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Original Article · Originalarbeit

Onkologie 2008;31:447–453 Published online: August 12, 2008

DOI: 10.1159/000140453

Weekly Vinorelbine versus Docetaxel for Metastatic

Breast Cancer after Failing Anthracycline Treatment
Carl Richard Meiera Hans-Jochen Illiger†b Martin Stederc Jan Janssenb
Holger Deertzd Manfred Braune Hueseyin-Taylan Oeneyf Burkhard Deussg
Thomas Küchlerh Susanne Rotermunda
aKlinikum Bremen-Mitte, Bremen; bStädtische Kliniken; cPius-Hospital, Oldenburg; dEvangelisches Hospital, Oberhausen;
eKlinikum Bremen-Nord; fKlinikum Links der Weser, Bremen; gClinAssess GmbH, Leverkusen; hUniversitätsklininiken Schleswig-Holstein,
Kiel, Germany

Key Words Schlüsselwörter

Metastatic breast cancer · Vinorelbine · Docetaxel · Metastasiertes Mammakarzinom · Vinorelbin ·
Crossover studies · Quality of life Docetaxel · Therapiewechselstudie · Lebensqualität

Summary Zusammenfassung
Background: Vinorelbine and docetaxel are active in an- Hintergrund: Vinorelbin und Docetaxel sind auch nach
thracycline-pretreated, metastatic breast cancer. We Anthrazyklin-Vorbehandlung erwiesenermaßen wirksam
compared their efficacy. Patients and Methods: Patients bei metastasiertem Mammakarzinom. Wir haben ihre
were randomized to receive weekly vinorelbine (VIN) or Wirksamkeit verglichen. Patienten und Methoden: Pa-
weekly docetaxel (DOC), 6 weekly doses per 8-week cycle, tientinnen wurden randomisiert zwischen Behandlung
with optional crossover (X-DOC vs. X-VIN. The primary mit Vinorelbin (VIN) bzw. Docetaxel (DOC), je 6 wöchent-
end point was time to progression (TTP) on initial treat- liche Gaben pro 8-Wochen-Zyklus, mit optionalem Wech-
ment. Remission induction, survival, and quality of life sel zur Gegenseite (X-DOC bzw. X-VIN). Primärer End-
were secondary end points. Results: Among 122 poor punkt war Zeit bis zur Progression (time to progression,
risk patients, a non-significant trend for better TTP was TTP) bei Initialbehandlung. Remissionsquote, Überle-
seen for DOC, both on initial and on crossover treatment. benszeit und Lebensqualität waren sekundäre Endpunk-
Responses were seen on either treatment, but progres- te. Ergebnisse: Die 122 rekrutierten Patientinnen hatten
sion was more common with VIN than with DOC, while ein ungünstiges Risikoprofil. Die Prüfung ergab einen
more patients had a response with X-DOC than with (nicht signifikanten) Trend für längere TTP im DOC-Arm,
X-VIN. Survival was identical in those receiving only the bei initialer Therapie wie auch nach Wechsel auf X-DOC.
initial VIN vs. DOC and in the subgroups receiving cross- Beide Behandlungen bewirkten Remissionen, aber mit
over treatments. Grade 3–4 toxicity, especially hemato- VIN war die Progression häufiger als mit DOC, während
logical toxicity resulting in treatment delay, was more X-DOC häufiger Remission bewirkte als X-VIN. Die Über-
common with VIN. Non-graded toxicity contributed to lebenszeit war identisch mit VIN vs. DOC bzw. beim Ver-
abandoning DOC. Quality of life scores reflected worse gleich der Subgruppen der Therapiewechsler. Mit VIN
results in patients crossing treatment arms, in either waren Toxizitäten Grad 3–4 (vor allem hämatologische)
direction. Conclusions: DOC showed marginally better häufiger, oft einhergehend mit Therapieverzug. Nicht
activity but did not improve TTP or other endpoints over graduierbare Toxizität trug zum Teil zur Aufgabe der
VIN in this poor risk population. DOC-Therapie bei. Lebensqualtität-Indizes waren eindeu-
tig schlechter für Therapiewechsler, unabhängig von der
Richtung des Wechsels. Schlussfolgerungen: Bei der
untersuchten Population mit ungünstigem Risikoprofil
war DOC marginal wirksamer als VIN, aber ohne signifi-
kanten Vorteil für TTP oder andere Endpunkte. - 1/26/2016 8:39:05 PM

