Chemotherapy-Induced Neuropathy and Diabetes: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Oncology
Contributor:
Omar Cauli

Diabetes mellitus and cancer are among the four most common chronic diseases, and are two of the leading causes of death worldwide [1]. Treatment of cancer patients with chemotherapy is influenced by multiple aspects, including neuropathy induced by chemotherapy drugs their self.

  • toxicity
  • side effects
  • cold sensitivity
  • autonomic dysfunction
  • regimens
  • cytostatic drugs

1. Introduction

Chemotherapy-induced neuropathy is a significant source of morbidity in cancer patients, with high incidences (Table 1) and can be a dose-limiting side effect for many classes of chemotherapy drugs [1]. Diabetes mellitus is a commonly encountered comorbidity among patients with solid tumors [2][3][4]. Diabetes mellitus and its accompanying metabolic syndrome have been shown to correlate with the development and outcomes of a number of solid tumors [2][3][5]. Outcomes are often worse in cancer patients who also have diabetes [6]. It is well known that high blood glucose can damage peripheral nerves [7][8]; as such, patients with diabetes who are treated with chemotherapy drugs may be at greater risk of developing chemotherapy-related peripheral neuropathy [9]. Despite the high prevalence of neuropathy among cancer and diabetes patients, little is known about neuropathic symptoms among cancer patients with comorbid diabetes. Because peripheral neuropathy is commonly observed in patients with diabetes, most studies of chemotherapy-induced peripheral neuropathy exclude patients with diabetes [1]. An analysis of the trial E1199, which included 5052 patients with axillary node-positive or high-risk, node-negative breast cancer showed that patients who received adjuvant taxanes containing therapy, glycemic instability and obesity were associated with an increased risk of neuropathy. However, information regarding a pre-existing history of diabetes was not available in this study [10].
Table 1. Incidence of neuropathy induced by main classes of cancer chemotherapy drugs.
Class of Chemotherapy Drugs Drug Name Neuropathy Incidence (%) (Classified by Neurotoxicity Degrees) Reported Neurotoxic Doses
Anthracyclines Doxorubicin (Adriamycin) 75% (cognitive impairment “chemobrain”) [11] -
Taxanes Paclitaxel All grades: 60% [12]
Grade 3–4 motor: 11%
Grade 3–4 sensory: 33% [13]		 1000 mg/m2 cumulative dose [14]
Docetaxel All grades: 15% [12][15]
Grade 3–4: 2% [15]		 400 mg/m2 cumulative dose [14]
Platinum-based agents Cisplatin Grade 1:14–33%
Grade 2: 0–33%
Grade 3: 2–19%
Grade 4: 0–4% [16]		 250–450 mg/m2, and all patients develop neuropathy [16][17], at cumulative dose of 500–600 mg/m2 [18]
Oxaliplatin Grade 1: 21–94%
Grade 2: 5–42%
Grade 3–4: 3–19% [16][19]		 >550 mg/m2
Severe neurotoxicity at cumulative dose of 750–850 mg/m2 [20]
Chronic neuropathy with a cumulative dose between 850 mg/m2 and 1800 mg/m2 [16]
Carboplatin All grades: 4–6% [21] >400 mg/m2
Neurotoxicity only with high doses or in combination with other drugs [17]
Vinca alkaloids Vincristine Grade 1–2: 60% [12] 30–50 mg [12][17]
Vinorelbine All grades: 44% [22]
Grade 3–4: ≈ 2% [23]		 125 mg/m2 [22]
Antimetabolites 5-fluorouracil
(5-FU)		 All grades: 0.6–7% [24][25]
or 12.9% [26]
Grade 3–4: 0% [26]		 Uncertain [27]
High doses and use of 5-FU in combined treatment, increase the risk of neuropathy [28]
  Gemcitabine All grades: 6% [29] -
  Methotrexate All grades: 3–10% [28] -

