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Neuro-oncology
Research paper
Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients
  1. Roser Velasco1,
  2. Jordi Bruna1,
  3. Chiara Briani2,
  4. Andreas A Argyriou3,
  5. Guido Cavaletti4,
  6. Paola Alberti4,
  7. Barbara Frigeni5,
  8. Mario Cacciavillani6,
  9. Sara Lonardi7,
  10. Diego Cortinovis8,
  11. Marina Cazzaniga8,
  12. Cristina Santos9,
  13. Haralabos P Kalofonos3
  1. 1Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-ICO Duran i Reynals, Barcelona, Spain
  2. 2Department of Neurosciences, University of Padova, Padova, Italy
  3. 3Division of Clinical Oncology-Department of Medicine, University Hospital of Patras, Rion-Patras, Greece
  4. 4Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy
  5. 5Department of Neurology, S. Gerardo Hospital, Monza, Italy
  6. 6EMG Unit, CEMES, Gruppo Data Medica, Padova, Italy
  7. 7Oncology Unit 1, Veneto Oncology Institute–IRCCS, Padova, Italy
  8. 8Department of Oncology, S. Gerardo Hospital, Monza, Italy
  9. 9Unit of Colorectal Cancer, Hospital Universitari de Bellvitge-ICO Duran i Reynals, Barcelona, Spain
  1. Correspondence to Dr Jordi Bruna, Neuro-Oncology Unit, Hospital Universitari de Bellvitge and ICO Duran i Reynals, C/Feixa Llarga s/n, L'Hospitalet de Llobregat, Barcelona 08907, Spain; 35078jbe{at}comb.cat

Abstract

Objectives Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN).

Methods 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded.

Results According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow-up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN.

Conclusions High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid-treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN.

  • EMG
  • NEUROONCOLOGY
  • NEUROPATHY
  • ONCOLOGY

https://doi.org/10.1136/jnnp-2013-305334

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    Introduction

    Oxaliplatin (OXA) is a platinum analogue that has emerged as a cornerstone in the systemic treatment of colorectal cancer (CRC) both in the adjuvant and metastatic settings.1–3 At present, combination regimes of infusional OXA and 5-fluorouracil with leucovorin (FOLFOX) or oral capecitabine (XELOX) represent standard options in the treatment of CRC.4 Furthermore, OXA is increasingly administered against other malignancies.

    OXA exhibits a good tolerability profile, with usually low grade easily manageable myelosuppression, nausea and vomiting to rank among its common toxicities.5 OXA-induced peripheral neuropathy (OXAIPN) is its most prominent toxicity, both during and after the completion of chemotherapy.6 Two patterns of OXA neurotoxicity are displayed: the acute form, characterised by cold-triggered symptoms that occur immediately after infusion in most patients, and the cumulative neurotoxicity that is characterised by distal paresthesias and numbness in the extremities, resulting in sensory ataxia and functional impairment.7

    Acute neurotoxicity is reversible, usually resolving within the same cycle, and, when present and severe, only requires prolonging the time of OXA infusion. Instead, cumulative OXAIPN occurs at a threshold dose of 600–700 mg and may become clinically important for several reasons. First, it is dose-limiting, representing as such the main cause of dose reductions and discontinuation of OXA treatment, thereby compromising therapeutic outcomes.2 ,6 ,8 Second, it is frequent, occurring in up to 80% of patients after completing OXA-based regimen.6 ,8 Third, the OXAIPN is long-lasting, leaving often long-term neurological sequelae9–11 with minor or incomplete recovery in many patients.12 Finally, patients with OXAIPN experience significant functional difficulties with daily tasks that seriously reduce their quality of life.11 ,13 Recent evidence suggests that the acute OXA neurotoxicity may be associated with the occurrence and severity of cumulative neuropathy.7 ,14

    To date, there is lack of reliable methods able to distinguish patients who are susceptible to developing severe OXAIPN during the OXA-based treatment. The present study has explored the relationship between early clinical and neurophysiological changes in a homogenous cohort of CRC patients treated with OXA and their neurological outcome. The study aimed at identifying early predictors of treatment emergent cumulative OXAIPN in order to enable clinicians to optimise the OXA treatment avoiding its most feared adverse event. Part of the results on acute OXAIPN included herein have been recently reported elsewhere by our group.7 However, this study is solely focused on the prediction of treatment emergent, cumulative OXAIPN and data on acute neurotoxicity were considered only to assess their ability to predict the cumulative form of OXAIPN.

