Resource use in the last three months of life by lung cancer patients in southern Ontario.

Background: End-of-life cancer care involves multidisciplinary teams working in various settings. Evaluating the quality of care and the feedback from such processes is an important aspect of health care quality improvement. Our retrospective cohort study reviewed health care use by lung cancer patients at end of life, their reasons for visiting the emergency department (ed), and feedback from regional health care professionals. Methods: We assessed 162 Ontario patients with small-cell and relapsed or advanced non-small-cell lung cancer. Demographics, disease characteristics, and resource use were collected, and the consenting caregivers for patients with ed visits were interviewed. Study results were disseminated, and feedback about barriers to care was sought. Results: Median patient age was 69 years; 73% of the group had non-small-cell lung cancer; and 39% and 69% had received chemotherapy and radiation therapy respectively. Median overall survival was 5.6 months. In the last 3 months of life, 93% of the study patients had visited an oncologist, 67% had telephoned their oncology team, 86% had received homecare, and 73% had visited the ed. Death occurred for 55% of the patients in hospital; 23%, at home; and 22%, in hospice. Goals of care had been documented for 68% of the patients. Homecare for longer than 3 months was associated with fewer ed visits (80.3% vs. 62.1%, p = 0.022). Key themes from stakeholders included the need for more resources and for effective communication between care teams. Conclusions: Use of acute-care services and rates of death in an acute-care facility are both high for lung cancer patients approaching end of life. In our study, interprofessional and patient-provider communication, earlier connection to homecare services, and improved access to community care were highlighted as having the potential to lower the need for acute-care resources.

Initial management of small-cell lung cancer (limited- and extensive-stage) and the role of thoracic radiotherapy and first-line chemotherapy: a systematic review.

Background: Patients with limited-stage (ls) or extensive-stage (es) small-cell lung cancer (sclc) are commonly given platinum-based chemotherapy as first-line treatment. Standard chemotherapy for patients with ls sclc includes a platinum agent such as cisplatin combined with the non-platinum agent etoposide. The objective of the present systematic review was to investigate the efficacy of adding radiotherapy to chemotherapy in patients with es sclc and to determine the appropriate timing, dose, and schedule of chemotherapy or radiation for patients with sclc. Methods: The medline and embase databases were searched for randomized controlled trials (rcts) comparing treatment with radiotherapy plus chemotherapy against treatment with chemotherapy alone in patients with es sclc. Identified rcts were also included if they compared various timings, doses, and schedules of treatment for patients with es sclc or ls sclc. Results: Sixty-four rcts were included. In patients with ls sclc, overall survival was greatest with platinum-etoposide compared with other chemotherapy regimens. In patients with es sclc, overall survival was greatest with chemotherapy containing platinum-irinotecan than with chemotherapy containing platinum-etoposide (hazard ratio: 0.84; 95% confidence interval: 0.74 to 0.95; p = 0.006). The addition of radiation to chemotherapy for patients with es sclc showed mixed results. There was no conclusive evidence that the timing, dose, or schedule of thoracic radiation affected treatment outcomes in sclc. Conclusions: In patients with ls sclc, cisplatin-etoposide plus radiotherapy should remain the standard therapy. In patients with es sclc, the evidence is insufficient to recommend the addition of radiotherapy to chemotherapy as standard practice to improve overall survival. However, on a case-by-case basis, radiotherapy might be added to reduce local recurrence. The most commonly used chemotherapy is platinum-etoposide; however, platinum-irinotecan can be considered.

Canadian Cancer Trials Group (CCTG) IND215: A phase Ib study of Selumetinib in patients with untreated advanced or metastatic NSCLC who are receiving standard chemotherapy regimens.

Introduction Selumetinib (AZD6244, ARRY-142886) is a potent inhibitor of MEK1/2, thereby inhibiting phosphorylation of ERK2. We investigated the toxicity and the recommended phase II dose of the combination of selumetinib with two platinum based first line chemotherapy combinations in non-small cell lung cancer. Methods This was a phase I trial of escalating doses of selumetinib with carboplatin (AUC 6), paclitaxel (200 mg/m2) (cohort 1) or pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) (cohort 2) in patients with chemotherapy naïve, advanced or metastatic NSCLC. Patients enrolled on cohort 2 had non-squamous histology. Dose escalation of selumetinib proceeded using a 3 + 3 design: 50 mg b.i.d. days 2-19 (dose level 1); 75 mg b.i.d. days 2-19 (dose level 2); and 75 mg b.i.d. continuously. Adverse events were evaluated using CTC AE v4 and response by RECIST 1.1. Results Thirty-nine patients were enrolled (cohort 1 n = 16; cohort 2, n = 23). There were no dose limiting toxicities in either cohort and the recommended phase II dose for both regimens was standard doses of carboplatin, paclitaxel or pemetrexed and cisplatin with continuous selumetinib at a dose of 75 mg b.i.d. Most adverse events were grade 1 or 2 and were predominantly diarrhea, nausea, stomatitis, peripheral edema, neutropenia, and skin rash. Response rate was 37.5% for cohort 1 and 30.4% for cohort 2. Conclusion Selumetinib at a dose of 75 mg b.i.d continuously can be safely combined with paclitaxel and carboplatin or pemetrexed and cisplatin in patients with advanced or metastatic NSCLC. This trial provided the dose for the regimens used in a randomized phase II trial in NSCLC (CCTG IND.219).

