Breakthrough cancer pain: review and calls to action to improve its management.

In this paper, we review the current state of breakthrough cancer pain (BTcP) management. BTcP is a heterogeneous condition and a global problem for cancer patients. It is often managed suboptimally, which results in a negative outcome for patients, healthcare providers, and healthcare systems. Several barriers to the appropriate management of BTcP have been identified. These include, among others, an incomplete definition of BTcP, poor training of healthcare providers and patients alike, a lack of a multidisciplinary approach and the absence of specific protocols and tools. We provide some actions to help physicians and patients improve their approach to BTcP, including specific training, the design of easy-to-use tools for BTcP identification and assessment (such as checklists and pocket-sized cards), individualized treatment, and the use of multidisciplinary teams.

Active study: undetected prevalence and clinical inertia in the treatment of breakthrough cancer pain (BTcP).

AIMS: To prove if there is clinical inertia in the identification and treatment of episodes of breakthrough cancer pain (BTcP), comparing actual results from clinical practice with clinical oncologists' prior perception. DESIGN: Observational and descriptive study, using information collected by practising medical oncologists, at three moments: (a) questionnaire regarding their professional judgement of the handling of patients with BTcP in their practice, (b) cross-sectional clinical screening, to detect possible existing cases of BTcP in a representative sample of their patients, (c) retrospective self-audit of clinical case histories of patients diagnosed with BTcP to find out about how it has been handled. PARTICIPANTS AND STUDY PERIOD: A random sample on a state level of 108 specialists in medical oncology. 540 patients who suffer some type of cancer pain on the designated study date for each specialist (July-December 2016). RESULTS: The global prevalence of BTcP in the study sample covered 91.3% of the patients who were suffering some type of cancer pain. Barely 2% of the doctors surveyed suspected figures around this mark. 40.9% of the cases had not been previously detected as BTcP by their doctors. Although 90% of the patients who had previously been diagnosed with BTcP received a specific analgesic treatment for the symptoms, 42% of those patients with known BTcP were not able to control their episodes of pain. CONCLUSIONS: Clinical inertia is a serious problem in the handling of BTcP in medical oncology services, where it is the subject of a significantly low level of detection and treatment, despite the contrasting perception of specialists.

Oncologist's knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study

Purpose. Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP. Methods. Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline. Results. A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines. Conclusion. Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation

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Oncologist's knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study.

PURPOSE: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP. METHODS: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline. RESULTS: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines. CONCLUSION: Despite oncologist's clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.

A prognostic index for locoregional recurrence after neoadjuvant chemotherapy.

BACKGROUND: The appropriate selection criteria for breast-conserving surgery (BCS) or mastectomy after neoadjuvant chemotherapy (NAC) are poorly defined. The aim of this study is to analyse the incidence and prognostic factors for locoregional recurrence (LRR) in patients with breast cancer (BC) treated with NAC to develop a prognostic score to help with clinical decision-making. MATERIALS AND METHODS: Using our retrospective maintained BC database, we identified 730 patients treated with NAC (327 patients treated with BCS and 403 patients treated with mastectomy) between 1998 and 2014. To identify variables associated with an increased LRR rate, we performed firstly Kaplan-Meier curves, with comparisons among groups using log-rank test, and then, significant variables were included in a multivariate analysis using Cox proportional hazards. The prognostic index was developed by assigning score 0 (favourable) or score 1 (unfavourable) for each significant variable of multivariate analysis and was created separately for patients with BCS and mastectomy. RESULTS: At a median follow-up of 72 months, the 6-year cumulative incidence of LRR was 7.2% ( ± 3%) for BCS and 7.9% ( ± 3%) for mastectomy. By univariate analysis, variables associated with an increased LRR were for BCS: HER2 positive, grade III, ductal carcinoma in situ (DCIS), No-pCR (ypTis, ypN0), and age < 40 years; and for mastectomy, HER2-positive, DCIS, No-pCR, and LVI. By multivariate analysis, variables associated with an increased LRR were for BCS: HER2 positive (HR: 11.1, p = 0.001), DCIS (HR: 3.1, p = 0.005), and age < 40 years (HR: 2.8, p = 0.02); and for mastectomy: HER2 positive (HR: 9.5, p = 0.03), DCIS (HR: 2.7, p = 0.01), No-pCR (HR: 11.4, p = 0.01), and age < 40 years (HR: 2.8, p = 0.006). The score stratified patients into three subsets with statistically different levels of risk for LRR. For BCS, the six-year LRR rates were 3%, 13%, and 33% for the low (score 0, n = 120), intermediate (score 1, n = 95) and high (score 2-3, n = 27) risk groups, respectively (p = 0.001). For mastectomy, the six-year LRR rates were 0%, 8%, and 27% for the low (score 0, n = 20), intermediate (score 1-2, n 191), and high (score 3-4, n = 30) risk groups, respectively (p = 0.001). Of note, 21 patients that had a LRR event were HER2 positive, all of them had received trastuzumab. CONCLUSIONS: Patients with a score of 0, which made up to 19% of the study population, had very low risk of LRR. The score enabled the identification of a small group (7%) of patients with very high risk of LRR, and who may benefit from alternative treatment.

