What is chemotherapy induced peripheral neurophathy?
- Chemotherapy-induced peripheral neuropathy (CIPN) is defined as any injury, inflammation, or degeneration of the peripheral nerves because of the administration of a chemotherapeutic agent[1]
- CIPN affects any of the three functions of peripheral nerves: sensory, motor, autonomic.
How chemotherapy causes peripheral neuropathy
- Specific to the chemotherapy used[2] (see Table 1 below)
- Neurotoxic affect may increase when combined with other agents.
| Chemotherapeutic agent | Type of neuronal damage | Neurotoxic dose (mg/m2) | Use in paediatric cancers |
| Vincristine | Microtubule destabilization and axonopathy; Sensory and motor | >4 | ALL, lymphomas, solid tumours, brain tumours |
| Cisplatin | Binding to DRG cell DNA and induces apoptosis; primarily sensory | 250-350 | Brain tumours, bone tumours, testicular cancer, other solid tumours |
| Taxanes | Microtubule-stabilizing agent; sensory common, motor less frequent | 1000 paclitaxel 400 docetaxel | Rare, ovarian tumours |
| Epothilones | Microtubule polymerization agent; sensory common, motor and autonomic can also occur | Unclear, may be different based on dosing schedule | Refractory solid tumours |
| Bortezomib | mRNA, mitochondrial, and endoplasmic reticulum damage; sensory with neuropathic pain | Higher cumulative dose (>27-35), occurs at lower doses with previous vincristine treatment3 | Refractory or recurrent cancers |
| Thalidomide | Unclear, related to immunomodulation and antiangiogenesis effects | Unclear | Medulloblastoma and hepatocellular carcinoma |
Table 1 Chemotherapy: neurotoxicity and use in paediatric cancers (From Gilchrist, L2)
How do we recognise it?
- Symptoms may include:
- numbness, tingling, loss of position sense, or pain (sensory nerves)
- weakness or poor coordination (motor nerves)
- altered thermoregulation, blood pressure, intestinal motility (autonomic nerves)
- Reduced or absent reflexes.
- Early symptoms usually seen in hands and feet
- Seen in the arms and legs as it progresses [3]
- In general, but not always, CIPN is dose-related; that is, the more intense the treatment schedule, the more severe the symptoms
- Children may have difficulty in reporting symptoms: dependent on vocabulary/language development
- Diagnosis may be complicated by CNS (central nervous system) signs and symptoms if treatment includes intrathecal chemotherapy and/or if the cancer is within the CNS (e.g. brain tumour).
Assessing CIPN in children
There are various assessment tools available although currently there is not one used nationally.
The paediatric CIPN tool: Ped-mTNS[4] was developed specifically for use in paediatrics and will be used with the faces pain scale in the upcoming CIPN research that is running alongside the UKALL 2011 trial.
Other tools available are:
- ACTG Brief Peripheral Neuropathy Screening Tool [5]
- Utah Early Neurophathy scale [6]
- Quality of life measure, e.g. PedsQL[8], a quality of life measure is also used, this measure has a cancer component but it is not specific to CIPN.
- Criteria for Adverse Events (CTCAE)—Sensory and Motor Neuropathy Scales[7](Table 2)
Electrophysiological testing (nerve conduction studies) are often used alongside the tools to confirm a diagnosis.
