Lung Cancer (2006) 54, 371—377

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The association of chemotherapy inducedneutropenia on treatment outcomesin small cell lung cancer

Udai Banerji, Sue Ashley, Jim Coward, Sarah Hughes, Ying Zee,Taqdir Benepal, Alison Norton, Tim Eisen, Mary O’Brien ∗

The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK

Received 6 April 2006; received in revised form 9 August 2006; accepted 14 August 2006

KEYWORDSChemotherapy;Neutropenia;Small cell lung cancer

SummaryBackground: Chemotherapy induced neutropenia has been shown to be associated withimproved treatment outcomes in selected solid tumours. We studied the association ofchemotherapy induced neutropenia with treatment related outcomes in small cell lung can-cer (SCLC).Methods: This is a retrospective analysis of patients receiving chemotherapy for SCLC at theRoyal Marsden Hospital, UK over an 8 year period. The chemotherapy included Carboplatin AUC5, IV and Etoposide 100 mg/m2 IV on day 1 and 100 mg/m2 PO, B.I.D. on day 2 and 3 every 21days. Patients were stratified into two groups (A) those experiencing grades 0—2 neutropeniaand group (B) those experiencing grades 3—4 neutropenia. The outcomes studied were responserate, time to progression (TTP) and overall survival (OS).Results: 173 patients were studied. The median age 64 (range 39—83) and M/F ratio was 112:61.The response rates in groups A and B was 90% versus 90%, p = 1.0. The median TTP in groups Aand B was 30 and 38 weeks, p = 0.05. The median OS in groups A and B was 47 weeks versus 60weeks, p = 0.008. The differences in TTP and OS were not significant in patients with extensivestage disease.Conclusions: Occurrence of chemotherapy induced grade 3 or 4 neutropenia correlated with OS

in patients with SCLC receiving carboplatin and etoposide chemotherapy. Trials exploring con-trolled, safe intra-patient dose escalation with the intent of achieving grade 3 or 4 neutropeniain patients with SCLC are warranted.© 2006 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author. Tel.: +44 208 6446011x3278; fax: +44 208 6430373.E-mail address: Mary.O’Brien@rmh.nhs.uk (M. O’Brien).

0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.lungcan.2006.08.001

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. Introduction

mall cell lung cancer (SCLC) accounts for 14% of new lungancer cases in the USA and Europe [1]. The majority ofatients present with extensive stage disease [2].

Combination chemotherapy, radiotherapy or chemo-adiotherapy remains the cornerstone of treatment ofmall cell lung cancer [1]. Chemotherapy based on plat-num and etoposide combined with radiotherapy has showno double the 5 year survival of patients with lim-ted stage SCLC to approximately 12% [3]. Combinationhemotherapy is also used to treat patients with exten-ive stage disease for whom the median survival is less thanyear [2].Attempts to improve survival in patients with SCLC have

ncluded addition of a third agent such a irinotecan [4] Ifos-amide [5], topotecan [6] and paclitaxel [6] to etoposidend platinum combinations. Other attempts to improve out-omes include increasing dose intensity by either increasinghe dose or shortening the interval between cycles [7]. Tri-ls with higher dose intensity have met with mixed successith a few trials reporting a longer albeit modest survivaldvantage [8—11] and others not so [12—14]. The use of G-SF [10,11,15] and stem cell rescue [16,17] have allowedxploration of dose intensification but in the context of pal-iative treatment have to date not been incorporated intotandard practice.

The concept of individualizing cytotoxic chemotherapyased on haematological toxicity comes from the observa-ion that patients who do not achieve a significant degree ofeutropenia during chemotherapy had inferior clinical out-omes in osteosarcoma [18], ovarian [19], breast [20—22]nd non small cell lung cancers [23].

This study is an attempt to explore the association ofeutropenia on treatment outcomes of SCLC which has noteen studied before. The outcomes of this study could besed to design trials exploring chemotherapy regimens withntra-patient dose escalation for SCLC.

. Materials and methods

.1. Population

ll patients with small cell lung cancer who received at leastcycles of first line chemotherapy over an 8 year period

1998—2004) were studied. The data relating to the dose ofhemotherapy, dates of administration, radiological assess-ent and grade of neutropenia were retrieved from the

lectronic patient data base at the hospital. The study pro-osal was reviewed and approved by the institutional auditommittee.

