Management Of Tyrosine Kinase Inhibitor–Induced Hand–Foot Skin Reaction: Viewpoints from the Medical Oncologist, Dermatologist, and Oncology Nurse

February 13, 2011|The Journal of Community and Supportive Oncology

We are living in an era of “molecularly targeted therapy.” This targeted approach has developed as advances in science have led to a more detailed understanding of the inner workings of the cell, both in health and in illness. Once a molecular pathway has been implicated in the development and progression of cancer, modulators can be developed to intervene in this

Table 1. Summary of Efficacy Data for Sorafenib and Sunitinib

DRUG, DISEASE, AND STUDY	EFFICACY DATA
Sorafenib
Advanced RCC
Phase III TARGET ^[9]^and ^[10]	• Largest phase III trial ever conducted in second-line setting in patients with advanced RCC • Median PFS was 5.5 months in sorafenib group vs 2.8 months in placebo group (P < 0.001) • 28% improvement in OS vs placebo (HR = 0.72, P = 0.02) • Significant prolongation of OS (HR = 0.78, 95% CI 0.62–0.97, P = 0.029) • Clinical benefit (CR + PR + SD) in 84% of patients
Expanded-access programs ^[11]^and ^[12]	Data from expanded-access programs in community-based populations (NA- and EU-ARCCS) were consistent with data from TARGET
Unresectable HCC
Phase III SHARP trial ¹³	• First phase III trial to demonstrate a significant survival advantage for a systemic therapy in advanced HCC • Median OS was 10.7 months in sorafenib group vs 7.9 months in placebo group (HR = 0.69, 95% CI 0.55–0.87, P < 0.001) • Median TTRP was 5.5 months in sorafenib group vs 2.8 months in placebo group (HR = 0.58, 95% CI 0.45–0.74, P < 0.001) • Disease control rate (CR + PR + SD) was 43% in sorafenib group vs 32% in placebo group (P = 0.002)
Phase III Asia-Pacific trial ¹⁴	• Median OS was 6.5 months in sorafenib group vs 4.2 months in placebo group (HR = 0.68, 95% CI 0.50–0.93, P = 0.014) • Median TTP was 2.8 months in sorafenib group vs 1.4 months in placebo group (HR = 0.57, 95% CI 0.42–0.79, P = 0.0005)
Sunitinib
Advanced RCC
Phase III registration trial ¹⁸	• Median PFS was 11 months in sunitinib group vs 5 months in interferon-α group (HR = 0.539, 95% CI 0.451–0.643, P < 0.001) • Objective response rate (CR + PR) was 47% in sunitinib group vs 12% in interferon-α group (P < 0.001) • Median OS was 26.4 months in sunitinib group vs 21.8 months in interferon-α group (P = 0.051)
Expanded-access program ²⁰	• In a broad population of patients with metastatic RCC who were treated with sunitinib: – Median PFS was 10.9 months – Median OS was 18.4 months
Imatinib-resistant GIST
Phase III registration trial ¹⁵	• Median TTP was 27.3 weeks in sunitinib group vs 6.4 weeks in placebo group (HR = 0.33, 95% CI 0.23–0.47, P < 0.0001) • Median PFS was 24.1 weeks in sunitinib group vs 6.0 weeks in placebo group (HR = 0.33, 95% CI 0.24–0.47, P < 0.0001) • 16% of sunitinib-treated patients were progression-free for at least 26 weeks compared with 1% of those who received placebo
Expanded-access program ¹⁷	• In a broad population of patients with imatinib-resistant GIST who were treated with sunitinib: – Estimated median TTP was 41 weeks – Estimated median OS was 75 weeks

Full-size table

CI = confidence interval; CR = complete response; EU-ARCCS = European Union Advanced Renal Cell Carcinoma Sorafenib; GIST = gastrointestinal stromal tumor; HCC = hepatocellular carcinoma; HR = hazard ratio; NA-ARCCS = North American ARCCS; OS = overall survival; PFS = progression-free survival; PR = partial response; RCC = renal cell carcinoma; SD = stable disease; SHARP = Sorafenib CCC Assessment Randomized Protocol; TARGET = Treatment Approaches in Renal Cancer Global Evaluation Trial; TTP = time to progression; TTRP = time to radiologic progression