| Adverse Event | 1 | 2 | 3 | 4 | 5 | |
|---|---|---|---|---|---|---|
| Neuropathy: Motor | Asymptomatic; clinical or diagnostic observations only; intervention not indicated | Moderate symptoms; limiting instrumental ADL | Severe symptoms; limiting self-care ADL; assistive device indicated | Life-threatening consequences; urgent intervention indicated | Death | |
| Neuropathy: Sensory | Asymptomatic, loss of deep tendon reflexes or paresthesias | Moderate symptoms; limiting instrumental ADL | Severe symptoms; limiting self-care ADL | Life-threatening consequences; urgent intervention indicated | Death | |
Table 2: Common Terminology Criteria for Adverse Events v4.03 (CTCAE)—Sensory and Motor Neuropathy Scales
Management of CIPN
Managing CIPN is a challenge and will require input from appropriate allied health professionals such as physiotherapists and occupational therapists. Prevention is the optimum management, dose limitations of chemotherapies known to cause CIPN and increased intervals in between doses. Dose omissions or reductions during a child or adolescents treatment may need to be considered especially if there is grade 3 neurotoxicity on the Criteria for adverse Events scale CTCAE[7](table 2). In the adult population there are some studies into neuroprotective medications. With CIPN often comes neuropathic pain, this tends to be manged with medications, traditional analgesics are used alongside drugs such as gabapentin and pregabalin. It can take a while to get this type of pain under control and combinations of analgesics will often be required.
Management of physical signs and symptoms
- Referral to appropriate allied health professionals: occupational therapist, physiotherapist
- Intervention dependent on signs and symptoms and may include:
- Maintenance of range of movement: stretches, orthotic support (inner soles, ‘foot ups’ ankle foot orthoses)
- Transcutaneous electrical nerve stimulation (TENS) for pain relief
- Home exercise programme: balance, strength
- ADL particularly handwriting, fine motor activities affected by sensory alteration and distal muscle weakness
- May require assistive/adaptive equipment.
The long term outcome for CIPN is difficult to predict due to the lack of prognostic indicators available for the paediatric population, however studies of adult survivors of childhood acute lymphoblastic leukaemia show long terms effects such as quality of life and physical activity levels. Persistent sensory loss and muscle weakness related to peripheral neuropathy are likely to be factors in these findings [9], [10].
References
Much of this page is a summary of Laura Gilchrist’s article: Chemotherapy-induced peripheral neuropathy in Pediatric Cancer Patients Seminars in Pediatric Neurology Volume 19, Issue 1, March 2012, Pages 9–17
[1] Armstrong,T.; Almadrones, L. Gilbert, MR (2005) Chemotherapy-induced peripheral neuropathy Oncol Nurs Forum, 32 pp. 305–311
[2] Gilchrist, L. (2012) Chemotherapy-induced peripheral neuropathy in Pediatric Cancer Patients Seminars in Pediatric Neurology 19 (1) March pp 9–17
[3] Argyriou,Andreas A.; Bruna,Jordi; Marmiroli,Paola; Cavaletti,Guido (2012) Chemotherapy-induced peripheral neurotoxicity (CIPN): An update Critical reviews in oncology/hematology 82(1) April pp 51–77
[4] Gilchrist L.S.; Tanner, L.; Hooke, M.C. (2009) Measuring chemotherapy-induced peripheral neuropathy in children: Development of the Ped-mTNS and pilot study results Rehabil Oncol, 27, pp. 7–15
[5] http://www.hiv.va.gov/provider/manual-primary-care/peripheral-neuropathy-tool1.asp
[6] Singleton, J.R.; Bixby, B.; Russell, J.W.; Feldman, E.L.; Peltier, A.; Goldstein, J.; Howard, J.; Smith, A.G. (2008) The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy J Peripher Nerv Syst. Sep;13(3) pp 218-27
[7] Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events. Version 4.03, DCTD, NCI, NIH, DHHS, 2010
[8] Varni, J.W.; Burwinkle, T.M.; Katz E.R. et al. (2002) The PedsQL in paediatric cancer: Reliability and validity of the paediatric quality of life inventory generic core scales, multidimensional fatigue scale, and cancer module Cancer, 94, pp. 2090–2106
[9] Ramchandren, S.; Leonard, M.; Mody R.J. et al. (2009)Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia J Peripher Nerv Syst, 14, pp. 184–189[10] Ness, K.K. ; Hudson, M.M. ; Pui C.H. et al. (2011)Neuromuscular impairments in adult survivors of childhood acute lymphoblastic leukemia: Associations with physical performance and chemotherapy doses Cance r, 113, pp. 828–838