The data base included 33 patients with SCLC who hadess than 4 cycles of chemotherapy. Reasons for cessation ofreatment included: 14 patients had radiological progressiveisease, 11 patients stopped due to symptomatic progres-ive disease, 3 patients stopped due to chest infections

2/3 had febrile neutropenia), 2 had pulmonary emboli, 2atient choice, 1 skin rash and 1 renal toxicity. Though notormally documented, a large proportion of these patientsad poor a performance status. These patients were notncluded in the analysis because it was felt that less than 4

U. Banerji et al.

cycles of chemotherapy would not have a consistent effecton treatment outcomes such as time to progression andsurvival.

2.2. Chemotherapy

Chemotherapy delivered consisted of carboplatin AUC 5,IV and etoposide 100 mg/m2, IV on day 1 followed byoral etoposide 100 mg/m2 PO BID on day 2 and 3 every21 days.

2.3. Neutrophil count

Bloods were routinely taken on day 19—22 prior to thenext course of chemotherapy and also during any out-patient/inpatient attendance for symptomatic toxicity orfebrile neutropenia. The worst grade of neutropenia experi-enced during cycles 1—4 was recorded and used for anal-ysis. If patients were found to have a neutrophil count<1.5 × 109/L, chemotherapy was delayed till a count of≥1.5 × 109/L was achieved. Routine nadir blood countsbetween days 10—14 were not done, thus it is not possi-ble to compare neutropenic events at the same time pointin all patients. The authors recognize this as a limitation ofa retrospective study and future trials exploring this ques-tion prospectively, should have a nadir count at a predefinedtime between days 7 and 14. National Cancer Institute (NCI)Common toxicity criteria (CTC) version 3 was used to gradeneutropenia. Grades I, II, III and IV neutropenia was definedas <2—1.5 × 109/L, <1.5—1.0 × 109/L, <1.0—0.5 × 109/L and<0.5 × 109/L, respectively.

2.4. Antibiotic/growth factor policy for febrileneutropenia

The Royal Marsden Hospital treatment guidelines definesfebrile nutropenia as neutropenia associated with oneepisode of fever ≥38.5 ◦C or fever of ≥38 ◦C documented ontwo separate occasion at least 1 h apart over a 12 h period.The hospital policy did not advocate the routine prophylacticuse of antibiotics and/or growth factors in patients receivingchemotherapy for small cell lung cancer. If the patients areadmitted with febrile neutropenia, G-CSF was administeredtill the neutrophil count is >1.0 × 109/L.

2.5. Dose intensity

Target dose intensity for carboplatin was calculated as dose(AUC 5) × 4/84 (number of days in 4 cycles). Target doseintensity for etoposide was the sum of etoposide 100 mg/m2

IV on day 1 and 100 mg/m2 PO BD for 2 days × 4/84. Actual(achieved) dose intensity for carboplatin and etoposide wasdetermined as the total dose of the individual drug receivedin the first 4 cycles divided by the number of days betweenthe first four cycles of chemotherapy. Relative dose intensity

for each individual drugs were calculated as dose intensityachieved divided by target dose intensity. The relative doseintensity quoted in the text is the mean of the relative doseintensity of carboplatin and etoposide.

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Chemotherapy induced neutropenia and treatment outcome

2.6. Study outcomes

The outcomes studied included, overall response rates, timeto progression and overall survival. Overall response ratesincluded patients who were recorded to have radiologicalcomplete or partial response.

2.7. Statistical analysis

Patients were stratified into two groups based on the gradeof neutropenia they experienced (grades 0—2 versus grades3—4). The characteristics of these groups were comparedby means of Fisher’s exact test, the chi-squared test andthe Mann Whitney non parametric test. Overall survival andtime to progression were calculated by the method of KaplanMeier and groups were compared by means of the log ranktest. SPSS software (SPSS Inc., Chicago, IL) was used for sta-tistical analysis and GraphPad software was used to generatefigures (GraphPad Software Inc., San Diego, CA).

3. Results

3.1. Demographics

One hundred and seventy three patients were studied.The median age was 64 years (range 38—83 years). Themale:female ration was 112:61. Ninety-one patients hadlimited stage disease and 82 patients had extensive stagedisease, 67% patients with limited stage lung diseasereceived consolidation thoracic radiotherapy Table 1.

3.2. Response rates

The overall response rate for all patients was 90% (155/173).The overall response rates in patients with limited stage andextensive stage disease was 90% (82/91) and 89% (73/82).

