A prospective study of patients with chemotherapy-induced febrile neutropenia in the South West London Cancer Network (SWLCN)

Introduction

Neutropenic complications in cancer patients are associated with substantial morbidity, mortality, and healthcare costs (Kuderer 2006, Crawford 2004, Lyman 1998). Febrile neutropenia (FN) is considered a medical emergency and generally prompts immediate hospitalization for evaluation and administration of empirical broad-spectrum antibiotics. In addition, FN frequently leads to chemotherapy dose reductions and treatment delays that may compromise long-term clinical outcomes

(Lyman 2005, Pettengell 1992).Clinical trials routinely underestimate the risk of FN and its complications in cancer patients, because of the highly selected nature of such patients (Kuderer 2006).This audit analyses current patterns and details of admissions for FN in an unselected population across the South-West London Cancer Network.

Materials and Methods

The audit was jointly performed at 6 hospitals of the South West London Cancer Network (Epsom and St. Helier, Kingston, Royal Marsden (Fulham Road and Sutton), and St George's Hospital). During a 4 month period, all new admissions with febrile neutropenia, defined as temperature above 38 degrees centigrade and neutrophils below 1 x 10⁹/L, were documented and input on to a shared database. Details obtained included: patient demographics, cllinical details, treatment history and outcome data,. In total, 58 items were obtained for each case and the results correlated.

Results

The details below refer to all cases of neutropenia in the study. The results are further reported by treating hospital in Appendix 1.

Patient and Treatment Details

71 admissions for febrile neutropenia were reported involving 65 patients, 39 female (60%) and 26 male (40%). The median age was 59 years.

Sites of underlying malignancies are summarised in table 1.

Table 1. Primary sites of underlying malignancies of cancer patients presenting with FN

Chemotherapy had been given in palliative intent in 39 cases (54%) and for curative / (neo-)adjuvant treatment in 32 cases (45%). The commonest regimens were CHOP (8 cases, 11%), Docetaxel (6 cases), AC (5 cases), Folfiri (4 cases), and FEC (3 cases). Febrile neutropenia occurred at a median of 10 days after starting chemotherapy. 36 episodes (50%) occurred after cycle 1 or 2 and of these patients, only 6 (16%) had received prophylactic granulocyte colony-stimulating-factor (G-CSF) - compared with 11 (31%) of the remaining patients.

In total 17 patients (23%) had prophylactic G-CSF. The most common diagnoses in this group were lymphoma (6 patients) and sarcoma (4 patients). 10 (52%) of these patients had received a chemotherapy regimen with a more than 20% risk for febrile neutropenia.

Looking at all patients together, almost all (98%) had level I/II evidence patient-related risk factors for the development of febrile neutropenia as laid out in the American Society of Clinical Oncology (ASCO) and European Organization of Research and Treatment of Cancer (EORTC) guidelines (table 2): 39 (54%) had advanced stage disease, 25 patients (35%) were at least 65 years old, 18 (25%) had a previous neutropenic event. 23 patients (32%) had treatment-related risk factors (according to ASCO/EORTC guidelines > 20% risk for neutropenic events).

Table 2: Prevalence of level I/II evidence risk factors for the development of febrile neutropenia (according to ASCO and EORTC guidelines)

19 patients (25%) had prophylactic antibiotics. 43 (60%) had no prophylaxis (antibiotics and / or G-CSF) at all.

Assessment Details

Only 11 patients (15%) admitted with febrile neutropenia were asymptomatic. All others had one or more symptoms as detailed below (Table 3). Eight patients presented with a blood pressure of less than 90 systolic.

Table 3. Symptoms on admission

Patient Management

49 patients (69%) were admitted directly to an oncology / haematology ward, 22 (31%) were seen in the accident and emergency department first. The median time from arrival to first assessment was 19 minutes, the median time to first administration of an antibiotic was 135 minutes.

Routine chest X-rays were performed in 62 (87%) patients, routine urine dip-sticks in 55 (71%). Blood cultures were obtained in 66 (92%), urine cultures in 52 (73%), and stool cultures in 27 cases (38%).

All patients received intravenous antibiotics, 22 (30%) required 2^nd line treatment, and 12 had additional antifungal regimens. 45 patients (63%) received secondary treatment with G-CSF.

Outcome

The median duration of hospital admissions was 5 days. Patients with no symptoms (11 cases) had the shortest stay (median of 4 days) compared with patients presenting with three or more symptoms (9 cases), who remained in hospital for a median of 22 days.

Chemotherapy was delayed in 19 patients (26%) and was stopped in 5 patients (7%). Dose reduction for further cycles was required in 10 patients (14%). One patient was on adjuvant treatment and had already received prophylactic G-CSF. The other 9 patients had advanced disease. The median age of all patients who had dose reductions was 67.5 years.

