Professional Documents
Culture Documents
DOI 10.1007/s10549-011-1799-1
CLINICAL TRIAL
Received: 7 June 2011 / Accepted: 21 September 2011 / Published online: 5 October 2011
Ó Springer Science+Business Media, LLC. 2011
123
484 Breast Cancer Res Treat (2012) 131:483–490
neutropenia’s favorable impact on survival is that it is a who received radiotherapy were those with positive lymph
surrogate marker for a sufficient antitumor dose of cyto- nodes more than three, or the women who received breast-
toxic chemotherapy. However, the nature of the relation- conserving surgery. The dosage was 45–50 Gy in 18–25
ship between chemotherapy-induced neutropenia and the fractions over 5 weeks after six cycles of chemotherapy.
survival, in particular, remains controversy. In this report, Estrogen receptor (ER) status was determined by immu-
we described a retrospective analysis of patients with early- nohistochemistry and tumors with 10% or more positively
stage breast cancer, who were treated with the first-line stained tumor cells were classified positive for ER. Histo-
chemotherapy of CEF, to evaluate any possible association logical grade was determined according to the modified
between chemotherapy-induced neutropenia occurring Scarff-Bloom-Richardson criteria [12]. Patients with ER-
during chemotherapy and survival. positive or PR-positive tumors were administered hor-
monal therapy. Adjuvant trastuzumab was administered in
17 patients (5%). After treatment, the patients were fol-
Patients and methods lowed up at 3 to 4 month intervals for the first 2 years
and thereafter at 6-month intervals for at least 5 years.
Patients Staging investigations included clinical investigation, liver
enzymes, chest X-ray, liver ultrasound, and bone scintig-
The study population comprised primary breast cancer raphy. The dose intensity was calculated as the total dose
patients in Tianjin Medical University Cancer Institute and administered divided by the duration of time over which it
Hospital between April 2005 and April 2007, 335 patients was given. The relative dose intensity (RDI) was then
with early-stage breast cancer were identified who met calculated as the ratio of the actual dose intensity to the
the inclusion criteria. The inclusion criteria were as fol- ideal value if planned doses were all given on schedule.
lows: sufficient bone marrow function (leukocyte count
4.0 9 109/l, neutrophil count 2.0 9 109/l, platelet count Evaluation of neutropenia and supportive therapy
100 9 109/l, hemoglobin 9.0 g/dl); normal liver and renal
functions; no history of prior chemotherapy for advanced Routine blood counts were taken during every chemo-
disease; and no history of chemotherapy before the com- therapy cycle, day one before treatment and approximately
mencement of CEF treatment. The patients were selected on day 7 and day 14, in all patients during all chemo-
from those who survived beyond 180 days of treatment. therapy cycles. Hematologic toxicity, including neutrope-
Febrile neutropenia patients were excluded from this study. nia, leukopenia, thrombocytopenia and decreased
The patients were followed up until December 2010 to hemoglobin level, was graded according to the National
obtain survival information. Cancer Institute Common Terminology Criteria for
One hundred and eighty patients were stage I breast Adverse Events(NCI-CTCAE), version 3. Chemotherapy
cancer and 155 patients were stage II breast cancer. was delayed until recovery for a neutrophil count of
Estrogen receptor (ER) values were available for 329 1.5 9 109/l or any significant persisting nonhematologic
patients, 66% of whom were positive. Progesterone toxicity. The treatment was discontinued if the patient
receptor (PR) values were available for 329 patients, 60% developed unacceptable toxic effects, refused treatment, or
of whom were positive. The human epidermal growth withdrew consent. Patients with treatment delay due to
factor receptor 2 (HER-2) values were available for 327 toxicity were followed up with weekly or more frequent
patients, 21% of whom were positive. One hundred and blood counts. The most severe grade of neutropenia was
