Breast Cancer Res Treat (2013) 142:109–118 DOI 10.1007/s10549-013-2728-2
CLINICAL TRIAL
Risk of docetaxel-induced peripheral neuropathy among 1,725 Danish patients with early stage breast cancer L. Eckhoff • A. S. Knoop • M.-B. Jensen B. Ejlertsen • M. Ewertz
•
Received: 25 September 2013 / Accepted: 3 October 2013 / Published online: 17 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Docetaxel-induced peripheral neuropathy (PN) can lead to sub-optimal treatment in women with early breast cancer. Here, we compare the frequency of dose reduction as a result of PN in two different adjuvant regimens. From the Danish Breast Cancer Cooperative Group READ trial we included 1,725 patients with early stage breast cancer who randomly were assigned to three cycles of epirubicin and cyclophosphamide followed by three cycles docetaxel (D100) or six cycles of cyclophosphamide and docetaxel (D75). Eligible patients completed chemotherapy, received docetaxel, and provided information on patient-reported outcome (secondary outcome of trial) including PN. Associations between PN and risk factors were analyzed by multivariate logistic regression. Overall 597 patients (34 %) reported PN, grades 2–4, during treatment, 194 (11 %) after the first cycle [early onset peripheral neuropathy (EPN)] and 403 (23 %) after subsequent cycles [later-onset peripheral neuropathy (LPN)].
The odds ratio (OR) of EPN was significantly increased for the D100 regimen (OR 3.10; 95 % CI 2.18–4.42) while this regimen was associated with reduced OR of LPN (OR 0.69; 95 % CI 0.54–0.88). Patients with PN received significantly lower cumulative doses of docetaxel than patients with no PN. Explorative analysis showed that OR of PN was significantly reduced if patients wore frozen gloves and socks during treatment (OR 0.56; 95 % CI 0.38–0.81) in the EPN group. Patients developing PN after the first cycle are less likely to receive docetaxel at the planned dose intensity and usage of frozen gloves and socks may modify the risk. Keywords Breast cancer Docetaxel Chemotherapy-induced peripheral neuropathy Dose reduction
Introduction
L. Eckhoff (&) M. Ewertz Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense, Denmark e-mail:
[email protected] L. Eckhoff Institute of Clinical Research, University of Southern Denmark, Odense, Denmark A. S. Knoop B. Ejlertsen Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark M.-B. Jensen B. Ejlertsen Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Adjuvant chemotherapy with taxanes plays a role in reducing the risk of recurrence and death after early stage breast cancer [8, 14]. Peripheral neuropathy (PN) is the most important non-hematological side effect of docetaxel which may lead to dose reductions and have a negative impact on health-related quality of life [5, 7, 41]. PN may occur after the first treatment cycle [early onset peripheral neuropathy (EPN)] but is more frequent after two or more cycles [later-onset peripheral neuropathy (LPN)] [22, 30]. Different risk factors for EPN and LPN has been established for bortezomib and vincristine [9, 18], but it is uncertain whether this is the case concerning EPN and LPN following taxanes. The reported incidence of taxane-induced PN varies from 18 to 50 % when all grades (0–4) are considered and
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from \1 % up to 18 % for the more severe grades [15, 26, 45]. Risk factors for paclitaxel-induced PN include dose per cycle, treatment schedule, duration of infusion, cumulated dose, menopausal status, preexisting neuropathy, concurrent administration of cisplatin or carboplatin, and comorbidities, e.g., diabetes, or alcoholism [26, 36, 45]. However, very little is known of risk factors of docetaxelinduced PN and only comprises cumulated dose of docetaxel [21, 25, 26]. The mechanism underlying taxaneinduced PN remains to be elucidated and so far there are no validated predictive markers for docetaxel-induced PN [29, 40]. The immediate consequence of PN is to reduce, delay, or to interrupt the planed treatment. Retrospective data from two studies indicate that only 2–4 % of patients experienced dose limitation caused by PN after treatment with docetaxel or paclitaxel [42, 46], while a prospective study reported dose limitation in 13/50 (26 %) after treatment with paclitaxel [20]. In the randomized E1199 trial of 4,554 patients with early stage breast cancer all receiving taxanes, there was no significant difference in the proportion of patients who required a dose reduction among patients who developed grade 2–4 neuropathy compared with those who did not [36]. The objectives of the present analysis were to evaluate the first and later occurrences of sensory PN as patientreported outcome among patients who received at least one dose of docetaxel, to identify risk factors for developing PN, and to identify patients at risk of a dose limiting event (DLE).
