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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4821-4828 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.7395 Rational Selection of Patients for Antibacterial Prophylaxis After Chemotherapy
From the University Hospital Birmingham Cancer Centre; Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom Address reprint requests to Michael Cullen, MD, University Hospital Birmingham, NHS Foundation Trust, Birmingham B15 2TH, United Kingdom; e-mail: michael.cullen{at}uhb.nhs.uk
Purpose The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy ± Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis. Patients and Methods The risk of FE was calculated for control patients on first versus nonfirst cycles, with or without first-cycle FE, and within subgroups defined by cancer type, performance status (PS), age, and treatment context (adjuvant v nonadjuvant). Using the randomized trial data, the prophylactic efficacy of levofloxacin was examined for the same subgroups. Results The per-cycle FE incidence was much lower on nonfirst (3.3%) versus first cycles (8.0%). Prophylaxis was less effective for nonfirst (odds ratio [OR] = 0.78; P = .16) compared with first cycles (OR = 0.42; P < .001). However, FE on cycle 1 predicted a much higher risk of FE and a trend to continued prophylactic efficacy on subsequent cycles. FE rate was greatest for testicular cancer (27.9%), then small-cell lung cancer (17.3%), and lowest for breast cancer (11.5%). Prophylactic efficacy was consistent across age, sex, PS, treatment context, and disease type (except possibly non-Hodgkin's lymphoma). Conclusion Under pressure to limit antibacterial use, these exploratory data support offering prophylactic levofloxacin on cycle 1 only of myelosuppressive cancer chemotherapy and on subsequent cycles after a cycle-1 fever. Prophylactic levofloxacin is effective regardless of age, PS, or tumor type.
After decades of uncertainty and controversy, recently published evidence has provided a basis for antibacterial prophylaxis with fluoroquinolones to reduce the chance of infection after myelosuppressive chemotherapy. Two large, double-blind, placebo-controlled trials of levofloxacin including 2,325 patients demonstrated very significant reductions in infection-related events, good tolerance of treatment, and evidence of cost-effectiveness in both solid cancer and lymphoma in patients undergoing moderately myelosuppressive cyclical chemotherapy,1 and in hematologic malignancies and patients undergoing high-dose chemotherapy.2 Neither trial was powered to demonstrate an effect on mortality. However, a meta-analysis of 15 trials (including these most recent ones, and totaling 3,440 patients) involving quinolones versus placebo or no intervention reports a significant impact on all-cause mortality.3 The conclusion from these trials and meta-analyses is that the use of prophylactic antibacterial therapy is justified to reduce the risk of neutropenic sepsis during cancer treatment. The concern is that, although there is no specific evidence of adverse clinical outcomes in this context, the general increase in antibiotic use selects for resistant microbial strains.4-8 This article addresses the question of whether there is a rational basis for a more selective application of fluoroquinolones to prevent fever and hospitalization from infection during cancer chemotherapy. It uses data from the SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy ± Antibiotic in a Number of Tumours) trial,1 in which we demonstrated a reduction in risk of febrile episodes (FEs) among 1,565 patients undergoing cyclical, myelosuppressive chemotherapy (ie, expected to cause grade 4 neutropenia [< 500/mm3]) for solid cancers or lymphomas. During the entire chemotherapy course (averaging 4.4 cycles) the incidence of FE was reduced from 15.2% to 10.8% of patients receiving placebo and levofloxacin 500 mg daily for 7 days (covering the anticipated neutropenic period) per cycle, respectively (relative risk, [RR] = 0.71; 95% CI, 0.55 to 0.92; P = .01). Patients in the control arm are used to identify groups at greatest risk of fever and hospitalization from infection without antibacterial prophylaxis. Data from the whole trial are used to identify whether particular subgroups gain greater benefit.