© 2008 S. Karger GmbH, Freiburg Carl Richard Meier, MD

Division of Hematology and Medical Oncology
Kungliga Tekniska Hogskolan

Fax +49 761 4 52 07 14 Accessible online at: UTHSCSA MC 7880, 7703 Floyd Curl Drive
E-mail 78229 San Antonio, TX, USA Tel. +49 210 597-4848, Fax -1956
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Introduction Table 1. Patient demographics according to initial treatment arm

Patients, n (%)
Patients with metastatic breast cancer not treatable with ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯
hormonal therapies have been reported to have a median sur- VIN DOC
(n = 62) (n = 58)
vival of approximately 15 months [1]. Various chemotherapy
regimes, traditionally incorporating anthracyclines or mitox- Age, median (range), years 60 (35–77) 60 (31–78)
antrone, often induce remission [2–6]. However, upon relapse, Months to distant metastasis, median (range) 25 (0–214) 30 (0–199)
prior anthracycline therapy is an adverse factor, and subse- ER positivea 33 (53) 35 (60)
quent survival averages only a few months [3, 7]. In this situa- PR positivea 36 (58) 38 (66)
Adjuvant irradiation 31 (50) 21 (36)
tion, the toxicity of salvage treatment could conflict with pal-
Adjuvant chemotherapy 34 (55) 31 (53)
liative treatment goals. Taxanes and vinorelbine have shown Prior palliative chemotherapy regimens
clinical activity after anthracycline failure [8–15], and appear 0 8 (13) 6 (10)
to lack cross-resistance [16]. Weekly administration schedules 1 29 (47) 25 (43)
with favorable toxicity profiles have been reported for either 2 20 (32) 23 (40)
>2 5 (8) 4 (7)
drug [12–15, 17–20]. In the current study, anthracycline-
Metastatic sites
pretreated patients were randomized to receive weekly vino- Liver 41 (66) 39 (67)
relbine (VIN) or docetaxel (DOC) – with option for crossover Lungb 19 (31) 22 (38)
– with study endpoints being time to progression (TTP), sur- Boneb 35 (56) 30 (52)
vival, response, and quality of life (QoL). Lymph nodeb 19 (31) 22 (38)
All visceral 53 (85) 52 (90)
Number of sites
1 9 (15) 10 (17)
Patients and Methods 2 22 (35) 19 (33)
3 19 (31) 18 (31)
Patients were required to have histologically confirmed breast cancer, at ≥4 12 (19) 11 (19)
least 1 measurable distant metastasis, and pretreatment with doxorubicin, Performance status (ECOG)
epirubicin, or mitoxantrone (for adjuvant or palliative therapy). Further 0 10 (16) 13 (22)
inclusion criteria were performance status ≤ 2 (ECOG); creatinine 1 37 (60) 30 (52)
≤ 1.5 × ULN, bilirubin ≤ 3 × ULN, transaminases ≤ 5 × ULN, platelets 2 12 (19) 11 (19)
≥ 100,000, and granulocytes ≥ 2,000/μl. Exclusion criteria were pretreat-
ment with taxanes or vinca alkaloids, ongoing other chemotherapy or hor- VIN = Vinorelbine; DOC = docetaxel; ER = estrogen receptor;
monal therapy, significant comorbidities, or the presence of neuropathy, PR = progesterone receptor.
aStatus unknown in 10 patients.
pregnancy, or human immunodeficiency virus (HIV) infection.
bMore than 1 site may be listed per patient.
Eligible and consenting patients were centrally randomized, and within 8
days of randomization were started on either VIN (30 mg/m2) or DOC
(35 mg/m2), administered intravenously once weekly × 6 every 8 weeks,
for up to 4 consecutive cycles. The use of granulocyte-colony stimulating
observed scored), and overall survival, using either Fisher’s exact test or
factor (G-CSF) was permitted. DOC treatment required dexamethasone
the log-rank test. QoL results were evaluated by simple variant and de-
prophylaxis. Dose reductions and/or delays were advised for excessive
scriptive analysis, especially stepwise comparison of means.
toxicity. For disease progression during or within 6 months of treatment as
Case number recalculation was planned after enrollment of at least 60 pa-
well as for intolerable toxicity, crossover to the other treatment arm was
tients on each initial treatment arm [23]. At that interim analysis regard-
offered (X-VIN vs. X-DOC). The resumption of the prior regimen was
ing differences in TTP, for a p > 0.3, the study was to be stopped without
recommended for progression after more than 6 months off treatment.
refuting the null hypothesis. For 0.3 > p > 0.017779, the number of cases
Toxicity was scored by CTCv2. Serious adverse events (SAE) per good
needed for further testing was to be recalculated (two-step group-sequen-
clinical practice (GCP) guidelines [21] included death within 30 days of
tial adaptive design with constant critical limits for each step).
treatment, and serious hypersensitivity to DOC. For QoL assessment, the
EORTC QLQ-C30 patient questionnaire was used (by permission from
EORTC), with global health/function scales (low to high range, 0–100),
and symptom scales, supplemented with a disease- and treatment-specific Results
module focusing on symptoms (high to low range, 100–0). Questionnaires
were to be completed at the start of each treatment cycle. The study pro-
Between November 1998 and January 2004, 122 patients were
tocol was consistent with the ethical standards of the Declaration of
Helsinki in its revised version of 1975 and its amendments of 1983, 1989, randomized. 120 patients who had received at least 1 treat-
and 1996 [22]. Study design and conduct were approved by central ethical ment dose were regarded as evaluable. The database was
review boards for several German states (Bremen, Hamburg, Niedersach- closed October 31, 2004. Table 1 shows patient demographics.
sen, Nordrhein). Overall, 380 treatment cycles were started (table 2). From
cycle 2, patients crossed over to the alternate treatment arm.
Primary endpoint was TTP on initial treatment, using a one-sided test at More DOC than VIN cycles were initiated (209 vs. 171), re-
the level of 2.5% by log-rank (assuming superiority of DOC). Compar- flecting slightly longer average duration on DOC treatment.
isons were to be exploratory regarding toxicity, response (best response More VIN than DOC treated patients progressed on their ini- - 1/26/2016 8:39:05 PM

