Breast Cancer Research and Treatment

, Volume 125, Issue 3, pp 767–774 | Cite as

Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy

  • Dawn L. HershmanEmail author
  • Louis H. Weimer
  • Antai Wang
  • Grace Kranwinkel
  • Lois Brafman
  • Deborah Fuentes
  • Danielle Awad
  • Katherine D. Crew
Clinical trial


Neurotoxicity is a common side-effect during taxane therapy. The prevalence and severity of long-term neurotoxicity following therapy is unknown. The authors conducted a cross-sectional study of 50 consecutive patients with stage I–III BC, who were within 6 months and 2 years of completing adjuvant taxane therapy and a prospective study of 50 women initiating taxane therapy. Patients in the cross-sectional study underwent a one-time evaluation while patients in the prospective study underwent evaluation at baseline, following therapy, and 3, 6, 9, and 12 months after completing therapy. Assessments included quantitative sensory testing (QST) for touch perception and vibration threshold and the FACT-GOG Neurotaxane (FACT/GOG-Ntx). For the cross-sectional study, 81% of the women reported symptoms of numbness and/or discomfort in the hands and/or feet in the past week. Severe symptoms were reported in 27% of patients for the hands and 25% for the feet. In the cross-sectional analysis, hand numbness/discomfort correlated with hand vibration QST. In the prospective study, the mean scores on the FACT/GOG-Ntx decreased from 37.5 to 28.7 post-treatment (P = 0.0002), and remained low 12 months after treatment. The changes in hand/foot numbness/discomfort were significantly associated with change in vibration threshold. No significant change was seen in touch perception. Numbness and discomfort in the hands and feet are common for up to 2 years following taxane therapy, and are associated with vibration threshold. The FACT/GOG-Ntx is an appropriate outcome measure for clinical trials evaluating ways to prevent long-term neurotoxicity in BC survivors.


