Hematologic toxicities of cancer chemotherapy are common and often limit the ability to provide treatment in a timely and dose-intensive manner. These limitations may be of utmost importance in the adjuvant and curative intent settings. Hematologic toxicities may result in febrile neutropenia, infections, fatigue, and bleeding, all of which may lead to additional complications and prolonged hospitalization. The older cancer patient and patients with significant comorbidities may be at highest risk of neutropenic complications. Colony-stimulating factors (csfs) such as filgrastim and pegfilgrastim can effectively attenuate most of the neutropenic consequences of chemotherapy, improve the ability to continue chemotherapy on the planned schedule, and minimize the risk of febrile neutropenia and infectious morbidity and mortality. The present consensus statement reviews the use of csfs in the management of neutropenia in patients with cancer and sets out specific recommendations based on published international guidelines tailored to the specifics of the Canadian practice landscape. We review existing international guidelines, the indications for primary and secondary prophylaxis, the importance of maintaining dose intensity, and the use of csfs in leukemia, stem-cell transplantation, and radiotherapy. Specific disease-related recommendations are provided related to breast cancer, non-Hodgkin lymphoma, lung cancer, and gastrointestinal cancer. Finally, csf dosing and schedules, duration of therapy, and associated acute and potential chronic toxicities are examined.
Canadian recommendations; neutropenia; febrile neutropenia; supportive care; colony-stimulating factors; chemotherapy-induced neutropenia; safety
Primary prophylaxis with granulocyte colony–stimulating factors (pp-g-csf) is recommended in patients undergoing chemotherapy carrying a febrile neutropenia (fn) risk of 20% or more. In the present study, we examined clinical practice patterns and the impact of pp-g-csf on fn incidence in women with early-stage breast cancer (ebc) treated with modern adjuvant chemotherapy (act).
This single-centre retrospective cohort study of women with ebc, who were identified from the pharmacy database and who received at least 1 cycle of modern act from January 2009 to December 2011, was conducted at the Cancer Centre of Southeastern Ontario. Data on patient demographics, pathology, stage distribution, chemotherapy, pp-g-csf use, dose reductions, chemotherapy delays, treatment discontinuation, relative dose intensity, and fn events were collected. Chi-square tests, t-tests, univariate and multivariate logistic regression analyses, and nonparametric Mann–Whitney U-tests were used for data analysis.
Of the 239 women eligible for analysis, 145 (61%) received pp-g-csf, and 50 (21%) developed at least 1 episode of fn. Use of pp-g-csf was associated with a significantly lower rate of fn (14% vs. 31%, p = 0.002) and trends to fewer dose delays (17% vs. 27%, p = 0.060) and dose reductions (19% vs. 25%, p = 0.28). Among women receiving pp-g-csf, higher fn rates were associated with an age of 65 years or older, taxane-based chemotherapy, and prophylaxis with filgrastim
Clinical practice patterns at our institution showed that more than 50% of ebc patients treated with modern act received pp-g-csf, which led to fewer fn episodes and increased delivery of planned act. The observed high fn risk despite pp-g-csf was linked to older age, taxane-based chemotherapy, and filgrastim.
Adjuvant chemotherapy; early-stage breast cancer; febrile neutropenia; filgrastim; pegfilgrastim; practice patterns; primary prophylaxis with granulocyte colony-stimulating factors
Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.
Non-Hodgkin lymphoma; neutropenia; chemotherapy; risk factors
We report an extremely rare and complex case of a 44-year-old woman diagnosed with an early stage triple negative breast cancer in the setting of primary autoimmune neutropenia with a pre-existing severe neutropenia. This case-report demonstrates that adjuvant chemotherapy for breast cancer can be administered in a patient with severe neutropenia. The management is however complicated and requires careful monitoring of side-effects related to both chemotherapy and treatment of autoimmune neutropenia. The role of chemotherapy in the treatment of triple negative breast cancer, the approach to autoimmune neutropenia and potential interactions are reviewed. To our knowledge, this is the first case reporting on the use of chemotherapy in a patient with severe pre-existing primary autoimmune neutropenia.
breast cancer; autoimmune neutropenia; chemotherapy
Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.
