Vivianne C. G. Tjan-Heijnen

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.

Randomized Controlled Trial of Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non–Small-Cell Lung Cancer

BACKGROUND Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC). We hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. METHODS Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan-Meier analyses from time of randomization. RESULTS Induction chemotherapy resulted in a response rate of 61% (95% confidence interval [CI] = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. CONCLUSION In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.

Multicenter Validation of a Gene Expression–Based Prognostic Signature in Lymph Node–Negative Primary Breast Cancer

PURPOSE We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions. PATIENTS AND METHODS Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment. RESULTS In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis. CONCLUSION Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

EORTC Cancer in the Elderly Task Force guidelines for the use of colony-stimulating factors in elderly patients with cancer.

Increasing age is not, in itself, a contraindication to cancer chemotherapy. Myelosuppression, however, a common adverse consequence of the administration of many standard-dose chemotherapy regimens to both young and elderly patients with cancer, increases with age. The risk of development of febrile neutropenia may contribute to a reluctance to administer chemotherapy in the elderly patient population. We conducted a detailed literature search (1992-2002) to derive evidence-based conclusions on the value of prophylactic colony-stimulating factor (CSF) administration in elderly patients receiving chemotherapy. Sufficient evidence allows us to affirm that prophylactic granulocyte colony-stimulating factor (G-CSF) reduces the incidence of chemotherapy-induced neutropenia, febrile neutropenia and infections in elderly patients receiving myelotoxic chemotherapy for non-Hodgkins lymphoma (NHL), small-cell lung cancer (SCLC) or urothelial tumours. Lack of available trial data does not allow similar conclusions to be drawn for other cancers studied, but it is likely that similar benefits would accrue from the use of prophylactic G-CSF. There is insufficient evidence to extend this recommendation to include the use of granulocyte-macrophage colony-stimulating factor (GM-CSF). There are insufficient data available to allow the evaluation of the impact of prophylactic CSF on the incidence of toxic deaths in elderly patients with cancer and this is a crucial question for geriatric oncology practice. There is no evidence in elderly patients that the delivery of standard-dose chemotherapy on schedule improves efficacy measures. The data show that febrile neutropenic events are more likely to occur during the first and second cycles of chemotherapy, thus prophylactic measures should be considered early in the course of treatment. Furthermore, since systematic dose reduction can impact on outcome, primary prophylactic use of G-CSF for all elderly patients receiving curative myelotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like) is indicated and we suggest a risk-adapted strategy with primary prophylactic G-CSF administration in high-risk patients. Dose intensification, through dose interval reduction, facilitated by prophylactic G-CSF, improved survival in elderly patients with some specific diseases. There is a need for further well-designed studies to identify the elderly patients who will benefit most from prophylactic G-CSF. To achieve this, we strongly urge the design of and participation in further trials.

Prevention of Chemotherapy-Induced Febrile Neutropenia by Prophylactic Antibiotics Plus or Minus Granulocyte Colony-Stimulating Factor in Small-Cell Lung Cancer: A Dutch Randomized Phase III Study

PURPOSE Febrile neutropenia (FN) is a major complication of chemotherapy. Antibiotics as well as granulocyte colony-stimulating factor (G-CSF) are effective in preventing FN. This multicenter randomized phase III trial determines whether the addition of G-CSF to antibiotic prophylaxis can further reduce the incidence of FN in patients with small-cell lung cancer (SCLC) at the risk of FN. PATIENTS AND METHODS Patients (N = 175) were stratified for stage of disease, performance status, age, and prior chemotherapy treatment, and were randomly assigned for treatment with cyclophosphamide, doxorubicin, and etoposide (CDE), followed by prophylactic antibiotics alone (ciprofloxacin and roxithromycin) or by antibiotics in combination with G-CSF on days 4 to 13. RESULTS In cycle 1, 20 patients (24%) in the antibiotics group developed FN compared with nine patients (10%) in the antibiotics plus G-CSF group (P = .01). In cycles 2 to 5, the incidences of FN were practically the same in both groups (17% v 11%). Only the treatment parameters (odds ratio, 0.33; 95% CI, 0.14 to 0.78) and age (1.067 per year; 95% CI, 1.013 to 1.0124) were related to the probability of FN in cycle 1. CONCLUSION Primary G-CSF prophylaxis added to primary antibiotic prophylaxis is effective in reducing FN and infections in SCLC patients at the risk of FN with the first cycle of CDE chemotherapy. For patients with similar risk of FN, the combined use of prophylactic antibiotics plus G-CSF can be considered, specifically in the first cycle of chemotherapy.

Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: A systematic review

BACKGROUND As neoadjuvant chemotherapy (NAC) is increasingly used to downstage patients with breast cancer, the timing of the sentinel node (SN) biopsy has become an important issue. This review was conducted to determine the accuracy of SN biopsy following NAC. METHODS We searched Medline, Embase and Cochrane databases from 1993 to February 2009 for studies on patients with invasive breast cancer who underwent SN biopsy after NAC followed by an axillary lymph node dissection (ALND). RESULTS Of 574 eligible studies, 27 were included in this review with a total study population of 2148 patients. The pooled SN identification rate was 90.9% (95% confidence interval (CI)=88.0-93.1%) and the false-negative rate was 10.5% (95% CI=8.1-13.6%). Negative predictive value and accuracy after NAC were 89.0% (95% CI=85.1-92.1%) and 94.4% (95% CI=92.6-95.8%), respectively. The reported SN success rates were heterogeneous and several variables were reported to be associated with decreased SN accuracy, i.e. initially positive clinical nodal status. CONCLUSIONS There is a potential role for SN biopsy following NAC which could be considered on an individual basis. However, there is insufficient evidence to recommend this as a standard procedure. Further research with subgroup analysis using variables reported to be associated with decreased SN accuracy is required in order to clearly define its value in the subgroups of breast cancer patients.