Cancer survivorship Neurotoxicity Patient reported outcomes 


  1. 1.
    Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH et al (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21(6):976–983CrossRefPubMedGoogle Scholar
  2. 2.
    De Laurentiis M, Cancello G, D’Agostino D, Giuliano M, Giordano A, Montagna E, Lauria R, Forestieri V, Esposito A, Silvestro L et al (2008) Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26(1):44–53CrossRefPubMedGoogle Scholar
  3. 3.
    Jones SE, Savin MA, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R et al (2006) Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24(34):5381–5387CrossRefPubMedGoogle Scholar
  4. 4.
    Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Freeman J, Goodwin JS (2006) Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst 98(6):382–388CrossRefPubMedGoogle Scholar
  5. 5.
    Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN (1993) The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rev 19(4):351–386CrossRefPubMedGoogle Scholar
  6. 6.
    Quasthoff S, Hartung HP (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249(1):9–17CrossRefPubMedGoogle Scholar
  7. 7.
    Loprinzi CL, Maddocks-Christianson K, Wolf SL, Rao RD, Dyck PJ, Mantyh P, Dyck PJ (2007) The Paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism. Cancer J 13(6):399–403CrossRefPubMedGoogle Scholar
  8. 8.
    Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munarriz B, Rodriguez CA, Crespo C, de Alava E et al (2008) Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer. J Natl Cancer Inst 100(11):805–814CrossRefPubMedGoogle Scholar
  9. 9.
    Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358(16):1663–1671CrossRefPubMedGoogle Scholar
  10. 10.
    Cancer therapy evaluation program, common terminology Criteria for adverse events, version 3.0, DCTD, NCI, NIH, DHHS. Accessed 31 Mar, 2003Google Scholar
  11. 11.
    Cella D, Peterman A, Hudgens S, Webster K, Socinski MA (2003) Measuring the side effects of taxane therapy in oncology: the functional assesment of cancer therapy-taxane (FACT-Taxane). Cancer 98(4):822–831CrossRefPubMedGoogle Scholar
  12. 12.
    Calhoun EA, Fishman DA, Roland PY (2000) Validity and sensitivity of the functional assessment of cancer therapy/Gynecologic oncology group-neurotoxicity (FACT/GOG-Ntx). Proc Am Soc Clin Oncol 19:2000Google Scholar
  13. 13.
    Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J et al (1993) The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 11(3):570–579PubMedGoogle Scholar
  14. 14.
    Huang HQ, Brady MF, Cella D, Fleming G (2007) Validation and reduction of FACT/GOG-Ntx subscale for platinum/paclitaxel-induced neurologic symptoms: a gynecologic oncology group study. Int J Gynecol Cancer 17(2):387–393CrossRefPubMedGoogle Scholar
  15. 15.
    Drobek W, De Laat A, Schoenaers J (2001) Tactile threshold and pressure pain threshold during treatment of orofacial pain: an explorative study. Clin Oral Investig 5(3):185–193CrossRefPubMedGoogle Scholar
  16. 16.
    Goldberg JM, Lindblom U (1979) Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatr 42(9):793–803CrossRefPubMedGoogle Scholar
  17. 17.
    Rowinsky EK, Flood WA, Sartorius SE, Bowling MK, Wagner J, Ettinger DS (1995) Phase I study of paclitaxel as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small cell lung cancer. Semin Oncol 22(4 Suppl 9):48–54PubMedGoogle Scholar
  18. 18.
    Cavaletti G, Cavalletti E, Oggioni N, Sottani C, Minoia C, D’Incalci M, Zucchetti M, Marmiroli P, Tredici G (2000) Distribution of paclitaxel within the nervous system of the rat after repeated intravenous administration. Neurotoxicology 21(3):389–393PubMedGoogle Scholar
  19. 19.
    Sahenk Z, Barohn R, New P, Mendell JR (1994) Taxol neuropathy electrodiagnostic and sural nerve biopsy findings. Arch Neurol 51(7):726–729PubMedGoogle Scholar
  20. 20.
    Schmidt Y, Unger JW, Bartke I, Reiter R (1995) Effect of nerve growth factor on peptide neurons in dorsal root ganglia after taxol or cisplatin treatment and in diabetic (db/db) mice. Exp Neurol 132(1):16–23CrossRefPubMedGoogle Scholar
  21. 21.
    Apfel SC, Lipton RB, Arezzo JC, Kessler JA (1991) Nerve growth factor prevents toxic neuropathy in mice. Ann Neurol 29(1):87–90CrossRefPubMedGoogle Scholar
  22. 22.
    Cavaletti G, Bogliun G, Marzorati L, Zincone A, Piatti M, Colombo N, Franchi D, La Presa MT, Lissoni A, Buda A et al (2004) Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy. Ann Oncol 15(9):1439–1442CrossRefPubMedGoogle Scholar
