Chemotherapy in patients with early breast cancer: clinical overview and management of long-term side effects

Figures & data

Figure 1. Long-term side effects of chemotherapy for early breast cancer.

Table 1. Summary of main management strategies.

Side effect	Prevention	Management	References
Fatigue	N/A	Non-pharmacological: Moderate intensity exercise Cognitive-behavioral therapy Yoga Complementary medicine: Wisconsin Ginseng Acupuncture Pharmacological: Methylphenidate: 5–30/40 mg Dexmethylphenidate: 10–50 mg/day	[14, 15] [18] [20, 21][22] [24][25–27] [28]
Insomnia	N/A	Non-pharmacological: Moderate intensity exercise Yoga [57, 58] Cognitive-behavioral therapy Pharmacological: Lorazepam: 1–2 mg/day Zolpidem: 10 mg/day Melatonin: 6 mg/day	[58, 59] [62, 63] [64–66][72] [72] [73]
Peripheral neuropathy	Exercise Functional training	Non-pharmacological: Moderate intensity exercise Functional and balance training Complementary medicine: Acupuncture Pharmacological: Duloxetine: (30 mg/day for 1 week, then 60 mg/day for 4 weeks) Venlafaxine (37.5 –225 mg daily) Amitriptyline (10 –50 mg/day)	[85, 88] [88][86] [90] [91] [92] Prevention: [75, 82]
Cognitive Impairment	N/A	Non-pharmacological: Relaxation and mindfulness training Moderate intensity exercise Brain-training computer programs Pharmacological: Modafinil (200 mg day for 4 weeks) Donepezil (5 mg/day for 6 weeks, then 10 mg/day for 18 weeks)	[107, 108] [109] [110][112] [113]
Fertility and sexual health	Embryos/oocytes/ovarian tissue cryopreservation Gonadotropin-releasing hormone agonist Vit. D supplementation and regular exercise (for bone health)	Non-pharmacological: Cognitive behavioral therapy Non-hormonal vaginal lubricants Vaginal dilators (associated with pelvic floor exercises) Physical exercise and yoga Pharmacological: Gabapentin (900–2,400 mg/day) Venlafaxine (37.5 –75 mg/day)	[119, 120] [119, 120] [119, 120][124, 125][132] [134] Prevention: [117, 118, 139]
Cardiotoxicity	Correction of basal risk factors Liposomal formulations Dexrazoxane (1 mg for each 10 mg of doxorubicin, given at least 30 min prior to each doxorubicin infusion) Enalapril (2.5– 20 mg daily) Candesartan (32 mg q.d)	Treatment suspension and cardiologist evaluation for initiation of a cardioprotective treatment.	Prevention: Liposomal formulations: [155–158] Dexrazoxane: [159, 160] Enalapril: [166] Candesartan: [167]

Table 2. Summary of clinical presentation of the main chemotherapy drugs for breast cancer inducing CIPN.

Drugs	CIPN incidence (%)	Clinical presentation and specific features	References
Carboplatin	G 1–4: 10–27%	Paresthesia, ataxia, mild pain; less frequent and severe than other platinum compounds, mostly in higher doses.	[74]
Vincristine	G 1–4: 35–61%	Sensory: pain and temperature sensation. Autonomic: constipation, less frequently orthostatic hypotension, bladder dysfunction and impotence. Early manifestation (after 3 doses): Raynaud syndrome. Motor: mononeuropathies including tibial and peroneal nerves, distal weakness, cranial nerve palsy. Rarely Guillain–Barrè Syndrome, very occasionally accompanied by fulminant tetraplegia	[74]
Docetaxel	G 3/4: 10%	Pain, paresthesias, loss of temperature sensation, loss of proprioception with ataxia. Proximal weakness with concomitant sensory neuropathy (17%) Acute: Paclitaxel: musculoskeletal pain within 72 h in up to 60% of patients, (painful arthralgias, axial- and limbs myalgias) Docetaxel: arthralgias nab-paclitaxel: shorter time to improvement after completion of chemotherapy	[78]
Paclitaxel	G 3/4: 20–35% (250 mg/m^2 every 3 weeks) 5–12% (≤200 mg/m^2 every 3 weeks		[78]
Nab-paclitaxel	G 3/4: 9% (100 mg/m^2 days 1, 8, 15 every 4 weeks) to 21–22% (300 mg/m^2 every 3 weeks and 150 mg/m^2 days 1, 8, 15 every 4 weeks, respectively)		[79]

• CIPN: chemotherapy-induced peripheral neuropathy. G: Grade (as defined by the Common Toxicity Criteria for Adverse Events (CTCAE) scale).