Although there is considerable evidence that patients with pre-existing symptoms of diabetic neuropathy or other types of neuropathies are at increased risk of developing a higher grade following chemotherapy with cytostatic agents [30], there are no published reviews on the effect of chemotherapy administration in diabetic patients who do not have neuropathy or the evolution of neuropathy during cancer treatment in diabetic patients. The incidence of chemotherapy-induced peripheral neuropathy depends largely on the type of agent used, the duration of treatment (number of chemotherapy cycles received) and the dose used. In the case of diabetic patients it has been postulated that the loss of axonal integrity due to decreased regeneration makes diabetic patients prone to neuronal toxicity from drugs such as chemotherapy [31].

Among the pharmacological agents that have the greatest ability to induce peripheral neuropathy in oncological patients, taxanes and platinum derivatives have been the most studied [32]. For example, in treatment with the oxaliplatin derivative, a drug widely used in colorectal and other cancers, neurotoxicity usually presents mainly as peripheral sensory neuropathy, which can become persistent and therefore can be a dose-limiting toxicity of oxaliplatin or even treatment discontinuation. Persistent peripheral sensory neuropathy is cumulative with doses received, and in the case of oxaliplatin for example, severe neuropathy (Grade 3 and 4) occurs in 10–20% of patients receiving total doses of this drug from >750–850 mg/m 2 [33]. Paclitaxel (taxanes family) induced peripheral neuropathy usually begins with paresthesia and numbness and is also cumulative and may result in patient functional impairment and limitation of use [34].

It is well known that diabetic patients with neuropathy have a lower quality of life, an increased risk of falls [35], and are at increased risk of ulcerations, which in turn can lead to lower extremity amputation [36]. Although in some cases symptoms may improve with appropriate glycemic control, a significant number of patients continue to experience neuropathic symptoms many years after the end of treatment [6].

2. Relationship between Chemotherapy, Neuropathy and Diabetes

The analysis reveals that most neuropathic symptoms or the onset of neuropathy occurs at an early stage [37] or at lower doses [1] in diabetic patients than in non-diabetic patients treated by chemotherapy. Moreover, among diabetic patients receiving chemotherapy, neuropathy rates were higher in patients with a longer duration of diabetes [38]. However, this deleterious effect was not associated with differences in cancer treatment including chemotherapy, which suggests that diabetes mellitus rather than chemotherapy could be responsible for these symptoms. In addition, the effects seem to last longer, since two years after treatment, peripheral neuropathy persisted in a higher proportion of diabetic patients than in non-diabetic patients (68.7% vs. 29.2%). Furthermore, it was a functionally significant peripheral neuropathy in 18.2% of the cases [34]. Since not all chemotherapeutic drugs have the same ability to cause peripheral neuropathy, the drugs investigated are chemotherapy drugs with a high potential to induce neuropathy, such as platinum compounds and taxanes, which are currently the mainstay of treatment for various common tumors. Clinical studies report incidences of neuropathy after chemotherapy of up to 60% with cisplatin, paclitaxel, docetaxel and oxaliplatin, among other drugs [39][40][41]. In particular, oxaliplatin, which is widely used in the treatment of colon cancer, causes acute and transient neurotoxicity in almost all patients treated, and subsides after about 48 h [16][42], and becomes chronic in a few cases [39]. Some of these studies mention that the risk of paresthesia is increased in diabetic patients during the first minutes of infusion [43] and development takes place in a shorter time or with lower cumulative doses compared with non-diabetic patients [1][37]. Future studies should evaluate the influence of the severity and duration of diabetes. As for acute chemotherapy-induced neurological symptoms, Abdel-Rahman (2018) [37], found no differences between diabetic and non-diabetic patients, although diabetic patients developed oxaliplatin-induced paresthesia in a shorter time. Vissers et al. (2015) [6] concluded that diabetic patients suffered a higher burden of neuropathic symptoms than non-diabetic patients, regardless of the antineoplastic treatment.