Patients Random assignment of patients in the SIGNIFICANT trial was stratified by age (< 40, 40 to 59, and  60 years) and cancer type (breast, testicular, small-cell lung, Hodgkin's disease [HD], and Hodgkin's lymphoma [NHL], and others). The small number of HD cases are included with others in the analysis. In addition, there were six baseline patient characteristics of interest; sex, WHO performance status (PS), previous myelosuppressive chemotherapy, previous myelosuppressive radiotherapy, adjuvant versus nonadjuvant chemotherapy, and presence of indwelling venous catheter. Patients were on study for a mean of 4.4 cycles of chemotherapy, with 45% of patients completing six cycles. The SIGNIFICANT trial was an investigator-led trial; all patients gave written, informed consent, and the research was conducted with ethical committee approval.
Outcome Measures Hospitalization for the treatment of suspected infection (HTSI) is an important clinical (and health economic) event (and a secondary trial outcome), and factors influencing the risk of this are analyzed. HTSI occurred in a subset of patients with FE, and also in some patients not meeting the trial criteria for FE.
Statistical Analysis The overall treatment effect on FE incidence was measured in the original article using relative risk. In this more detailed article, logistic regression modeling is used to allow multivariable analysis and, thus, treatment effect here is measured using OR together with 95% CI. RR and OR are measures of the association between treatment and outcome and, with a relatively low event rate, the two are comparable. Subgroup analysis aims to identify categories of patient behaving inconsistently with the overall treatment effect. The treatment effect within subgroups defined by baseline characteristics is assessed descriptively using OR from a logistic regression model and 95% CI presented as a forest plot. In all analyses, treatment benefit is calculated for all randomly assigned patients on intention-to-treat basis. Unbiased treatment comparison can be guaranteed only within subgroups defined by the two stratification factors (type of cancer and age). Tests for heterogeneity10 were used to formally assess whether the treatment effect differs across tumor type subgroups.
Identifying Risk Factors for Infection and Hospitalization Without Antibacterial Prophylaxis Tumor type. The different tumor types carried significantly different risks for both FE and HTSI across all cycles of chemotherapy and in cycle 1 (Tables 1 and 2). Multivariable analysis identified testicular cancer as the tumor type at significantly greatest risk for FE and HTSI in all cycles and in cycle 1, with SCLC an additional significant independent risk factor for HTSI in cycle 1 (Table 3). Borderline evidence from univariable analysis (Tables 1 and 2) suggesting that males were at increased risk is likely caused by association between sex and tumor type (ie, testicular cancer).
Performance status. Patients with a PS of 2, 3, or 4 are considered clinically distinct from those with a PS of 0 or 1, but only 10% of randomly assigned patients were PS 2 to 4. With these small numbers, there was no evidence that PS 2 to 4 was a significant risk factor for FE (Table 1). There was, however, some evidence of PS 2 to 4 being a risk factor for HTSI both in univariable (Table 2) and multivariable (Table 3) analysis.
Other pretreatment factors.
There was no evidence of an association between FE risk and patient age (<40, 40 to 59, First versus later cycles. Seven hundred eighty-four patients were randomly assigned to the placebo arm and received 3,459 cycles of chemotherapy (mean, 4.4 cycles per patient). One hundred nineteen controls, of whom 62 (52%) experienced an FE during the first cycle, had at least one FE during the chemotherapy program, giving a per-patient FE rate of 15.2%. The per-cycle FE rate for the first cycle was 8.0% (62 of 772; data missing for 12 patients) compared with 3.3% (89 of 2687) in nonfirst cycles. Of the 784 control patients, 169, of whom 81 (48%) experienced HTSI during the first cycle, had HTSI at least once during their chemotherapy, giving a per-patient hospitalization rate of 21.6%. The per-cycle HTSI rate during first and nonfirst cycles was 10.5% and 4.8%, respectively. The risk of both outcomes was much greater for the first cycle, and approximately 50% of episodes occurred in cycle one. FE in cycle 1. If there was no FE in cycle 1, the rate of FE was 2.6% on cycle 2 and 2.5%/cycle for cycles 2 to 6. However, if there was FE in cycle 1, then the corresponding rates were much higher: 15.5% in cycle 2 and 12.6%/cycle in cycles 2 to 6 (Fig 1).