seventy-nine (53%) patients were over 50 years old. The based on the neutrophil count for a given patient between
median follow-up time was 65 month. the first day of CEF administration and 2 weeks after the
last CEF cycle was administered. The grade was according
Treatment delivery to the National Cancer Institute Common Toxicity Criteria
version 3.0. (grade 0 equates to Within normal limits; grade
The patients had received six cycles of intravenous CEF as 1 equates to a neutrophil count of between 1.5 and
adjuvant postoperative chemotherapy for a diagnosis of 2.0 9 109 cells/l; grade 2 equates to a neutrophil count of
invasive breast cancer. All patients had been undergone between 1.0 and 1.5 9 109 cells/l; grade 3 equates to a
surgery with modified radical mastectomy or breast-con- neutrophil count of between 0.5 and 1 9 109 cells/l; and
serving resection and axillary lymph node dissection. grade 4 equates to a neutrophil count of lower than
Patients were treated with adjuvant chemotherapy, which 0.5 9 109 cells/l.) To evaluate neutropenia during che-
consisted of cyclophosphamide (600 mg/m2), epirubicin motherapy, patients were divided into three categories:
(60 mg/m2), and fluorouracil (600 mg/m2) administered neutropenia absent (grade 0), mild (grades 1–2), and severe
intravenously on day 1 at 3-week intervals. The patients (grades 3–4). The indication for using granulocyte-colony-
123
Breast Cancer Res Treat (2012) 131:483–490 485
stimulating factor (G-CSF) was generally used in grade 4 in 139 (42%) of 335 patients and severe neutropenia
neutropenia or in febrile neutropenia, and no use as pro- (grades 3–4) occurred in 37 (11%). The other 159 patients
phylaxis was allowed. To avoid bias from different fre- (47%) did not experience neutropenia during treatment
quencies of neutrophil counting, the worst grade of with CEF. The relative dose intensity was not significantly
neutropenia was evaluated by the lowest recorded neutrophil different between each group. In 176 patients experiencing
count of six cycles of chemotherapy regimen. neutropenia, the worst grade was seen during the first cycle
in 32 patients, during the second cycle in 38, during the
Statistical analysis third cycle in 32, during the fourth cycle in 31 and during
the fifth cycle 22 or thereafter in 20, indicating that 76% of
The association between neutropenia and various clinico- patients with neutropenia experienced their worst grade
pathological parameters was assessed using the v2 test or within four cycles. On the other hand, 43 of 202 patients
Fisher’s exact test. Overall survival (OS) was the primary (21%) without neutropenia within four cycles experienced
endpoint of the analysis. OS was defined as the time from neutropenia (35 patients with mild neutropenia and 8
surgery to death or follow up. The survival curves of the patients with severe neutropenia) (Fig. 2).
three categories were estimated by the Kaplan–Meier
method and compared by the log-rank test. What is more,
we treated chemotherapy-induced neutropenia as a time- Relationship between neutropenia and prognosis
dependent variable. For each patient, the worst grade of
neutropenia occurring during the CEF treatment was The survival curves of the three categories were estimated
defined as the value of the variable at T. The variable value by the Kaplan–Meier method and compared by the log-
for each patient could change over time according to the rank test. Neutropenia status was significantly associated
worst grade of neutropenia experienced by that time. To with OS. Patients without neutropenia showed a signifi-
quantify the impact of time-dependent neutropenia on cantly lower 5-year OS rate (65%) than those with mild
survival, Clinical and pathological factors were tested by neutropenia (P \ 0.001) (89%) and severe neutropenia
univariate and multivariate analyses according to the worst (P = 0.033) (84%) (Fig. 3). The result of a Cox regression
grade of neutropenia, which was considered to be a time- analysis for the association between overall survival and
dependent variable. All of the statistical tests and P values the worst grade of neutropenia, which was treated as a