Subsequent studies that have also worked directly with the diabetic population have observed that diabetes acts as a risk factor in terms of the incidence and severity of peripheral neuropathy in those patients treated with chemotherapy [34][38]. Kus et al. (2016) [38] jointly evaluated the influence of taxanes and their combination with platinum derivatives and found that the incidence was higher in diabetic patients who received the combination of both agents. They also grouped patients by degree of hyperglycemia, but this did not show any difference in the development of peripheral neuropathy [38].

At present it is known that chemotherapy-induced neuropathy interferes with the quality of life and it is often accompanied by depressive symptoms and apathy and abandonment of leisure activities and physical activity [44][45][46]. It should be taken into account that the symptoms of neuropathy can last between two to eleven years after its diagnosis in more than half of the patients, where tingling and numbness affect 70% of the patients with chemotherapy-induced peripheral neuropathy [46] and those patients displaying higher neuropathy symptoms also showed a reduced quality of life after chemotherapy discontinuation as recently reported for taxanes in patients with breast cancer [47] and for oxaliplatin in colorectal cancer patients [48] or carboplatin/taxanes regimen in patients with gynecologic cancer survivors [49]. Regarding diabetic patients and chemotherapy-induced neuropathy in terms of health-related quality of life, the study by Visser et al. by using the European Organization for Research and Treatment of Cancer quality of life questionnaire—chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) evaluated the differences in neuropathic symptoms between colorectal cancer patients with and without diabetes. Those with diabetes reported a decreased quality of life associated with higher impairment in sensitive symptoms such as tingling in fingers, hands, toes and feet, numbness, aching or burning pain in toes or feet, and trouble while standing or walking. In contrast, no differences were reported for neuropathic symptoms regarding motor symptoms or autonomic dysfunction except for getting or maintaining an erection in men [6].

Future studies investigating the risk of neuropathy in cancer patients with comorbid diabetes need to be analyzed considering the duration of diabetes, cancer-induced neuropathic effects per se, prior cancer management strategies such as radiotherapy and surgery, and the type and dose of chemotherapy used.

