Bone matters in lung cancer Brodowicz, T.; O'Byrne, K.; Manegold, C.
Annals of oncology,
09/2012, Volume:
23, Issue:
9
Journal Article
Peer reviewed
Open access
Bone metastases are a significant and undertreated clinical problem in patients with advanced lung cancer.
We reviewed the incidence of bone metastases and skeletal-related events (SREs) in patients ...with lung cancer and examined the burden on patients' lives and on health care systems. Available therapies to improve survival and lessen the impact of SREs on quality of life (QoL) were also investigated.
Bone metastases are common in lung cancer; however, owing to short survival times, data on the incidences of SREs are limited. As with other cancers, the costs associated with treating SREs in lung cancer are substantial. Bisphosphonates reduce the frequency of SREs and improve measures of pain and QoL in patients with lung cancer; however, nephrotoxicity is a common complication of therapy. Denosumab, a recently approved bone-targeted therapy, is superior to zoledronic acid in increasing the time to first on-study SRE in patients with solid tumours, including lung cancer. Additional roles of bone-targeted therapies beyond the prevention of SREs are under investigation.
With increasing awareness of the consequences of SREs, bone-targeted therapies may play a greater role in the management of patients with lung cancer, with the aim of delaying disease progression and preserving QoL.
Synovial sarcomas are a rare subgroup of soft-tissue sarcoma arising in adolescents and young adults (AYA) and in adult patients. The objective of our analysis was to investigate the outcomes and ...potential differences of AYA versus adult patients with initially localised disease.
In total, 51 patients (25 AYA and 26 adult) were identified and evaluated in this retrospective single centre analysis. Baseline characteristics, treatment and outcome were assessed.
The predominant subtype in both groups was monophasic synovial sarcoma (17 AYA and 21 adult) and the most common site was the extremities (14 and 19 patients) with deep tumour location in both groups (33 and 24 patients). More AYA patients had tumours >5 cm (13/25 patients) when compared with adults (10/26 patients, P = n.s.). Primary wide resection was carried out in 15 AYAs and in 18 adults. Postoperative radiation therapy was the only statistical difference between AYA (n = 19) and adult patients (n = 12; P = 0.029). Nineteen and 17 patients, respectively, received adjuvant chemotherapy with no evidence of disease after six cycles. Nine and 11 patients relapsed after initial therapy and the most common metastatic site was the lung (eight versus nine patients). Five-year overall survival rates were 85% and 75%. Female gender, tumour size ≤5 cm and absence of progressive disease showed a significant association with overall survival in AYA patients (P = 0.013, P = 0.04 and P < 0.001), whereas non-extremity tumours and progression after initial therapy were significant for worse overall survival in adult patients (P = 0.012 and P < 0.001). No difference in overall survival between AYA and adult patients was observed (P = 0.899).
AYA and adult patients showed no significant difference in terms of overall survival. Male gender, tumour size >5 cm and progressive disease were prognostic markers for worse outcome, whereas tumour location (non-extremity) and progression after initial therapy were markers for worse outcome in adult patients.
•No significant differences in terms of overall survival have been shown between AYA and adult patients.•Female gender, tumour size >5 cm and progressive disease are predictive markers for worse outcome.•Tumour location (non-extremity) and progression after initial therapy are markers for worse outcome in adult patients.•Adjuvant chemotherapy is feasible and safe in AYA as well as in adult patients with synovial sarcomas.
Abstract Background Pulmonary metastasectomy when possible has become therapeutic standard in soft tissue sarcoma patients. However, published reports frequently describe mixed series of patients ...with bone or soft tissue sarcoma. We report the outcome of 46 soft tissue sarcoma (STS) patients who underwent pulmonary metastasectomy (PM). Methods This current analysis includes retrospective survival data from 46 consecutive STS patients with pulmonary metastases who underwent PM at the Medical University of Vienna between January 2003 and December 2013. Results In total 72 pulmonary metastasectomies were performed. 322 metastatic nodules were resected with a median number of four nodules per intervention and the R0 resection rate was 97.2%. The postoperative complication rate as documented was low. Median follow-up (mFU) was 31.8 months (range 3.7–127.4). Median overall survival as calculated from first detection of metastatic disease was 47.1 months (95% confidence interval (CI) = 36.2–58.1 months) and 45.3 months (95% CI = 33.3–57.4 months) when calculated from first PM until death or last follow-up ( n = 46). Five-year overall survival calculated from primary diagnosis was 62% and 32% when estimated from first PM. Previous disease free interval (DFI) as calculated from date of surgery of the primary tumour until the date of diagnosis of lung metastasis was 12.2 months (range 0–140.1 months). Median relapse-free survival (mRFS) after first PM to the date of recurrence of lung metastasis, death or last follow-up was 13.4 months (95% CI = 3–23.8 months). Conclusion Median overall survival in this selected patient cohort is 45.3 months. Despite the lack of prospective randomised controlled trials, PM is a reasonable treatment strategy in selected patients.
