The mean age in the patient group was 52 years (range 38–74) and in the healthy control group 54 years (range 28–77). Five patients decided not to participate for personal reasons in the 3–4 month assessment and two in the 6–8 month assessment without, however, interrupting or modifying the overall treatment schedule. Table
1 summarizes the number of chemotherapy cycles, median dose intensities and cumulative doses for the two administered drugs while Table
2 includes survival data (progression-free and overall survival) for the patient group.
Table 1
Number of chemotherapy cycles, median dose intensities and median cumulative doses. Combined paclitaxel and carboplatin chemotherapy was administered to the 31 ovarian cancer patients
Total number of cycles administered | 195 |
Median number of cycles (range) | 6 (4–8) |
Median cumulative dose (mg) (range) |
Paclitaxel | 1737 (1108–2664) |
Carboplatin | 3915 (1550–6220) |
Median dose intensity (mg/m2/week) (range) |
Paclitaxel | 164.3 (109.2–247.8) |
Carboplatin | 396.0 (141.1–558.9) |
Table 2
Survival data for the patient group (n = 31)
Progression-free survival (PFS) |
Progressions [n (%)] | 14 (45.2) |
3-year PFS (%) | 61.3 |
Range (months) | 6.2–47.8 |
Overall survival (OS) |
Deaths [n (%)] | 9 (29.0) |
3-year OS (%) | 79.8 |
Range (months) | 14.9–52.9 |
Median follow-up (months) | 39.7 |
ANS assessments
Autonomous nervous system assessment results did not differ significantly between the patient and healthy control groups at baseline.
At the 3–4 months ANS assessment, the number of patients with orthostatic hypotension (OH) increased compared to baseline. After 3 min of active standing, reduction in systolic blood pressure (SBP) of ≥20 mmHg wasn’t observed in any patient at baseline but in five patients (19.2 %) at 3–4 months. A reduction in diastolic blood pressure (DBP) of ≥10 mmHg was observed in two patients (7.7 %) at baseline but on five patients (19.2 %) at the 3–4 months evaluation. These differences, however, failed to reach statistical significance possibly as a result of a type II error due to small sample size. The values of the 30/15 ratio were significantly reduced at the 3–4 months assessment compared to baseline (Wilcoxon signed ranks test,
P = 0.016) whereas the SSR was not affected (Table
3).
Table 3
Three to four months evaluation of 30/15 ratio and sympathetic Skin Response (SSR)
30/15 ratio | 1.13 (0.09) | 1.10 (1.00–1.43) | 1.10 (0.20) | 1.03 (0.89–1.94) |
0.016
|
SSR |
Upper limbs | 1.46 (0.34) | 1.38 (1.10–3.01) | 1.61 (0.45) | 1.53 (1.10–3.01) | 0.17 |
Lower limbs | 2.22 (0.42) | 2.20 (1.60–3.13) | 2.27 (0.47) | 2.25 (1.60–3.13) | 0.74 |
At the 6–8 month evaluation, 26 patients (89.7 %) among the 29 patients, who were examined, had completed chemotherapy. The results of the orthostatic hypotension testing were clearly improved compared to the 3–4 month assessment. Thus, no patient had a reduction of ≥20 mmHg after 3 min of active standing at the 6–8 months evaluation, similarly to baseline. Four patients (13.8 %) had a reduction in DBP of ≥10 mmHg after 3 min of active standing compared to three patients (9.7 %) at baseline. The values of the 30/15 ratio were significantly reduced compared to baseline (
P = 0.002) whereas the SSR wasn’t affected (Table
4).
Table 4
Six to eight months evaluation of 30/15 ratio and sympathetic Skin Response (SSR)
30/15 ratio | 1.13 (0.09) | 1.10 (1.00–1.43) | 1.07 (0.09) | 1.06 (0.94–1.30) |
0.002
|
SSR |
Upper limbs | 1.46 (0.34) | 1.38 (1.10–3.01) | 1.50 (0.41) | 1.46 (1.00–3.01) | 0.58 |
Lower limbs | 2.22 (0.42) | 2.20 (1.60–3.13) | 2.13 (0.41) | 2.08 (1.59–3.13) | 0.74 |
On an individual patient level, the incidence of abnormal 30/15 ratio varied longitudinally as follows: three patients had abnormal values at both baseline and the 3–4 months time points whereas one patient had an abnormal baseline value which subsequently normalized. Twelve patients had normal values at baseline, which became abnormal at 3–4 months (McNemar’s test, P = 0.003), whereas ten patients had consistently normal values. One patient had abnormal value at both baseline and the 6–8 months time point and two patients had abnormal baseline values, which subsequently normalized. Twelve patients had normal values at baseline, which became abnormal at 6–8 months (McNemar’s test, P = 0.013), whereas 14 patients had consistently normal values.