This entry is adapted from the peer-reviewed paper 10.3390/curroncol28040273

References

  1. Uwah, A.N.; Ackler, J.; Leighton, J.C.; Pomerantz, S.; Tester, W. The effect of diabetes on oxaliplatin-induced peripheral neuropathy. Clin. Colorectal Cancer 2012, 11, 275–279.
  2. Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and cancer: A consensus report. Diabetes Care 2010, 33, 1674–1685.
  3. Vona-Davis, L.; P. Rose, D. Type 2 Diabetes and Obesity Metabolic Interactions: Common Factors for Breast Cancer Risk and Novel Approaches to Prevention and Therapy. Curr. Diabetes Rev. 2012, 8, 116–130.
  4. Tuccori, M.; Convertino, I.; Galiulo, M.T.; Marino, A.; Capogrosso-Sansone, A.; Blandizzi, C. Diabetes drugs and the incidence of solid cancers: A survey of the current evidence. Expert Opin. Drug Saf. 2017, 16, 1133–1148.
  5. Wilde, L.; Roche, M.; Domingo-Vidal, M.; Tanson, K.; Philp, N.; Curry, J.; Martinez-Outschoorn, U. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin. Oncol. 2017, 44, 198–203.
  6. Vissers, P.A.J.; Mols, F.; Thong, M.S.Y.; Pouwer, F.; Vreugdenhil, G.; van de Poll-Franse, L.V. The impact of diabetes on neuropathic symptoms and receipt of chemotherapy among colorectal cancer patients: Results from the PROFILES registry. J. Cancer Surviv. 2015, 9, 523–531.
  7. Soroku, Y.; Mizukami, H.; Sugimoto, K. Mechanism of diabetic neuropathy: Where are we now and where to go? J. Diabetes Investig. 2011, 2, 18–32.
  8. Dewanjee, S.; Das, S.; Das, A.K.; Bhattacharjee, N.; Dihingia, A.; Dua, T.K.; Kalita, J.; Manna, P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur. J. Pharmacol. 2018, 833, 472–523.
  9. Hershman, D.L.; Till, C.; Wright, J.D.; Awad, D.; Ramsey, S.D.; Barlow, W.E.; Minasian, L.M.; Unger, J. Comorbidities and risk of chemotherapy-induced peripheral neuropathy among participants 65 years or older in southwest oncology group clinical trials. J. Clin. Oncol. 2016, 34, 3014–3022.
  10. Schneider, B.P.; Zhao, F.; Wang, M.; Stearns, V.; Martino, S.; Jones, V.; Perez, E.A.; Saphner, T.; Wolff, A.C.; Sledge, G.W.; et al. Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer. J. Clin. Oncol. 2012, 30, 3051–3057.
  11. Alhowail, A.H.; Bloemer, J.; Majrashi, M.; Pinky, P.D.; Bhattacharya, S.; Yongli, Z.; Bhattacharya, D.; Eggert, M.; Woodie, L.; Buabeid, M.A.; et al. Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation. Toxicol. Mech. Methods 2019, 29, 457–466.
  12. Argyriou, A.A.; Kyritsis, A.P.; Makatsoris, T.; Kalofonos, H.P. Chemotherapy-induced peripheral neuropathy in adults: A comprehensive update of the literature. Cancer Manag. Res. 2014, 6, 135–147.
  13. Winer, E.P.; Berry, D.A.; Woolf, S.; Duggan, D.; Kornblith, A.; Harris, L.N.; Michaelson, R.A.; Kirshner, J.A.; Fleming, G.F.; Perry, M.C.; et al. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and leukemia group B trial 9342. J. Clin. Oncol. 2004, 22, 2061–2068.
  14. Grisold, W.; Cavaletti, G.; Windebank, A.J. Peripheral neuropathies from chemotherapeutics and targeted agents: Diagnosis, treatment, and prevention. Neuro. Oncol. 2012, 14 (Suppl. S4), iv45–iv54.
  15. Kruijtzer, C.M.F.; Verweij, J.; Schellens, J.H.M.; Beijnen, J.H.; Pronk, L.; Bo, M.; Lustig, V.; Van Tinteren, H.; Mackay, M.; Ten Bokkel Huinink, W.W. Docetaxel in 253 previously treated patients with progressive locally advanced or metastatic breast cancer: Results of a compassionate use program in The Netherlands. Anticancer Drugs 2000, 11, 249–255.