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Table 2. Overall number of treatment cycles started Table 3. Response to initial and on crossover treatment; 1 patient on
each initial therapy arm had transient complete response
Treatment Cycles, n
⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯ ⎯ Response Patients, n (%)
1 2 3 4 5 6 7 8 9 Total ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯
VIN 62 33 11 8 1a 115
DOC 58 39 18 6 121 62 58 33 39
X-VIN 0 9 20 12 6 2 2 1 52 CR + PR 11 (18) 17 (29)a 1 (3) 14 (36)c
X-DOC 0 19 24 16 14 9 4 1 1 88 Stable disease 23 (37) 24 (41)a 14 (42) 9 (23)a
VIN-VINb 1 1 1 1 4 Progression 25 (40) 11 (19)b 18 (55) 14 (36)a
Total 120 100 73 42 22 12 7 3 1 380 Not evaluable 3 (5) 6 (10) 0 (0) 2 (5)

VIN = Vinorelbine; DOC = docetaxel; X-VIN/X-DOC = denotes patients VIN = Vinorelbine; DOC = docetaxel; X-VIN/X-DOC = denotes
having crossed to this treatment arm. patients having crossed to this treatment arm; CR = complete response;
aOne patient started a fifth cycle in violation of protocol. PR = partial response.
bOne patient resumed VIN upon progression more than 6 months ap > 0.05 (Fisher’s exact test, two-sided).

without chemotherapy. bp = 0.0162 (Fisher’s exact test, two-sided).

cp = 0.00062 (Fisher’s exact test, two-sided).

Table 4. Toxicity, treatment delay, and adher-

ence to treatment Patients, n (%)

Total 62 (100) 58 (100) 33 (100) 39 (100)

Leukopenia ≥ grade 3 39 (63) 9 (16)a 20 (61) 1 (3)a
Neutropenia ≥ grade 3 29 (47) 5 (9)a 13 (39) 1 (3)a
Infection ≥ grade 3 0 (0) 3 (5) 2 (6) 1 (3)
Stomatitis/mucositis ≥ grade 3 0 (0) 5 (9)a 1 (3) 3 (8)
All toxicities ≥ grade 3 46 (74) 28 (48)a 26 (79) 18 (46)a
Non-hematological toxicities ≥ grade 3 15 (24) 19 (33) 13 (39) 16 (41)
Treatment without delay 17 (27) 28 (48)a 5 (15) 24 (62)b
D/C treatmentd for disease progression 46 (74) 32 (55)c 25 (76) 24 (62)
D/C treatmentd because of toxicitye 8 (13) 13 (22) 5 (15) 8 (21)
D/C treatmentd as per patient preference 1 (2) 5 (9) 2 (6) 4 (10)
Crossed treatment armd because of toxicity 1 (2) 6 (10) N/A N/A