We evaluated risk factors for neutropenic fever and febrile prolonged neutropenia during vincristine-including chemotherapy to treat HIV-related lymphoma to investigate whether protease inhibitor (PI) treatment is associated with infectious complications due to drug interactions with chemotherapeutic agents. We included all HIV patients who received chemotherapy including vincristine for lymphoma at a single referral center in 1999-2010. Neutropenic fever was defined as absolute neutrophil count < 500 cells/µL with body temperature over 38℃; and prolonged neutropenia was defined if it persisted over 7 days. CODOX-M/IVAC and Stanford regimens were considered high-risk regimens for prolonged neutropenia. We analyzed 48 cycles of chemotherapy in 17 HIV patients with lymphoma. There were 22 neutropenic fever and 12 febrile prolonged neutropenia events. In multivariate analysis, neutropenic fever was associated with old age and low CD4 cell count, but not with PI use or ritonavir-boosted PI use. Low CD4 cell count and high-risk regimens were associated with febrile prolonged neutropenia. Neutropenic fever and febrile prolonged neutropenia is associated with old age, low CD4 cell count, and high-risk regimens, but not PI use, in HIV patients undergoing chemotherapy including vincristine for lymphoma.
Human Immunodeficiency Virus; Lymphoma; Neutropenia
Lipegfilgrastim is a novel glyco-pegylated granulocyte-colony stimulating factor in development for neutropenia prophylaxis in cancer patients receiving chemotherapy. This phase III, double-blind, randomized, active-controlled, noninferiority trial compared the efficacy and safety of lipegfilgrastim versus pegfilgrastim in chemotherapy-naïve breast cancer patients receiving doxorubicin/docetaxel chemotherapy.
Patients with high-risk stage II, III, or IV breast cancer and an absolute neutrophil count ≥1.5 × 109 cells/L were randomized to a single 6-mg subcutaneous injection of lipegfilgrastim (n = 101) or pegfilgrastim (n = 101) on day 2 of each 21-day chemotherapy cycle (4 cycles maximum). The primary efficacy endpoint was the duration of severe neutropenia during cycle 1.
Cycle 1: The mean duration of severe neutropenia for the lipegfilgrastim and pegfilgrastim groups was 0.7 and 0.8 days, respectively (λ = −0.218 [95% confidence interval: –0.498%, 0.062%], p = 0.126), and no severe neutropenia was observed in 56% and 49% of patients in the lipegfilgrastim and pegfilgrastim groups, respectively. All cycles: In the efficacy population, febrile neutropenia occurred in three pegfilgrastim-treated patients (all in cycle 1) and zero lipegfilgrastim-treated patients. Drug-related adverse events in the safety population were reported in 28% and 26% of patients i006E the lipegfilgrastim and pegfilgrastim groups, respectively.
This study demonstrates that lipegfilgrastim 6 mg is as effective as pegfilgrastim in reducing neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy.
The study protocol, two global amendments (Nos. 1 and 2), informed consent documents, and other appropriate study-related documents were reviewed and approved by the Ministry of Health of Ukraine Central Ethics Committee and local independent ethics committees (IECs).
Neutropenia; Febrile neutropenia; Breast cancer; Recombinant granulocyte-colony stimulating factor; Lipegfilgrastim; Pegfilgrastim
Thirty-four evaluable patients were treated with vinorelbine, a novel, semisynthetic vinca alkaloid, as first-line chemotherapy for advanced breast cancer. They received vinorelbine 25 mg m-2 i.v. given weekly for a maximum of 16 cycles. Two patients achieved a complete remission and 15 a partial remission, giving a response rate of 17/34 (50%; 95% CI of 34-66%); median response duration was 5.8 months. The median progression-free interval was 4.4 months and median survival 9.9 months. Treatment was generally well tolerated. Fatigue was the most common side-effect. The main reason for dose adjustments was myelosuppression; 68% of patients had WHO grade 3 or 4 neutropenia and there was one death attributed to neutropenic sepsis. Nausea/vomiting and neuropathy were mild and alopecia was uncommon. This study confirms vinorelbine as a highly active, well-tolerated agent in advanced breast cancer worthy of evaluation in combination chemotherapy regimens.