  16. Staff, N.P.; Cavaletti, G.; Islam, B.; Lustberg, M.; Psimaras, D.; Tamburin, S. Platinum-induced peripheral neurotoxicity: From pathogenesis to treatment. J. Peripher. Nerv. Syst. 2019, 24, S26–S39.
  17. Quasthoff, S.; Hartung, H.P. Chemotherapy-induced peripheral neuropathy. J. Neurol. 2002, 249, 9–17.
  18. Argyriou, A.A.; Bruna, J.; Marmiroli, P.; Cavaletti, G. Chemotherapy-induced peripheral neurotoxicity (CIPN): An update. Crit. Rev. Oncol. Hematol. 2012, 82, 51–77.
  19. Soularue, É.; Cohen, R.; Tournigand, C.; Zaanan, A.; Louvet, C.; Bachet, J.B.; Hentic, O.; Samalin, E.; Chibaudel, B.; de Gramont, A.; et al. Efficacité et tolérance du trastuzumab en association avec oxaliplatine et fluoropyrimidine; pour des patients avec adénocarcinome métastatique de l’estomac ou de la jonction œso-gastrique: Une étude rétrospective. Bull. Cancer 2015, 102, 324–331.
  20. Park, S.B.; Goldstein, D.; Krishnan, A.V.; Lin, C.S.-Y.; Friedlander, M.L.; Cassidy, J.; Koltzenburg, M.; Kiernan, M.C. Chemotherapy-induced peripheral neurotoxicity: A critical analysis. CA Cancer J. Clin. 2013, 63, 419–437.
  21. Amptoulach, S.; Tsavaris, N. Neurotoxicity Caused by the Treatment with Platinum Analogues. Chemother. Res. Pract. 2011, 2011, 1–5.
  22. Wu, Y.; Wang, Q.; Zhang, J.; Cao, J.; Wang, B.; Hu, X. Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: Sub-group analysis of a randomized phase III study. Support. Care Cancer 2020, 28, 3819–3829.
  23. Martín, M.; Ruiz, A.; Muñoz, M.; Balil, A.; García-Mata, J.; Calvo, L.; Carrasco, E.; Mahillo, E.; Casado, A.; García-Saenz, J.Á.; et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: Final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007, 8, 219–225.
  24. Ray, J.; Mahmood, A.; Dogar, M.; Guo, J.; Nwamaghinna, F.; Salciccioli, L.; McFarlane, S.I. Simultaneous Cardiotoxicity and Neurotoxicity Associated with 5-fluorouracil Containing Chemotherapy: A Case Report and Literature Review. Am. J. Med. Case Rep. 2020, 8, 73–75.
  25. Nguyen, M.T.; Stoianovici, R.; Brunetti, L. Chemotherapy induced stroke mimic: 5-Fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy. Am. J. Emerg. Med. 2017, 35, 1389–1390.
  26. Esin, E.; Telli, T.A.; Yuce, D.; Yalcin, S. A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity. Tumori 2018, 104, 157–164.
  27. Moore, D.H.; Fowler, W.C.; Crumpler, L.S. 5-Fluorouracil neurotoxicity. Gynecol. Oncol. 1990, 36, 152–154.
  28. Pellacani, C.; Eleftheriou, G. Neurotoxicity of antineoplastic drugs: Mechanisms, susceptibility, and neuroprotective strategies. Adv. Med. Sci. 2020, 65, 265–285.
  29. Dormann, A.J.; Grünewald, T.; Wigginghaus, B.; Huchzermeyer, H. Gemcitabine-associated autonomic neuropathy. Lancet 1998, 351, 644.
  30. Verstappen, C.C.P.; Heimans, J.J.; Hoekman, K.; Postma, T.J. Neurotoxic Complications of Chemotherapy in Patients with Cancer. Drugs 2003, 63, 1549–1563.
  31. Khoshnoodi, M.A.; Ebenezer, G.J.; Polydefkis, M. Epidermal innervation as a tool to study human axonal regeneration and disease progression. Exp. Neurol. 2017, 287, 358–364.
  32. Nurgalieva, Z.; Xia, R.; Liu, C.C.; Burau, K.; Hardy, D.; Du, X.L. Risk of chemotherapy-induced peripheral neuropathy in large population-based cohorts of elderly patients with breast, ovarian, and lung cancer. Am. J. Ther. 2010, 17, 148–158.
  33. de Gramont, A.; Figer, A.; Seymour, M.; Homerin, M.; Hmissi, A.; Cassidy, J.; Boni, C.; Cortes-Funes, H.; Cervantes, A.; Freyer, G.; et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J. Clin. Oncol. 2000, 18, 2938–2947.