were two-tailed, and P \ 0.05 was considered significant. time-dependent variable is showed in Table 2. Univariate
and multivariate analyses including neutropenia and vari-
ous clinicopathological parameters of breast cancer was
Results done. In univariate analysis, the HR for mild (grade 1–2)
neutropenia in comparison with no neutropenia (grade 0)
Incidence of neutropenia was 0.424 (95% CI, 0.280–0.642; P \ 0.001). Similarly,
the HR for severe (grade 3–4) neutropenia in comparison
Figure 1 shows the worst grade of neutropenia recorded at with no neutropenia was 0.579 (95% CI, 0.415–0.807;
each cycle of chemotherapy in the 335 patients. Table 1 P = 0.001). In multivariate analysis, the HR for mild
shows characteristics of patients in the analysis. Relation- (grade 1–2) neutropenia in comparison with no neutropenia
ship between neutropenia and various clinicopathological (grade 0) was 0.434 (95% CI, 0.298–0.634; P \ 0.001),
parameters overall, mild neutropenia (grades 1–2) occurred which translated into a 24% lower risk of death. Similarly,
the HR for severe (grade 3–4) neutropenia in comparison
with no neutropenia was 0. 640 (95% CI, 0.42–0.975;
severe mild absent P = 0.038), which represented a 19% lower risk of
100% death. Therefore, patients who experienced neutropenia
90%
80% had a more favorable prognosis, and the presence of mild
ratio of patientas
123
486 Breast Cancer Res Treat (2012) 131:483–490
Table 1 Baseline demographics and clinical/hematologic characteristics in all patients and in subgroups stratified according to the worst grade
of neutropenia during six cycles
All patients (n = 335) Neutropenia P
Absent (n = 159) Mild (n = 139) Severe (n = 37)
30
25 Both mild and severe neutropenia tended to be associ-
20 ated with improved prognosis in almost all subgroups
15 (Fig. 4). In all subgroups, both mild and severe neu-
10 tropenia were favorable prognostic factors almost to the
5 same degree.
0 Finally, we performed similar analysis for other hema-
1 2 3 4 5 6
tologic manifestations of toxicity, including leukopenia,
cycle
hemoglobin decrease, and thrombocytopenia. However,
Fig. 2 The timing of occurrence of neutropenia with worst grade in none of these variables remained as significant factors in
176 patients during six cycles of CEF the multivariate model (data not shown).
123
Breast Cancer Res Treat (2012) 131:483–490 487
Table 2 Univariate and multivariate Cox models for the association between survival and chemotherapy-induced neutropeniaa
Univariate analysis Multivariate analysis
Adjusted hazard ratio (95% CI) P Adjusted hazard ratio (95% CI) P
Neutropeniaa
Mild vs. 0 0.424 (0.280–0.642) \0.001 0.434 (0.298–0.634) \0.001
Severe vs. 0 0.579 (0.415–0.807) 0.001 0.640 (0.42–0.975) 0.038
Age
\50 y vs. C 50 y 0.846 (0.541–1.322) 0.463
BSA
[1.50 m2 vs. B 1.50 m2 0.660 (0.419–1.039) 0.072
Clinical tumor size, n
T B 50 mm vs. T [ 50 mm 1.981 (1.365–2.875) \0.001 1.762 (1.118–2.777) 0.015
Clinical nodal status, n
N0 vs. N1–3 2.614 (1.629–4.193) \0.001 1.92 (1.098–3.383) 0.022
ER, n
Positive vs. negative 0.609 (0.388–0.955) 0.031 0.601 (0.37–0.978) 0.04
PR, n
Positive vs. negative 0.657 (0.420–1.028) 0.066
HER-2, n
Positive vs. negative 1.730 (1.376–2.175) \0.001 1.377 (1.067–1.777) 0.014
Histological grade
IvsII–III 1.946 (1.112–3.404) 0.02 1.964 (1.098–3.513) 0.023
a
BSA body surface area, Neutropenia is treated as a time-dependent variable
123
488 Breast Cancer Res Treat (2012) 131:483–490
123
Breast Cancer Res Treat (2012) 131:483–490 489
of patients with neutropenia (133 of 176 patients) experi- [20090139] and Talented Professionals Scientific Research Funds of
enced their highest grade within four cycles, and those Tianjin Medical University Cancer Institute and Hospital. The authors
would like to thank Yue Li, Hongmeng Zhao, Yanqun Song for their
without neutropenia occurring in the first four cycles rarely help with data collecting.
experienced severe late-onset neutropenia (8 of 202
patients). However, the number of patients who remained Conflict of interest None of the authors has any competing interest
at grade 1–2 neutropenia in the first four cycles but to declare. The authors have no relevant financial interests to disclose.
thereafter developed neutropenia or one of the above
toxicities to a grade 3–4 level was only 43. Taking into
consideration, an early dose increase would not be a prob-
lem for most of the patients targeted in our approach. References
Therefore, neutropenia in earlier cycles can be used as a
surrogate marker for adequate-intensity CEF treatment. 1. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N
(2009) Triple-negative breast cancer—current status and future
The sample size of the current study was relatively
directions. Ann Oncol 20:1913–1927
large, the patients were treated in a single institution by a 2. Early Breast Cancer Trialists’ Collaborative Group (1998)
limited number of physicians, and follow-up was relatively Polychemotherapy for early breast cancer: an overview of the
long and complete. Unlike a typical exposure of interest randomised trials. Lancet 352:930–942
3. (2005) Effects of chemotherapy and hormonal therapy for early
such as treatment assignment, neutropenia is less likely to
breast cancer on recurrence and 15-year survival: an overview of
be influenced by the investigator’s intention. What is more, the randomised trials. Lancet 365:1687–1717
taking into consideration the analyses of the time-varying 4. Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon
nature of neutropenia as TVCs, along with Cox propor- J, Camps C, Carrato A, Casado A, Candel MT, Albanell J,
Aranda J, Munarriz B, Campbell J, Diaz-Rubio E (2003) Doxo-
tional hazards modeling, is also one of the strengths of this
rubicin in combination with fluorouracil and cyclophosphamide
study. However, our study has several limitations. First, it (i.v. FAC regimen, day 1, 21) versus methotrexate in combination
is a retrospective design evaluating the association between with fluorouracil and cyclophosphamide (i.v. CMF regimen, day
neutropenia as an exposure of interest and overall survival. 1, 21) as adjuvant chemotherapy for operable breast cancer: a
study by the GEICAM group. Ann Oncol 14:833–842
The current study data related to this question suffer from
5. Di Maio M, Gridelli C, Gallo C, Shepherd F, Piantedosi FV,
the limited number of interim blood counts that were per- Cigolari S, Manzione L, Illiano A, Barbera S, Robbiati SF,
formed. Patients who were included in the ‘‘no toxicity’’ Frontini L, Piazza E, Ianniello GP, Veltri E, Castiglione F, Ro-
group may have had occult myelosuppression at other setti F, Gebbia V, Seymour L, Chiodini P, Perrone F (2005)
Chemotherapy-induced neutropenia and treatment efficacy in
times or during other cycles when no blood counts were
advanced non-small-cell lung cancer: a pooled analysis of three
available. What is more, several factors such as PR were randomised trials. Lancet Oncol 6:669–677
not significantly associated with OS, although a large 6. Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y,
randomized trial has demonstrated such an association. Fukushima M (2007) Predictive value of chemotherapy-induced
neutropenia for the efficacy of oral fluoropyrimidine S-1 in
The patients with mild and severe grade in their neu-
advanced gastric carcinoma. Br J Cancer 97:37–42
trophil count had significantly better survival outcomes 7. Shitara K, Matsuo K, Takahari D, Yokota T, Inaba Y, Yamaura
than did patients without such toxicity, indicating that H, Sato Y, Najima M, Ura T, Muro K (2009) Neutropaenia as a
chemotherapy-induced neutropenia may provide an index prognostic factor in metastatic colorectal cancer patients under-
going chemotherapy with first-line FOLFOX. Eur J Cancer
of delivering an optimal dose of chemotherapy that is
45:1757–1763
required for generating an active antitumor effect. It would 8. Saarto T, Blomqvist C, Rissanen P, Auvinen A, Elomaa I (1997)
be instructive to study the influence of myelosuppression Haematological toxicity: a marker of adjuvant chemotherapy
within one arm of a prospective trial in which the patients efficacy in stage II and III breast cancer. Br J Cancer 75:301–305
9. Poikonen P, Saarto T, Lundin J, Joensuu H, Blomqvist C (1999)
are treated uniformly and in which interim blood counts are
Leucocyte nadir as a marker for chemotherapy efficacy in node-
performed repeatedly at specific times in the cycles of positive breast cancer treated with adjuvant CMF. Br J Cancer
chemotherapy, or a prospective trial such as a dose-esca- 80:1763–1766
lating study until neutropenia occurs. In conclusion, our 10. Cameron DA, Massie C, Kerr G, Leonard RC (2003) Moderate
neutropenia with adjuvant CMF confers improved survival in
finding might indicate that neutropenia is a surrogate
early breast cancer. Br J Cancer 89:1837–1842
marker for adequate antitumor doses of chemotherapy and 11. Ishitobi M, Komoike Y, Motomura K, Koyama H, and Inaji H
better survival. Using a tailored regimen of fluorouracil, Prognostic significance of neutropenia on day one of anthracy-
epirubicin, and cyclophosphamide guided by toxic effects cline-based neoadjuvant chemotherapy in operable breast cancer.