Leukocytes play an important role in cancer development. However, the impact of chemotherapy-associated neutropenia/lymphopenia on the prognosis of adjuvant chemotherapy is unknown. Here, we aimed to explore the impact of chemotherapy-associated neutrophil/lymphocyte counts on prognosis of adjuvant chemotherapy in colorectal cancer (CRC) and the risk factors for developing neutropenia/lymphopenia which showed impact on the prognosis of CRC receiving adjuvant chemotherapy.
From February 2003 to January 2011, 243 stage II and III CRC patients receiving adjuvant chemotherapy were enrolled in this retrospective study. The associations between neutrophil/ lymphocyte counts and disease free survival (DFS)/overall survival (OS) of CRC, and the risk factors for neutropenia/lymphopenia were investigated.
No association of chemotherapy-associated neutrophil counts and CRC recurrence (AUC = 0.474, P = 0.534), death (AUC = 0.449, P = 0.249) was found by ROC analysis. However, the chemotherapy-associated lymphocyte counts could significantly affect CRC recurrence (AUC = 0.634, P = 0.001), or death(AUC = 0.607, P = 0.015), with a optimized cut-off of 0.66 × 109/L for recurrence, and 0.91 × 109/L for death, respectively. Kaplan–Meier method showed chemotherapy-associated lymphopenia <0.66 × 109/L was associated with shorter DFS (P < 0.0001), and chemotherapy-associated lymphopenia <0.91 × 109/L was associated with shorter OS (P = 0.003). Cox regression model showed chemotherapy-associated lymphopenia <0.66 × 109/L was the independent prognostic factor for DFS (HR, 3.521; 95%CI = 1.703-7.282), and chemotherapy-associated lymphopenia <0.91 × 109/L was the independent prognostic factor for OS (HR, 2.083; 95% CI = 1.103-3.936). Multivariate logistic regression showed the risk of developing chemotherapy-associated lymphopenia <0.66 × 109/L was found in those with pretreatment CEA ≥10 ng ml-1 (OR, 3.338; 95% CI = 1.523-7.315), and the risk of developing chemotherapy-associated lymphopenia <0.91 × 109/L was found in those with age >60 years (OR, 2.872; 95% CI = 1.344-6.136).
Chemotherapy-associated lymphopenia <0.66 × 109/L /0.91 × 109/L has a significant impact on the prognosis of CRC receiving adjuvant chemotherapy. Pretreatment CEA ≥10 ng ml-1 is the independent risk factor for developing lymphopenia <0.66 × 109/L, and age >60 years is the independent risk factor for developing lymphopenia <0.91 × 109/L during adjuvant chemotherapy of CRC.
Colorectal cancer; Chemotherapy; Lymphopenia; Neutropenia; Prognosis
Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization.
This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis.
We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35–0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim.
In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis.
In 2005, 224 patients received adjuvant/neoadjuvant chemotherapy for breast cancer in a single institution according to daily practices. Regimens consisted of epirubicin-based chemotherapy (FEC100, four or six cycles), or three cycles of FEC100 followed by three cycles of docetaxel. An absolute blood count was carried out every 3 weeks, 1–3 days before planned chemotherapy cycle. Overall, 1238 cycles were delivered. An absolute neutrophil count (ANC) <1.5 × 109 l−1 before planned chemotherapy was found in 171 cycles. Of these, 130 cycles (76%) were delivered as planned regardless of whether ANC levels recovered, and 41 (24%) were delayed. None of these patients developed a febrile neutropaenia. Haematopoietic support (granulocyte colony-stimulating factor (G-CSF)) was required in 12 cycles. We found that the majority of patients with an ANC <1.5 × 109 l−1 before planned chemotherapy received planned doses, without complications and need for G-CSF.
breast; chemotherapy; adjuvant; neutropaenia; dose intensity
Reductions in the dose intensity (DI) of adjuvant anthracycline-based chemotherapy in early stage breast cancer are frequently required due to treatment toxicity or poor tolerance, but the implications of a minimal reduction in DI on clinical outcome remain uncertain.