Brown JC, Huedo-Medina TB, Pescatello LS, et al. Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2011;20(1):123–133.

 PubMed Web of Science ®Google Scholar

Tomlinson D, Diorio C, Beyene J, et al. Effect of exercise on cancer-related fatigue: a meta-analysis. Am J Phys Med Rehabil. 2014;93(8):675–686.

 PubMed Web of Science ®Google Scholar

Gielissen MFM, Verhagen S, Witjes F, et al. Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol. 2006;24(30):4882–4887.

 PubMed Web of Science ®Google Scholar

Buffart LM, van Uffelen JGZ, Riphagen II, et al. Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2012;12(1):559.

 PubMedGoogle Scholar

Danhauer SC, Addington EL, Cohen L, et al. Yoga for symptom management in oncology: a review of the evidence base and future directions for research. Cancer. 2019;125(12):1979–1989.

 PubMed Web of Science ®Google Scholar

Barton DL, Liu H, Dakhil SR, et al. Wisconsin ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2. J Natl Cancer Inst. 2013;105(16):1230–1238.

 PubMedGoogle Scholar

Zhang Y, Lin L, Li H, et al. Effects of acupuncture on cancer-related fatigue: a meta-analysis. supportive care in cancer. J Multinat Assoc Support Care Cancer. 2018;26(2):415–425.

 PubMed Web of Science ®Google Scholar

Lower EE, Fleishman S, Cooper A, et al. Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage. 2009;38(5):650–662.

 PubMed Web of Science ®Google Scholar

King AC, Oman RF, Brassington GS, et al. Moderate-intensity exercise and self-rated quality of sleep in older adults. a randomized controlled trial. JAMA. 1997;277(1):32–37.

 PubMed Web of Science ®Google Scholar

Tworoger SS, Yasui U, Vitiello MV, et al. Effects of a year long moderate-intensity exercise and a stretching intervention on sleep quality in postmenopausal women. Sleep. 2003;26(7):830–836.

 PubMed Web of Science ®Google Scholar

Mustian KM, Palesh O, Sprod L, et al. Effect of YOCAS yoga on sleep, fatigue, and quality of life: a URCC CCOP randomized, controlled clinical trial among 410 cancer survivors. J Clin Oncol. 2010;28(15_suppl):9013.

 Google Scholar

Mustian KM, Sprod LK, Janelsins M, et al. Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol. 2013;31(26):3233–3241.

 PubMed Web of Science ®Google Scholar

Costantini C, Ale-Ali A, Helsten T. Sleep aid prescribing practices during neoadjuvant or adjuvant chemotherapy for breast cancer. J Palliat Med. 2011;14(5):563–566.

 PubMed Web of Science ®Google Scholar

Chen WY, Giobbie-Hurder A, Gantman K, et al. A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes. Breast Cancer Res Treat. 2014;145(2):381–388.

 PubMed Web of Science ®Google Scholar

Kleckner IR, Kamen C, Gewandter JS, et al. Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial. Support Care Cancer. 2018;26(4):1019–1028.

 PubMed Web of Science ®Google Scholar

Tamburin S, Park SB, Schenone A, et al. Rehabilitation, exercise, and related non-pharmacological interventions for chemotherapy-induced peripheral neurotoxicity: systematic review and evidence-based recommendations. Crit Rev Oncol Hematol. 2022;171:103575.

 PubMed Web of Science ®Google Scholar

Lu W, Giobbie-Hurder A, Freedman RA, et al. Acupuncture for chemotherapy-induced peripheral neuropathy in breast cancer survivors: a randomized controlled pilot trial. Oncologist. 2020;25(4):310–318.

 PubMed Web of Science ®Google Scholar

Smith EML, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309(13):1359.

 PubMed Web of Science ®Google Scholar

Durand JP, Deplanque G, Montheil V, et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase iii trial. Ann Oncol. 2012;23(1):200–205.

 PubMed Web of Science ®Google Scholar

Kautio A, Haanpää M, Saarto T, et al. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008;35(1):31–39.