Patients and methods Patients The study population derived from patients enrolled into the Danish Breast Cancer Cooperative Group (DBCG)-07 READ trial, an open-label, randomized, prospective phase III trial of epirubicin and cyclophosphamide followed by docetaxel versus docetaxel and cyclophosphamide in patients with TOP2A normal early stage breast cancer (http://clinicaltrials.gov/ct2/show/NCT00689156). Patients eligible for this analysis had available data (randomized before August 1, 2012), had received at least one cycle of docetaxel, and provided information on neuropathy after the first treatment cycle. The CONSORT diagram (Fig. 1) shows that 1,725 out of 2,015 enrolled patients were available for the present analysis. The treatment arms were: three cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 followed by three cycles of docetaxel 100 mg/m2 (D100) against six cycles of cyclophosphamide 600 mg/m2 and docetaxel
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Fig. 1 Diagram of included patients
75 mg/m2 (D75); all cycles were given intravenously at 3-week intervals. Prior to treatment with docetaxel, patients received dexamethasone and G-CSF was administered after each cycle of docetaxel. Trastuzumab to HER2-positive patients, radiotherapy, and endocrine treatment followed the DBCG guidelines [1]. The study was approved by the ethical committees (H-D-2008-009). Patients gave written, informed consent. The study complied with the Declaration of Helsinki and Good Clinical Practice. A questionnaire with side effects was recorded by the patients prior to start of treatment (baseline) and on day 20 after each cycle from week 3 to week 18 (after cycles 1–6). The questionnaire contained side effects from National Cancer Institute, Common Toxicity Criteria (NCI CTC), version 2.0 translated into Danish and ranked from grade 0 (normal) to 4 (extensive problems that interferes with function) except edema that only ranked from 0 to 3. This analysis includes stomatitis, muscle and joint pain, fatigue, edema, and sensory neuropathy. Prior to treatment, dose reductions were performed in patients with a co-morbidity score of 1–2 (Charlson Comorbidity Index) [11] to 75 and 60 mg/m2, respectively, in the D100 and D75 regimen. During treatment, dose reductions were performed in case of persistent hematologic side effects, and dose delays of 1 week in case of grade 2 neuropathy or grades 3 or 4 other non-hematologic side effects. If the side effects resolved to grade 0 or 1, chemotherapy was resumed, but if they persisted, dose
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reduction was preformed. In case of persistent grade 2–4, neuropathy docetaxel was discontinued. To reduce the extent of nail injury, frozen gloves and socks were offered to patients while receiving docetaxel. These were stored at about -20 °F for 3 h prior to use. The patients wore the gloves and socks for a total of 90 min, i.e., 15 min before and 15 min after a 60-min infusion of docetaxel. After the first 45 min, patients received a second set of gloves and socks to maintain the cold temperature. Statistical analysis All data were entered prospectively onto an electronic case record form developed by the Datacenter of DBCG. The primary outcome variable in this study was PN grouped into three categories: no neuropathy (NCI CTC grades 0 and 1), early onset peripheral neuropathy (EPN) with grades 2–4 neuropathy after the first cycle of docetaxel, and later-onset peripheral neuropathy (LPN) with grades 2–4 neuropathy subsequent to the following cycles of docetaxel. The second outcome was a DLE, defined as no modifications, no modifications but with a dose delay [28 days, dose reduction defined as dose reduction ?10 % margin (D100 B82, 5 mg/m2, D75 B66 mg/m2), or discontinuation. These events were calculated by cycle. All dose reductions in patients with neuropathy were presumed to be due to neuropathy. v2 test and Kruskal–Wallis rank test, excluding unknowns, were used to identify differences in patients characteristics. Logistic regression models were used to calculate odds ratio (OR) and 95 % confidence interval (95 % CI). Levels of significant were set to 5 %. Associations between baseline patient characteristics and PN