Patients and methods:
Women with stage I–II breast cancer treated with adjuvant adriamycin and cyclophosphamide (AC) from 1990–95 were identified in a provincial breast cancer database. Cases were classified into four cohorts: (1) all cycles delivered at full dose and on time; (2) one single dose reduction or dose delay; (3) >1 dose reduction or dose delay; (4) <2 cycles of chemotherapy delivered.
484 eligible cases were identified (cohort (1): n = 268; (2): n= 88; (3): n= 89; (4) n= 39). Slight imbalances in lymph node status (p=0.05) and adjuvant hormonal therapy (p=0.05) were observed between the cohorts. Fifty-five per cent (267/484) of the patients had node-positive disease and 33% (158/484) were ER+. 45% of cases had a reduction in DI. With a median follow-up of 9.6 years, there were no significant differences in relapse-free survival (p=0.94), breast cancer-specific survival (p=0.87) or overall survival (p=0.86) between the four cohorts. Outcomes were independent of hormone receptor status.
Although toxicity related reductions in the DI of adjuvant AC chemotherapy for early stage breast cancer are common, they did not appear to significantly impact on clinical outcomes in this population-based cohort of women with stage I–II breast cancers.
LÓPEZ-POUSA A., RIFÀ J., CASAS DE TEJERINA A., GONZÁLEZ-LARRIBA J.L., IGLESIAS C., GASQUET J.A. & CARRATO A. (2010) European Journal of Cancer Care Risk assessment model for first-cycle chemotherapy-induced neutropenia in patients with solid tumours
Chemotherapy-induced neutropenia, the major dose-limiting toxicity of chemotherapy, is directly associated with concomitant morbidity, mortality and health-care costs. The use of prophylactic granulocyte colony-stimulating factors may reduce the incidence and duration of chemotherapy-induced neutropenia, and is recommended in high-risk patients. The objective of this study was to develop a model to predict first-cycle chemotherapy-induced neutropenia (defined as neutropenia grade ≥3, with or without body temperature ≥38°C) in patients with solid tumours. A total of 1194 patients [56% women; mean age 58 ± 12 years; 94% Eastern Cooperative Oncology Group (ECOG) status ≤1] with solid tumours were included in a multi-centre non-interventional prospective cohort study. A predictive logistic regression model was developed. Several factors were found to influence chemotherapy-induced neutropenia. Higher ECOG status values increased toxicity (ECOG 2 vs. 0, P= 0.003; odds ratio 3.12), whereas baseline lymphocyte (P= 0.011; odds ratio 0.67) and neutrophil counts (P= 0.026; odds ratio 0.90) were inversely related to neutropenia occurrence. Sex and treatment intention also significantly influenced chemotherapy-induced neutropenia (P= 0.012). The sensitivity and specificity of the model were 63% and 67% respectively, and the positive and negative predictive values were 17% and 94% respectively. Once validated, this model should be a useful tool for clinical decision making.
solid tumours; neutropenia; predictive model
Fatigue is one of the most common and distressing complaints among cancer patients, not only during radiation and chemotherapy, but also for months to years after the completion of treatment. Fatigue interferes with patients’ daily lives, reduces their quality of life, and is often a significant reason why patients discontinue treatment. We hypothesized that some of the fatigue may be related to disrupted circadian rhythms and low light exposure. The main objective of this study therefore was to investigate the association between fatigue and light exposure among patients with breast cancer.
As part of a larger, ongoing prospective study on fatigue, sleep, and circadian rhythms in patients with breast cancer, an analysis of 63 women newly diagnosed with stage I–IIIA breast cancer and scheduled to receive four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy was conducted. Data were collected before and during weeks 1, 2, and 3 of cycle 1 and cycle 4. Fatigue was assessed using the Short Form of Multidimensional Fatigue Symptom Inventory. Light exposure was recorded with a wrist actigraph.
There were significant correlations between fatigue levels and light exposure (r=−0.28 to −0.45) within both cycle 1 and cycle 4, such that higher levels of fatigue were associated with less light exposure. There were also significant correlations between changes in light exposure and changes in fatigue within the first 2 weeks of each cycle (r=−0.28 to −0.52).