This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer.
Patients received FOLFOX4 plus either ...standard weekly cetuximab (arm 1) or cetuximab (500 mg/m2) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences.
Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs 53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74–2.66, PFS median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63–1.34, OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56–1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%).
Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.
Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do ...not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting.
The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib.
Only 4.6% of progression-free patients developed mucositis/stomatitis (grade≥2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm.
This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit–risk ratio of therapies in their treatment choice.
NCT01900743.
Epithelioid sarcoma is a soft tissue sarcoma associated with a high rate of local recurrence after wide resection and high incidence of distant metastasis. Little is known about the clinical course ...and response to systemic treatments in epithelioid sarcoma patients. We carried out a retrospective analysis of clinical data from epithelioid sarcoma patients to provide a reference for the design of future epithelioid sarcoma-specific studies.
Data from patients with epithelioid sarcoma entered in prospective multi-sarcoma phase II/III trials were pooled: EORTC trial 62012 (doxorubicin versus doxorubicin/ifosfamide), 62043 (pazopanib), 62072 (pazopanib versus placebo) and 62091 (doxorubicin versus trabectedin). Patients had either a local or a centrally confirmed diagnosis of epithelioid sarcoma, had inoperable/metastatic disease at study entry and were eligible for the according trial. Response was assessed according to RECIST 1.1. Progression-free survival (PFS) and overall survival were calculated from date of entry.
Among 976 patients with advanced sarcomas, 27 epithelioid sarcoma patients (2.8%) were eligible for the analysis (17 men, median age at diagnosis 50 years, range 19–72). Eighteen (66.7%) received chemotherapy as first-line treatment (five doxorubicin, eight doxorubicin/ifosfamide, two pazopanib, three trabectedin) and nine (33.3%) received pazopanib as second line or later. The primary tumour was located in the lower extremity (n = 8; 29.6%), upper extremity (n = 5; 18.5%), retro/intra-abdominal (n = 4; 14.8%) and in other locations (n = 10; 37.0%). At entry, metastases were mainly found in lung (n = 17; 63%), lymph nodes (n = 9; 33.3%), bone (n = 8; 29.6%) and soft tissue (n = 7; 25.9%). The best response for first-line patients was four partial responses (22.2%), 10 stable disease (55.6%) and four progressive disease (22.2%). In subsequent lines, pazopanib achieved one partial response (11.1%), four stable disease (44.4%) and four progressive disease (44.4%). All patients but one progressed on treatment. The median PFS and overall survival were 3.8 (95% confidence interval 2.2–4.8) and 10.8 months (95% confidence interval 8.1–21.3), respectively. Five patients were still alive at the time of the according trial analysis.
With all limitations of such a rare disease and small data set, objective response and survival outcomes are similar in epithelioid sarcoma to non-selected sarcoma populations. The clinical testing of novel systemic treatments for epithelioid sarcoma remains an unmet medical need and a high priority.
•Epithelioid sarcoma is a rare disease representing only 2.8% of patients treated with systemic therapy into EORTC trials.•Objective response and survival outcomes are similar in epithelioid sarcoma to non-selected sarcoma populations.•This study reinforces the existing knowledge on systemic therapy in this rare type of sarcoma, notably with pazopanib.•The clinical testing of novel systemic treatments for epithelioid sarcoma remains an unmet medical need and a high priority.
The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian ...Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs.
A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point.
Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation.
Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.
The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer ...(LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.
Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs.
The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP.
A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).
Cancer patients are at increased risk of venous thromboembolism (VTE).
We investigated the association of a history of VTE, superficial thrombophlebitis, or the presence of varicose veins with the ...occurrence of VTE during the course of cancer.
Cancer patients were recruited in a prospective cohort study, the Vienna Cancer and Thrombosis Study. Patients who had VTE within 3 months before study inclusion were excluded. At study inclusion, history of VTE, history of superficial thrombophlebitis, and presence of varicose veins were recorded. Primary end point was the occurrence of symptomatic VTE. Hazard ratios were obtained using the competing risk analysis according to Fine and Gray.
The cohort consisted of 1270 patients followed over a median of 590 days. A history of VTE was found in 66 patients (5.2%), superficial thrombophlebitis in 79 patients (6.2%), and varicose veins in 160 patients (12.6%). Ninety-eight patients (7.7%) developed VTE during follow-up. The hazard ratios for the risk of VTE in patients with a history of VTE or superficial thrombophlebitis were 1.44 (95% confidence interval: 0.67-3.07) and 1.94 (1.04-3.61), respectively, and 2.01 (1.26-3.21) in those with varicose veins. In multivariable analysis including history of VTE, history of superficial thrombophlebitis, presence of varicose veins, and other patient-related factors, the presence of varicose veins (2.10 1.29-3.41) remained significantly associated with an increased risk of VTE.
The presence of varicose veins is associated with an elevated risk of VTE in cancer patients. This clinical parameter could be useful for individual risk assessment of VTE in these patients.
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