  34. De La Morena Barrio, P.; Vicente Conesa, M.Á.; González-Billalabeitia, E.; Urrego, E.; García-Garre, E.; García-Martínez, E.; Poves, M.Z.; Vicente, V.; de la Peña, F.A. Delayed recovery and increased severity of paclitaxel-induced peripheral neuropathy in patients with diabetes. J. Natl. Compr. Cancer Netw. 2015, 13, 417–423.
  35. Van Schie, C.H.M. Neuropathy: Mobility and quality of life. Diabetes. Metab. Res. Rev. 2008, 24 (Suppl. S1), S45–S51.
  36. Bruun, C.; Siersma, V.; Guassora, A.D.; Holstein, P.; de Fine Olivarius, N. Amputations and foot ulcers in patients newly diagnosed with type 2 diabetes mellitus and observed for 19 years. The role of age, gender and co-morbidity. Diabet. Med. 2013, 30, 964–972.
  37. Abdel-Rahman, O. Impact of diabetes comorbidity on the efficacy and safety of FOLFOX first-line chemotherapy among patients with metastatic colorectal cancer: A pooled analysis of two phase-III studies. Clin. Transl. Oncol. 2019, 21, 512–518.
  38. Kus, T.; Aktas, G.; Kalender, M.E.; Sevinc, A.; Kul, S.; Suner, A.; Ulker, E.; Camci, C. Taxane-induced peripheral sensorial neuropathy in cancer patients is associated with duration of diabetes mellitus: A single-center retrospective study. Support. Care Cancer 2016, 24, 1175–1179.
  39. Velasco, R.; Bruna, J. Neuropatía inducida por quimioterapia: Un problema no resuelto. Neurologia 2010, 25, 116–131.
  40. Seretny, M.; Currie, G.L.; Sena, E.S.; Ramnarine, S.; Grant, R.; Macleod, M.R.; Colvin, L.A.; Fallon, M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain 2014, 155, 2461–2470.
  41. Colvin, L.A.; Europe PMC Funders Group. Chemotherapy-induced peripheral neuropathy (CIPN): Where are we now? Pain 2019, 160 (Suppl. S1), S1–S10.
  42. Gebremedhn, E.G.; Shortland, P.J.; Mahns, D.A. The incidence of acute oxaliplatin-induced neuropathy and its impact on treatment in the first cycle: A systematic review. BMC Cancer 2018, 18, 1–10.
  43. Bano, N.; Ikram, R. Effect of diabetes on neurological adverse effects and chemotherapy induced peripheral neuropathy in advanced colorectal cancer patients treated with different FOLFOX regimens. Pak. J. Pharm. Sci. 2019, 32, 125–130.
  44. Postma, T.J.; Aaronson, N.K.; Heimans, J.J.; Muller, M.J.; Hildebrand, J.G.; Delattre, J.Y.; Hoang-Xuan, K.; Lantéri-Minet, M.; Grant, R.; Huddart, R.; et al. The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: The QLQ-CIPN20. Eur. J. Cancer 2005, 41, 1135–1139.
  45. Mols, F.; Beijers, T.; Lemmens, V.; van den Hurk, C.J.; Vreugdenhil, G.; van de Poll-Franse, L.V. Chemotherapy-Induced Neuropathy and Its Association with Quality of Life Among 2- to 11-Year Colorectal Cancer Survivors: Results from the Population-Based PROFILES Registry. J. Clin. Oncol. 2013, 31, 2699–2707.
  46. Ibrahim, E.Y.; Ehrlich, B.E. Prevention of chemotherapy-induced peripheral neuropathy: A review of recent findings. Crit. Rev. Oncol. Hematol. 2020, 145, 102831.
  47. Salehifar, E.; Janbabaei, G.; Alipour, A.; Tabrizi, N.; Avan, R. Taxane-induced peripheral neuropathy and quality of life in breast cancer patients. J. Oncol. Pharm. Pract. 2020, 26, 1421–1428.
  48. Soveri, L.M.; Lamminmäki, A.; Hänninen, U.A.; Karhunen, M.; Bono, P.; Osterlund, P. Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy. Acta Oncol. 2019, 58, 398–406.
  49. Matsuoka, H.; Nakamura, K.; Matsubara, Y.; Ida, N.; Saijo, M.; Ogawa, C.; Masuyama, H. The Influence of Chemotherapy-Induced Peripheral Neuropathy on Quality of Life of Gynecologic Cancer Survivors. Int. J. Gynecol. Cancer 2018, 28, 1394–1402.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback