Title: Side effects of tyrosine kinase inhibitors

* Second of a new series of ‘Mini-Editorials’ in ‘Thyroid News’

While accounting for only 1% of solid malignancies, thyroid carcinoma is the most common malignancy of the endocrine system. The majority are patients with well-differentiated thyroid carcinoma of follicular cell origin who are cured with adequate surgical management and radioiodine therapy. However, some thyroid malignancies, such as medullary thyroid carcinoma (MTC) or poorly differentiated thyroid carcinoma, frequently metastasize, precluding patients from a curative resection.

The molecular bases of differentiated thyroid carcinoma, MTC, and anaplastic thyroid cancer are well characterized and the critical genetic pathways involved in the development of specific tumor histological types have been elucidated. Of primary importance has been the recognition of key oncogenic mutations such as BRAF, RET and RAS in papillary (PTC) and RET in medullary (MTC) carcinomas. These genes code for kinases that activate signalling through the MAPK pathway, regulating growth and function 1. In addition, non thyroid specific genes also play a critical role in tumor cell growth and metastasis, such as genes regulating angiogenesis 2. Of the identified pro-angiogenic factors, vascular endothelial growth factor (VEGF) is key, binding to two tyrosine kinase receptors, the VEGF receptor (VEGFR-1 and VEGFR-2) that also triggers MAPK signalling. In PTC, the intensity of VEGF expression correlates with a higher risk of metastasis and recurrence, and a shorter disease-free survival.

In recent years, translational research in oncology has produced multiple agents targeting signalling kinases. Some exert direct effects against RET (in MTC) and against BRAF, RET/PTC (in PTC), while others target common mechanisms of tumor growth, invasion and metastases, such as VEGF-mediated angiogenesis, or both (see Table 1 ). Several drugs that have recently been used in clinical trials (phase II-III) are listed in Table 2 . The Table shows the rate of disease stabilization (between 40-81%) and partial responses on tumor growth (between 2-29%). Although these targeted agents have produced promising clinical results, their overall effectiveness is hampered by the development of a variety of toxic effects: diarrhoea, nausea vomiting, fatigue, and alopecia are the most common adverse events associated with tyrosine kinase inhibitors (TKIs). However, they only rarely reach toxicity grades 3-4, thereby implicating the need to discontinue treatment. Hematologic complications have also been reported, such as grades 3-4 neutropenia, trombocytopenia, lymphopenia, anemia and other hematological toxicities, hence requiring therapeutic dose reduction.

Patients on therapy with TKIs also have a significant risk of developing hypertension (the incidence ranges from 16% – 50%). This association might be directly related to inhibitory effects on the VEGF receptor. Possible mechanisms include impaired angiogenesis leading to a decrease in micro-vessels density (a process known as rarefaction), endothelial dysfunction associated with a decrease in nitric oxide production and increase in oxidative stress, as well as changes in neuro-hormonal factors or the renin-angiotensin-aldosterone system 3. Early detection and effective management of hypertension may allow for safer use of these drugs.

Asymptomatic QTc prolongation and cardiac toxicity are other common adverse events that have been reported and, therefore, cardiac function must be tested periodically.

Skin toxicity typically occurs after 3-4 weeks of treatment in more than 50% of the patients. A number of different skin changes may be observed, including hand-foot syndrome, changes in hair colour, skin rash, dry skin, skin discoloration, acral erythema, folliculitis, and has been reported with almost all drugs. Folliculitis occurs in 43-85% of patients and experimental models have shown that the blockage of EGFR profoundly increases chemokine expression in keratinocytes, leading to skin inflammation. The most clinically significant skin toxicity is the hand-foot syndrome and palmar-plantar erythrodysesthesia, which occurs in 9%-62% of patients receiving sorafenib or sunitinib. Hand-foot syndrome presents as painful symmetric erythematous and edematous areas on the palms and soles, commonly preceded or accompanied by paresthesia, tingling or numbness. The exact pathogenesis of this type of hand-foot syndrome is still unknown, but evidence suggests that it may be due to the direct anti-VEGFR or anti-PDGFR effects of sunitinib on dermal endothelial cells 4. Management strategies for hand-foot syndrome include dose reduction or treatment interruption until the symptoms improve. Although fastidious for the patients, the appearance of side effects, particularly skin toxicity and hair loss, is associated with significant tumor response.

Finally, TKIs can lead to hypothyroidism. Various hypotheses have been proposed to explain their effects on thyroid function. It is supposed that the therapy may induce a destructive type thyroiditis via follicular cell apoptosis. In patients treated with thyroidectomy, the increase in serum TSH may be due to alterations in the absorption of or metabolism of L-thyroxine. Regular surveillance of thyroid function is warranted for patients receiving treatment with TKIs.

In contrast to conventional chemotherapy, which is given only over a defined period of time, treatment with TKIs is a chronic, continuous treatment that may be given over a prolonged period of time (sometimes years). Therefore, a better understanding of the mechanisms underlying these side effects, and possibly their prevention or treatment is critical to ensure long term treatment.

References

  • Fagin JA: How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183: 249-256, 2004.
  • Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nature Medicine 6: 389-395, 2000.
  • Wu S, Chen JJ, Kudelka A, Lu J, Zhu X: Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncology 9: 117-123, 2008.
  • Kollmannsberger C, Soulieres D, Wong R, Scalera A, Gaspo R, & Bjarnason G: Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. Canadian Urology Association J 1 (Suppl 2): S41-S54, 2007.
Table 1: List of drugs and their molecular target under clinical trial in thyroid cancer
Target à Drug VEGFR1 (nM) VEGFR2 (nM) VEGFR3 (nM) RET (IC50) (nM) BRAF (IC50) (nM) PDGFR (IC50) (nM)
Axitinib 12 0.25 0.29 2.5
Gefitinib
Motesanib > 10,000 3,700 100
Motesanib 2 3 6 59 84
Sorafenib 90 20 47 57
Sunitinib 2 9 17 41 22 2
Vandetanib 1,600 40 110 130
XL 184 0.035 4 234
Table 2: Cumulative rates of stable disease (SD) and partial response (PR) in patients with thyroid cancer treated with TKIs
Drug Phase SD (%) PR (%) Tumor
Axitinib II 40 22 DTC-MTC
Sorafenib II 64 28 DTC-MTC
Sorafenib II 61 15 PTC
Motesanib II 66 14 DTC
Motesanib II 81 2 MTC
Vandetanib 300 II 70 29 hMTC
Vandetanib 100 II 68 16 hMTC
Range 40 – 81 2 – 29

Editorial written by Furio Pacini, Lucia Brilli, & Stefania Marchisotta (Related to Chapter 18 of TDM)