Oncology 78:213–219
in patients with breast cancer probably would have a better
12. Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyr-
result in many patients. atos F, Brunet M (1989) Prognostic value of histologic grade
nuclear components of Scarff-Bloom-Richardson (SBR). An
Acknowledgments This study is supported by The Science Tech- improved score modification based on a multivariate analysis of
nology Development Project of Colleges and Universities in Tianjin 1262 invasive ductal breast carcinomas. Cancer 64:1914–1921
123
490 Breast Cancer Res Treat (2012) 131:483–490
13. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, 25. Gurney H (2002) How to calculate the dose of chemotherapy. Br
Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin J Cancer 86:1297–1302
R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, 26. Ratain MJ (1998) Body-surface area as a basis for dosing of
Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher anticancer agents: science, myth, or habit? J Clin Oncol
L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, 16:2297–2298
Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C (2005) Adju- 27. Newell DR (2002) Getting the right dose in cancer chemother-
vant docetaxel for node-positive breast cancer. N Engl J Med apy–time to stop using surface area? Br J Cancer 86:1207–1208
352:2302–2313 28. de Jongh FE, Verweij J, Loos WJ, de Wit R, de Jonge MJ,
14. Trudeau M, Charbonneau F, Gelmon K, Laing K, Latreille J, Planting AS, Nooter K, Stoter G, Sparreboom A (2001)
Mackey J, McLeod D, Pritchard K, Provencher L, Verma S Body-surface area-based dosing does not increase accuracy of
(2005) Selection of adjuvant chemotherapy for treatment of predicting cisplatin exposure. J Clin Oncol 19:3733–3739
node-positive breast cancer. Lancet Oncol 6:886–898 29. Singh S, Parulekar W, Murray N, Feld R, Evans WK, Tu D,
15. Pettengell R, Schwenkglenks M, Leonard R, Bosly A, Paridaens Shepherd FA (2005) Influence of sex on toxicity and treatment
R, Constenla M, Szucs TD, Jackisch C (2008) Neutropenia outcome in small-cell lung cancer. J Clin Oncol 23:850–856
occurrence and predictors of reduced chemotherapy delivery: 30. Edlund P, Ahlgren J, Bjerre K, Andersson M, Bergh J, Mouridsen
results from the INC-EU prospective observational European H, Holmberg S B, Bengtsson N O, Jakobsen E, Moller S, Lind-
neutropenia study. Support Care Cancer 16:1299–1309 man H, and Blomqvist C Dose-tailoring of FEC adjuvant che-
16. Crawford J, Dale DC, Lyman GH (2004) Chemotherapy-induced motherapy based on leukopenia is feasible and well tolerated.
neutropenia: risks, consequences, and new directions for its Toxicity and dose intensity in the Scandinavian Breast Group
management. Cancer 100:228–237 phase 3 adjuvant Trial SBG 2000-1. Acta Oncol 50:329–337
17. Kvinnsland S (1999) The leucocyte nadir, a predictor of 31. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Gold-
chemotherapy efficacy? Br J Cancer 80:1681 stein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk
18. Mayers C, Panzarella T, Tannock IF (2001) Analysis of the KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E
prognostic effects of inclusion in a clinical trial and of myelo- 3rd, Schilsky RL, Wood WC, Muss HB, Norton L (2003)
suppression on survival after adjuvant chemotherapy for breast Improved outcomes from adding sequential Paclitaxel but not
carcinoma. Cancer 91:2246–2257 from escalating Doxorubicin dose in an adjuvant chemotherapy
19. Nakata B, Tsuji A, Mitachi Y, Yamamitsu S, Hirata K, Takeuchi regimen for patients with node-positive primary breast cancer.
