Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel

doi:10.4236/ijcm.2011.23060

Paper Menu >>

Journal Menu >>

International Journal of Clinical Medicine, 2011, 2, 346-351

doi:10.4236/ijcm.2011.23060 Published Online July 2011 (http://www.SciRP.org/journal/ijcm)

Quality of Life of Patients with Metastatic Breast

Cancer Treated with Epirubicin and Docetaxel*

Jaana Korpela1, Pekka Mali1, Anne Kaljonen2, Eeva Salminen1

1Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland; 2 Turku Institute for Child and Youth

Research, University of Turku, Turku, Finland.

Email: [email protected]

Received April 24th, 2011; revised May 28th, 2011; accepted June 16th, 2011.

ABSTRACT

This phase II study assessed the clinical response and short-term quality of life of patients receiving first-line chemo-

therapy with epirubicin-docetaxel combination for metastatic breast cancer. Thirty-one breast cancer patients were

treated with epirubicin (75 mg/m2 for 15 minutes) followed one hour later by a one-hour infusion of docetaxel (75

mg/m2) q3w. EORTC QLQ-C30 and EORTC QLQ-BR23 forms were filled in at baseline, and at th e second and eighth

cycle of chemotherapy. The combination of epirubicin and docetaxel provided a high degree of clinical benefit. Clinical

response was observed in 17 patients (55 %), including five (16%) complete responses and 12 (39%) partial responses.

Of responding and stable patients 23 (74%) maintained the same status for at least six months (clinical benefit). The

mean survival time was 40.8 months. Du ring the treatment the emotional fun ctioning improved and the concerns abou t

the future were relieved. Some aspects of quality of life were impaired, with slightly decreased physical and cognitive

functioning, distress related to body image and hair loss, and adverse effects of chemotherapy. Overall, the global

quality of life was maintained.

Keywords: Metastatic Breast Cancer, Chemotherapy, Epirubicin, Docetaxel, Quality of Life

1. Introduction

As metastatic breast cancer still remains essentially in-

curable, the main goals of therapy include treatment of

symptoms and maintaining the quality of life, as well as

a delay in disease progression and prolongation of over-

all survival. As women with metastatic breast cancer

have a relatively short expected survival time, the im-

pact on quality of life is an important factor to consider

when making treatment decisions. The adverse effects of

treatment should be kept as low as possible and small

gains must be weighed against the severity of adverse

effects. Collection of data from formal quality of life

instruments can broaden the parameters of benefit be-

yond response and survival, and can allow more accu-

rate determination of the supportive and ameliorative

interventions needed by the patients. Nevertheless, per-

haps due to methodological difficulties, many clinical

trials in metastatic breast cancer have been published

without quality of life data [1].

Chemotherapy is the mainstay of treatment for me-

tastatic breast cancer patients with hormone receptor-

negative disease or with hormone receptor-positive dis-

ease which h as become resis tant to en docr ine ther apy, or

is rapidly progressive and life-threatening. Anthracy-

cline- and taxane- based therapies have shown the high-

est degree of response in metastatic breast cancer. Tax-

ane-containing regimens are associated with increased

overall survival [2]. Relatively few studies have reported

the effect of the combination of anthracyclines and tax-

anes on the quality of life among women treated

first-line for metastatic breast cancer [3-8]. Even less is

known about the effects of epirubicin and docetaxel

combination on the quality of life. To our knowledge

previously only Yeo et al. have reported the effects of an

epirubicin and docetaxel combination on the quality of

life in metastatic breast cancer [9].

Previously, we have reported the efficacy, toxicity

and cost of treatment with the combination of epirubicin

and docetaxel in metastatic breast cancer [10-12]. This

report assessed the short-term quality of life outcome.

2. Methods

2.1. Patients and Treatment

Originally thirty-eight patients with metastatic breast

*Supported by the Cancer Society of South-Western Finland (JK).

Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel347

cancer were treated with the combination of epirubicin

and docetaxel. In this report on ly the 35 Finnish-speaking

patients were included. Eligibility criteria for the epiru-

bicin-docetaxel study included written informed consent,

age 18 - 75 years, ECOG performance status <2, white

blood cell count >3000/mm3, platelet count >130,000/

mm3, and liver function <3 times the normal value. Pre-

vious adjuvant treatment with CMF (cyclophos- phamide,

methotrexate and 5-fluorouracil) or CEF (cyclo-phos-

phamide, epirubicin and 5-fluorouracil) was allowed, as

were prior hormonal therapy or radiotherapy. Exclusion

criteria included brain or leptomeningeal involvement

and active infection. The study was conducted according

to the ethical standards described in the Helsinki Decla-

ration. The protocol was approved by the Ethical Com-

mittee of Turku University Hospital and written informed

consent w as obtained f rom the pat ients.