VIN = Vinorelbine; DOC = docetaxel; X-VIN/X-DOC = denotes patients having crossed to this
treatment arm; D/C = discontinued.
ap < 0.05 (Fisher’s exact test, two-sided).
bTreatment delay mostly due to myelosuppression, more often with VIN; p = 0.02371 (Fisher’s exact

test, two-sided).
cTreatment discontinued mostly because of disease progression, more often with VIN; p = 0.03579

(Fisher’s exact test, two-sided).

dMore than 1 reason for discontinuation of treatment may individually apply.
eIncludes non-graded toxicity.

tial treatment. After crossover, more patients on X-DOC had DOC) days. TTP was slightly longer on X-DOC than on
a response as compared to those on X-VIN (table 3). 103 of X-VIN, but not significantly so, again with similar survival
120 patients died, mostly of progressive disease; 16 were alive (table 5, fig. 1). The database was generally too small for retro-
(some after additional treatment), 1 was lost to follow-up. Me- spective detailed analysis, e.g. for correlation of risk factor pro-
dian follow-up was 291 (5–1,338) days for initial VIN, and 281 files with outcomes in treatment subgroups.
(8–1,867) days for initial DOC treatment. On initial treatment, SAEs were evenly distributed. Overall, 2 DOC and 2 VIN pa-
more patients receiving VIN than those on DOC terminated tients were hospitalized with infection/neutropenic fever, with
treatment because of disease progression (tables 4 and 5). fatal outcome for 1 X-VIN case. One fatal pulmonary em-
However, TTP on initial DOC was only slightly longer than bolism occurred briefly after a VIN dose. One DOC patient
on initial VIN, and survival was identical. The 72 crossover died from multiorgan failure with disseminated intravascular
patients were followed a median of 223 (X-VIN) vs. 246 (X- coagulation (DIC). Respiratory failure due to disease progres- - 1/26/2016 8:39:05 PM

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Table 5. Duration of treatment, time to

progression, and survival (days) Duration, median (range), days
VIN (n = 62) DOC (n = 58) X-VIN (n = 33) X-DOC (n = 39)

Treatment 70 (7–259) 84 (14–227) 55 (7–238) 84 (14–238)

TTPa 84 (70–105)b 105 (98–146) 74 (56–114)d 109 (55–168)
p = 0.3601c p = 0.3446e
Survivala 284 (191–376)f 283 (231–402) 209 (147–332)h 246 (170–355)
p = 0.8999g p = 0.9733i

VIN = Vinorelbine; DOC = docetaxel; X-VIN/X-DOC = denotes patients having crossed to this
treatment arm; TTP = time to progression.
aMedian (95% confidence interval for median) according to Kaplan-Meier; p-values from log-rank

b6 censored cases. c6 censored cases. d2 censored cases. e5 censored cases. f10 censored cases.
g7 censored cases. h2 censored cases. i6 censored cases.

Table 6. Patient risk factors and survival results in quoted studies

Author [Ref.] Patients, n Regi- Hep Visc >2 s, >1 s, nC, aC, >1C, ANT, CO TTP, OS,
men met, % met, % % % % % % % days days

Clark [1] 1,015 NR 12 40 NR 34 70 30 30 NR NA NR 690

Gasparini [12] 67 VIN 19 60 NR 46 0 26 51 52 NA 126 406
Degardin [13] 100 VIN 25 64 NR NR 0 NR NR 100 NA 90a 560
Jones [14] 115 VIN 30 NR NR 75 0 NR 0 100 N 84 245
64 Mel 30 NR NR 66 0 NR 0 100 N 56 217
Nistico [15] 40 VIN 33 38 5 62 15 NR 75 100 NA 270 570
Ravdin [9] 35 Doc3 36 66 46 74 0 63 74 100 NA 140 NR
Valero [10] 35 Doc3 46 77 66 NR 0 71 57 100 NA 120 270
Sjöström [11] 143 Doc3 51 73 25 65 0 49 49 100 Y 189 312
139 MF 41 69 29 52 0 45 45 100 Y 90 330
Nabholtz [8] 203 Doc3 50 75 39 77 0 51 34 100 N 143 342
189 MV 65 73 52 79 0 50 29 100 N 83 261
Burstein [17] 29 DOC 66 79 70 90 34 52 34 31 NA 150a NR
Hainsworth [18] 41 DOC 73 ? 51 34 10 17 NA NR 390
Tabernero [19] 42 Doc3 48 88 26 74 2 50 26 79 N 159 603
41 DOC 42 73 29 73 2 56 27 83 N 171 873
Current study 62 VIN 66 81 50 84 0 55 74 100 Y 84 284
58 DOC 67 90 50 83 0 53 78 100 Y 105 283