were analyzed with univariate logistic regression. If the p value of the unadjusted OR was below 0.05, the variable was included in the multivariate logistic regression analyses. Baseline patient characteristics were age (\50 or C50 years), menopausal status (premenopausal vs postmenopausal), BMI (\25, 25–29, 30?), type of breast surgery (mastectomy vs breast conserving surgery), tumor size (\2 vs 2? cm), histological type (ductal, lobular, or others), tumor grade (I, II, III, or unknown), estrogen receptor status ([10, 1–9, or 0 %), HER2-status (positive vs negative), number of positive lymph nodes (0 vs C1), regimen (D100 vs D75), preexisting neuropathy (grade 0 vs, grades 1–2), muscle and joint pain (grades 0–1 vs 2–4), stomatitis (grades 0–1 vs 2–4), edema (grades 0–1 vs 2–4), and fatigue (grades 0–1 vs 2–4). Usage of frozen gloves and socks was scored as ‘‘yes’’ in the EPN group if patients wore these during the first cycle of docetaxel and in the LPN group if these were worn for more than 50 % of the time they received docetaxel. Two multivariate models for risk factors for PN were constructed, one including
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preexisting risk factors only, and the second including other side effects. Tests for interaction between covariates on PN were performed pairwise in separate models applying the Wald test. For EPN interactions of regimen versus preexisting neuropathy and frozen gloves and socks versus preexisting neuropathy were investigated, whereas regimen versus frozen gloves and socks was investigated for both EPN and LPN. Dose modifications were calculated as events per cycle and the v2 test used to test the difference in modification events. Stata version 11.2 (StataCorp, College Station, Texas, USA) was used to perform the analyses.
Results Peripheral neuropathy Overall 597 of 1,725 patients (35 %) reported PN (NCI CTC-like version 2.0, grades 2-4) during docetaxel treatment with 194 (11 %) patients in the EPN group and 403 (23 %) in the LPN group from weeks 3–18. In the EPN and LPN groups, grade 2 PN was reported in 57 and 73 %, respectively; grade 3: 35 and 18 %; and grade 4: 9 % in both groups. In the D100 regimen, the median cumulative dose of docetaxel was significantly lower (P = 0.0001) in the EPN group (250 mg/m2) than in the LPN and no PN groups both being 300 mg/m2 (Table 1). In the D75 regimen, the median cumulative doses of docetaxel were higher and significantly associated with onset of PN (P = 0.0001), the EPN group being 389 mg/m2, the LPN group 432 mg/m2, and the no PN group 450 mg/m2. Table 1 shows baseline clinical characteristics of the study population in relation to onset of PN. No significant associations were found between PN and age, menopausal status, BMI, type of surgery, histological type, tumor grade, ER status, or HER2 status, while significantly more patients who developed EPN had tumors less than 2 cm (P = 0.03) and node negative disease (P = 0.001). At baseline, 5 % of the patients suffered from neuropathy (Table 2). During treatment 81 % of the patients reported Cgrade 2 muscle and joint pain, 71 % Cgrade 2 fatigue, 17 % edema Cgrade 2, and 44 % stomatitis Cgrade 2. All these side effects were significantly more frequent among patients with EPN and LPN than among those without PN. Overall, 40 % of the patients wore frozen gloves and socks during treatment, which was associated significantly with onset of neuropathy (P \ 0.0001) (Table 2). In the multivariate modeling of OR of EPN (Table 3), the OR estimates were attenuated slightly by adjusting for preexisting factors but when other side effects were added to the model, all OR estimates were reduced compared
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Table 1 Clinical characteristics of 1,725 Danish breast cancer patients according to onset of neuropathy
Total patients
All N = 1,725
Patients with neuropathy after first cycle of docetaxel (grades 2–4)
Patients with neuropathy subsequent to the first cycle of docetaxel (grades 2–4)
Patients without neuropathy (grades 0–1)
No.
No.
No.
No.
%
%
%
1,725
194
403
1,128
Median
51
52
51
51
Range
23–74
30–73
30–73
23–74
P
%
Age, years 0.17*
BMI \25
856
50
99
51
201
50
556
49
25–29
564
33
66
34
137
34
361
32
30?