The patients were treated with epirubicin (75 mg/m2

15-minute infusion) followed one hour later by docetaxel

(75 mg/m2, one-hour infusion) every three weeks. The

doses were based on earlier studies that have demon-

strated the applicable levels without growth factor sup-

port [13,14]. Mid -cycle co unts were taken on d ay 10 - 11.

The aim was to give eight cycles to responding/stable

patients. The starting dose of 75 mg/m2 for both epirubi-

cin and docetaxel was reduced by 25% if the patient was

hospitalized due to febrile neutropenia, required antibi-

otics, or developed prolonged neutropenia. Premedica-

tion of prednisolone (40 mg) was given orally the night

before treatment and continued b.i.d. on days 1 - 3. A

prophylactic anti-emetic was given according to routine

practice (5HT-blocker prior to chemotherapy infu sion).

2.2. Response

Response was defined according to WHO criteria after

the third cycle and at close of treatment [15]. Clinical

benefit was calculated for responding and stable patients

maintaining the same status for at least six months. The

mean follow-up time was 79.9 months.

2.3. Quality of Life Evaluations and Statistical

Analysis

Quality of life was assessed with the European Organ iza-

tion for Research and Treatment of Cancer Quality of

Life Questionnaire EORTC QLQ-C30 version +3 [16]

and the QLQ-BR23 Breast module [17]. The patients

filled in the EORTC QLQ-C30 forms at baseline, just

before the second and eighth cycle, and three months

after the last cycle. EORTC QLQ-C30 raw scores were

calculated according to guidelines, yielding a range of 0

- 100. A high score on the functiona l or global qu ality of

life scale represents a better level of functioning, and a

high score on the symptom or item scale represents more

symptoms. According to Osoba et al., a difference of 5

to 10 points on a 0 to 100 scale is considered a small

clinically significant change, a difference of 10 to 20

points a moderate change, and changes greater than 20

points would be interpreted as large changes in quality

of life [18].

The comparisons of quality of life scores at different

time points were carried out with analysis of variance

for repeated measurements. The analyses were per-

formed using the MIXED procedure (SAS system for

Windows XP version 9 .1.3 2003) which offers a sophis-

ticated tool for analysis of follow-up data with possible

missing data during follow-up (Littell R, Milliken GA,

Stroup W, Wolfinger RD. SAS® system for Mixed

Models. Cary, NC: SAS Institute, Inc, 1996). P-values

less than 0.05 were considered statistically significant.

The survival analysis was estimated using the Kaplan-

Meier technique.

3. Results

3.1. Patient Characteristics and Treatment

Patient characteristics are shown in Table 1. The mean

age was 50 years (range 35 - 72 years). The mean ECOG

performance status was 1 (range 0 - 2) before chemo-

therapy. Twenty-seven patients (87%) received all the

planned eight cycles.

3.2. Response

Clinical response was achieved by seventeen patients

(55%), including five (16%) complete responses (CR)

and twelve (39%) partial responses (PR). Twenty-three

patients (74%) showed clinical benefit, i.e. responding

and stable patients (CR, PR and NC) maintaining the

same status for at least six months (Table 2). The mean

overall survival time was 40.8 months (SD 23.8).

3.3. Quality of life

Of the 35 Finnish-speaking patients originally in the

epirubicin-docetaxel study, four patients had to be ex-

cluded: baseline data were missing for two patients, one

patient filled in the baseline questionnaire one day after

the first cycle instead of on the recommended date, and

one patient was non-evaluable for response and was

therefore excluded. Thirty-one patients filled in the

questionnaire at baseline before the first cycle, twenty-

four just before the second, and twenty-five before the

eighth cycle. Because only seven patients filled in the

questionnaire at the control visit three months after the

treatment, it was decided to leave this last visit out of the

analysis. The patients whose disease progressed (4 pa-

tients) did not fill in the questionnaires at the last cycle

as they did not attend the last visits either.

The results from the quality of life questionnaires are

Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel

348

Table 1. Patient characteristics.