Increased fatigue was significantly correlated with decreased light exposure among patients with breast cancer. Although the cause and effect of exacerbated fatigue and decreased light exposure cannot be confirmed by the current study, and lower light exposure may just in part be due to the fatigued patients spending less time outdoors in bright light, two hypotheses are proposed about the mechanisms by which light may alleviate the fatigue of patients with breast cancer. These results suggest the need for prospective intervention studies of light therapy for breast-cancer-related fatigue.
Breast cancer; Fatigue; Light; Chemotherapy
The purpose of this retrospective study was to assess the tolerability and efficacy of sequential chemotherapy and radiotherapy for the treatment of high risk endometrial cancer.
We conducted a retrospective study of previously untreated high risk endometrial cancer patients who received sequential chemotherapy and radiotherapy in accordance with the sandwich approach from June 2008 until June 2011. High risk endometrial cancer patients underwent complete surgical staging followed by adjuvant therapy encompassing sequential chemotherapy, radiation therapy and consolidation chemotherapy.
The study analysis comprised 32 endometrial cancer patients. All subjects were treated with carboplatin and paclitaxel chemotherapy; currently, 186 cycles have been administered and 94% of patients have completed the planned number of cycles. Grade 3 neutropenia developed in 1 (3.1%) patient; there was no incidence of grade 4 neutropenia. Moreover, we observed grade 3 anemia in four (12.5%) patients and grade 4 anemia in one (3.1%) patient. One (3.1%) patient developed grade 3 thrombocytopenia; grade 4 thrombocytopenia was not observed. Five patients exhibited progressive disease, three of whom have since expired; mean progression free survival and follow-up were 17.4 months and 18.9 months, respectively.
The preliminary results from our study suggest that the sandwich approach to treating high risk endometrial cancer patients is feasible. Hematologic toxicity was well tolerated and non-hematologic toxicity was mild and easily managed. Further study of this novel regimen in a larger patient population with extended follow-up is necessary.
Chemotherapy; Endometrial cancer; Gynecologic oncology; Radiotherapy
This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia.
Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules.
The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μg m−2 tri-weekly, is G-CSF, 300 μg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m−2, is optimally supported by the slightly less cost-effective G-CSF 300 μg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μl) under Doc, 100–150 mg m−2 tri-weekly.
The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.
granulocyte colony-stimulating factor; neutropenia; Doc; mechanistic PK/PD; mathematical modelling; optimisation
AIMS—To evaluate the
pharmacokinetics of once daily (OD) gentamicin and its effectiveness as
part of an OD regimen for the empirical treatment of febrile
neutropenia in children with cancer.
aged 6 months to 16 years (mean (SD) 5.7 (4) years) with febrile
neutropenia (neutrophil count < 0.5 × 109/l) after chemotherapy.
METHODS—Over one year,
113 febrile neutropenic episodes were treated empirically with an OD
antibiotic regimen of ceftriaxone (80 mg/kg; maximum 4 g) and
gentamicin (7 mg/kg; infused over 60 minutes, no maximum). The
patients were assessed after 48hours.
RESULTS—86 of the 113 episodes settled with the first line antibiotic regimen. In 29 episodes, blood cultures identified a causative bacterial pathogen; for
17 of these, the first line antibiotic regimen was adequate; in four
episodes, although the episode settled, ceftriaxone was replaced by a
more appropriate antibiotic and OD gentamicin was continued; in the
remaining eight episodes, a glycopeptide antibiotic was deemed
necessary. There was no failure of treatment in organisms sensitive to
gentamicin, including Pseudomonas aeruginosa. In 27 episodes (24%),
resolution was obtained by the empirical introduction of a second line
regimen of ceftazidime and a glycopeptide antibiotic, and/or
amphotericin. Gentamicin concentrations were measured in 110 episodes
and they were all below the 24 hour line indicating that there was no
need to change the dosing interval. In two episodes
(2%), serum creatinine rose transiently by more
than 50% of the baseline concentration. Although there was no
vestibular toxicity, three of 30 children who underwent pure tone
audiometry reported high frequency hearing loss in one ear.
gentamicin can be used safely and effectively to treat febrile
neutropenia in children with cancer. When used for a short period
(< 5 days), in children not receiving other nephrotoxic drugs and who
have normal serum creatinine, serum gentamicin estimations are unnecessary.
