Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR. METHODS: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated. RESULTS: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months. CONCLUSIONS: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

Two-Year Follow-Up of a Multi-centre Randomized Controlled Trial to Study Effectiveness of a Hospital-Based Work Support Intervention for Cancer Patients.

Purpose Purpose is to: (1) study effectiveness of the hospital-based work support intervention for cancer patients at two years of follow-up compared to usual care and (2) identify which early factors predict time to return-to-work (RTW). Methods In this multi-center randomised controlled trial (RCT), 106 (self-)employed cancer patients were randomized to an intervention group or control group and provided 2 years of follow-up data. The intervention group received patient education and work-related support at the hospital. Primary outcome was RTW (rate and time) and quality of life (SF-36), and secondary outcomes were, work ability (WAI), and work functioning (WLQ). Univariate Cox regression analyses were performed to study which early factors predict time to full RTW. Results Participants were diagnosed with breast (61%), gynaecological cancer (35%), or other type of cancer (4%). RTW rates were 84% and 90% for intervention versus control group. They were high compared to national register-based studies. No differences between groups were found on any of the outcomes. Receiving chemotherapy (HR = 2.43, 95% CI 1.59-3.73 p < 0.001), low level of education (HR = 1.65, 95% CI 1.076-2.52 p = 0.02) and low work ability (HR = 1.09 [95% CI 1.04-1.17] p = 0.02) were associated with longer time to full RTW. Conclusions We found high RTW rates compared to national register-based studies and we found no differences between groups. Future studies should therefore focus on reaching the group at risk, which consist of patients who receive chemotherapy, have a low level of education and have a low work ability at diagnosis. TRIAL REGISTRATION: Netherlands Trial Registry (NTR) (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1658): NTR1658.

A hospital-based work support intervention to enhance the return to work of cancer patients: a process evaluation.

PURPOSE: To perform a process evaluation of a hospital-based work support intervention for cancer patients aimed at enhancing return to work and quality of life. The intervention involves the delivery of patient education and support at the hospital and involves the improvement of the communication between the treating physician and the occupational physician. In addition, the research team asked patient's occupational physician to organise a meeting with the patient and the supervisor to make a concrete gradual return-to-work plan. METHODS: Eligible were cancer patients treated with curative intent and who have paid work. Data were collected from patients assigned to the intervention group (N = 65) and from nurses who delivered the patient education and support at the hospital (N = 4) by means of questionnaires, nurses' reports, and checklists. Data were quantitatively and qualitatively analysed. RESULTS: A total of 47 % of all eligible patients participated. Nurses delivered the patient education and support in 85 % of the cases according to the protocol. In 100 % of the cases at least one letter was sent to the occupational physician. In 10 % of the cases the meeting with the patient, the occupational physician and the supervisor took place. Patients found the intervention in general very useful and nurses found the intervention feasible to deliver. CONCLUSIONS: We found that a hospital- based work support intervention was easily accepted in usual psycho-oncological care but that it proved difficult to involve the occupational physician. Patients were highly satisfied and nurses found the intervention feasible.

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours.

BACKGROUND: In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours. METHODS: In this phase I study successive patient cohorts received docetaxel 60 or 75mg/m(2) every 3weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle. RESULTS: Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75mg/m(2) in combination with SU-014813 50mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy. CONCLUSIONS: Oral SU-014813 50mg/day with docetaxel 75mg/m(2) is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.

Aurora kinase inhibitors.

Most human cancer cells are characterized by changes in the amount or organization of DNA resulting in chromosome instability and aneuploidy. Several mitotic kinases, Aurora kinases amongst others, regulate the progression of the cell through mitosis. So far three Aurora kinases have been identified in man: Aurora-A, Aurora-B and Aurora-C. Aurora kinases were recently identified as a potential target in anticancer therapy, and various Aurora-A and Aurora-B kinase inhibitors are in development. In this review we provide a brief insight into the mechanism of action as far as currently available. We review the available pre-clinical data, discuss the clinical phase I data and try to give a direction for future headings.

Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours.

Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.