N %

Number of patients

Age (mean)

-Range

Performance status (WHO), mean

-Range

Prior treatment

-CMF

-CEF

-Antiestrogen

Postoperative radiotherapy

Number of metastatic organs

involved

-1

-2

-3

Disease sites

-Bone

-Liver

-Lungs

Receptors

-Er+/Pr+, Er+/Pr- or Er-/Pr+

-Er-/Pr-

Number of epirubicin-docetaxel

cycles

6-7

3-4

35 - 72

0 - 2

Table 2. Clinical response and clinical benefit.

Clinical response N % Stable for at least. 6 months

Complete response

Partial response

Stable disease

Progressive disease

Clinical benefit no./ % 23/74%

shown in Tables 3-5. Comparison of mean scores of

EORTC QLQ-C30 function scales and the global quality

of life scale at baseline, prior to the 2nd and 8th cycle are

shown in Table 3. The statistically and clinically sig-

nifica nt changes we re as follows : after the first cycle th e

emotional functioning improved a little (change of mean

by 7.7 points), the physical functioning decreased

slightly after the first cycle (8 points), and the cognitive

functioning decreased slightly as well (6.7 points). The

global quality of life remained unchanged. The mean

scores of EORTC QLQ-C30 symptom scales are shown

in Table 4. There were no both statistically and clini-

cally significant changes, although there was a trend

towards increased fatigue. Table 5 shows the com-

pare-son of mean scores of EORTC QLQ-BR23 breast

cancer items during the treatment. A few statistically

and clinically significant changes were observed. The

concerns about the future were modestly relieved

(change of 17 points), while distress related to body im-

age increased modestly (16.1 points). Systemic therapy

advers e effects, such as eye and mout h symptoms, he ad-

Table 3. Comparison of mean scores of EORTC QLQ-C30

function scales at baseline, and prior to the 2 nd and 8th cy cle.

Standard deviations are in parentheses.

Function

scales Baseline

Mean (SD) Prior to 2nd cycle

Mean (SD) Prior to 8th cycl e

Mean (SD) P-value

1.-2. cycle

1.-8. cycle

2.-8. cycle

Physical 79.3 (27.5) 71.3 (26.9) 72.7 (21.0) 0.046*

0.14

0.96

Ro le 76.9 (15.4) 73.9 (27.4) 81.3 (23.2) 0.36

0.87

0.30

Cognitive 91.4 (15.4) 93.8 (11.8) 84.7 (19.6) 0.27

0.039*

0.0012*

Emo-

tional 71.8 (21.1) 79.5 (18.1) 78.7 (19.8) 0.0018*

0.25

0.10

Social 83.3 (24.3 ) 74.3 (25.5) 78.7 (22.8) 0.11

0.30

0.70

Global

QoL 68.1 (19.1) 64.3 (20.3) 68.6 (19.5) 0.47

0.78

0.73

Higher score means better functioning, scale 0 - 100. *statistically signifi-

cant difference.

ache and menopausal symptoms, increased significantly

(22 points) especially at the beginning of the treatment,

and similar changes could be seen throughout the treat-

ment regimen. Distress related to hair loss increased

significantly by 75 points.

4. Discussion

The combination of epirubicin and docetaxel provided a

high degree of clinical benefit with manageable adverse

effects in first-line chemotherapy of metastatic breast

cancer without compromising global quality of life dur-

ing the treatment.

During the treatment some positive effects were ob-

served in the quality of life. Anxiety about the future

decreased and emotional functioning also improved.

This finding of improved emotional functioning after the

start of the treatment is in line with previous studies as-

sessing the quality of life with anthracycline and taxane

combinations in metastatic breast cancer [3,8]. Accord-

ing to Ramirez et al., the improvement in emotional

functioning might merely reflect the fact that in a

life-threatening situation something was being done,

irrespective of what it was, and thus it could simply be

an indication of hope [19].

During the treatment, the quality of life declined due

to systemic chemotherapy adverse effects. In addition,

the quality of life also declined in terms of physical

functioning, distress related to body image, and upset

Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel349

Table 4. Comparison of mean scores of EORTC QLQ-C30

symptom scales at baseline, and prior to the 2nd and 8th cy-

cle. Standard deviations are in parentheses.