305
18
29
15
65
16
211
19
837
49
85
46
188
47
564
50
0.62
Menopausal status Premenopausal Postmenopausal
797
46
101
54
188
47
508
45
Unknown
91
5
8
4
27
7
56
5
0.19
Surgery Mastectomy
493
29
48
25
133
33
312
28
BCSà
1,232
71
146
75
270
67
816
72
\2 cm
936
54
123
63
215
53
598
53
C2 cm
789
46
71
37
188
47
530
47
Ductal
1,485
86
175
90
348
86
962
85
Lobular
135
8
12
6
28
7
95
8
Other
87
5
5
3
24
6
58
5
Unknown
18
1
2
1
3
1
13
1
293
18
36
19
62
15
195
17
0.06
Tumor size 0.03
Histology** 0.48
Grade I II
764
47
92
47
185
46
487
43
III
542
33
55
28
124
31
363
32
Unknown
21
1
11
6
32
8
83
7
ER? ([10 %)
1,225
71
136
70
288
71
801
71
ER 1–9 %
37
2
6
3
7
2
24
2
ER 0 %
443
26
49
25
103
26
291
26
Unknown
20
1
3
2
5
1
12
1
Positive
189
11
16
8
37
9
136
12
Negative
1,472
85
166
86
349
87
957
85
Unknown
64
4
12
6
17
4
35
3
None
767
44
110
57
181
45
476
42
[1
958
56
84
43
222
55
652
58
D100
847
49
145
75
165
41
537
48
D75
878
51
49
25
238
59
591
52
0.72
ER-status 0.96
HER2 0.08
Number of positive lymph nodes 0.001
Regimen \0.0001
D100 regimen cumulative dose of docetaxel mg/m2 Median
297
250
300
300
Range
74–366
75–366
74–315
74–318
D75 regimen cumulative dose of docetaxel mg/m2
123
0.0001*
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Table 1 continued All N = 1,725
Patients with neuropathy after first cycle of docetaxel (grades 2–4)
Patients with neuropathy subsequent to the first cycle of docetaxel (grades 2–4)
Patients without neuropathy (grades 0–1)
No.
No.
No.
No.
%
%
%
P
%
Median
394
389
432
450
Range
75–489
75–456
75–480
75–489
0.0001*
* Kruskal–Wallis rank test ** Only ductal and lobular carcinomas are graded. The rest are recoded as unknown à
v2- test Breast conserving surgery
Table 2 Side effects to docetaxel among 1,725 Danish breast cancer patients according to onset of neuropathy, weeks 3–18 NCI CTC version 2.0
Preexisting neuropathy (baseline)
Maximum muscle and joint pain Maximum fatigue
Maximum edema
Maximum stomatitis
Frozen gloves and socks
Grade
Patients with neuropathy after first cycle of docetaxel (grades 2–4)
Patients with neuropathy subsequent to the first cycle of docetaxel (grades 2–4)
Patients without neuropathy (grades 0–1)
N = 194
%
N = 403
%
N = 1,128
%
P*
All (%)
%
0
161
83
361
90
1,009
89
1,531
89
1–2
17
7
20
5
48
4
85
5
Missing
16
8
22
5
71
6
109
6
0–1
10
5
53
13
269
24
332
19
2–4
184
95
350
87
859
76
1,393
81
0–1
27
14
73
18
395
35
2–4 Missing
166 1
86 1
330 0
82 0
733 0
65 0
0–1
158
81
311
77
956
85
2–4
35
18
92
23
172
15
Missing
1
1
0
0
0
0
0–1
70
36
203
50
697
62
2–4
124
64
200
50
430
Missing
0
0
0
0
1
No
127
65
228
57
507
45
Yes
46
24
141
35
499
44
Unknown
21
11
34
8
122
0.06
N = 1,725
\0.0001 \0.0001
0.001
495
29
1,229 1
71 0
1,425
83
299
17
1
0
970
56
38
754
44
0
1
0
862
50
686
40
177
10
11
\0.0001
\0.0001 à
(0.66 )
2
* v test
To be included in group of frozen gloves and socks. Patients with neuropathy after first cycle with docetaxel had to wear frozen gloves and socks at first cycle. Patients with neuropathy subsequent to the first cycle of docetaxel had to wear frozen gloves and socks more than half the time they received docetaxel
à
There is no difference in the numbers of missing in the frozen gloves and socks