    Methods

    Subjects

    Adult patients with a histologically confirmed diagnosis of CRC, scheduled to receive first-line OXA-based chemotherapy, were recruited and prospectively evaluated at four European centres, that is, in Greece (1), Italy (2) and Spain (1), during an 18-month period. Eligible patients were required to be chemotherapy-naive, have a satisfactory liver and renal function, life expectancy of at least 9 months, and a Karnofsky performance score ≥70. Patients with pre-existing neuropathy, diabetes mellitus, alcoholic abuse or central nervous system metastasis, and patients on any medication that would interfere with the clinical assessments were excluded.

    Chemotherapy schedules

    Patients received standard OXA-containing regimens. FOLFOX-4 and modified FOLFOX-6 were administered every 2 weeks and consisted of infusion of OXA 85 mg/m2 on day 1 combined with leucovorin and 5-fluorouracil, in a 2-week cycle. XELOX schedule consisted of OXA 130 mg/m2 infusion on day 1 plus oral capecitabine for 2 weeks in a 3-week cycle. OXA was initially infused intravenously in 2 h to all the participants. Dose modifications of OXA administration were done as per the protocol.1 In brief, OXA dose was reduced by 20%–30% in case of persisting paresthesias between cycles and OXA was discontinued if paresthesias were associated with functional impairment. Time of OXA infusion was prolonged to 4–6 h when severe acute neurotoxicity was present. Routine antiemetic and dexamethasone were prescribed. Calcium and magnesium infusions or other drugs, suggested as potential neuroprotectants, were not allowed.

    Neurological assessment

    Neurological assessment, including the outcome measures described below, was performed in all patients at three time points of the follow-up: prior to starting chemotherapy (baseline), after 6 or 4 courses of FOLFOX or XELOX, respectively (mid-treatment), and 1 month after completion of the OXA-based therapy at the 12-course for FOLFOX and 8-course for XELOX (final).

    The incidence and severity of cumulative OXAIPN was rated using the National Common Institute-Common Toxicity Criteria V.3 (NCI-CTCv3)15 and the clinical version of the Total Neuropathy Score (TNSc).16 ,17 NCI-CTCv3 sensory subscale is the commonly employed scale by oncologists to rate toxicity (table 1), and table 2 describes the items of the TNSc, which have already been validated against the most common neurotoxicity scales, and demonstrated to be more responsive to changes in chemotherapy-induced peripheral neuropathy severity than the NCI-CTC.11 ,16 ,18 ,19 The severity of OXAIPN was classified according to TNSc as grade 1 (scores 1–7), grade 2 (scores 8–14), grade 3 (scores 15–21) and grade 4 (scores >21), as previously described.11 ,20

    View this table:
    Table 1

    NCI-CTCv3 sensory subscale

    View this table:
    Table 2

    Clinical version of the Total Neuropathy Score (TNSc)

    Acute neurotoxicity due to OXA was assessed with a descriptive questionnaire, evaluating the presence of the 11 most common hyperexcitability symptoms associated with the acute OXAIPN, as previously described.7 Symptoms were recorded as present or absent and the severity scored based on the sum of the symptoms reported by patients at each evaluation (table 3).

    View this table:
    Table 3

    Acute neurotoxic symptoms scored in patients receiving oxaliplatin

    Nerve conduction studies (NCS) were measured unilaterally using the standardised techniques for surface recording and stimulation and the widely accepted criteria for identification of abnormalities.21 ,22 Sensory conductions were evaluated in ulnar, radial, sural and dorsal sural nerves (antidromic technique) by measuring the peak-to-peak amplitude of sensory nerve action potentials (a-SAP) and sensory conduction velocity. Motor conduction was tested in peroneal nerves with measurements of peak-to-baseline amplitude of compound muscle action potential and motor conduction velocity. Electrodiagnostic tests were performed at constant temperature. NCS results were compared with normative age-matched reference data from each laboratory. NCS were repeated at each clinical assessment by the same physician who was blind to results of previous testing.