Symptom

scales/items Baseline

(SD) Prior to 2nd

cycle

Mean (SD)

Prior to 8th

cycle

Mean (SD)

P-value

1.-2. cycle

1.-8. cycle

2.-8. cycle

Fatigue 24.4 (21.4) 33.3 ( 21.2) 31.5 (24.4) 0.064

0.12

0.99

Nausea and

vomiting 5.9 (16.4) 7.6 (11.0) 7.3 (21.0) 0.72

0.73

0.96

Pain 18.8 (21.4) 16.0 (18.7) 14.7 (18.8) 0.26

0.49

0.82

Dyspnea 23.0 (25.4) 20.8 (27.5) 16.0 (19.5) 0.17

0.23

0.88

Insomnia 30.1 (2 4.9) 25.0 (26.5) 30.7 (33.2) 0.31

0.94

0.31

Appetite loss 7.5 (16.6) 12.5 (16.5) 10.7 (24.9) 0.18

0.54

0.52

Constipation 6.5 (13.4) 9.7 (15.5) 6.7 (16.7) 0.31

0.98

0.33

Diarrhoea 4.3 (11.4) 11.1 (18.8) 6.7 ( 16 .7) 0.083

0.52

0.32

Financial

difficulties 12.2 (18.5) 15.3 (24.0) 12.0 (21.3) 0.39

0.99

0.43

Higher score indicates more symptoms, scale 0 - 100.

caused by hair loss, which are in line with the effect of

the doxorubicin and paclitaxel combination on the qual-

ity of life [3]. Moreover, the cognitive functioning de-

clined slightly. Subjective cognitive functioning and

objective tests measuring cognitive functioning do not

always correlate. Subjective cognitive decline often cor-

relates with anxiety, depression or fatigue [20,21].

However, true decline in cognitive functioning is possi-

ble as emerging evidence indicates that cognitive

changes can be associated with chemotherapy, at least in

an adjuvant setting [22]. The negative changes in quality

of life in this study could be observed throughout the

treatment. However, the negative changes did not ad-

versely influence the global quality of life. Nor have

other studies assessing the quality of life with other an-

thracycline and taxane combinations shown any signify-

cant change in the overall quality of life. This may re-

flect the difficulties encountered with data collection and

interpretation [2]. In addition, in the majority of metas-

tatic breast cancer studies, despite the different toxicity

Table 5. Comparison of mean scores of EORTC QLQ-BR23

breast cancer items at baseline, and prior to the 2nd and 8th

cycle. Standard deviations are in parentheses.

Functional

scales/items 1)Baseline

Mean (SD) Cycle 2

Mean (SD) Cycle 8

Mean (SD) P-value

1.-2. cycle

1.-8. cycle

2.-8. cycle

Body image 68.1 (22.9) 58.3 (28.1) 52.0 (30.6) 0.044*

0.0026*

0.079

Sexual

functioning 24.4 (20.4) 22.5 (18.5) 21.7 (22.7) 0.84

0.55

0.63

Sexual

enjoyment 53.8 (21.7) 48.5 (34.5) 42.4 (26.2) 0.47

0.36

0.72

Future

perspective 24.7 (25.8) 41.7 (26.5) 36.0 (27.1) 0.0006*

0.091

0.15

Symptom

scales/ items 2)

Systemic

therapy side

effects

13.0 (7.5) 35.0 (12.1) 29.2 (15.1) <0.0001*

<0.0001*

0.067

Upset by

hair loss 25.0 (16.7) 68.1 (30.6) 100.0 (0) 0.047*

0.017*

0.15

Breast

symptoms 8.0 (8.2) 6.9 (9.1) 6.3 (9.4) 0.047*

0.27

0.56

Arm symptoms11.9 (12.4) 11.1 (13.9) 16.0 (14.7) 0.95

0.18

0.14

*statistically significant difference; 1) higher score indicates better func-

tioning; 2) higher score indicate s more symptoms.

profiles of the chemotherapeutic agents, only minor or

no differences among the different treatment groups

have been reported in terms of quality of life [23-25]. It

has been reported that physical functioning and treat-

ment toxicity explain only 16% of the variance in global

quality of life, perhaps mostly due to the psychic work

that patien ts are forc ed to ap ply to the sense of hope that

the treatment offers [26]. Therefore, it can be concluded

that treatment-related adverse effects do not usually sig-

nificantly impair the global quality of life.