Identifying Patients Who Benefit Most From Antibacterial Prophylaxis Treatment benefit across all cycles. As reported, the per-patient FE rate was 10.8% (84 of 781) for patients receiving levofloxacin compared with 15.2% for patients receiving placebo (119 of 784), giving a statistically significant reduction in the risk of FE (OR = 0.67; 95% CI, 0.50 to 0.91; P = .009).1 First versus later cycles. For the first cycle only, the per-patient FE rate was 3.5% in patients receiving levofloxacin compared with 7.9% in controls (OR = 0.42; 95% CI, 0.26 to 0.66; P = .0001)1 whereas for nonfirst cycles, the per-patient FE rate was 7.8% (61 of 781) and 9.8% (77 of 784), respectively (OR = 0.78; 95% CI, 0.55 to 1.11; P = .16). FE in cycle 1. Per-cycle FE rates in cycle 2 and cycles 2 to 6 indicate that prophylactic benefit is gained in the small number of patients who experience FE in cycle 1, but not in the much larger number who do not (Fig 1). This per-cycle analysis is descriptive because the trial was not designed to accumulate sufficient patients with early-cycle FE to formally test prophylactic benefit on subsequent cycles. Tumor type. Figures 2 and 3 show the OR and 95% CI for the effect of levofloxacin on FE across all cycles and cycle 1 only, respectively. With the exception of NHL there is a consistency of prophylactic efficacy throughout tumor types with OR less than 1. However, both for first and all cycles the effect is particularly pronounced for testicular cancer and SCLC. The OR for NHL suggested a detrimental effect of levofloxacin, but the 95% CIs are wide and include the point estimate of the overall effect. The test for heterogeneity showed some evidence of a difference between tumor types in treatment effect on FE rates across all cycles (P = .03), but not for cycle 1 (P = .18).
Other pretreatment factors. The treatment effect across subgroups defined by age, sex, PS, adjuvant chemotherapy, presence of a catheter, previous chemotherapy, and previous radiotherapy were all consistent with the overall treatment effect (Figs 2 and 3).
The SIGNIFICANT trial, reported in 2005, demonstrated that the use of prophylactic levofloxacin reduced the incidence of FEs on the first cycle and across all cycles for patients receiving conventional-dose, moderately myelosuppressive chemotherapy for solid tumors and lymphomas.1 A recently published meta-analysis including our data reports a significant reduction in 30-day (ie, first cycle) all-cause mortality in solid cancers and lymphomas from fluoroquinolone prophylaxis.3 The conclusion is that evidence now supports the use of this inexpensive and relatively nontoxic strategy for all patients in this context. Whether or not to implement this strategy is a matter for local policy making, taking into account multiple issues including, for example, the risk of infection and policy for treating neutropenic sepsis. The issue addressed here is whether prophylaxis can be more selectively targeted to reduce the burden of antibiotic use in the cancer patient community because of concerns regarding selection for microbial resistance. Half of all patients without prophylaxis experiencing FE or HTSI did so in the first cycle, with FE and HTSI rates more than double those in subsequent cycles. Other studies have made similar observations, albeit in smaller numbers of patients, generally with SCLC and breast cancer,11-14 and in surveys of larger numbers of patients with lymphoma15 and multiple tumor types.16 This phenomenon is not well appreciated.17 There are several possible explanations for this first-cycle effect. Neutropenia, which is not accurately predictable for a given patient, may be more severe for the first cycle, whereas subsequent cycles are subject to secondary modification, such as by dose reduction. The cytoreductive effects of the first chemotherapy cycle may enable resolution of a cancer-related focus of infection (eg, beyond an obstructed airway in lung cancer patients) or improvement in performance status. As reported, there is evidence for clear prophylactic benefit for levofloxacin during cycle 1 and during all cycles.1 Here, we show that on a per-patient, intention-to-treat basis, the prophylactic benefit is much less on nonfirst cycles, with too few events to demonstrate a true prophylactic effect with certainty. This pattern is also reflected in the per-cycle analysis (Fig 1). Multiple factors might contribute to this effect. Events and actions in earlier cycles may well influence subsequent events. Of particular importance is that levofloxacin might have progressively selected for microbial resistance, compromising prophylactic efficacy on subsequent cycles. Fluoroquinolone resistance has been shown to occur after routine prophylaxis although the change was not statistically significant in the recent meta-analysis by Gafter-Gvili et al.18 The first cycle of chemotherapy is noteworthy not only because of the high frequency of FE compared with later cycles, but also because FE in cycle 1 appears to separate patients into low- and high-risk groups for subsequent episodes. If no FE occurred in the first cycle, only one in 40 subsequent cycles was complicated by FE. Conversely, after a first-cycle FE, the chance of further episodes remains high (> 1 in 7 without prophylaxis). Differences in individual pharmacokinetic handling of chemotherapy agents leading to more severe and/or prolonged neutropenia, susceptibility to mucosal damage from chemotherapy, and many other possibilities may contribute to this phenomenon. The data in Figure 1 suggest little evidence of prophylactic efficacy after an FE-free first cycle, but a trend to continuing efficacy at least in the second cycle after FE in cycle one, although the numbers of FE become too small for statistical testing. One possible explanation for efficacy after an earlier-cycle FE might be that preexisting levofloxacin-resistant strains are eradicated by empirical treatment of infection. The analysis of patient groups showed benefit for all tumor types with the exception of NHL. However, the 95% CIs for NHL are wide and encompass the point estimate for the overall treatment effect, so this observation may simply be attributable to small numbers. Alternatively, tumor-related fever and virus infections commonly complicate lymphoma and may have confounded the data. The data do not support offering NHL patients a different preventative strategy for infection compared with those for solid cancers, but indicate scope for further research. Infection incidence is a rational basis for selection because, for a fixed treatment effect, the number needed to treat (NNT) to prevent one FE will be greatest for those groups at lowest risk. For example, assuming OR = 0.42, in breast cancer patients with a first-cycle FE risk of 5.4%, the NNT to prevent one first cycle FE is 32. SCLC has been studied previously,12,13 and we confirm that it is associated with a moderately high FE rate of 9.1% in cycle 1 and associated NNT of 19. The highest risk of infection is in testicular cancer for which the all-cycle FE rate in controls (28%) was almost identical to that seen in a previous trial of prophylactic filgrastim (29%),19 and with a first-cycle FE risk of 18%, the NNT is only 10. Intuitively, one might expect that young, generally fit patients would not require prophylaxis, but the realistic curative potential of chemotherapy leads to an uncompromisingly intensive approach. In both SCLC and testicular cancers, the majority of patients received etoposide, which can cause severe and, when administered orally, unpredictable neutropenia.20 Mucositis is also a frequent consequence of etoposide exposure that predisposes to infection. Poor PS has been linked to a higher risk of FE.21 In this analysis, we found that a clinically relevant separation between PS 0/1 (the majority of patients) and PS of 2 or higher did not aid prediction of patients at risk of FE, although pretreatment PS of 2 or higher did predict risk of hospitalization for infection. In large retrospective studies in single