4 patients died. A 67 year old patient with NK cell lymphoma died 25 days after admission from an unrelated cause. However the other 3 cases were likely sepsis-related: A 59 year-old with relapsed lymphoma on palliative chemotherapy died on the day after admission, a 60 year old patient with small cell lung cancer on second line treatment died on the day of admission, and a 61 year old with acute myelogenous leukaemia on palliative chemotherapy died 9 days after admission.

Discussion

This study demonstrates that FN in the SWLCN was generally recognised early and managed accordingly. However, the seriousness of the condition is shown by the fact that three patients died as a consequence of neutropenic sepsis. This translates into a mortality rate of 4.2%. The general risk of mortality is still estimated at 2-10% (Klastersky 2007). More recently, a review of over 55,000 hospital admissions for adult FN in USA health centres reported a mean mortality risk of 2.8% when patients had FN as the main cause of hospital admission (Kuderer 2006).

The diagnostic management in this audit varied between different patients and the various hospitals. The NCCN guidelines (Smith 2006, Aapro 2006, NCCN guidelines on cancer-related infections 2008) recommend routine blood tests and blood cultures for all patients, but other tests like chest X-rays, urine dip-stick, urine and stool cultures etc. are left at the discretion of the clinician involved. Since time is a significant factor in the successful management of neutropenic sepsis, many hospitals have their own protocols of diagnostic tests to be followed automatically to speed up the assessment process. In this audit there was not a common pro-forma, which explains the variability of diagnostics undertaken.

Almost all patients included in the audit had certain well established risk factors for the development of FN. American and European guidelines (Smith 2006, Aapro 2006) acknowledge the following factors as significant for consideration of prophylactic administration of myeloid growth factors: chemotherapy regimens with a risk of more than 20% for the development of FN or regimens with a risk between 10% and 20% in conjunction with certain patient-related risk factors. Of the patients in this audit meeting the conditions of the recommendations, 21% to 43% did actually receive G-CSF (table 4).

Table 4. Risk stratification according to ASCO/EORTC guidelines and extent of prophylactic administration of CSF

In a recent review of seventeen randomised controlled trials, it was demonstrated that prophylactic G-CSF reduced the risk for FN by 46% and even for infection-related mortality by 45%. In addition, the relative dose-intensity was significantly higher in patients who received CSFs (Kuderer 2007).

In this audit, G-CSF was used in 63% of patients for secondary treatment of febrile neutropenia. ASCO and EORTC guidelines commend CSF only for patients with febrile neutropenia, who are at high risk for infection-associated complications.
A Meta-Analysis (Clark 2005) showed a significant reduction of the length of hospitalization but only a marginally significant result for the use of CSF in reducing infection-related mortality. The overall mortality was not influenced significantly.

Antibiotic prophylaxis was used in 25% of cases. Its efficacy to reduce infections, FN and hospital admissions has been clearly stated (Cullen 2005, Engels 1998). Because of concerns about antimicrobial resistance (Goossens 2005) its use is discouraged for standard chemotherapy regimens in most solid tumours. However, it may be considered in intermediate risk groups, such as lymphoma patients or treatments with anticipated neutropenia of seven to 10 days, and it is of course essential for many high risk haematology treatment regimens (NCCN Guidelines on myeloid growth factors 2008, Cullen 2007).

One third all patients with FN in this audit were above age 65. This supports the notion that increasing age is an independent predictor of the development of febrile neutropenia (Crawford 2004, Aapro 2006). There is sufficient evidence to affirm that prophylactic CSF reduced the incidence of chemotherapy-induced neutropenia, febrile neutropenia and infections in elderly patients (Repetto 2003). Older patients are frequently under-treated because of misperceptions of their frailty; however, such dose reductions may compromise treatment efficacy (Lyman 2004, Pietropaolo 2003).

50% of all episodes of FN were found at the start of chemotherapy (cycle 1 and 2). This is in line with previous reports (Lyman 2005) and has led to the recommendation to start prophylactic measures “upfront” in the appropriate risk groups (Smith 2006, Aapro 2006, NCCN on myeloid growth factors).

Recent advances in the management of FN have highlighted the value of risk stratification and the evolving role of oral antibiotics with early hospital discharge in low-risk patients (Freifeld 1999, Kern 1999, Hughes 2002). The Multinational Association for Supportive Care in Cancer (MASCC) have developed a risk index (Klastersky 2000) and subsequent investigations showed that out-patient oral antibiotics or intravenous regimes are feasible in low risk patients (Vidal 2004, Innes 2003, Klastersky 2007). This stratification is not yet routine practice in the UK (Innes 2005). In this audit, only three patients were deemed suitable for discharge within the first two days of admission.