Guideline for the Initial Management of Small Cell Lung Cancer (Limited and Extensive Stage) and the Role of Thoracic Radiotherapy and First-line Chemotherapy.

AIMS: We investigated the efficacy of adding radiotherapy to chemotherapy in patients with extensive stage small cell lung cancer (ES-SCLC) and the appropriate timing, dose and schedule of treatment for patients with ES-SCLC or limited stage SCLC (LS-SCLC). MATERIALS AND METHODS: The guideline was developed by Cancer Care Ontario's Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of randomised controlled trials. KEY RECOMMENDATIONS: In patients with LS-SCLC (stage I, II and III), the addition of thoracic radiotherapy to standard chemotherapy is recommended. However, there is no clear evidence to inform definitive recommendations for optimal timing, sequential versus concurrent therapies and optimal dose or regimen. In patients with LS-SCLC, etoposide-cisplatin is the preferred regimen for adults who are being treated with combined modality therapy with curative intent. In patients with ES-SCLC (stage IV), there is insufficient evidence to recommend the addition of thoracic radiotherapy to standard chemotherapy as a standard practice for survival benefit; however, it could be considered on a case-by-case basis to reduce local recurrence. In patients with ES-SCLC, a platinum agent plus etoposide is the preferred regimen for adult patients who are being treated with combined modality therapy. Cisplatin and irinotecan represents an alternative treatment option to this, but is associated with increased rates of adverse events such as diarrhoea.

Implementing low-dose computed tomography screening for lung cancer in Canada: implications of alternative at-risk populations, screening frequency, and duration.

BACKGROUND: Low-dose computed tomography (ldct) screening has been shown to reduce mortality from lung cancer; however, the optimal screening duration and "at risk" population are not known. METHODS: The Cancer Risk Management Model developed by Statistics Canada for the Canadian Partnership Against Cancer includes a lung screening module based on data from the U.S. National Lung Screening Trial (nlst). The base-case scenario reproduces nlst outcomes with high fidelity. The impact in Canada of annual screening on the number of incident cases and life-years gained, with a wider range of age and smoking history eligibility criteria and varied participation rates, was modelled to show the magnitude of clinical benefit nationally and by province. Life-years gained, costs (discounted and undiscounted), and resource requirements were also estimated. RESULTS: In 2014, 1.4 million Canadians were eligible for screening according to nlst criteria. Over 10 years, screening would detect 12,500 more lung cancers than the expected 268,300 and would gain 9200 life-years. The computed tomography imaging requirement of 24,000-30,000 at program initiation would rise to between 87,000 and 113,000 by the 5th year of an annual nlst-like screening program. Costs would increase from approximately $75 million to $128 million at 10 years, and the cumulative cost nationally over 10 years would approach $1 billion, partially offset by a reduction in the costs of managing advanced lung cancer. CONCLUSIONS: Modelling various ways in which ldct might be implemented provides decision-makers with estimates of the effect on clinical benefit and on resource needs that clinical trial results are unable to provide.

Diagnosing lung cancer in the 21st century: are we ready to meet the challenge of individualized care?

BACKGROUND: Histologic and molecular subtyping have become increasingly important as predictors of treatment benefit in lung cancer. The objective of the present study was to determine whether current diagnostic approaches provide adequate tissue to allow for individualized treatment decisions. METHODS: Our retrospective cohort study of new lung cancer patients seen at an academic centre between July 2007 and June 2008 collected baseline demographic and diagnostic information, including mode of diagnosis, type of diagnostic material, and pathology diagnosis. RESULTS: Of the 431 study patients, 20% had stage i or ii non-small-cell lung cancer (nsclc), 24% stage iii disease, and 39% stage iv nsclc. Three quarters of the small-cell lung cancer (sclc) cases were extensive stage. Diagnostically, 18% of patients had sclc; 30%, adenocarcinoma; 27%, squamous-cell cancer; 2%, large-cell carcinoma; 1%, bronchoalveolar carcinoma; 1%, mixed histology; 18%, nsclc not otherwise specified; 4%, other; and 2%, no pathology diagnosis. Surgical pathology material was available in 80% of cases, and cytology material alone in 20%. Surgical pathology material was more common in patients with early-stage than with advanced disease (89% for stages i and ii vs. 74% for stages iii and iv, p < 0.0001). The pathology report included ambiguous terms in 24% of cases: "consistent" (12%), "suspicious" (3%), "favour" (2%), "suggestive" (2%), "likely" (1%), "compatible" with malignancy (1%), "at least" (1%), "atypical" (0.5%), and "no pathology" (1.5%). CONCLUSIONS: Current diagnostic approaches in most lung cancer patients appear adequate, but complete histopathologic identification is missing in nearly 20% of cases, and some uncertainty as to the final diagnosis is expressed in 24% of pathology reports. Some improvement in diagnostic sampling and pathology reporting are required to allow for implementation of current treatment approaches.

Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases.

BACKGROUND: The prognosis of patients with brain metastases from non-small-cell lung cancer (nsclc) is poor. However, some reports suggest that patients with brain metastases at the time of initial diagnosis have a more favourable survival than do patients with advanced nsclc without brain metastases. METHODS: In a retrospective cohort of all new lung cancer patients seen at a Canadian tertiary centre between July 2005 and June 2007, we examined survival after a diagnosis of brain metastases for patients with brain metastases at initial diagnosis and patients who developed brain metastases later in their illness. RESULTS: During the 2-year period, 91 of 878 patients (10.4%) developed brain metastases. Median age in this cohort was 64 years. In 45, brain metastases were present at initial diagnosis, and in 46, brain metastases developed later in the course of the illness. Median survival in the entire cohort was 7.8 months. Survival after the diagnosis of brain metastases was similar for patients with brain metastases at diagnosis and later in the illness (4.8 months vs. 3.7 months, p = 0.53). As a result, patients who developed brain metastases later in their illness had a longer overall survival than did patients with brain metastases at diagnosis (9.8 months vs. 4.8 months). Among patients who received chemotherapy, the survival of patients with brain metastases at diagnosis was still poor (6.2 months). CONCLUSIONS: Our data show limited survival in patients with brain metastases from nsclc. Careful patient selection for more aggressive treatment approaches is necessary.

A comparison of patient knowledge of clinical trials and trialist priorities.

BACKGROUND: Recruitment to clinical trials remains poor, and patient knowledge of clinical trials is one barrier to recruitment. To identify knowledge deficits, we conducted and compared surveys measuring actual patient knowledge and clinical trialist priorities for patient knowledge. METHODS: Consenting patients at a tertiary cancer centre answered a survey that included 2 opinion questions about their own knowledge and willingness to join a trial, and22 knowledge questions. Clinical researchers at the centre were asked 13 questions about the importance of various trials factors. RESULTS: Of 126 patients surveyed, 16% had joined a clinical trial, and 42% had a secondary school education or less. The mean correct response rate on the knowledge questions was 58%. Higher rates of correct responses were associated with lower age (p = 0.05), greater education (p = 0.006), prior trial participation (p < 0.001), agreement or strong agreement with perceived understanding of trials (p < 0.001), and willingness to join a clinical trial (p = 0.002). Trialists valued an understanding of the rationale for clinical trials and of randomization, placebo, and patient protection, but those particular topics were poorly understood by patients. CONCLUSIONS: Patient knowledge about clinical trials is poor, including knowledge of several concepts ranked important by clinical trialists. The findings suggest that when developing education interventions, emphasis should be placed on the topics most directly related to patient care, and factors such as age and education level should be considered.

Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment.

BACKGROUND: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

The difference between study recommendations, stated policy, and actual practice in a clinical trial.

BACKGROUND: We determined whether physicians involved in a clinical trial adhere to the study recommendations or the stated policy of their treatment centre with respect to the administration of boost radiation after breast conserving surgery. PATIENTS AND METHODS: Boost radiation treatment policy was determined by survey at 25 oncology centres involved in a randomised trial of breast or breast plus nodal radiation in Canada. Actual practice was compared with stated policy and study recommendations. RESULTS: Among 248 subjects, 201 (81%) were treated according to stated policy [kappa=0.40, 95% confidence intervals (CI) 0.27-0.52; P<0.0001], indicating only a fair to moderate agreement between stated and actual practice, while 232 (94%) were treated according to study recommendations (kappa=0.59, 95% CI 0.40-0.77; P<0.0001), indicating moderate to near substantial agreement between study recommendations and actual practice (P=0.88 for z-test of difference). In a multivariate analysis, subjects who had invasive disease at a resection margin were more likely to get a boost than those with margins clear of invasive tumour by 2 mm [odds ratio (OR) 49, 95% CI 7.6-322; P<0.0001]. CONCLUSIONS: Physicians appear compliant with study recommendations for a non-randomised manoeuvre in a clinical trial, possibly at the expense of compliance with stated local policy. Clinical trial protocols should incorporate standard practice.

Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer.

Glomeruloid microvascular proliferation (GMP) in breast cancer independently adversely affected survival (relative risk 1.9, 95% CI: 1.2-3.0), particularly among women who received adjuvant chemotherapy (10-year survival 27 vs 69%, P=0.0003), and was significantly associated with p53 overexpression and BRCA1 germline mutations. The presence of GMP may influence treatment decisions.