DISCUSSION
The temporal course of the HFSR suggests a palbociclibinduced etiology. The skin changes appeared a few weeks after initiating palbociclib and resolved rapidly after discontinuation, which is consistent with other reports of drug-induced HFSR. For example, in the setting of tyrosine kinase inhibitor (TKI) induced HFSR, the skin changes typically appear during the first month of treatment and remit within weeks of discontinuing therapy.4,6 The patient was not on other medications that could have caused the HFSR.
Drug induced HFSR is a well described side effect of selective Raf inhibitors as well as multikinase inhibitors that target Raf. Interestingly, Raf inhibition has been shown to upregulate expression of endogenous CDK inhibitors (p16, p27, p57).7 Thus, there may be a mechanistic link between Raf-inhibition-induced and CDK4/6-inhibitor-induced HFSR, though this relationship remains undefined and warrants further study. The currently accepted theory for the pathogenesis of HFSR is that of dermal capillary micro-trauma leading to drug extravasation, tissue damage, and inhibition of vascular repair at sites prone to mechanical and frictional stress.8
Physicians should be aware of this potential side effect of palbociclib as early consultation with dermatology and early intervention may avoid the need for dose interruption of lifesustaining oncologic therapy.9 Treatment centers around symptomatic therapy with urea-containing keratolytic emollients followed by high-potency topical steroids or oral corticosteroids in severe cases.4,6,8 Patients should also avoid tight-fitting shoes, use shock absorbers, and keep skin well moisturized.4,6,8 For cases requiring dose interruption or discontinuation, whether palbociclib can be reinitiated without recurrence of HFSR remains to be determined.
Drug induced HFSR is a well described side effect of selective Raf inhibitors as well as multikinase inhibitors that target Raf. Interestingly, Raf inhibition has been shown to upregulate expression of endogenous CDK inhibitors (p16, p27, p57).7 Thus, there may be a mechanistic link between Raf-inhibition-induced and CDK4/6-inhibitor-induced HFSR, though this relationship remains undefined and warrants further study. The currently accepted theory for the pathogenesis of HFSR is that of dermal capillary micro-trauma leading to drug extravasation, tissue damage, and inhibition of vascular repair at sites prone to mechanical and frictional stress.8
Physicians should be aware of this potential side effect of palbociclib as early consultation with dermatology and early intervention may avoid the need for dose interruption of lifesustaining oncologic therapy.9 Treatment centers around symptomatic therapy with urea-containing keratolytic emollients followed by high-potency topical steroids or oral corticosteroids in severe cases.4,6,8 Patients should also avoid tight-fitting shoes, use shock absorbers, and keep skin well moisturized.4,6,8 For cases requiring dose interruption or discontinuation, whether palbociclib can be reinitiated without recurrence of HFSR remains to be determined.
DISCLOSURES
The authors have no conflicts to disclose.
REFERENCES
1. Thill M, Schmidt, M. Management of adverse events during cyclindependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther Adv Med Oncol. 2018;10:1-12.
2. Guo L, Hu Y, Chen X, et al. Safety and efficacy profile of cyclin-dependent kinases 4/6 inhibitor palbociclib in cancer therapy: A meta-analysis of clinical trials. Cancer Med. 2019;8(4):1389-1400.
3. Khan, NAJ, Alsharedi, M. Bullous skin rash: a rare case of palbociclib-induced dermatological toxicity. Cureus. 2020;12(9): e10229.
4. Porta, C, Paglino, C, Imarisio, I, Bonomi, L. Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med. 2007;7:127-134.
5. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute.
6. Autier, J, Escudier, B, Wechsler, J, et al. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol. 2008;144(7):886-892.
7. Curry, JL, Falchook, GS, Hwu, W, et al. Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor. Am J Dermatopathol. 2013;35:125-128.
8. Miller, KK, Gorcey, L, McLellan, BN. Chemotherapy-induced hand-foot skin syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol. 2014;71(4):787.
9. Barrio, D, Ciccolini, D, Phillips, G, et al. Anticancer therapy interruption and diagnostic concordance between referring clinicians and dermatologists at Memorial Sloan Kettering Cancern Center. J Am Acad Dermatol. 2017;76(6):AB45.
2. Guo L, Hu Y, Chen X, et al. Safety and efficacy profile of cyclin-dependent kinases 4/6 inhibitor palbociclib in cancer therapy: A meta-analysis of clinical trials. Cancer Med. 2019;8(4):1389-1400.
3. Khan, NAJ, Alsharedi, M. Bullous skin rash: a rare case of palbociclib-induced dermatological toxicity. Cureus. 2020;12(9): e10229.
4. Porta, C, Paglino, C, Imarisio, I, Bonomi, L. Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med. 2007;7:127-134.
5. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Published: November 27. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute.
6. Autier, J, Escudier, B, Wechsler, J, et al. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol. 2008;144(7):886-892.
7. Curry, JL, Falchook, GS, Hwu, W, et al. Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor. Am J Dermatopathol. 2013;35:125-128.
8. Miller, KK, Gorcey, L, McLellan, BN. Chemotherapy-induced hand-foot skin syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol. 2014;71(4):787.
9. Barrio, D, Ciccolini, D, Phillips, G, et al. Anticancer therapy interruption and diagnostic concordance between referring clinicians and dermatologists at Memorial Sloan Kettering Cancern Center. J Am Acad Dermatol. 2017;76(6):AB45.
AUTHOR CORRESPONDENCE
Angad A. Chadha MD chadha@medicine.bsd.uchicago.edu