    Statistical analysis

    Descriptive data analysis presented categorical variables as observed counts and weighted percentages, and continuous variables as mean or median with the corresponding SE or range, depending on the nature of the variable. χ2 And student t tests were used for identifying differences among OXAIPN severity groups. To compare the changes in NCS during the treatment between patients classified according to the neuropathy grade repeated measures, ANOVA test and Bonferroni test as post hoc tests were used. The NCS values were normalised and expressed as a percentage with respect to baseline values for each patient. In order to estimate the most discriminating cut-off of decrement in NCS at mid-treatment with respect to the established severity of OXAIPN (grade ≥3) according to TNSc scale at the end of treatment, receiver-operated characteristics (ROC) analyses were performed. Finally, to predict the probability of developing severe OXAIPN, a multivariate logistic binary regression analysis introducing in a backward stepwise method the following variables (sex, age, OXA dose per cycle, OXA cumulative dose at mid-treatment, number of acute OXAIPN-symptoms and the NCS results according the ROC classification) were performed. Considering that acute and cumulative OXAIPN are due to an axonopathy and a neuronopathy,23 ,24 respectively, only the a-SAP was considered to avoid multi-collinearity in the multivariate analysis. All calculations were performed using SPSS software package V.18.0 (SPSS Inc., Chicago, Illinois, USA) and p values <0.05 were considered significant.

    Results

    A total of 254 patients were initially screened and eventually a total of 200 subjects were included into the study. During screening, 54 patients were excluded for evidence of pre-existing neuropathy (n=23), change in the treatment plan (n=12), presence of conditions that would have complicated accurate assessment (n=11), refusal (n=6) and other reasons (n=2). Demographics and clinical characteristics of the patients are summarised in table 4.

    View this table:
    Table 4

    Demographic and baseline clinical characteristics of the whole series and by severity of neuropathy

    Overall, 36 (18%) patients developed severe (grade ≥3) cumulative OXAIPN according to TNSc scale. Conversely, 27 (13.5%) patients using NCI-CTCv3 criteria presented grade ≥3 OXAIPN at the end of treatment (table 5).

    View this table:
    Table 5

    Clinical outcomes of the whole series and by severity of neuropathy

    In all, 33 (16.5%) patients needed OXA dose reduction, according to treatment protocol. In 18 (54.5%) of them, the reduction was performed during the second half of the OXA treatment schedule, although no differences were observed in the development of severe cumulative neurotoxicity depending on the timing of OXA reduction (first vs mid-treatment).

    At the end of treatment, 18 (59.4%), 11 (27.3%) and 4 (13.2%) out of the 33 patients who needed OXA dose reduction developed grade ≥3 and grade 1–2 and no cumulative OXAIPN according to TNSc scale, respectively. None of the patients developed high-grade cumulative neuropathy at mid-treatment evaluation according to TNSc scale. NCS results along the treatment and the cut-off values established using ROC analysis are presented in table 6 and figure 1, respectively. The frequency of neurological symptoms and signs according to the single items of TNSc obtained at the end of treatment are summarised in table 7.

    View this table:
    Table 6

    Comparison between nerve conduction studies (NCS) at baseline and at the end of treatment

    View this table:
    Table 7

    Single Total Neuropathy Score items according to neuropathy grade at the end of treatment

    Figure 1
    Figure 1

    Graphics represent the percentage change of a-SAP or a-CMAP of the nerves at midtreatment and final assessment compared with baseline data. a-CMAP, amplitude of compound muscle action potential; a-SAP, amplitude of sensory nerve action potential.

    Predictive factors

    In the univariate analysis, patients who developed severe cumulative OXAIPN were more frequently men (p=0.005), received higher cumulative OXA dose at the end of treatment (p=0.003), higher OXA single dose (p=0.006), reported higher number of acute OXAIPN symptoms (p<0.001) and presented a decreased a-SAP of all sensory nerves tested at the end of treatment (p<0.001) (tables 4⇑–6). On the other hand, the ROC analysis of TNSc scale at mid-treatment showed that a score >2 has a sensitivity of 80.6% and a specificity of 77.2 (p=0.041) to identify the patients who will develop high-grade neuropathy at the end of treatment.

    In the multivariate analysis, the binary logistic regression revealed that the following three factors at mid-treatment were independently associated with the risk of developing a severe OXAIPN: (1) the number of acute OXAIPN symptoms (OR 1.9; CI 95% 1.2 to 3.2; coefficient b: 0.65; p=0.012), (2) radial nerve a-SAP decrease >33.5% (OR 41.4; CI 95% 4.98 to 343.1; coefficient b: 3.72; p=0.001) and (3) dorsal sural nerve a-SAP decrease >31.5% (OR 24.96; CI 95% 2.6 to 239.4; coefficient b: 3.22; p=0.005). The predicted probabilities for each patient to develop severe OXAIPN provided by the logistic multivariate model (constant: -7.57; R2=0.74) obtained a sensitivity of 96.3%, a specificity of 79.1% with a positive and negative predictive values of 53% and 98.9%, respectively.