 PubMed Web of Science ®Google Scholar

Jordan B, Margulies A, Cardoso F, et al. Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO-EONS-EANO clinical practice guidelines for diagnosis, prevention, treatment and follow-up. Ann Oncol. 2020;31(10):1306–1319.

 PubMed Web of Science ®Google Scholar

Crevenna R, Ashbury FD. Physical interventions for patients suffering from chemotherapy-induced polyneuropathy. Support Care Cancer. 2018;26(4):1017–1018.

 PubMed Web of Science ®Google Scholar

Chiesa A, Calati R, Serretti A. Does mindfulness training improve cognitive abilities? a systematic review of neuropsychological findings. Clin Psychol Rev. 2011;31(3):449–464.

 PubMed Web of Science ®Google Scholar

Duval A, Davis CG, Khoo EL, et al. Mindfulness-based stress reduction and cognitive function among breast cancer survivors: a randomized controlled trial. Cancer. 2022;128(13):2520–2528.

 PubMed Web of Science ®Google Scholar

Hartman SJ, Nelson SH, Myers E, et al. Randomized controlled trial of increasing physical activity on objectively measured and self-reported cognitive functioning among breast cancer survivors: the memory & motion study. Cancer. 2018;124(1):192–202.

 PubMed Web of Science ®Google Scholar

Von Ah D, Carpenter JS, Saykin A, et al. Advanced cognitive training for breast cancer survivors: a randomized controlled trial. Breast Cancer Res Treat. 2012;135(3):799–809.

 PubMed Web of Science ®Google Scholar

Kohli S, Fisher SG, Tra Y, et al. The effect of modafinil on cognitive function in breast cancer survivors. Cancer. 2009;115(12):2605–2616.

 PubMed Web of Science ®Google Scholar

Shaw EG, Rosdhal R, D’Agostino RB, et al. Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J Clin Oncol. 2006;24(9):1415–1420.

 PubMed Web of Science ®Google Scholar

Franzoi MA, Agostinetto E, Perachino M, et al. Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer. Lancet Oncol. 2021;22(7):e303–13.

 PubMed Web of Science ®Google Scholar

Bober SL, Fine E, Recklitis CJ. Sexual health and rehabilitation after ovarian suppression treatment (SHARE-OS): a clinical intervention for young breast cancer survivors. J Cancer Survivorship. 2020;14(1):26–30.

 PubMed Web of Science ®Google Scholar

Carson JW, Carson KM, Porter LS, et al. Yoga of awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer. 2009;17(10):1301–1309.

 PubMed Web of Science ®Google Scholar

Walker EM, Rodriguez AI, Kohn B, et al. Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor–positive breast cancer: a randomized controlled trial. J Clin Oncol. 2010;28(4):634–640.

 PubMed Web of Science ®Google Scholar

Loprinzi CL, Sloan J, Stearns V, et al. Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol. 2009;27(17):2831–2837.

 PubMed Web of Science ®Google Scholar

Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356(9247):2059–2063.

 PubMed Web of Science ®Google Scholar

Arecco L, Ruelle T, Martelli V, et al. How to protect ovarian function before and during chemotherapy? J Clin Med. 2021;10(18):4192.

 PubMed Web of Science ®Google Scholar

Moore HCF, Unger JM, Phillips K, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;372(10):923–932.

 PubMed Web of Science ®Google Scholar

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194–1220.

 PubMed Web of Science ®Google Scholar

van Dalen EC, Caron HN, Dickinson HO, et al. Cardioprotective interventions for cancer patients receiving anthracyclines. edited by Cochrane gynaecological, neuro-oncology and orphan cancer group. Cochrane Database Syst Rev. 2011;2016(9).

 Google Scholar

Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10(1):337.

 PubMed Web of Science ®Google Scholar

Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin converting enzyme inhibition. Circulation. 2006;114(23):2474–2481.

 PubMed Web of Science ®Google Scholar

Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671–1680.

 PubMed Web of Science ®Google Scholar

Cavaletti G, Marmiroli P, and Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nat Rev Neurol. 2010;6(12):657–666.

 PubMed Web of Science ®Google Scholar

Argyriou AA, Koltzenburg M, Polychronopoulos P, et al. Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol. 2008;66(3):218–228.

 PubMed Web of Science ®Google Scholar

Rivera E, Cianfrocca M. Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer. Cancer Chemother Pharmacol. 2015;75(4):659–670.

 PubMed Web of Science ®Google Scholar