Previously, Yeo et al. have assessed the quality of life

of Chinese metastatic breast cancer patients during six

cycles of an epirubicin-docetaxel combination treatment,

after which responding patients received an additional

three cycles of docetaxel [9]. They assessed the quality

of life using a linear analogue self-assessment scale on

nine indices in three major aspects: emotional, physical,

and selected symptoms. Yeo et al. reported deteriora-

tion of quality of life in all three aspects after the third

cycle of ch emotherapy, after which there appeared to be

Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel

350

some improvement. However, the quality of life did not

return to baseline level although there was a trend to-

wards improved emotional functioning at the end of the

treatment. Our assessment was more comprehensive and

detailed using validated quality of life questionnaires.

Due to the differences in the methods, it is somewhat

difficult to compare the results between the studies. In

terms of physical functioning, our results are quite simi-

lar, but we found no statistically significant changes in

terms of pain, nausea or appetite. The results concern-

ing emotional functioning were different during the

chemotherapy. Nevertheless, in both studies, there was a

trend towards better emotional functioning at the end of

the treatment.

The major limitation of our quality of life study, in

addition to the small sample size, is the number of

missing questionnaires. The most common reasons for

missing data were progressive disease (four patients)

and administrative factors such as incomplete collection

of questionnaires. In the literature, many other authors

have shown that institutional and administrative factors

tend to be more influential than patient factors at least

until performance status deteriorates [3,27,28]. The

dropout of the patients with progressive disease is of

major concern because it distorts the results. The num-

ber of dropouts overestimates the effect of therapy on

quality of life as patients with progressive disease and

poor performance tolerated treatments poorly. Missing

data form one of the greatest methodological challenges

in cancer quality of life research [29].

In conclusion, the combination of epirubicin and do-

cetaxel showed clinical benefit among a good number of

patients in first-line chemotherapy of metastatic breast

cancer with manageable adverse effects. During the

treatment the emotional functioning improved and con-

cerns about the future were relieved. Some aspects of

quality of life were impaired, with slightly decreased

physical and cognitive functioning, distress related to

changes in body image and hair loss, and other adverse

effects of chemotherapy. However, the global quality of

life was maintained.

REFERENCES

[1] N. Wilcken and R. Dear, “Chemotherapy in Metastatic

Breast Cancer: A Summary of All Randomised Trials

Reported 2000-2007,” European Journal of Cancer, Vol.

44, No. 15, 2008, pp. 2218-2225.

doi:10.1016/j.ejca.2008.07.019

[2] D. Ghersi, N. Wilcken and R. J. Simes, “A Systematic

Review of Taxane-Containing Regimens for Metastatic

Breast Cancer,” British Journal of Cancer, Vol. 93, No. 3,

2005, pp. 293-301. doi:10.1038/sj.bjc.6602680

[3] A. Bottomley, L. Biganzoli, T. Cufer, et al., “Randomize d,

Controlled Trial Investigating Short-Term Health-Related

Quality of Life with Doxorubicin and Paclitaxel versus

Doxorubicin and Cyclophosphamide as First-Line Che-

motherapy in Patients with Metastatic Breast Cancer: Eu-

ropean Organization for Research and Treatment of Can-

cer Breast Cancer Group, Investigational Drug Branch for

Breast Cancer and the New Drug Development Group

Study,” Journal of Clinical Oncology, Vol. 22, No. 13,

2004, pp. 2576-2586. doi:10.1200/JCO.2004.02.037

[4] P. A. Cassier, S. Chabaud, V. Trillet-Lenoir, et al., “A

Phase-III Trial of Doxorubicin and Docetaxel versus

Doxorubicin and Paclitaxel in Metastatic Breast Cancer:

Results of the ERASME 3 Study,” Breast Cancer Re-

search and Treatment, Vol. 109, No. 2, 2008, pp. 343-

350. doi:10.1007/s10549-007-9651-3

[5] J. M. Nabholtz, C. Falkson, D. Campo, et al., “Docetaxel

and Doxorubicin Compared with Doxorubicin and

Cyclophosphamide as First-Line Chemotherapy for Me-

tastatic Breast Cancer: Results of a Randomized, Multi-

center, Phase III Trial,” Journal of Clinical Oncology,

Vol. 21, No. 6, 2003, pp. 968-975.

doi:10.1200/JCO.2003.04.040

[6] J. Jassem, T. Pienkowski, A. Pluzanska, et al., “Doxoru-

bicin and Paclitaxel versus Fluorouracil, Doxorubicin and

Cyclophosphamide as First-Line Therapy for Women with

Metastatic Breast Cancer: Final Results of a Randomized

Phase III Multicenter Trial,” Journal of Clinical Oncol-

ogy, Vol. 19, No. 6, 2001, pp. 1707-1715.