Signalling pathways in vasculogenic mimicry.

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.

Non–Sentinel Lymph Node Metastases Associated With Isolated Breast Cancer Cells in the Sentinel Node

There are many reports on the frequency of non-sentinel lymph node involvement when isolated tumor cells are found in the sentinel node, but results and recommendations for the use of an axillary lymph node dissection differ among studies. This systematic review was conducted to give an overview of this issue and to provide recommendations for the use of an axillary lymph node dissection in these patients. We searched Medline, Embase, and Cochrane databases from January 1, 2002, through November 27, 2007, for articles on patients with invasive breast cancer who had isolated tumor cells in the sentinel lymph node (according to the sixth edition of the Cancer Staging Manual of the American Joint Committee on Cancer) and who also underwent axillary lymph node dissection. Of 411 selected articles, 29 (including 836 patients) were included in this review. These 29 studies were heterogeneous, reporting a wide range of non-sentinel lymph node involvement (defined as the presence of isolated tumor cells or micro- or macrometastases) associated with isolated tumor cells in the sentinel lymph node, with an overall pooled risk for such involvement of 12.3% (95% confidence interval = 9.5% to 15.7%). This pooled risk estimate was marginally higher than the risk of a false-negative sentinel lymph node biopsy examination (ie, 7%-8%) but marginally lower than the risk of non-sentinel lymph node metastases in patients with micrometastases (ie, approximately 20%) who are currently eligible for an axillary lymph node dissection. Because 36 (64%) of the 56 patients with isolated tumor cells in their sentinel lymph node also had non-sentinel lymph node macrometastases, those patients with isolated tumor cells in the sentinel lymph node without other indications for adjuvant systemic therapy might be candidates for axillary lymph node dissection.

Standard Versus Intensified Chemotherapy With Granulocyte Colony-Stimulating Factor Support in Small-Cell Lung Cancer: A Prospective European Organization for Research and Treatment of Cancer–Lung Cancer Group Phase III Trial—08923

PURPOSE To assess the impact on survival of increasing dose-intensity (DI) of cyclophosphamide, doxorubicin, and etoposide (CDE) in small-cell lung cancer (SCLC). PATIENTS AND METHODS Previously untreated SCLC patients were randomized to standard CDE (cyclophosphamide 1,000 mg/m(2) and doxorubicin 45 mg/m(2) on day 1, and etoposide 100 mg/m(2) on days 1 to 3 every 3 weeks, for five cycles) or intensified CDE (cyclophosphamide 1,250 mg/m(2) and doxorubicin 55 mg/m(2) on day 1, and etoposide 125 mg/m(2) on days 1 to 3 with granulocyte colony-stimulating factor [G-CSF] 5 micro g/kg/d on days 4 to 13 every 2 weeks, for four cycles). Projected cumulative dose was almost identical on the two arms, whereas projected DI was nearly 90% higher on the intensified arm. Two hundred forty-four patients were enrolled. The first 163 patients were also randomized (2 x 2 factorial design) to prophylactic antibiotics or placebo to assess their impact on preventing febrile leukopenia (FL). This report focuses on chemotherapy DI results. RESULTS With a median follow-up of 54 months, 216 deaths have occurred. Actually delivered DI on the intensified arm was 70% higher than on the standard arm. Intensified CDE was associated with more grade 4 leukopenia (79% v 50%), grade 4 thrombocytopenia (44% v 11%), anorexia, nausea, and mucositis. FL and number of toxic deaths were similar on the two arms. The objective response rate was 79% for the standard arm and 84% for the intensified arm (P =.315). Median survival was 54 weeks and 52 weeks, and the 2-year survival rates were 15% and 18%, respectively (P =.885). CONCLUSION A 70% increase of CDE actual DI does not translate into an improved outcome in SCLC patients.

Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: An EORTC double-blind placebo-controlled phase III study

BACKGROUND CDE (cyclophosphamide, doxorubicin, etoposide) is one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this trial the impact of prophylactic antibiotics on incidence of febrile leucopenia (FL) during chemotherapy for SCLC was evaluated. PATIENTS AND METHODS Patients with chemo-naïve SCLC were randomized to standard-dose CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v., q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks, x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on survival (n = 240 patients). Patients were also randomized to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163 patients). This manuscript focuses on the antibiotics question. RESULTS The incidence of FL during the first cycle was 25% of patients in the placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an overall incidence through all cycles of 43% vs. 24% respectively (P = 0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative (20 vs. 5) and clinically documented (38 vs. 15) infections in the antibiotics arm. The use of therapeutic antibiotics was reduced (P = 0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17 patients, P = 0.013: 1-sided). However, the overall number of days of hospitalization was not reduced (P = 0.05; 1-sided). The number of infectious deaths was nil in the antibiotics vs. five (6%) in the placebo arm (P = 0.022; 2-sided). CONCLUSIONS Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalizations due to FL by approximately 50%, with reduced number of infectious deaths. For patients with similar risk for FL, the prophylactic use of antibiotics should be considered.