  23. 23.
    Aloe L, Manni L, Properzi F, De Santis S, Fiore M (2000) Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis. Auton Neurosci 86(1–2):84–93CrossRefPubMedGoogle Scholar
  24. 24.
    Verstappen CC, Heimans JJ, Hoekman K, Postma TJ (2003) Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 63(15):1549–1563CrossRefPubMedGoogle Scholar
  25. 25.
    Postma TJ, Heimans JJ, Muller MJ, Ossenkoppele GJ, Vermorken JB, Aaronson NK (1998) Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 9(7):739–744CrossRefPubMedGoogle Scholar
  26. 26.
    Brundage MD, Pater JL, Zee B (1993) Assessing the reliability of two toxicity scales: implications for interpreting toxicity data. J Natl Cancer Inst 85(14):1138–1148CrossRefPubMedGoogle Scholar
  27. 27.
    Shimozuma K, Ohashi Y, Takeuchi A, Aranishi T, Morita S, Kuroi K, Ohsumi S, Makino H, Mukai H, Katsumata N et al (2009) Feasibility and validity of the patient neurotoxicity questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02. Support Care Cancer 17(12):1483–1491CrossRefPubMedGoogle Scholar
  28. 28.
    Postma TJ, Aaronson NK, Heimans JJ, Muller MJ, Hildebrand JG, Delattre JY, Hoang-Xuan K, Lanteri-Minet M, Grant R, Huddart R et al (2005) The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 41(8):1135–1139CrossRefPubMedGoogle Scholar
  29. 29.
    Cavaletti G, Jann S, Pace A, Plasmati R, Siciliano G, Briani C, Cocito D, Padua L, Ghiglione E, Manicone M et al (2006) Multi-center assessment of the total neuropathy score for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 11(2):135–141CrossRefPubMedGoogle Scholar
  30. 30.
    Thornton LM, Carson WE 3rd, Shapiro CL, Farrar WB, Andersen BL (2008) Delayed emotional recovery after taxane-based chemotherapy. Cancer 113(3):638–647CrossRefPubMedGoogle Scholar
  31. 31.
    Kopec J, Land S, Cecchini R (2006) Validation of self-reported neurotoxicity scale in patients with operable colon cancer receiving oxaliplatin. J of Supp Oncol 4:W1–W8Google Scholar
  32. 32.
    Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D (2003) Psychometric evaluation of the functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13(6):741–748CrossRefPubMedGoogle Scholar
  33. 33.
    Hegarty A, Portenoy RK (1994) Pharmacotherapy of neuropathic pain. Semin Neurol 14(3):213–224CrossRefPubMedGoogle Scholar
  34. 34.
    Argyriou AA, Chroni E, Koutras A, Iconomou G, Papapetropoulos S, Polychronopoulos P, Kalofonos HP (2006) Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation. J Pain Symptom Manage 32(3):237–244CrossRefPubMedGoogle Scholar
  35. 35.
    Argyriou AA, Chroni E, Koutras A, Ellul J, Papapetropoulos S, Katsoulas G, Iconomou G, Kalofonos HP (2005) Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology 64(1):26–31PubMedGoogle Scholar
  36. 36.
    von Delius S, Eckel F, Wagenpfeil S, Mayr M, Stock K, Kullmann F, Obermeier F, Erdmann J, Schmelz R, Quasthoff S et al (2007) Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Invest new drugs 25(2):173–180CrossRefGoogle Scholar
  37. 37.
    Rao RD, Michalak JC, Sloan JA, Loprinzi CL, Soori GS, Nikcevich DA, Warner DO, Novotny P, Kutteh LA, Wong GY (2007) Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled, crossover trial (N00C3). Cancer 110(9):2110–2118CrossRefPubMedGoogle Scholar
  38. 38.
    Wang WS, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Chiou TJ, Liu JH, Yen CC, Chen PM (2007) Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 12(3):312–319CrossRefPubMedGoogle Scholar
  39. 39.
    Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G (2002) Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 20(16):3478–3483CrossRefPubMedGoogle Scholar
  40. 40.
    Cascinu S, Cordella L, Del Ferro E, Fronzoni M, Catalano G (1995) Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol 13(1):26–32PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Dawn L. Hershman
    • 1
    • 3
    • 4
    Email author
  • Louis H. Weimer
    • 2
  • Antai Wang
    • 3
  • Grace Kranwinkel
    • 1
  • Lois Brafman
    • 1
  • Deborah Fuentes
    • 1
  • Danielle Awad
    • 1
  • Katherine D. Crew
    • 1
    • 3
  1. 1.Department of MedicineCollege of Physicians and SurgeonsNew YorkUSA
  2. 2.Department of NeurologyCollege of Physicians and SurgeonsNew YorkUSA
  3. 3.Herbert Irving Comprehensive Cancer Center and the Department of EpidemiologyMailman School of Public Health, Columbia UniversityNew YorkUSA
  4. 4.Columbia UniversityNew YorkUSA

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