    Age, gender, all other variables obtained by NCS and the cumulative OXA-dose at mid-treatment did not show a predictive value.

    Discussion

    The current study provides the results of the largest so far prospective, multicentre, international study, which aimed at identifying clinical risk factors and early markers of cumulative neuropathy following OXA treatment. Three variables assessed at mid-chemotherapy seem to provide a sensitive predictive measure of neurotoxicity in OXA-treated patients.

    Treatment emergent, NCI grade ≥3 cumulative OXAIPN developed in 13.5% of our patients in line with the percentages of neurotoxicity (between 12.4% and 18%) previously reported.1 ,2 ,4 The univariate analysis revealed that the main differences between patients who developed high-grade neuropathy and patients with low grades or no neuropathy were the total cumulative OXA dose, gender, the severity of acute OXAIPN and the nerve conduction data. Cumulative OXA dose is a well-recognised factor associated with a higher incidence and severity of chronic neuropathy.12 ,20 ,25 In contrast with other studies that did not find gender predominance,26 ,27 we found a male predominance that could be explained by the fact that men usually present a higher body mass index, therefore receiving higher OXA total cumulative doses (men 1717.53±263.04 mg vs women 1548.23±286.78 mg, p<0.001).

    Acute neurotoxicity has recently been found to correlate with the development of cumulative neuropathy,7 supporting earlier evidence provided by the measure of sensory axonal excitability techniques and quantitative sensory tests,14 ,28 thereby further pointing to the possible link between the acute and chronic OXA-induced neurotoxicity. Other risk factors, such as the chemotherapy schedule (XELOX vs FOLFOX), age, comorbidities like diabetes mellitus, pre-existing neuropathy and renal impairment, have been proposed to be associated with a higher incidence of clinically relevant neuropathy in several studies.25–27 29–31 However, data from previous studies are often controversial, likely for some limits of these studies, such as the relatively small size, the retrospective design and the lack of statistical approach with multivariate regression analysis.

    The current study allowed us to identify predictive factors of cumulative treatment emergent OXAIPN based on multivariate analysis in a large CRC population. An increased number of acute neuropathic symptoms and the amplitude decrease of a-SAP of radial and dorsal sural nerves at mid-treatment are independently associated with the risk of developing high-grade OXAIPN. Commonly employed strategies to avoid severe OXAIPN, such as OXA dose reduction, seem not to be useful because they are applied when neuropathy is already established and the recovery of nerve damage is slow and unsuccessful in up to 35% of patients.10 However, data collection of acute neuropathy symptoms and the record of two standard NCS after completing half of chemotherapy schedule seem to be sensitive and suitable tools, easily implementable in daily oncology practice and able to identify patients at risk of developing severe neuropathy during OXA treatment.

    One of the main findings of our study is the demonstration of the usefulness of NCS in early predicting severe OXAIPN. NCS constitute an objective measure of the nerve damage, although the role of electrodiagnostic studies in the assessment of neuropathy during chemotherapy is controversial.32–34 Several small studies reporting NCS monitoring during OXA treatment have been published. In most of them, the reported decline of the potential action amplitudes occur over time and usually late.35–38 To the best of our knowledge, Pietrangeli et al10 were the only ones to detect early signs of sensory peripheral neurotoxicity due to OXA in sural nerve amplitude at 9 weeks after OXA treatment in a series of 18 patients. The present study identified two sensitive nerves crucial for monitoring nerve function in OXA treatment, simplifying the electrophysiological studies of these patients. It is noteworthy that we observed a prominent reduction of radial nerve amplitude, similar to what was previously reported.12 ,36 Radial nerve is known to be usually spared in dying-back neuropathies until late stages, and its relative early impairment supports a neuronopathy pattern of the OXA-induced neurotoxicity related with the dorsal-root ganglia nerve primary damage.24

    Interestingly, the current work is the first to reveal that dorsal sural nerve conduction would be more sensitive than the commonly used conduction of sural nerve in order to detect early nerve damage, therefore demonstrating as such the usefulness of dorsal sural nerve conduction study in the assessment of chemotherapy-induced neuropathies, whose normative reference values have recently been reported.22 Our results support previous findings demonstrating that the diagnostic sensitivity of sensory NCS in peripheral neuropathies may be significantly improved by evaluating the a-SAP of dorsal sural nerve. This effect can be attributed to its ability to evaluate the distal branches of the sural nerve, corresponding to the most distal segments of the lower extremities, thereby documenting postganglionic pathology at the early stage.