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Table 1 Patient characteristics and outcomes stratified into thosecarboplatin and etoposide chemotherapy

N

0—

StageLimited stage 44Extensive stage 46

Age (median) 63Sex M:F 46

ResponseTotal 90Limited stage 90Extensive stage 90

Febrile neutropenia 1/Relative dose intensity (mean) (standard deviation) 95Adjuvant RT 67(Limited stage) (2

SCLC 373

.3. Rates of neutropenia

he rates of grade 3 or 4 neutropenia in the whole cohortere 55% (95/173). The rates of grade 3 or 4 neutropenia

n patients with limited stage and extensive stage diseaseas 56% (51/91) versus 54% (44/82), p = 0.8. The mediange of experiencing grades 0—2 and grades 3—4 neutropeniaas 63 years (range 44—83) and 65 years (range 39—81),= 0.2. The male to female ratio of patients experienc-

ng grades 0—2 neutropenia versus grades 3—4 neutropeniaas 46:32 versus 66:29, p = 0.2. The mean relative dose

ntensity of patients experiencing grades 0—2 and grades—4 neutropenia was 95.5% (S.D. 7) versus 86.6% (S.D.1.1).

.4. Febrile neutropenia

he incidence of febrile neutropenia in the whole cohort was5/175 (14.5%). The incidence in limited stage disease andxtensive stage disease was 10/91 (11%) and 15/82 (18.2%),= 0.17. Of the 25 patients with febrile neutropenia 1/25ad grades 0—2 neutropenia versus 24/25 who had grades—4 neutropenia, p < 0.0001.

.5. Treatment outcomes

he time to progression in patients experiencing grades—2 and grades 3—4 neutropenia for all patients was 30eeks (95% CI 27—34) versus 38 weeks (95% CI 34—44),= 0.05, respectively (Fig. 1a). The median time to pro-ression for patients with limited stage disease experiencing

rades 0—2 and grades 3—4 neutropenia was 39 weeks (95%I 25—53) versus 45 weeks (95% CI 41—49), p = 0.2, respec-ively (Fig. 1b). The corresponding values for extensive stageisease was 27 weeks (95% CI 23—31) versus 29 weeks (95%I 25—33), p = 0.08 (Fig. 1c).

experiencing grades 0—2 and grades 3—4 neutropenia during

eutropenia

2 3—4 Significance

p = 0.8% (40/91) 56% (51/91)% (38/82) 54% (44/82)

(44—83) 65 (39—81) p = 0.2:32 66:29 p = 0.2

% (70/78) 90% (85/95) p = 1.0% (36/40) 90% (46/51) p = 1.0% (34/38) 89% (39/44) p = 1.0

78 24/95 p < 0.0001.5 (7) 86.6 (11.1)% 67% p = 1.07/40) (33/49)

374 U. Banerji et al.

Fig. 1 Time to progression of patients receiving ≥4 cycles ofcarboplatin and etoposide chemotherapy stratified into thoseexperiencing grades 0—2 and grades 3—4 neutropenia: (a) timeto progression of all patients studied; (b) time to progression inld

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Fig. 2 Overall survival of patients receiving ≥4 cycles ofcarboplatin and etoposide chemotherapy stratified into thoseexperiencing grades 0—2 and grades 3—4 neutropenia: (a) over-as

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imited stage disease; (c) time to progression in extensive stageisease.

The survival in all patients with grades 0—2 versus grades—4 neutropenia was 47 weeks (95% CI 38—57) versus 60eeks (95% CI 44—76), p = 0.008 (Fig. 2a). This statistically

ignificant difference was maintained in patients with lim-

ted stage SCLC, 52 weeks (95% CI 36—68) versus 84 weeks95% CI 68—101), p = 0.04 (Fig. 2b). In patients with a exten-ive stage disease survival in patients experiencing grades—2 and grades 3—4 neutropenia was 42 weeks (95% CI4—49) versus 44 (95% CI 30—57), p = 0.1 (Fig. 2c).

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ll survival of all patients studied; (b) overall survival in limitedtage disease; (c) overall survival in extensive stage disease.

. Discussion

n the population of patients of SCLC patients studied, theresence of grade 3 or 4 neutropenia in patients was asso-iated with improved survival. The time to progression wasonger but this was not statistically significant.

Neutropenia during chemotherapy has been studied as

surrogate marker for improved treatment outcomes in

reast cancer [20—22], osteosarcoma [18], ovarian [19] andon small cell lung cancers [23].

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Chemotherapy induced neutropenia and treatment outcome

Differing outcomes of patients who experience higherdegrees of neutropenia could be due to several possiblefactors. Firstly, both the anti-cancer drugs used to treatSCLC, i.e. carboplatin and etoposide are known have vari-able plasma levels when dosed in relation to glomerular fil-tration rate [24] and body surface area [25,26]. It is possiblethat those patients with greater rates of myelotoxicity arethose with greater plasma drug levels. Studies have shownvarious genetic polymorphisms may affect the metabolismof anti-cancer agents and it is possible that these factorsmay lead to subgroups of patients with higher active druglevels [27,28]. Secondly, genetic polymorphisms are knownto predict chemosensitivity of anti-cancer drugs in normaltissue and tumour. Thus, patients could respond differentlyto an anti-cancer drug despite having similar pharmacoki-netic profiles [29,30].