Hep met = Hepatic metastasis; Visc met = visceral metastasis; >2 s,% = > 2 metastatic sites; >1 s = with >1 metastatic site; nC = without prior chemother-
apy; aC = with prior adjuvant chemotherapy; >1C = with more than one prior chemotherapy; ANT = prior anthracyclines; CO = planned crossover treat-
ment design; TTP = time to progression; OS = overall survival; NR = not reported; NA = not applicable; Y = yes; N = no; VIN = vinorelbine (weekly);
Mel = melphalan; Doc3 = docetaxel every 3 weeks; DOC = docetaxel (weekly); MF = methotrexate + fluorouracil; MV = mitomycin = vinblastin.
aTime to treatment failure.

sion was fatal in 3 cases within 4 weeks of treatment. Two pa- due to toxicity, 3 had mucosal or skin problems, 3 had effu-
tients had serious hypersensitivity after DOC; in 1 patient, sions, and 2 had myopathy. Two DOC patients who reached
DOC was continued (violating protocol), without recurrence remission also desired to discontinue treatment because of
of hypersensitivity. The assigned regimens were also contin- toxicity involving effusions, skin, and/or nails, respectively
ued in the remaining patients who experienced SAE. Grade (table 4).
3–4 hematological toxicity occurred more often on VIN than A total of 102 patients completed 301 QoL questionnaires. At
on DOC, both on initial treatment and after crossover, with 1 baseline, no significant difference between treatment groups
fatal outcome (as above) and significantly more treatment de- was detected (figs. 2 and 3). With successive treatment cycles,
lays. Hematological toxicity contributed to treatment termi- fewer questionnaires were completed (compliance declining
nation in 6 of 8 VIN patients. DOC showed more mucosal tox- from 85% at cycle 1, to 54% at cycle 4), progressively limiting
icity (table 4). Of 13 DOC patients who stopped treatment QoL comparisons of treatment arms, or analysis of sequence - 1/26/2016 8:39:05 PM

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Fig. 1. Kaplan-Meier product limit estimate

of survival (days); a initial treatment, time to
progression; b initial treatment, overall
survival; c after crossover, time to progression;
d after crossover, overall survival.

of therapies as a variable for QoL results (first VIN, then X- ously treated with MF. Of note, the largest TTP difference was
DOC vs. first DOC, then X-VIN). found within the subgroup of 103 patients (37%) with only
Patients crossing treatment arms from cycle 2 (either way) had 1 metastastic site. A higher survival impact of superior therapy
significantly worse QoL scores (global health status, and 6 of in better prognosis subgroups has also been observed with first
10 function/symptom scales) than those continuing their initial line chemotherapy [25]. In our study, the subgroup with just
treatment arm. The 5 patients crossing to X-VIN after the first 1 metastatic site was made up of only 19 cases (table 1), pre-
cycle of treatment complained of more fatigue, pain, diarrhea, cluding subgroup analysis. Tabernero et al. [19] found approxi-
and loss of appetite, compared to those (n = 14) crossing to X- mately equivalent efficacy of docetaxel given weekly vs. every
DOC; in this latter group, nausea and vomiting were promi- 3 weeks. Thus, the non-superiority of DOC vs. VIN in our study
nent (fig. 2). From cycle 3 onward, data are too sparse for de- is not likely to result from weekly scheduling.
tection of significant differences; a non-significant trend for Other studies which demonstrated improved survival using
better scores was seen for patients continuing on their original either docetaxel or vinorelbine for metastatic breast cancer
DOC treatment. did not have a crossover design [8, 14]. Nabholtz et al. [8] re-
ported superior response, TTP, and overall survival (OS) with
docetaxel compared to mitomycin and vinblastin, in a much
Discussion larger but less heavily pretreated study population. Jones et
al. [14] found better responses, TTP, and OS with VIN com-
Our study compared 2 antineoplastic agents known to be ac- pared to melphalan. Although crossover design studies have
tive in patients pretreated with anthracycline-containing regi- been termed to be closer to clinical reality, these studies are
mens. The treatment groups were well balanced for important less likely to show differences in OS [26].
risk factors, but did have a comparatively very poor risk pro- In summary, we were unable to demonstrate superior TTP
file (tables 1 and 6). with DOC compared to VIN. The poor risk profile of our pa-
On account of superior first line responses, docetaxel has been tients may have been responsible for masking a (possible)
termed the current reference cytostatic agent for metastatic TTP benefit, given the trend for other better treatment effects
breast cancer [24]. In line with that notion, significantly fewer with DOC. The non-significant advantage in TTP did not meet
DOC than VIN patients had progression while on treatment. the criteria for continuation of the study. Therefore, the study
Also, in the crossover phase, significantly more patients re- was terminated according to plan.
sponded to X-DOC than to X-VIN (table 3). Consequently, Regarding SAE, 1 fatal pulmonary embolism within hours of
disease progression necessitated treatment termination more VIN administration appears unlikely to be causally related.
often on the VIN than on the DOC regimen (table 4). How- One DOC patient suffered fatal multiorgan failure resulting
ever, despite inferior responses to VIN, there was an only non- from hemolysis and DIC. A single similar case has previously
significant tendency to longer TTP with DOC, be it as initial or been described, and the mechanism remains obscure [27].
crossover treatment (table 5, fig. 1). By comparison, in a study Three other deaths that were formally classified as SAE rep-
by Sjöström et al. [11], docetaxel not only showed more re- resented fatal progression of disease within a month of last
sponses than the alternative regimen methotrexate-fluorouracil treatment, not fatal treatment-related toxicity. VIN clearly
(MF), but also prolonged TTP over the MF regimen. That study caused more leukopenia/neutropenia than DOC, and conse-
recruited over twice as many patients, with a somewhat better quently more treatment delay (table 4), both with initial and
risk profile (table 6), and 31% of the patients had been previ- crossover treatment. Vinorelbine is known for causing leuko- - 1/26/2016 8:39:05 PM