with the unadjusted estimates except tumor size and number of positive lymph nodes. The most pronounced factor after adjustment for preexisting and other side effects was regimen D100 vs D75 (OR 3.10; 95 % CI 2.18–4.42), while EPN was significantly lower among patients using frozen gloves and socks (OR 0.56; 95 % CI 0.38–0.81). A similar correlation with LPN was observed
for frozen gloves and socks, whereas the effect of regimen D100 vs D75 was reversed with OR 0.69; 95 % CI 0.54–0.88 (Table 4). As shown in Table 1, patients in the D75 regimen received a higher cumulated dose of docetaxel than in the D100 regimen. A statistically significant interaction was observed for EPN between regimen and preexisting neuropathy (P = 0.04), the adjusted OR of
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Table 3 Risk of neuropathy after the first cycle with docetaxel in relation to preexisting factors and other side effects Neuropathy after first cycle (n = 194) Tumor size
\2 cm C2 cm
Unadjusted OR (95 % CI)
P
Adjusted for preexisting factors OR* (95 % CI)
P
Adjusted for preexisting factors and other side effects (95 % CI)
1.0
0.007
1.0
0.06
1.0
0.65
0.74
0.70
(0.48–0.89)
(0.54–1.01)
(0.51–0.98)
\0.0001
Numbers of positive lymph nodes
0
1.0
C1
0.57
1.0 0.59
0.001
0.59
(0.43–0.78)
(0.43–0.80)
(0.43–0.82)
Preexisting neuropathy
No Yes
1.0 2.13
Regimen
D75
1.0
D100
3.49
Maximum muscle and joint pain
0–1
1.0
2–4
4.90
Maximum fatigue
0–1
1.0
2–4
2.71
0.008
1.0 1.93 (1.09; 3.44)
(0.96–3.14)
\0.0001
1.0
1.0
(1.22; 3.71)
3.48
(2.49–4.91)
0.03
\0.0001
(2.47–4.90)
1.0
2–4
2.53
Frozen gloves and socks
No Yes
0.001
0.07
\0.0001
3.10 1.0
0.002
2.96 (1.51–5.83) \0.0001
1.0
0.003
1.88
(1.78–4.12) 0–1
1.0 1.73
0.03
(2.18–4.42)
\0.0001
(2.56–9.37)
Maximum stomatitis
1.0
P
(1.23–2.86) \0.0001
1.0
0.001
1.79
(1.86–3.45)
(1.23–2.49)
1.0 0.60
1.0 0.56
0.005
(0.42–0.86)
0.002
(0.38–0.81)
Age, menopausal status, BMI, type of breast surgery, histological type, tumor grade, estrogen receptor status, HER2-status, and edema were not significant in the univariate analysis and therefore not included in the multivariate analysis * Adjusted for tumor size, numbers of positive lymph nodes, regimen, preexisting neuropathy, and frozen gloves and socks
Adjusted for tumor size, numbers of positive lymph nodes, regimen, preexisting neuropathy, maximum stomatitis, maximum muscle and joint pain, maximum fatigue, and frozen gloves and socks
EPN for preexisting neuropathy for regimen D100 1.28; 95 % CI 0.62–2.67 opposed to regimen D75 OR 4.33; 95 % CI 1.79–10.5. A similar interaction was found in the model adjusting also for other side effects. No statistically heterogeneity for frozen gloves and socks were found [preexisting neuropathy and EPN (P = 0.98), regimen and EPN (P = 0.16), or regimen and LPN (P = 0.77)].
D75 regimen received treatment without dose modification (P \ 0.0001). No differences were observed between patients with LPN or no PN in the D100 regimen (P = 0.66), where about 20 % of cycles were given in reduced doses, and 1–2 % were discontinued. More patients had dose reductions in the LPN compared to the no PN group (21 % vs 11 %) in the D75 regimen (P \ 0.00001) and 4–5 % of treatments cycles discontinued.