Social value of a quality-adjusted life year (QALY) in Spain: the point of view of oncologists

PURPOSE: The economic situation showed that the resources devoted to health spending are limited, making rationalisation of their consumption necessary. The relevance of pharmacoeconomic analyses is becoming crucial. The ECO Foundation, promoting the quality of oncology care, set out to analyse the consensus on the new therapeutic targets inclusion and the integration of pharmacoeconomics when evaluating their effectiveness. METHODS: Study about pharmacoeconomic estimations was performed during the first ECO-Seminar (2010). It was developed using a modified Delphi method, in four stages: (1) committee coordinator establishment, (2) expert-panel selection, (3) preparation and submission of survey (1 question) by email, and (4) analysis of the degree of consensus reached. RESULTS: Results were obtained from surveys completed by 35 experts. Regarding the tolerable annual cost for the approval of new drugs, 68.8 % of the respondents considered a cost per quality-adjusted life year (QALY) gained between 30,000 and 100,000 acceptable (34.4 % 30,000-60,000; 34.4 % 60,000-100,000), 21.9 % of the respondents found costs between 100,000-150,000/QALY and 9.3 % of the respondents found costs above 150,000/QALY acceptable. CONCLUSIONS: The costs of new drugs are higher than traditional treatments, making it a priority to identify subgroups of patients with specific molecular profiles as candidates for higher-efficiency-targeted therapies. The allocation of the available resources to the most effective interventions, to achieve the best clinical outcomes with lower costs and best subjective profile possible, allows expenditure to be rationalised. Pharmacoeconomic studies are a basic tool for obtaining better health outcomes according to the available resources, while also considering the other needs of the population (AU)

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Social value of a quality-adjusted life year (QALY) in Spain: the point of view of oncologists.

PURPOSE: The economic situation showed that the resources devoted to health spending are limited, making rationalisation of their consumption necessary. The relevance of pharmacoeconomic analyses is becoming crucial. The ECO Foundation, promoting the quality of oncology care, set out to analyse the consensus on the new therapeutic targets inclusion and the integration of pharmacoeconomics when evaluating their effectiveness. METHODS: Study about pharmacoeconomic estimations was performed during the first ECO-Seminar (2010). It was developed using a modified Delphi method, in four stages: (1) committee coordinator establishment, (2) expert-panel selection, (3) preparation and submission of survey (1 question) by email, and (4) analysis of the degree of consensus reached. RESULTS: Results were obtained from surveys completed by 35 experts. Regarding the tolerable annual cost for the approval of new drugs, 68.8 % of the respondents considered a cost per quality-adjusted life year (QALY) gained between €30,000 and 100,000 acceptable (34.4 % €30,000-60,000; 34.4 % €60,000-100,000), 21.9 % of the respondents found costs between €100,000-150,000/QALY and 9.3 % of the respondents found costs above €150,000/QALY acceptable. CONCLUSIONS: The costs of new drugs are higher than traditional treatments, making it a priority to identify subgroups of patients with specific molecular profiles as candidates for higher-efficiency-targeted therapies. The allocation of the available resources to the most effective interventions, to achieve the best clinical outcomes with lower costs and best subjective profile possible, allows expenditure to be rationalised. Pharmacoeconomic studies are a basic tool for obtaining better health outcomes according to the available resources, while also considering the other needs of the population.

Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

PURPOSE: Letrozole is superior to tamoxifen in terms of response and breast preservation rates as primary systemic therapy (PST) in postmenopausal women with ER-positive early breast cancer. However, the optimum duration of endocrine PST remains uncertain. METHODS: A phase 2 multicentre, open-label trial was conducted to evaluate the efficacy of letrozole over a preoperative period of 4 months to 1 year. Seventy postmenopausal patients (over 65 years) were recruited in four centers. The primary endpoint was to establish the optimal duration of treatment defined as the time required to attain the maximum response by clinical palpation. RESULTS: The median age of the group was 79 years (66-91) and the median tumour size 35 mm (range 25-100 mm). No severe adverse events were reported. Fifty-six patients were evaluable for the primary objective. A total of 43 patients (76.8%) achieved an objective response; 29 (51.8%) being partial and 14 (25.0%) complete. The median time to objective response was 3.9 months (95% CI, 3.3-4.5) and the median time to maximum response was 4.2 months (95% CI, 4.0-4.5), although 20 (37.1%) patients achieved the maximal response within 6-12 months. CONCLUSIONS: Letrozole shows a high activity and excellent tolerability as neoadjuvant therapy in elderly patients with endocrine-dependent breast cancer. Four to six months of letrozole as PST is an optimum duration with modest benefits thereafter (AU)

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial.

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.