The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer
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.