Associations of dose modifications with planed regimen and onset of neuropathy Discussion Overall, 75 % of cycles in the D100 regimen and 79 % of cycles in the D75 regimen were completed with no dose modifications (Table 5). Patients in the EPN group received significantly fewer cycles without dose modifications; 56 % in the D100 group and 54 % in the D75 regimen compared to patients with no PN were 79 % in the D100 and 83 % in the
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Based on 1,725 patients enrolled into the DBCG-07 READ trial, this study demonstrates that about a third of the patients receiving docetaxel reported PN, and severe (grade 3 ? 4) in 11 % of patients. Usage of frozen gloves and socks during treatment was significantly correlated with
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Table 4 Risk of neuropathy after docetaxel cycles subsequent to the first in relation to other factors Neuropathy developed after more than one cycle with docetaxel (n = 403)
Unadjusted OR (95 % CI)
Type of surgery of breast
Mastectomy
1.0
BCS**
0.78
0.78
0.84
D 75
(0.61; 0.99) 1.0
(0.61–0.99) 1.0
(0.66–1.09) 1.0
D 100
0.76
Regimen
P
0.04
0.02
(0.61–0.96)
Adjusted for preexisting factors* (95 % CI)
P
1.0
0.04
0.02
Adjusted for preexisting factors, other side effects and intervention (95 % CI) 1.0
0.2
0.76
0.69
(0.61–0.96)
(0.54–0.88)
\0.0001
P
Maximum muscle and joint pain
0–1
1.0
2–4
2.07
1.56
(1.50–2.85)
(1.11–2.21)
Maximum fatigue
0–1
1.0
2–4
2.44
Maximum stomatitis
0–1
1.0
2–4
1.60
Frozen gloves and socks
No
1.0
Yes
0.63
0.59
(0.49––0.80)
(0.46–0.76)
0.002
1.0
\0.0001
0.01
\0.0001
1.0 2.03
(1.84–3.23)
(1.50–2.75) 0.001
1.0
0.001
1.50
(1.27–2.01)
(1.18–1.92) \0.0001
\0.0001
1.0
Age, menopausal status, BMI, tumor size, histological type, tumor grade, estrogen receptor status, HER2-status, number of positive lymph nodes, preexisting neuropathy, and edema were not significant in the univariate analysis and therefore not included in the multivariate analysis * Adjusted for type of operation and regimen
Adjusted for regimen, maximum stomatitis, maximum muscle and joint pain, maximum fatigue, and frozen gloves and socks
Table 5 Modifications of docetaxel dose pr cycle according to regimen and onset of neuropathy N = number of events
Early neuropathy
P* \0.0001
Late neuropathy
P
No neuropathy
All
N = 495 (%)
0.66
D100
N = 435 (%)
N = 1,611 (%)
N = 2,541 (%)
No dose modifications (100 % on time)
245 (56)
379 (77)
1,280 (79)
1,904 (75)
Dose delays ([28 days, 100 % dose)
3 (1)
7 (1)
7 (0)
17 (1)
Dose reductions (\82.5 mg/m )
151 (35)
101 (20)
300 (19)
552 (22)
Discontinuations
36 (8)
8 (2)
24 (1)
68 (3)
D75 No dose modifications (100 % on time)
N = 294 (%) 159 (54)
N = 3,546 (%) 2,953 (83)
N = 5,268 (%) 4,140 (79)
Dose delays ([28 days, 100 % dose)
0 (0)
21 (1)
20 (1)
41 (1)
Dose reductions (\66 mg/m2)
81 (28)
304 (21)
415 (12)
800 (15)
Discontinuations
54 (18)
75 (5)
158 (4)
287 (5)
2
\0.0001
N = 1,428 (%) 1,028 (72)
\0.0001
2
* v -testing EN group versus no PN group
v2-testing LN group versus no PN group
PN. PN was associated with a significantly lower cumulative dose of docetaxel, i.e., with more dose reductions and discontinuations. More patients reported grades 2–4 neuropathy (35 %) and grades 3–4 (11 %) than expected from the literature with a reported maximum incidence of up to 9 % (grades 3–4) after treatment with docetaxel [16, 26]. One
explanation for this difference could be that we used patients reported outcome. Studies have showed that clinicians tend to report fewer outcomes than patients [6, 17, 33, 39] and it has been suggested that the incidence of PN is substantially under-reported in clinical trials due to limitation in available grading scales that are commonly used to assess PN [19, 43]. One study found that patient
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reported outcomes were significantly associated with changes over time in vibration threshold testing [20] and recommended use of patient reported outcome instead of clinician-reported outcome. Another reason may be that the Danish patient populations may differ with respect to prevalence of risk factors for PN with regards to genetic factors. Early reports on docetaxel indicated that PN may occur after just one dose of 50–100 mg/m2 [22, 30]. Other studies have reported the incidence of PN at the end of treatment [36], but we are not aware of studies of docetaxel-induced PN in relation to onset. These data indicate that patients who develop PN with neurotoxic drugs may not be a homogeneous group. For paclitaxel, there are data to support a dose–response relationship with risk of PN [25, 26, 47]. In our data the relationship between docetaxel dose and risk of PN was more complex. In the D100 regimen, the OR of EPN was 3.24 times higher when compared to the D75 regimen while the OR of LPN was 0.71 in the D100 regimen. This can be interpreted as patients prone to PN develop EPN more frequently with a high first dose and patients having PN are less likely to continue with a high dose. On the