The mean relative dose intensity in the patients expe-riencing grades 3 and 4 neutropenia was lower than thosewith lesser degrees of neutropenia (86.6% versus 95.5%).The lower relative dose intensity was due to dose delaysand dose reductions suggesting that dose intensity is not asimportant as a dose that achieves grades 3—4 neutropenia.It could be hypothesized that tumour chemo-sensitivity isrelated to bone marrow chemo-sensitivity. Several previoustrials have studied the role of dose intensity in the treatmentof SCLC. Studies have reported improved survival with highdose chemotherapy [8—11], however not all trials have beenconfirmed this [12—14] and high dose chemotherapy for SCLCis not standard practice [1]. The results of our study showan association between patients experiencing grade 3 or 4neutropenia and a better clinical outcome. The adequacy ofdosing cancer chemotherapy based on body surface area hasbeen criticised before [31—35]. The use of neutropenia asa pharmacodynamic marker could be used to individualisea biologically effective dose in the context of intra-patientdose escalation regimens [36].

The improved survival in patients with SCLC was seen inpatients with limited stage disease and not with those havingextensive stage disease. The lack of power to define a dif-ference due to the number of patients studied may explainthis. However, patients with extensive stage SCLC are likelyto have a poorer performance status and thus are likely toexperience greater non haematological toxicity which maynegate the improved outcome predicted by grade 3 or 4 neu-tropenia. Further studies in larger cohorts with patients withextensive stage SCLC with a good performance status (ECOG0—1), may show that this subgroup attain benefits similar topatients with limited stage SCLC.

There have been previous attempts to link neutropeniato disease outcomes in lung cancer [23]. Di Maio et al. havereported favourable survival of patients with metastatic nonsmall cell lung cancer (NSCLC) experiencing chemotherapyinduced neutropenia. Apart form the obvious differencesin histology (NSCLC versus SCLC) there are important dif-ferences between the study populations and findings. Ourstudy was based on a single chemotherapy regimen, i.e.carboplatin and etoposide) compared to seven different

arms in three different multicentre studies (ELVIS, MILES andGEMVIN3). Also the conclusions drawn form the Di Maio studyshowed an improved survival in patients with metastatic dis-ease who were rendered neutropenic while the data in ourstudy suggests that occurrence of neutropenia in patients

SCLC 375

ith non metastatic (limited stage) disease is associatedith improved survival. Further, in a study exploring the

nfluence of the sex of the patient on toxicity and treat-ent outcomes in SCLC, Singh et al. [37] have reported

hat female patients with SCLC have greater toxicity andmproved survival. Here again the cohort was fairly het-rogeneous with 4 different trials (BR3, BR4, BR6 and BR8)ith eight treatment arms being used for the pooled anal-sis. Extensive stage and limited stage disease was notnalysed separately. Our study did not show a differenceetween males and females in the occurrence of grade 3r 4 neutropenia on treatment outcomes as described byingh et al.

Individualizing dose of chemotherapy based on achiev-ng a predefined degree of myelotoxicity by intra-patientose escalation has been suggested before [36] and iseing prospectively studied in the setting of an ovarianancer trial [38]. The incidence of febrile neutropenia inhe cohort was 14.5% which is not dissimilar to what haseen described in literature [39—42]. The rates of febrileeutropenia were slightly higher in patients with exten-ive stage disease but this was not statistically significant.ntibiotic [39—41] and/or GCSF prophylaxis [42] has beenhown to reduce rates of chemotherapy induced febrileeutropenia. Routine prophylactic use of antibiotics androwth factors are not policy at our institution. However,here was a significantly higher incidence of febrile neu-ropenia in patients with grades 3—4 neutropenia and pro-ocols prospectively exploring escalation of dose intensityo achieve grades 3—4 neutropenia should carefully monitoreutrophil counts and could consider prophylactic antibioticse.

In conclusion, occurrence of chemotherapy inducedrades 3 or 4 neutropenia correlated with overall survivaln patients with SCLC receiving carboplatin and etoposidehemotherapy. Trials exploring intra-patient dose escalationf this regimen, with a target to achieve grade 3 or 4 neu-ropenia in patients with limited stage SCLC and patientsith extensive stage SCLC with a good performance status

ECOG 0—1) are warranted.

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