tumor types (eg, lymphoma15) age 65 years or older has been shown to confer a higher risk of FE. However, our study demonstrates a high FE rate in young patients with testicular cancer and does not demonstrate age-related differences in prophylactic benefit. The use of granulocyte colony-stimulating factor (G-CSF) is a different strategy to prevent neutropenic infection. Two trials have evaluated the combination of fluoroquinolones and G-CSF, and both conclude that G-CSF should be used in addition to the antibiotic rather than in place of it.13,22 G-CSF is much more costly and was not cost-effective in a recent combination trial.23 Physicians face the dilemma of balancing evidence-based individual treatment while limiting antibiotic usage responsibly. Our intention here has been to help oncologists use antibacterial prophylaxis rationally. Stratification within the SIGNIFICANT trial allowed unbiased comparisons of prophylactic effect by age and tumor type. However, subgroup analysis and the comparison of events on first and nonfirst cycles were unplanned and cannot be considered definitive. The threshold of FE incidence at which it is appropriate to offer antibacterial prophylaxis is a matter for local policy. However, on the basis of the evidence of prophylactic efficacy, there is no clear justification for failing to consider prophylaxis to any single disease group wherein the regimen employed causes grade 4 neutropenia (< 500/mm3), although further research is warranted in NHL. Young, well patients are at risk of infection and benefit from prophylaxis to a similar degree to that provided for older patients or those with poor PS. It is rational to ensure that patients receive prophylaxis on the first cycle, whereas in the context of concern to reduce antibacterial use, these exploratory data support omitting prophylaxis on subsequent cycles, particularly if there has been no FE on cycle 1, but further work is required to confirm this observation. Cycle-1 infections appear to identify patients at high risk of later FE who, paradoxically, may benefit from prophylactic levofloxacin on later cycles.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Michael H. Cullen, Daiichi Pharmaceuticals Research Funds: Michael H. Cullen, Hoechst Marion Roussel (now part of Sanofi Aventis) Testimony: N/A Other: N/A
Conception and design: Michael H. Cullen, Lucinda J. Billingham, Neil M. Steven Administrative support: Lucinda J. Billingham, Claire H. Gaunt Provision of study materials or patients: Michael H. Cullen, Lucinda J. Billingham, Claire H. Gaunt, Neil M. Steven Collection and assembly of data: Michael H. Cullen, Lucinda J. Billingham, Claire H. Gaunt, Neil M. Steven Data analysis and interpretation: Michael H. Cullen, Lucinda J. Billingham, Claire H. Gaunt, Neil M. Steven Manuscript writing: Michael H. Cullen, Lucinda J. Billingham, Neil M. Steven Final approval of manuscript: Michael H. Cullen, Lucinda J. Billingham, Neil M. Steven
We thank the contributors to the SIGNIFICANT Trial: Mark Hastings (Microbiology); Andrew Stanley and Susan Whitmarsh (Pharmacy); Sarah Bathers, Rebecca Hindle, Helen Howard, Mary Ann Macham, Julia Mason, Caroline Price, and Steve Harris (Trial Coordination & IT Support); and Christopher Gallagher, Gordon Rustin, Jim Slattery, and Michael Whitehouse (Data Monitoring and Ethics Committee). We also thank the following investigators who participated in the SIGNIFICANT trial: S. Al-Ismail (Singleton, Swansea), A. Al-Samarraie (Glan Clwyd, Rhyl), C. Alcock (Stoke Mandeville, Aylesbury), R. Allerton (New Cross, Wolverhampton), A. Anthony (Cookridge, Leeds), A. Axford (Bronglais General, Aberystwyth), N. Bailey (Derriford, Plymouth & Torbay), J. Barber (Velindre, Cardiff), D. Bareford (City Hospital, Birmingham), A. Barrett (Western Infirmary, Glasgow), P. Barrett-Lee (Velindre, Cardiff), N. Bates (Stoke Mandeville, Aylesbury), E. Bessell (Nottingham City), J. Bishop (Glan Clwyd, Rhyl & Ysbyty Gwynedd, Bangor), A. Biswas (Royal Preston), P. Bliss (Royal Devon and Exeter & Torbay), S. Bolam (Taunton and Somerset), M. Bond (Cookridge, Leeds), C. Brammer (Kidderminster & New Cross, Wolverhampton), M. Bower (Chelsea and Westminster, London), A. Brewster (Royal Gwent & Velindre), A. Brownell (Oldchurch, Romford), J. Carmichael (Nottingham City), P. Chakraborti (Derbyshire Royal Infirmary, Derby), A. Champion (Glan Clwyd, Rhyl), A. Chetiyawardana (Queen Elizabeth, Birmingham), M. Churn (Kidderminster & New Cross, Wolverhampton), P. Clark (Clatterbridge, Wirral), J. Clarke (Belvoir Park, Belfast), M. Collinson (Royal Cornwall, Truro), S. Crawford (Airedale, Keighley), D. Dearnley (Royal Marsden, London), D. Dodwell (Cookridge, Leeds), D. Dunlop (Western Infirmary, Glasgow), D. Edwards (Glan Clywd, Rhyl), S. Elyan (Cheltenham General), D. Farrugia (Cheltenham General), D. Fermont (Northwick Park, Harrow), I. Fernando (Queen Elizabeth, Birmingham), D. Fyfe (Nottingham City), C. Gaffney (Royal Gwent, Newport & Velindre, Cardiff), J. Gardiner (North Tyneside General, North Shields), D. Gilligan (Hinchingbrooke, Huntingdon), S .Gollins (Glan Clywd, Rhyll), A. Goodman (Royal Devon and Exeter & Torbay), D. Gozzard (Glan Clwyd, Rhyl), T. Gulliford (St Mary's, Portsmouth), D. Guthrie (Derbyshire Royal Infirmary, Derby), B. Hancock (Weston Park, Sheffield), P. Harper (Guy's and St Thomas', London), P. Harrison (Russell's Hall, Dudley), Y. Hassan (Sandwell General, West Bromwich), A. Hong (Royal Devon and Exeter & Torbay), A. Horwich (Royal Marsden, Sutton), S. Houston (Royal Surrey County, Guildford), R. Huddart (Royal Marsden, London), T. Iveson (Royal South Hants, Southampton), P. Jenkins (Cheltenham General), J. Joffe (Huddersfield Royal Infirmary), P. Johnson (Royal South Hants, Southampton), S. Kaye (Western Infirmary, Glasgow), S. Kumar (Pinderfields General, Wakefield), S. Lewis (Singleton, Swansea), F. MacBeth (Llandough, Cardiff), P. Mack (Diana Princess of Wales, Grimsby), E. Marshall (Clatterbridge, Wirral), T. Maughan (Velindre Hospital, Cardiff), K. McAdam (Addenbrookes, Cambridge & Peterborough), J. McAleer (Belfast City Hospital), G. Mead (Royal South Hants, Southampton), R. Mehra (New Cross, Wolverhampton), S. Morgan (Nottingham City), M. Muers (Leeds General Infirmary), J. Murray (Queen Elizabeth, Birmingham), P. Murray (Essex County, Colchester), A. Neal (Essex County, Colchester), J. Neilson (Russell's Hall, Dudley), A. Nethersell (Glan Clwyd, Rhyl), M. O'Brien (Royal Marsden, Sutton & Kent Oncology Centre, Maidstone), A. O'Callaghan (St Mary's, Portsmouth), S. O'Reilly (Clatterbridge, Wirral), C. Ottensmeier (Royal South Hants, Southampton), J. Owen (Cheltenham General), D. Peake (City Hospital, & Queen Elizabeth, Birmingham), I. Pedley (Newcastle General), C. Poole (City Hospital & Queen Elizabeth, Birmingham), D. Prangnell (Lincoln County), B. Pratt (Essex County, Colchester), M. Quigley (Oldchurch, Romford), A. Rathmell (James Cook, Middlesbrough), D. Rea (Queen Elizabeth and City Hospital, Birmingham), F. Roberts (Pontefract), S. Sadullah (James Paget, Great Yamouth), A. Samanci (Glan Clywd, Rhyl), J. Seale (Ysbyty Gwynedd, Bangor), D. Sebag-Montefiore (Pinderfields, Wakefield), J. Shamash (Oldchurch, Romford), P. Simmonds (Royal South Hampshire, Southampton), H. Smedley (Kent Oncology Centre, Canterbury), D. Smith (Clatterbridge, Wirral), I. Smith (Royal Marsden, London & Sutton), S. Smith (Torbay), M. Snee (Cookridge, Leeds), M. Sokal (Nottingham City), T. Sreenivasan (Scunthorpe General), P. Stableforth (Sandwell General, West Bromwich), N. Storey (James Cook University, Middlesbrough), N. Stuart (Ysbyty Gwynedd, Bangor), C. Tiplady (North Tyneside General, North Shields), D. Turner (Torbay), S. Upadhyay (Diana Princess of Wales, Grimsby), P. Vasey (Western Infirmary, Glasgow), N. Wadd (James Cook University, Middlesbrough), D. Wheatley (Royal Cornwall, Truro), M. Williams (Addenbrookes, Cambridge & Hinchingbrook, Huntingdon), P. Woll (Nottingham City), J. Wright (City Hospital, Birmingham), and H. Yosef (Hairmyres, East Kilbride).
Supported by an educational grant and trial medication for the SIGNIFICANT Trial, which was an investigator-led trial, from Hoechst Marion Roussel (now part of Sanofi Aventis) and by a core grant to the Institute of Cancer Studies Clinical Trials Unit, Birmingham, from Cancer Research UK. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Kern W, Linzmeier K, Kurrle E: Antimicrobial susceptibility of viridans group streptococci isolated from patients with acute leukemia receiving ofloxacin for antibacterial prophylaxis. Infection 17:396-397, 1989[CrossRef][Medline] 7. Kern WV, Klose K, Jellen-Ritter AS, et al: Fluoroquinolone resistance of Escherichia coli at a cancer center: Epidemiologic evolution and effects of discontinuing prophylactic fluoroquinolone use in neutropenic patients with leukemia. Eur J Clin Microbiol Infect Dis 24:111-118, 2005[CrossRef][Medline] 8. McWhinney PH, Patel S, Whiley RA, et al: Activities of potential therapeutic and prophylactic antibiotics against blood culture isolates of viridans group streptococci from neutropenic patients receiving ciprofloxacin. Antimicrob Agents Chemother 37:2493-2495, 1993 9. Collett D: Modelling Survival Data in Medical Research London, United Kingdom, Chapman and Hall, 1994 10. Cochran WG: The combination of estimates from different experiments. Biometrics 10:101-129, 1954[Medline] 11. Holmes FA, O'Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol 20:727-731, 2002 12. Tjan-Heijnen VC, Postmus PE, Ardizzoni A, et al: 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. Ann Oncol 12:1359-1368, 2001 13. Timmer-Bonte JN, de Boo TM, Smit HJ, et al: 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. J Clin Oncol 23:7974-7984, 2005 14. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 23:1178-1184, 2005 15. Lyman GH, Delgado DJ: Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate grade non-Hodgkin lymphoma. Cancer 98:2402-2409, 2003[CrossRef][Medline] 16. Crawford J, Wolff DA, Culakova E, et al: First cycle risk of severe and febrile neutropenia in cancer patients receiving systemic chemotherapy: Results from a prospective nationwide study. Proc Am Soc Hematol 104, 2004 (abstr 2210) 17. Timmer-Bonte JN, Tjan-Heijnen VC: Febrile neutropenia: Highlighting the role of prophylactic antibiotics and G-CSF during standard dose chemotherapy for solid tumors. Anticancer Drugs 17:881-889, 2006[CrossRef][Medline] 18. Gafter-Gvili A, Paul M, Fraser A, et al: Effect of quinolone prophylaxis in afebrile neutropenic patients on microbial resistance: Systematic review and meta-analysis. J Antimicrob Chemother 59:5-22, 2007 19. Fossa SD, Kaye SB, Mead GM, et al: Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy. European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom. J Clin Oncol 16:716-724, 1998[Abstract] 20. Harvey VJ, Slevin ML, Johnston A, et al: The effect of dose on the bioavailability of oral etoposide. Cancer Chemother Pharmacol 16:178-181, 1986[Medline] 21. Crawford J, Dale DC, Lyman GH: Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management. Cancer 100:228-237, 2004[CrossRef][Medline] 22. Von Minckwitz G, Blohmer J, Löhr A et al: Primary prophylaxis with 3 weekly pegfilgrastim and ciprofloxacin effectively prevent (febrile) neutropenia and infection during neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy in breast cancer patients. J Clin Oncol 23:731s, 2005 (suppl; abstr 8008) 23. Timmer-Bonte JN, Adang EM, Smit HJ, et al: Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer. J Clin Oncol 24:2991-2997, 2006 Submitted August 16, 2006; accepted July 9, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
