to identify independent risk factors for experiencing AKI and conducted survival analyses and multivariate Cox regression analyses to detect independent risk factors for patient survival.
Results
The study included 39 patients; 20 received 76 cycles of conventional intraperitoneal cisplatin, and 19 patients (13 with ovarian cancer and 6 with primary peritoneal cancer) received HIPEC. Patients who received HIPEC were older (63.4±20 years vs 56±8 years, p = 0.002) and received a lower dose of cisplatin both in absolute values (109.2±41.1 mg vs 159.2±15.2 mg, p<0.001) and adjusted by body surface area (63.4±19.9 mg/m2 vs 96.8±9.2 mg/m2, p<0.001). AKI was significantly more frequent in patients receiving HIPEC (42.1% vs 15.8%, p = 0.012), and was more severe after HIPEC with AKIN-I, AKIN-II and AKIN-III in 50% vs 83%, 12.5% vs 16.7% and 37.5% vs 0% respectively, p = 0.042. Recovery from AKI was more frequent in patients receiving conventional intraperitoneal cisplatin (100% vs 50%, p = 0.014) and 1 patient in the HIPEC group progressed to end stage kidney disease. In the multivariate logistic regression analysis, after adjusting for age, baseline serum creatinine and cisplatin dose, treatment with HIPEC compared to conventional high-dose intraperitoneal cisplatin remained a significant risk factor for developing AKI (OR 1550, CI 95% 19-128070).
Conclusion
Cisplatin-based HIPEC therapy is associated with an increased risk of severe AKI compared to conventional high-dose intraperitoneal cisplatin regimens, despite the use of prophylactic measures. Hyperthermic perfusion of the abdomen might be an important contributing factor in HIPEC-induced renal injury. To reduce the incidence of AKI and its associated morbidity after HIPEC, early implementation of preventive measures with adequate fluid management and closer monitoring of hemodynamic parameters and kidney function tests should be taken into consideration.
The pathologic and immunohistochemical features of familial epithelial ovarian cancers are not well understood. We have carried out a comprehensive immunohistochemical study of familial ovarian ...carcinomas from women with and without BRCA1 or BRCA2 mutations, in order to identify specific and/or common features among these different familial case groups (BRCA1, BRCA2 and non-BRCA1/2) and to identify markers of diagnostic value that might help to select more specific treatments. 73 familial primary ovarian carcinomas were analyzed for the expression of 40 antibodies involved in different genetic pathways using a tissue microarray. Serous carcinomas comprised the majority of all three familial case groups. On the other hand, BRCA1 and BRCA2 carcinomas have similar histopathologic features; i.e. they are often high-grade and are usually diagnosed at a more advanced FIGO stage than non-BRCA1/2 carcinomas. In our series, BRCA1 carcinomas had better clinical evolution and they also more frequently over-expressed PR and P53 than BRCA2 and non-BRCA1/2 carcinomas. Unsupervised cluster analysis and survival analysis identified ERCC1 as a potential marker of better clinical outcome for hereditary epithelial ovarian cancer.
The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a ...molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next‐generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio OR = 0.08, 95% confidence interval CI = 0.008–0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065–0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04–0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.
What's new?
Inhibitors of the mammalian Target of Rapamycin (mTOR) are key drugs for the treatment of renal cell carcinoma. However, only a subset of patients benefits clinically, and it is unclear why. Here the authors identified mutations in mTOR pathway, as well as loss of expression of the tumor suppressor PTEN, as markers of favorable outcome, underscoring the potential of these markers– either alone or in combination – to serve as clinical tools for patient stratification.
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