2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

Purpose To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels � 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration–approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations. This guideline was developed through a collaboration between the American Society of Clinical Oncology and the American Society of Hematology and has been published jointly by invitation and consent in both Journal of Clinical Oncology and Blood.

American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

Purpose: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Accuracy of Preoperative Endoscopic Ultrasound (EUS) to Distinguish Between Early and Locally Advanced Esophageal Cancer in Daily Clinical Practice

Introduction: Preoperative chemoradiotherapy is generally recommended for locally advanced esophageal cancer (clinical stage T3 or T4 or nodal positive disease) but not for early cancer (clinical stage T0 to T2, N0). EUS has been described as the most accurate method to distinguish between early and locally advanced stage in several studies. Recently however, the high accuracy of EUS (90% or higher) was questioned by some investigators. This raises the issue whether the results of studies focused on EUS accuracy may be directly translated into daily clinical practice. Aim & Methods: The aim of this retrospective analysis was to assess the accuracy of preoperative EUS to distinguish between early and locally advanced esophageal cancer in daily clinical practice outside a study setting. EUS was performed by several investigators, including trainees in one university hospital. For this purpose, EUS reports and patient files (medical and surgical) including histological reports of 300 consecutive pts with esophageal tumors were reviewed. In pts with adenocarcinoma or squamous cell cancer and surgical resection without previous radio-/chemotherapy, EUS tumor staging was compared with histological diagnosis. Results: Out of the 300 consecutive pts with esophageal tumor and EUS 102 pts had esophageal surgery after EUS-staging without any radio-/chemotherapy. In 93 pts oesophageal cancer was confirmed, whereas 9 had other tumors. The mean age was 65 years (range 27-89), sex ratio female:male was 1:3.2. To distinguish between early and late tumor stage, the accuracy was 85%. The sensitivity and specificity for early cancer was 59%, and 93%, respectively. The diagnostic accuracy for local tumor spread was 90%, 90%, 68%, 69%, 89% for pT0, pT1, pT2, pT3 and pT4 lesions, respectively. The overall accuracy for T-stage was 74%. For pN-positive staging the accuracy of EUS was 73%. Conclusion: In daily clinical practice, the accuracy of EUS in assessing esophageal tumor staging is lower than in specific studies focusing on EUS accuracy. Mainly early esophageal cancer stages were overstaged. Thus, the implementation of recommendations for diagnostic work-up of esophageal cancer patients resulting from highly specific studies should consider the appropriate clinical setting.

Role of plerixafor in autologous stem cell mobilization with vinorelbine chemotherapy and granulocyte-colony stimulating factor in patients with myeloma: a phase II study (PAV-trial)

Current practice in Switzerland for the mobilization of autologous stem cells in patients with myeloma is combining vinorelbine chemotherapy and granulocyte-colony stimulating factor (G-CSF) cytokine stimulation. We prospectively investigated adding intravenous plerixafor to the vinorelbine/G-CSF combination (VGP), and compared it with vinorelbine/plerixafor (VP) and G-CSF/plerixafor (GP) combinations. In a final cohort (VP-late), plerixafor was given on the first day of CD34 + cells increasing to > 15 000/mL peripheral blood. Four consecutive cohorts of 10 patients with myeloma were studied. We observed that intravenously administered plerixafor can be safely combined with vinorelbine/G-CSF. VGP was superior in mobilizing peripheral stem and progenitor cells compared to the three double combinations (VP, GP and VP-late), and GP mobilized better than VP. Our data indicate that the triple combination of VGP is an efficient strategy to collect autologous CD34 + cells, with G-CSF contributing predominantly in this concept. Plerixafor can be safely added to G-CSF and/or vinorelbine chemotherapy.

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids.

BACKGROUND Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review. RESULTS PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit. CONCLUSIONS PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Clinical Practice Recommendations For The Management And Prevention Of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field; (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment and management of cisplatin-induced hearing loss in children and adults; and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin based chemotherapy.

Medication double-checking procedures in clinical practice: a cross-sectional survey of oncology nurses' experiences.

BACKGROUND Double-checking is widely recommended as an essential method to prevent medication errors. However, prior research has shown that the concept of double-checking is not clearly defined, and that little is known about actual practice in oncology, for example, what kind of checking procedures are applied. OBJECTIVE To study the practice of different double-checking procedures in chemotherapy administration and to explore nurses' experiences, for example, how often they actually find errors using a certain procedure. General evaluations regarding double-checking, for example, frequency of interruptions during and caused by a check, or what is regarded as its essential feature was assessed. METHODS In a cross-sectional survey, qualified nurses working in oncology departments of 3 hospitals were asked to rate 5 different scenarios of double-checking procedures regarding dimensions such as frequency of use in practice and appropriateness to prevent medication errors; they were also asked general questions about double-checking. RESULTS Overall, 274 nurses (70% response rate) participated in the survey. The procedure of jointly double-checking (read-read back) was most commonly used (69% of respondents) and rated as very appropriate to prevent medication errors. Jointly checking medication was seen as the essential characteristic of double-checking-more frequently than 'carrying out checks independently' (54% vs 24%). Most nurses (78%) found the frequency of double-checking in their department appropriate. Being interrupted in one's own current activity for supporting a double-check was reported to occur frequently. Regression analysis revealed a strong preference towards checks that are currently implemented at the responders' workplace. CONCLUSIONS Double-checking is well regarded by oncology nurses as a procedure to help prevent errors, with jointly checking being used most frequently. Our results show that the notion of independent checking needs to be transferred more actively into clinical practice. The high frequency of reported interruptions during and caused by double-checks is of concern.