Women of African ancestry (AA) have lower WBC counts and are more likely to have treatment delays and discontinue adjuvant breast cancer therapy early compared with white women. We assessed the association between race and treatment discontinuation/delay, WBC counts, and survival in women enrolled onto breast cancer clinical trials.
Patients and Methods
AA and white women from Southwest Oncology Group adjuvant breast cancer trials (S8814/S8897) were matched by age and protocol. Only the treatment arms in which patients were scheduled to receive six cycles of chemotherapy were analyzed.
A total of 317 pairs of patients (n = 634) were analyzed. At baseline, AA women had higher body-surface area (P < .0001) and lower WBC (P = .0009). AA women were more likely to have tumors that were ≥ 2 cm (P = .01) and hormone receptor negative (P < .0001). AA women, versus white women, were marginally more likely to discontinue treatment early (11% v 7%, respectively; P = .07) or have one or more treatment delays (85% v 79%, respectively; P = .07) and were significantly more likely to experience the combined end point (discontinuation/delay; 87% v 81%, respectively; P = .04). The mean relative dose-intensity (RDI) was similar for both groups (87% in AA women v 86% in white women); however, overall, 43% had an RDI of less than 85%. After adjusting for baseline WBC and prognostic factors in a multivariate model, AA women had worse disease-free survival (hazard ratio [HR] = 1.56; 95% CI, 1.15 to 2.11; P = .005) and overall survival (HR = 1.95; 95% CI, 1.36 to 2.78; P = .0002). The inclusion of RDI and treatment delivery/quality in the regression had little impact on the results.
On cooperative group breast cancer trials, AA and white women had similar RDIs, but AA women were more likely to experience early discontinuation or treatment delay. Despite correcting for these factors and known predictors of outcome, AA women still had worse survival.
The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting.
Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period.
The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists.
Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.
The nadir value of the absolute neutrophil count (ANC) in the first cycle of chemotherapy is an effective predictor of subsequent neutropenic events. This study was designed to validate an earlier published study based on a retrospective data analysis from a prospective randomized clinical trial.
The original published model was applied to a trial of 143 patients to cross-validate the model. We also tested the specification of the model on our data by using a logistic regression model with several variables, including first-cycle nadir ANC, age, menopausal status, hormone-receptor status, previous radiotherapy, and first-cycle decrease in hemoglobin concentration. Patients received fluorouracil, doxorubicin, and cyclophosphamide every 21 or 28 days for six cycles without hematopoietic support from colony-stimulating factor.
In the cross-validation analysis, the original model successfully classified patients by risk of neutropenic events (C = 0.78). When the model specification was tested, first-cycle nadir ANC was the sole significant (P < 0.0001) predictor of neutropenic events and the model had a good predictive power (C = 0.78). The estimated relative risk of 4.8 did not differ from the risk cited in the original model (P = 0.91). A significantly higher percentage of our patients with a low first-cycle nadir ANC of 0.25 × 109/liter or less experienced febrile neutropenia (30% versus 10%, P = 0.04) and received at least 85% of the planned dose intensity (55% versus 32%, P = 0.05).
The original risk model used to predict neutropenic events was validated by our study. This information can be used to target high-risk patients for prophylactic treatment with filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) in chemotherapy cycles 2 to 6.
chemotherapy; filgrastim; hospitalization; myelosuppression; neutropenia
Radiation-induced dermatitis is a common side effect of breast irradiation, with hypofractionation being a well-known risk factor. In the context of the widespread adoption of hypofractionated breast radiotherapy, we evaluated the effect of hypofractionated radiotherapy on the incidence of skin toxicity in patients receiving adjuvant chemotherapy.
Patients and Methods
We retrospectively reviewed the records of patients with breast cancer treated from 2004 to 2006 at a single institution. Patients undergoing lumpectomy with or without adjuvant chemotherapy followed by hypofractionated radiotherapy consisting of 42.4 Gy in 16 fractions were included in the study. Using cosmetic and skin toxicity scales, all patients were evaluated weekly during treatment and at scheduled follow-up visits with the radiation oncologist.