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Fig. 2. A–D. Quality of life function scale

results, at start of cycles 1 through 4 (PF =
Physical functioning; RF = role functioning;
EF = emotional functioning; CF = cognitive
functioning; SF = social functioning;
QoL = global health status).

Fig. 3. A–D. Quality of life symptom scale

results, at start of cycles 1 through 4
(FA = Fatigue; NV = nausea/vomiting; PA = pain;
DY = dyspnea; SL = insomnia; AP = appetite loss;
CO = constipation; DI = diarrhea; FI = financial

penia. Fatal outcome of vinorelbine-induced neutropenic than non-crossing patients; however our data do not reveal if
fever is rare, and our case was ascribed to exceptional frailty. crossover paid off in terms of subsequent QoL. Overall, there
Use of G-CSF was permitted, but applied only occasionally in was a (non-significant) tendency for better scores on initial
our patients (data not shown); its use in similar patients is DOC as long as there were evaluable scores. A gain of QoL in
under discussion [28]. Patients on DOC had more stomatitis/ the face of toxicity is counterintuitive but no new finding, pro-
mucositis, but VIN scored higher for most graded toxicities. vided the treatment has efficacy [29]. The described undercur-
Some DOC toxicity qualities appeared to be more difficult to rent trend to quit DOC because of toxicity, while not signifi-
capture, yet contributed to decisions to cross treatment arms cant, is still disquieting and could be interpreted as suggesting
or to terminate treatment more often than on VIN (table 4). that certain treatments may preferentially benefit subpopula-
Our QoL data show well-balanced initial scores. The progres- tions which happen to tolerate them longer than others. In a
sive decline in compliance with our QoL data acquisition re- survey, breast cancer patients were willing to risk toxicity for
flects a common, unfortunate trend in cancer chemotherapy even small gains in life expectancy [30]. Given the toxicity en-
studies [29]. Also, with crossover starting with cycle 2, an in- countered, it would be comforting to be certain our patients
tention-to-treat analysis was impossible. There were sufficient enjoyed such benefit. At least 1 center reported long-term
data to perform stepwise comparison of means up to cycle 4. trends for improved survival in successive cohorts of metastat-
Consistent with the clinical indication for crossover, patients ic breast cancer patients, seen as the aggregate result of in-
crossing at cycle 2 in either direction had worse QoL scores creasingly effective drugs becoming available [31]. If true, it - 1/26/2016 8:39:05 PM

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would remain to be seen what patient group most benefits Acknowledgement

from what drug, and in what sequence. Choosing the best
treatment for patients as advanced in their disease as ours, This study received limited grant support from Aventis Germany and
Pierre Fabre Germany.
continues to be a formidable challenge.

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