T, Shirasaka T, Hirakawa K (2006) Moderate neutropenia with J Clin Oncol 21:976–983
S-1 plus low-dose cisplatin may predict a more favourable 32. Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens
prognosis in advanced gastric cancer. Clin Oncol (R Coll Radiol) JH, Grochow LB, Sparreboom A (2002) Role of body surface
18:678–683 area in dosing of investigational anticancer agents in adults,
20. Fumoleau P, Devaux Y, Vo Van ML, Kerbrat P, Fargeot P, 1991–2001. J Natl Cancer Inst 94:1883–1888
Schraub S, Mihura J, Namer M, Mercier M (1993) Premeno- 33. Gurney H (2006) Developing a new framework for dose
pausal patients with node-positive resectable breast cancer. Pre- calculation. J Clin Oncol 24:1489–1490
liminary results of a randomised trial comparing 3 adjuvant 34. Gurney HP, Ackland S, Gebski V, Farrell G (1998) Factors
regimens: FEC 50 9 6 cycles vs FEC 50 9 3 cycles vs FEC 75 9 affecting epirubicin pharmacokinetics and toxicity: evidence
3 cycles. The French Adjuvant Study Group. Drugs 45(Suppl against using body-surface area for dose calculation. J Clin Oncol
2):38–45 16:2299–2304
21. Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, 35. Sandstrom M, Freijs A, Larsson R, Nygren P, Fjallskog ML,
Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR et al (1994) Bergh J, Karlsson MO (1996) Lack of relationship between
Dose and dose intensity of adjuvant chemotherapy for stage II, systemic exposure for the component drug of the fluorouracil,
node-positive breast carcinoma. N Engl J Med 330:1253–1259 epirubicin, and 4-hydroxycyclophosphamide regimen in breast
22. Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, cancer patients. J Clin Oncol 14:1581–1588
Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, 36. Sandstrom M, Lindman H, Nygren P, Johansson M, Bergh J,
Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Karlsson MO (2006) Population analysis of the pharmacokinetics
Caggiano V, Grimaldi M, Jochimsen P, Deckers P (1997) and the haematological toxicity of the fluorouracil-epirubicin-
Increased intensification and total dose of cyclophosphamide in a cyclophosphamide regimen in breast cancer patients. Cancer
doxorubicin-cyclophosphamide regimen for the treatment of Chemother Pharmacol 58:143–156
primary breast cancer: findings from National Surgical Adjuvant 37. Lyman GH, Dale DC, Crawford J (2003) Incidence and predic-
Breast and Bowel Project B-22. J Clin Oncol 15:1858–1869 tors of low dose-intensity in adjuvant breast cancer chemother-
23. Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, apy: a nationwide study of community practices. J Clin Oncol
Malmstrom P, Kellokumpu-Lehtinen P, Bengtsson NO, Soderl- 21:4524–4531
und G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, 38. Lyman GH, Dale DC, Friedberg J, Crawford J, Fisher RI (2004)
Holte H, Nilsson J, Blomqvist C, Wilking N (2000) Tailored Incidence and predictors of low chemotherapy dose-intensity in
fluorouracil, epirubicin, and cyclophosphamide compared with aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin
marrow-supported high-dose chemotherapy as adjuvant treatment Oncol 22:4302–4311
for high-risk breast cancer: a randomised trial. Scandinavian 39. Leonard RC, Miles D, Thomas R, Nussey F (2003) Impact of
Breast Group 9401 study. Lancet 356:1384–1391 neutropenia on delivering planned adjuvant chemotherapy: UK
24. Gurney H (1996) Dose calculation of anticancer drugs: a review audit of primary breast cancer patients. Br J Cancer 89:
of the current practice and introduction of an alternative. J Clin 2062–2068
Oncol 14:2590–2611
123