During the study period, 162 patients underwent radiotherapy, and 30% of those (n = 48) received chemotherapy. Radiotherapy boost to the tumour bed was more common in the chemotherapy group [n = 20 (42%)] than in the radiotherapy-alone group [n = 30 (26%)]. We observed no statistically significant difference between the groups with regard to acute skin toxicity of grade 3 or higher (2.1% in the chemotherapy group vs. 4.4% in the radiation-alone group, p = 0.67) or of grades 1–2 toxicity (62.5% vs. 51.7% respectively, p = 0.23). There was also no significant difference in late grade 3 or higher skin toxicity between the groups (2.1% vs. 0% respectively, p = 0.30) or in grades 1–2 toxicity (20.8% vs. 25.5% respectively, p = 0.69). Similarly, excellent or good cosmetic result scores were similar in both groups (p = 0.80)
In our single-institution review, we observed no adverse effects of chemotherapy in combination with hypofractionated whole-breast irradiation. Further investigations are necessary to better elucidate the effects of chemotherapy on skin toxicity in the context of hypofractionated irradiation.
Breast cancer; hypofractionated radiotherapy; chemotherapy; skin toxicity
A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy.
Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m−2, epirubicin 100 mg m−2, cyclophosphamide 500 mg m−2 (FEC 100) followed by three cycles of docetaxel 100 mg m−2 delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis.
In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%).
Sequential dose-dense FEC 100 followed by docetaxel 100 mg m−2 is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.
adjuvant treatment; docetaxel; dose-dense regimen; early breast cancer; skin toxicity; taxanes
Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics.
Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy.
The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim.
These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics.
Neutrophils play an important role in immunological function. Neutropenic patients are vulnerable to infection, and except fever is present, inflammatory reactions are scarce in many cases. Additionally, because infections can worsen rapidly, early evaluation and treatments are especially important in febrile neutropenic patients. In cases in which febrile neutropenia is anticipated due to anticancer chemotherapy, antibiotic prophylaxis can be used, based on the risk of infection. Antifungal prophylaxis may also be considered if long-term neutropenia or mucosal damage is expected. When fever is observed in patients suspected to have neutropenia, an adequate physical examination and blood and sputum cultures should be performed. Initial antibiotics should be chosen by considering the risk of complications following the infection; if the risk is low, oral antibiotics can be used. For initial intravenous antibiotics, monotherapy with a broad-spectrum antibiotic or combination therapy with two antibiotics is recommended. At 3-5 days after beginning the initial antibiotic therapy, the condition of the patient is assessed again to determine whether the fever has subsided or symptoms have worsened. If the patient's condition has improved, intravenous antibiotics can be replaced with oral antibiotics; if the condition has deteriorated, a change of antibiotics or addition of antifungal agents should be considered. If the causative microorganism is identified, initial antimicrobial or antifungal agents should be changed accordingly. When the cause is not detected, the initial agents should continue to be used until the neutrophil count recovers.
Practice guideline; Neutropenia; Fever; Korea
Our aim was to study the feasibility of an intensified intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) schedule with the aim to escalate dose intensity (DI). Twenty-three premenopausal breast cancer patients received 6 cycles of adjuvant CMF intravenously on days 1 and 8 every 3 weeks and granulocyte colony-stimulating factor days 9–18. Endpoints were DI and toxicity. Twenty-one out of 23 patients (91%) received the projected total dose and reached ≥ 85% of the projected DI. Compared to ‘classical’ CMF, all patients reached ≥ 111% DI. Nine patients received the planned schedule without delay. Thirteen patients (57%) were treated for infection and four patients (17%) were hospitalized for febrile neutropenia. Twelve patients received red blood cell transfusions (52%). Radiation therapy (n= 6) had no adverse impact on dose intensity or haematological toxicity. This dose-intensified CMF schedule was accompanied by enhanced haematological toxicity with clinical sequelae, namely fever, intravenous antibiotics and red blood cell transfusions, but allows a high dose intensity in a majority of patients. © 2000 Cancer Research Campaign
adjuvant chemotherapy; breast cancer; CMF; dose intensity; granulocyte colony stimulating factor; premenopausal