Conclusion

The audit gave an insight into the practice of FN management in a representative cancer network in the UK. Neutropenic complications in cancer patients are associated with substantial morbidity, mortality and healthcare costs, thus underpinning the usefulness of audit and development. Following this assessment, several areas of potential improvement may be addressed: The uptake of prophylactic CSF according to ASCO and ESMO guidelines could be improved, particularly in patients above the age of 65, which comprised one third of all patients admitted with neutropenic sepsis. This could significantly reduce the risks of morbidity and mortality associated with neutropenic sepsis and should be instituted as up-front treatment, since 50% of all episodes were found with the first or second cycle of chemotherapy. In addition, the time interval to completion of assessment and start of treatment of neutropenic sepsis could be improved. To achieve this and - at the same time - ensure better uptake of evidence-based guidelines, common nursing practice protocols (Dolan 2005) for the whole network might be considered.
In view of the considerable costs incurred through in-patient management of FN, future audits should look into the use of common risk stratifications such as the MASCC risk index with potential out-patient management in low risk cases.

References

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APPENDIX 1: SWLCN audit of neutropenia- further analysis by hospital

A total of 71 cases were audited (65 patients with 6 patients each having 2 separate neutropenic episodes). The details below break down the results by hospital

Attending and treating hospitals

The breakdown by hospital is shown in table 1 below

Table 1: Cases by hospital

All the patients treated at St George's were recorded as receiving their chemotherapy at that hospital Of the 44 patients attending RMH 35 are shown as receiving their treatment there , but details are unknown for the remaining 9 . The 2 patients attending Epsom St Helier were RMH patients as was one of the patients attending Kingston. Of the other 2 attending Kingston, 1 was recorded as receiving treatment there and the other is unknown.

Patient Details

Table 2 gives demographic details of the patients plus details of their diagnosis. The most common malignancies were breast cancer (13 patients ) and Lymphoma (13 patients). Table 3 gives more details of the cases seen.

Table 2 Patient details

Table 3 Case details

Symptoms

11 patients were asymptomatic on admission. Others presented with 1 or more symptoms as detailed in Table 4. 8 patients presented with a systolic blood pressure of <90 mmHg.

Table 4 Presenting symptoms

Where admitted

Most patients were admitted directly to a specialist ward. .NB Royal Marsden hospital does not have an A & E department and Epsom St Helier and Kingston do not have specialist oncology wards.

Table 5: Where admitted

Time from admission to initial observations

This data was available for 47 patients. 78% were seen within half an hour of being admitted

Chart1 ; Time from admission to initial observations

Table 6 below shows the breakdown by hospital

Table 6: Time between admission and first observations

Time from doctors assessment to antibiotic administration

This data was available for 46 patients. 28% received their antibiotics within half an hour of being assessed by the doctor however over 30% waited more than 2 hours.

Chart 2: Time from Doctors assessment to antibiotic administration

The table below gives the details by hospital

Table 7: Time between doctors assessment and antibiotic administration

Time from admission to antibiotic administration

This information is known for 49 patients and details by hospital are given in table 5. The median time from admission to antibiotic administration was 2 hours 15 minutes.

Table 8: Time between arrival and antibiotic administration

Investigations

Table 9 gives details of the investigations carried out. The percentage in each column includes all patients where the investigation was documented. If documentation was unclear or unavailable this has not been counted

Table 9: Investigations

Treatment

Chart 3 below shows the number of patients receiving each line of neutropenic treatment according to the protocol. Most received the 1^st line only

Chart 3: Treatments administered- all

Chart 4 breaks down the figures by hospital. The patient who did not receive 1^st 2^nd or 3^rd line according to protocol had cefroxime and metrondiade and 2 of the 3 patients who received 2^nd line only were referred to another hospital and prescribed a different regimen (there are no further details for the third patient)

Chart 4: Treatments administered- by hospital

In addition to the antibiotics; 12 patients were prescribed anti fungals and 45 received secondary treatment with G-CSF (of these 12 had also received G-CSF prophylactically.

Outcome

Chart 5 below show the outcome for all patients in the audit. 4 patients (5.6%) died following the neutropenic episode (although one death is probably unrelated).

For 3 patients neutropenia occurred following their final cycle of chemotherapy; these are included with those patients who were neither delayed nor dose reduced. The 15 patients where chemo was delayed includes 1 patient where it is unknown if chemo was also dose reduced.

Chart 5: Outcome

Table 9 breaks down the outcome by hospital

Table 9:Outcome by hospital

Length of Stay (known for 67 cases)

The average length of stay for the discharged patients was 9 days. The median was 6 and the range 1-60

Of the 4 patients who died, one survived 25 days following admission another 9 days, another 1 day and the fourth died on the day of admission.

Details of LOS for discharged patients by admitting hospital are shown in table 5 below

Table 10: Length of stay by hospital