At the 6–8 months evaluation, four patients were still on treatment or <1 month after treatment completion and 25 patients had completed treatment more than a month earlier. These two groups were not significantly different in any of the examined ANS parameters. In the latter group of 25 patients, there were no significant differences in ANS parameters between the 3–4 month and the 6–8 month evaluation.
Questionnaire results
Regarding the incidence of positive responses in the ANS dysfunction questionnaire, there were no significant differences in the distribution of positive answers between healthy volunteers and patients at the baseline evaluation. However, the mean (2.35) and median (2) number of positive answers was higher at the 3–4 months (Wilcoxon signed ranks test, P = 0.002) but not the 6–8 months (mean = 1.66 and median = 2, P = 0.33) evaluations compared to baseline (mean = 1.29 and median = 1).
The present study was designed to investigate the ANS effects of paclitaxel in conjunction with carboplatin in patients with ovarian cancer. It is concluded that the intravenous administration of paclitaxel at a dose of 175 mg/m2 in combination with carboplatin affects the sympathetic heart innervation, resulting in primarily systolic orthostatic hypotension during the treatment period. In addition, this chemotherapeutic regimen affects parasympathetic heart innervation both during treatment, as well as during the period ensuing after the last chemotherapy session. Finally, this drug combination has minimal effects on the function of the ANS beyond the cardiovascular system.
In our cohort, no patient had systolic orthostatic hypotension at baseline but five out of 26 patients developed this side effect at the 3–4 month assessment. Interestingly, at the 6–8 month evaluation, when the vast majority of patients had completed treatment more than a month earlier, no subject had evidence of systolic orthostatic hypotension. These observations suggest that the effect of combined paclitaxel and carboplatin chemotherapy on the sympathetic heart innervation is short lived and confined during the treatment period only. It should be noted that in a study on the effects of oxalplatin on sympathetic heart innervation in patients with colorectal cancer, the effects were not transient [
9]. This difference may possibly be attributed to the mean age of patients participating in the present study being lower.
The ANS effects of combined paclitaxel and carboplatin chemotherapy were even more evident on the parasympathetic heart innervation, as the 30/15 ratio was significantly affected at all time points following the onset of treatment (i.e both at the 3–4 and 6–8 months assessments). However, this protracted decrease of the 30/15 ratio was not associated with the severity of a chemotherapy-induced sensory neuropathy.
The existing literature on the cardiotoxicity of paclitaxel suggests that transient, asymptomatic bradycardia may occur in up to 29 % of treated patients [
15]. Cardiac dysfunction may also occur due to combination of paclitaxel with other chemotherapeutics, such as the monoclonal antibody trastuzumab [
16] or epirubicin [
17,
18]. It is well known that the administration of paclitaxel in conjunction with doxorubicin in patients with breast cancer is cardiotoxic [
19‐
22]. However, in our study none of the patients received such combinations of chemotherapeutic regimens.
It could be argued that the cardiotoxicity observed in the present study may be due, at least in part, to carboplatin, the co-administered chemotherapeutic agent. Several publications have reported potential subtle cardiotoxic effects of carboplatin when administered in combination with paclitaxel [
23‐
25].
The fact that SSR remained unaffected, despite the development of a primarily sensory and to a lesser extent motor peripheral neuropathy in a sizeable proportion of our patients, is not surprising. It is well known that when fast-conducting, large-diameter myelinated fibers are affected (for instance in cases of carpal tunnel syndrome), the SSR remains intact and is not regarded diagnostically useful in this particular setting [
26].
The findings from the ANS evaluations corresponded temporally to increases in positive responses in the questionnaire completed by the patients at 3–4 and 6–8 months following the onset of chemotherapy. At baseline, the mean number of positive responses was 1.13, increasing to a maximum of 2.35 positive responses at the 3–4 months assessment and dropping to a mean of 1.66 at the 6–8 months time point, when the majority of patients had completed the treatment regimen. It is conceivable, however, that the increase in positive responses may simply reflect the general malaise induced by chemotherapy, rather than being the clinical expression of treatment side effects specifically induced on the ANS.