Characteristics of Hand–Foot Skin Reaction

Data from the clinical trials for sorafenib and sunitinib indicate that both agents are generally well-tolerated; common treatment-related adverse reactions include diarrhea, alopecia, nausea, fatigue, rash, and hypertension, as well as palmar–plantar erythrodysesthesia (PPE) syndrome, also known as hand–foot skin reaction (HFSR) (Table 2).^[10]^and ^[19] HFSR is a dermatologic toxicity that has been reported in 14%–62% of patients treated with sorafenib or sunitinib (Table 3).^[9]^,^[11]^,^[12]^,^[13]^,^[14]^,^[15]^,^[17]^,^[18]^,^[20]^,^[21]^,^[22]^,^[23]^,^[24]^and ^[25] In general, the term HFSR refers to a group of signs and symptoms affecting the hands and feet of patients taking sorafenib, sunitinib, or, to a lesser extent, other TKIs such as pazopanib (Votrient™; GlaxoSmithKline, Research Triangle Park, NC)^[26]^and ^[27] and axitinib (AG013736).^[28]^,^[29]^,^[30]^and ^[31]

Table 2. Selected Common Adverse Events in Patients Treated with Sorafenib (n = 452) or Sunitinib (n = 375) in Phase III Registration Trials (Updated and Final Results)^[10]^and ^[19]

ADVERSE EVENT	SORAFENIB 400 MG BID		SUNITINIB 50 MG QD
	ALL GRADES (%)	GRADE 3/4 (%)	ALL GRADES (%)	GRADE 3/4 (%)
Diarrhea	48	3	61	9
Rash	41	1	24	2
Hand–foot skin reaction	33	6	29	9
Alopecia	31	0	12	0
Fatigue	29	3	54	11
Nausea	19	<1	52	5
Hypertension	17	4	30	12
Dry skin	13	0	21	<1
Vomiting	12	1	31	4
Mucositis	5	0	26	2

Table 3. Rates of Hand–Foot Skin Reaction in Clinical Trials of Sorafenib and Sunitinib

REFERENCE	STUDY	ALL GRADES (%)	GRADE 3 (%)	GRADE 4 (%)
Sorafenib
9	Phase III TARGET ^a	30	6 (grade 3/4)
13	Phase III SHARP ^a	21	8	0
11	NA-ARCCS, first-line ^a	19 (≥2)	11 (grade 3/4)
11	NA-ARCCS, second-line ^c	17 (≥2)	8 (grade 3/4)
12	EU-ARCCS ^a	47	12 (grade 3/4)
14	Phase III Asia-Pacific ^a	45	11 (grade 3/4)
24	Phase II randomized discontinuation trial in advanced RCC ^b	62	13	0
25	Phase II study in advanced HCC ^b	31	5	0
21	Phase II, uncontrolled study in relapsed/refractory NSCLC ^a	37	10 (grade 3/4)
Sunitinib
18	Phase III registration trial in advanced RCC ^a	20	5	0
20	Expanded access program in advanced RCC ^c		5 (grade 3/4)
15	Phase III registration trial in imatinib-resistant GIST ^a	14	4	0
[17] and [22]	Expanded access program in imatinib-resistant GIST ^c	N/A	8 (grade 3/4)
23	Phase II trial of second-line treatment in advanced RCC ^a	15	7	0

EU-ARCCS = European Union Advanced Renal Cell Carcinoma Sorafenib; GIST = gastrointestinal stromal tumor; HCC = hepatocellular carcinoma; N/A = data not available; NA-ARCCS = North American ARCCS; NSCLC = non-small-cell lung cancer; RCC = renal cell carcinoma; SHARP = Sorafenib CCC Assessment Randomized Protocol; TARGET = Treatment Approaches in Renal Cancer Global Evaluation Trial

a Used version 3.0 of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)b Used version 2.0 of NCI-CTCAEc Version of NCI-CTCAE used not specified