[7] G. W. Sledge, D. Neuberg, P. Bernardo, et al., “Phase III

Trial of Doxorubicin, Paclitaxel, and the Combination of

Doxorubicin and Paclitaxel as Front-Line Chemotherapy

for Metastatic Breast Cancer: An Intergroup Trial (E11-

93),” Journal of Clinical Oncology, Vol. 21, No. 4, 2003,

pp. 588-592. doi:10.1200/JCO.2003.08.013

[8] H. Svensson, Z. Einbeigi, H. Johansson, T. Hatschek and

Y. Brandberg, “Quality of Life in Women with Metastatic

Breast Cancer during 9 Months after Randomization in

the TEX Trial (Epirubicin and Paclitaxel w/o Capecit-

abine),” Breast Cancer Research and Treatment, Vol.

123, No. 3, 2010, pp. 785-793.

doi:10.1007/s10549-010-1084-8

[9] W. Yeo, T. S. Mok, K. K. Tse, et al., “Phase II Study of

Docetaxel and Epirubicin in Chinese Patients with Me-

tastatic Breast Cancer,” Anticancer Drugs, Vol. 13, No. 6,

2002, pp. 655-662.

doi:10.1097/00001813-200207000-00013

[10] J. Korpela and E. Salminen, “Neutropenic Infections Add

Significant Costs to Palliative Chemotherapy in Breast

Cancer,” Anticancer Research, Vol. 22, No. 2B, 2002, pp.

1337-1340.

[11] E. Salminen, J. Korpela, M. Varpula, et al., “Epirubi-

cin/Docetaxel Regimen in Progressive Breast Cancer-A

Phase II Study,” Anticancer Drugs, Vol. 13, No. 9, 2002,

pp. 925-929. doi:10.1097/00001813-200210000-00004

[12] E. Salminen, K. Syvanen, J. Korpela, et al., “Docetaxel

with Epirubicin-Investigations on Cardiac Safety,” Anti-

cancer Drugs, Vol. 14, No. 1, 2003, pp. 73-77.

doi:10.1097/00001813-200301000-00010

Quality of Life of Patients with Metastatic Breast Cancer Treated with Epirubicin and Docetaxel

351

[13] V. Dieras, “Review of Docetaxel/Doxorubicin Combina-

tion in Metastatic Breast Cancer,” Oncology (Williston

Park), Vol. 11, No. 8, 1997, pp. 31-33.

[14] E. Salminen, M. Bergman, S. Huhtala and E. Ekholm,

“Docetaxel: Standard Recommended Dose of 100

mg/m(2) is Effective But not Feasible for Some Metas-

tatic Breast Cancer Patients Heavily Pretreated with Che-

motherapy-A Phase II Single-Center Study,” Journal of

Clinical Oncology, Vol. 17, No. 4, 1999, pp. 1127-31.

[15] A. B. Miller, B. Hoogstraten, M. Staquet and A. Winkler,

“Reporting Results of Cancer Treatment,” Cancer, Vol.

47, No. 1, pp. 207-214.

doi:10.1002/1097-0142(19810101)47:1<207::AID-CNCR

2820470134>3.0.CO;2-6

[16] N. K. Aaronson, S. Ahmedzai, B. Bergman, et al., “The

European Organization for Research and Treatment of

Cancer QLQ-C30: A Quality-of-Life Instrument for Use

in International Clinical Trials in Oncology,” Journal of

the National Cancer Institute, Vol. 85, No. 5, 1993, pp.

365-376. doi:10.1093/jnci/85.5.365

[17] M. A. Sprangers, M. Groenvold, J. I. Arraras, et al., “The

European Organization for Research and Treatment of

Cancer Breast Cancer-Specific Quality-of-Life Question-

naire Module: First Results from a Three-Country Field

Study,” Journal of Clinical Oncology, Vol. 14, No. 10,

1996, pp. 2756-2768.

[18] D. Osoba, G. Rodrigues, J. Myles, B. Zee and J. Pater,

“Interpreting the Significance of Changes in Health-Re-

lated Quality-of-Life Scores,” Journal of Clinical Oncol-

ogy, Vol. 16, No. 1, 1998, pp. 139-144.

