Oxaliplatin is an integral component of the various FOLFOX regimens, which have become a standard treatment for metastatic and node-positive colorectal cancer [3
]. Encouraging results have been reported from phase II trials using oxaliplatin in combination with pemetrexed, raltitrexed or capecitabine in patients with metastatic colorectal cancer [18
]. Enthusiasm regarding the efficacy of oxaliplatin/5-FU/LV regimens has been tempered by the associated neurotoxicity which can significantly impair the quality of life of patients and limits the optimal use of oxaliplatin. Many published trials provide limited details concerning the precise type and location of neurotoxicities experienced, and most appear to have focused on the cumulative sensory neuropathy. Data on the reported incidence of neuropathy from randomized trials, presented in Table , may be influenced by the toxicity scale employed, the cumulative oxaliplatin dose, and schedule of administration (3–5,1 7, 25–29). For three trials that employed 85 mg/m2
oxaliplatin given over 2 hours as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or worse neuropathy was reported to be a mean of 15.4%. A higher incidence of grade 3 neuropathy (31–34%) was reported when oxaliplatin was given at 20 mg/m2
as a 24-hour infusion daily for 5 days every 3 weeks or as 100 mg/m2
over 2 hours every 2 weeks. The incidence of grade 3 neuropathy was lower with IROX, in which 85 mg/m2
is given over 2 hours every 3 weeks. The lowest incidence of serious neurotoxicity has been reported in trials in which FOLFOX is used as second- or third-line salvage therapy, presumably because the cumulative dose of oxaliplatin is less than when employed as first-line therapy.
Cumulative chronic sensory neuropathy rates in selected phase III trials involving oxaliplatin and 5-FU based combination chemotherapy
Although the symptoms associated with acute peripheral sensory and motor nerve hyperexcitability seem to be transient in nature, they can cause distressing symptoms in patients. We used a questionnaire that was filled out by the research nurse during a face- to face interview with the patient. All patients kept a daily calendar diary of side effects, and were interviewed the morning after the initial dose of oxaliplatin. This approach provided detailed information on the incidence, type, location and duration of neuropathy experienced by patients. Since all research subjects were admitted for their first cycle of chemotherapy, close observation for acute neurological symptoms and next-day interviews with patients was possible. These measures may have facilitated identification of symptoms or signs that perhaps would otherwise have gone unreported.
Our study demonstrated that most patients experience either dysesthesia or paresthesia at some point during their treatment, although the worst toxicity grade was grade 1 in most patients. Due to stringent dose modification guidelines, only a small proportion of patients experience serious functional impairment. However, as the cumulative dose of oxaliplatin increases, patients are more likely to experience paresthesia due to a cumulative sensory neuropathy. In patients who receive more than 6 cycles of chemotherapy (projected maximum cumulative dose on this every 3-week schedule of 780 mg/m2
), the neuropathy can become persistent and affect the subject's ability to perform routine activities of daily living. Oxaliplatin-associated cumulative sensory neuropathy is slowly reversible in most patients [9
Among the various acute, transient neuropathic symptoms experienced by patients, cold sensitivity is the most common form, but it is rarely debilitating since patients can adapt to avoid cold stimuli. The temporary loss of awareness of breathing is relatively uncommon, but is probably the most alarming symptom. It is imperative that patients are warned about these symptoms and their transient nature prior to chemotherapy administration. Such patients can talk, and their breath exhalation is audible. Acute oxaliplatin-associated neurotoxicity can result in other disturbing symptoms such as visual field cuts, blurred vision and ptosis. Administration of FOLFOX regimens require a centrally implanted venous catheter to deliver outpatient infusional 5-FU. Since our study involved oral capecitabine, patients were not required to have central venous access. However, due to the occurrence of whole arm pain in the extremity used to infuse oxaliplatin, and due to extravasation injuries, we amended our protocol to recommend placement of central venous access devices.
There is no standard treatment for oxaliplatin-related neurotoxicity. A variety of strategies have been employed to prevent or treat oxaliplatin neurotoxicity [10
], including carbamazepine, gabapentin, alpha lipoic acid, amifostine, glutathione, and celecoxib. The largest experience is the retrospective analysis of the benefit of infusing magnesium and calcium prior to oxaliplatin administration in 96 patients compared to 65 patients who did not receive magnesium/calcium. The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7% vs 26%, p = 0.001), and acute symptoms such as distal and lingual paresthesia were much less frequent and severe in the Ca/Mg group. The authors concluded that Ca/Mg infusions seemed to reduce the incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy [32
]. A large, randomized trial will be required to clarify the link between acute, transient symptoms and the likelihood of development of chronic sensory neuropathy, and confirm whether strategies such as Ca/Mg infusions reduce the neurotoxicity without impacting on the anti-tumor efficacy.
Another approach involves the administration of six cycles of FOLFOX-7, followed by the use of biweekly FULV2 for 12 cycles; oxaliplatin was then re-introduced for six cycles, or earlier if disease progression occurred on FULV2 [40
]. The intention is to allow recovery from neurotoxicity during the oxaliplatin-free period which may allow the re-introduction of oxaliplatin. Preliminary results demonstrate that this is a convenient regimen with no detrimental effects on efficacy.
Several cases have been reported in the literature concerning peripheral neuropathy in association with 5-FU and capecitabine therapy. Stein reported two subjects who developed symptoms of pain and weakness in the lower extremities while receiving fluorouracil and levamisole [41
]. EMG revealed axonal and demyelinting polyneuropathy involving small and large fibers. Two patients treated in a phase I trial of oral 5-FU, leucovorin and eniluracil, an inhibitor of dihydropyrimidine dehydrogenase, developed delayed onset symptoms of unsteady gait and reduced sensation in the legs [42
]. EMG and NCS revealed sensorimotor polyneuropathy. Saif reported two patients who experienced either right leg weakness with foot drop or perioral and upper extremity paresthesias with capecitabine [43
]. EMG and NCS showed sensorimotor peripheral neuropathy in both patients. In each of these three reports, other common etiologies of peripheral neuropathy were excluded. Couch et al reported a patient given capecitabine who experience acute onset of neuromuscular symptoms, the most prominent of which was trismus, [44
]. Peripheral neuropathy may thus represent an extremely rare complication of fluorouracil or capecitabine therapy. The possible contribution of capecitabine to the neurologic symptoms in the patients in the current trial is unclear. However, the neurophysiologic studies obtained shortly after administration of oxaliplatin are unique and are reminiscent of neuromyotonia.