    Our study is the first to provide cut-off values that allow discriminating when a patient is at an increased risk of severe neuropathy. These findings and the clinical surveillance of acute symptoms demonstrate the importance of neurological monitoring during OXA treatment, as it has already been demonstrated in other chemotherapy regimens.39

    The lack of predictive power of cumulative-dose at mid-treatment in the multivariate analysis seems at odds with the well known dose-related OXA neurotoxicity. We could speculate that although a minimum cumulative dose is needed to damage the neurones, this factor does not directly reflect the nerve function and the different efficiency of cellular platinum detoxification mechanisms increase the variability of the tolerated dose among patients at least in early stages of the neuropathy development. It could also be hypothesised that there is no linear relationship between dose and neurotoxicity before reaching a cumulative dose level beyond which the toxicity becomes dose dependent.

    We should acknowledge some limitations in the study design. The strict selection criteria employed limit the generalisation of our findings to the global population of CRC patients’ candidates to OXA chemotherapy, especially in patients with pre-existing neuropathy, but this is an unsolvable problem of all clinical trials. However, the evidence provided by preclinical chemotherapy models did not show that mild neuropathy is a risk factor for developing more severe polyneuropathy.40 Nonetheless, like in all multivariate approaches, the model obtained in such analysis needs a cross-validation sample to generalise and apply its findings. Another potential criticism might relate to the use of TNSc scale as a main endpoint of the study analysis instead of the widespread oncological NCI-CTC scale. Nevertheless, TNSc has been extensively validated as a useful instrument for objectively measuring the severity of peripheral neuropathy caused by different chemotherapy agents, including OXA.11 ,16 ,18 Furthermore, it exhibits a good correlation with toxicity scales displaying a higher responsiveness in peripheral neuropathy severity than NCI-CTC.11 ,19 In any case, TNSc was employed in the current study as the main outcome tool and eventually appeared to be more sensitive than NCI-CTCv3 to grade the incidence and severity of cumulative OXAIPN. Finally, the evaluation of acute symptoms due to OXA was done according with a not-validated scale. However, to our knowledge, not-validated scales to the correct assessment of acute neurotoxicity have been reported.

    In conclusion, the present study is the largest one focused on prospectively evaluating risk factors and early predictor markers of nerve dysfunction and severe cumulative neuropathy induced by OXA-based chemotherapy. Neurological monitoring including a combination of clinical and neurophysiological measures that should be available in the clinical oncological daily practice will be of great value in clinical decision-making helping minimise the risk of severe OXA-induced neurotoxicity. The early identification of patients at risk of high-grade neuropathy could be useful to allow prompt reductions of the dose of OXA before nerve damage has occurred, and to continue treatment schedule without being necessary to withdraw it due to neurotoxicity. Besides, it would be of interest in order to stratify the patients in future clinical trials including OXA or aimed to test potential neuroprotective agents, according to the risk of neuropathy.

    Acknowledgments

    This work was partially supported by grant PI070493 from ISCIII (Spain) and by the unrestricted research grant provided by Fondazione ‘G.Benzi’. Otherwise, no funding source had a role in the preparation of this paper or in the decision to submit it for publication.

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    Footnotes

    • RV and JB contributed equally.

    • Contributors RV and CB: Study concept and design, acquisition of data, analysis or interpretation of data, draft and revision of the manuscript. JB: Study concept and design, acquisition of data, statistical analysis and interpretation of data, draft and revision of the manuscript, study supervision. AAA, PA, BF, MC, SL, DC, MC and CS: Study concept and design, acquisition of data, analysis or interpretation of data, critical revision of the manuscript. GC and HPK: Study concept and design, acquisition of data, analysis or interpretation of data, critical revision of the manuscript, study supervision.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study had obtained approval from the corresponding Ethics Review Board of each participating centre and participants provided written informed consent.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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