[19] A. J. Ramirez, K. E. Towlson, M. S. Leaning, M. A.

Richards and R. D. Rubens, “Do Patients with Advanced

Breast Cancer Benefit from Chemotherapy?” British

Journal of Cancer, Vol. 78, No. 11, 1998, pp. 1488-1494.

doi:10.1038/bjc.1998.711

[20] F. S. van Dam, S. B. Schagen, M. J. Muller, et al., “Im-

pairment of Cognitive Function in Women Receiving

Adjuvant Treatment for High-Risk Breast Cancer: High-

Dose versus Standard-Dose Chemotherapy,” Journal of

the National Cancer Institute, Vol. 90, No. 3, 1998, pp.

210-218. doi:10.1093/jnci/90.3.210

[21] S. A. Castellon, P. A. Ganz, J. E. Bower, L. Petersen, L.

Abraham and G. A. Greendale, “Neurocognitive Per-

formance in Breast Cancer Survivors Exposed to Adju-

vant Chemotherapy and Tamoxifen,” Journal of Clinical

and Experimental Neuropsychology, Vol. 26, No. 7, 2004,

pp. 955-969. doi:10.1080/13803390490510905

[22] J. Vardy, J. S. Wefel, T. Ahles, I. F. Tannock and S. B.

Schagen, “Cancer and Cancer-Therapy Related Cognitive

Dysfunction: An International Perspective from the Ven-

ice Cognitive Workshop,” Annals of Oncology, Vol. 19,

No. 4, 2008, pp. 623-629. doi:10.1093/annonc/mdm500

[23] L. Hakamies-Blomqvist, M. Luoma, J. Sjostrom, et al.,

“Quality of Life in Patients with Metastatic Breast Cancer

Receiving Either Docetaxel or Sequential Methotrexate

and 5-Fluorouracil. A Multicentre Randomised Phase III

Trial by the Scandinavian Breast Group,” European

Journal of Cancer, Vol. 36, No. 11, 2000, pp. 1411-1417.

doi:10.1016/S0959-8049(00)00126-X

[24] A. Bottomley and P. Therasse, “Quality of Life in Pa-

tients Undergoing Systemic Therapy for Advanced Breast

Cancer,” The Lancet Oncology, Vol. 3, No. 10, 2002, pp.

620-628. doi:10.1016/S1470-2045(02)00876-8

[25] G. Fountzilas, U. Dafni, M. A. Dimopoulos, et al., “A

Randomized Phase III Study Comparing Three Anthracy-

cline-Free Taxane-Based Regimens, as First Line Che-

motherapy, in Metastatic Breast Cancer: A Hellenic Co-

operative Oncology Group Study,” Breast Cancer Re-

search and Treatment, Vol. 115, No. 1, 2009, pp. 87-99.

doi:10.1007/s10549-008-0047-9

[26] L. Hakamies-Blomqvist, M. L. Luoma, J. Sjostrom, et

al.,“Timing of Quality of Life (QoL) Assessments as a

Source of Error in Oncological Trials,” Journal of Ad-

vanced Nursing, Vol. 35, No. 5, 2001, pp. 709-716.

doi:10.1046/j.1365-2648.2001.01903.x

[27] P. Hopwood, A. Harvey, J. Davies, et al., “Survey of the

Administration of Quality of Life (QL) Questionnaires in

Three Multicentre Randomised Trials in Cancer. The

Medical Research Council Lung Cancer Working Party

the CHART Steering Committee,” European Journal of

Cancer, Vol. 34, No. 1, 1998, pp. 49-57.

doi:10.1016/S0959-8049(97)00347-X

[28] P. Hopwood, R. J. Stephens and D. Machin. “Approaches

to the Analysis of Quality of Life Data: Experiences

Gained from a Medical Research Council Lung Cancer

Working Party Palliative Chemotherapy Trial,” Quality of

Life Research, Vol 3, No. 5, 1994, pp. 339-352.

doi:10.1007/BF00451726

[29] C. C. Gotay, J. Lipscomb and C. F. Snyder, “Reflections

on Findings of the Cancer Outcomes Measurement

Working Group: Moving to the Next Phase,” Journal of

the National Cancer Institute, Vol. 97, No. 21, 2005, pp.

1568-1574. doi:10.1093/jnci/dji337