other hand patients, in the D75 regimen, received a higher cumulated dose than the D100 regimen and also received cyclophosphamide concomitant with docetaxel which could be partly accountable for the higher risk of LPN in the D75 regimen. However, there seems to be a group of patients who are particularly vulnerable for developing PN after treatment with docetaxel and this may in part be explained by metabolic differences. The connection between preexisting neuropathy and PN has been brought to attention in other studies were patients exposed to other neurotoxic agents like cisplatin or other medical conditions were more prone to develop PN [3, 12, 13]. In our study, patients were chemotherapy naı¨ve but patients reporting neuropathy at baseline were more prone to develop EPN. Unfortunately, data regarding diabetes mellitus and other medical conditions were not available in this study. No other studies have found an inverse association between PN and lymph node positive disease and tumor size [2 cm [46] but this indicates that axillary dissection in node positive patients do not increase the risk of PN. In contrast to other studies, we found no association between age, and menopause status and PN [2, 4, 36, 46]. Loprinzi et al. has reported that the paclitaxel-associated acute pain syndrome was associated with development of PN and that paclitaxel-associated acute pain syndrome is a form of nerve pathology [27, 28, 34, 48]. Our data supports this finding. The exact mechanism of PN remains unclear but it has been suggested that inflammation around the dorsal root ganglion and peripheral nerves could be partly
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responsible for the paclitaxel-associated acute pain syndrome [24, 31, 32, 34]. Another theory regarding the mechanism of PN is that taxanes cause disruption of microtubules of the mitotic spindle that interferences with the axonal transport and thereby affect the sensory neurons as well as the axons [3]. The longest axons are in the hands and feet, requiring the most axonal transport, and therefore most likely affected. Frozen gloves and socks cause vasoconstriction in the applied area and could thereby prevent a high dose of docetaxel, the axonal transport being less affected and the likelihood of PN reduced. To our knowledge, no study has tested frozen gloves and socks effect on PN [10, 23, 37, 38]. So far no other preventive treatment has proven useful [35, 43]. While Schneider et al. [36] found that there was no significant difference in the proportion of patients who required a dose reduction among patients with PN, Hershman et al. found that up to 26 % of patients with PN required dose delay and dose reduction [44]. Our analysis identified a subgroup of patients who received significantly less docetaxel than patients with no PN. In our study, the implications of PN were that 20-25 % of cycles were not delivered with the planned dose of docetaxel, i.e., that patients with PN were treated at a lower dose intensity than patients without PN. The strengths of the present study are that it is based on a nationwide clinical trial; that patients by randomization were allocated to different docetaxel schedules; and the use of patients reported outcome after each cycle of chemotherapy by a standardized questionnaire. However, there are certain limitations of this material. Preferable, the questionnaire used to record patients reported outcome was properly validated before this study, however, more than 1,700 patients has completed the questionnaire and this may reduce some of the uncertainties of a non-validated questionnaire. Also we did not collect information on the specific reason for dose reductions or discontinuations. Finally, this study was not designed for testing an effect of frozen gloves and socks on PN. Today docetaxel is one of the most important drugs to reduce the risk of recurrence and death from breast cancer, but the use is limited by toxicity such as neuropathy. While this study has examined onset of PN, more knowledge is needed about the duration of PN after cessation of docetaxel and the implications for quality of life [5, 7, 41]. The mechanism underlying PN still needs to be identified as well as predictive biomarkers or treatment to prevent neuropathy. The association between frozen gloves and socks with the risk of PN needs to be confirmed by others, preferably in a randomized trial with the incidence of PN as the primary end-point.
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Conclusion Patients developing PN are less likely to receive docetaxel at the planned dose intensity. If confirmed by others, usage of frozen gloves and socks may be a new method to prevent PN. Acknowledgments The READ trial/Danish Breast Cancer Cooperative Group received an unrestricted grant from Sanofis-aventis. Conflict of interest Bent Ejlertsen MD, has received unrestricted grants from Norvatis, Amgen, and Roche. All other authors have no conflict of interest.
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