In 1984 Lokich and Moore at Harvard Medical School observed that in 25% of patients who received long-term repeated chemotherapy with 5-fluorouracil (5-FU) or liposomal doxorubicin, a specific skin syndrome occurred: hand-foot syndrome (HFS), also known as palmar-plantar sensory loss erythema (PPES). Today, let’s talk about this HFS.
Hand-foot syndrome involves drugs
1, chemotherapy drugs: Capecitabine, liposomal adriamycin, cytarabine, doxorubicin, vincristine, continuous infusion of adriamycin, gemcitabine, etc.
2.Targeted drugs: Sonitinib (Sotan), Sorafenib (Doximet), Imatinib (Gleevec), Erlotinib (Troche).
3. Biological agents: high-dose IL-2.
Clinical manifestations of hand-foot syndrome
The typical clinical manifestation of HFS is a progressively aggravated skin lesion, with the hands being more susceptible than the feet. The first symptoms are pruritus of the palms and soles of the feet, congestion of the palms, fingertips and soles of the feet, followed by painful sensations at the ends of the fingers/toes, erythema and tension of the skin of the hands/feet, dullness and numbness of sensation, and rough and cracked skin. A few patients may have cut finger-like skin breakdown with blistering, flaking, peeling, oozing, or even ulceration, and secondary infection. Patients may be unable to walk due to severe pain, and in severe cases, they may lose the ability to care for themselves. The clinical reaction is mostly self-limiting, but may recur after readministration.
Grading criteria for hand-foot syndrome
There are several grading methods for HFS, among which the National Cancer Institute (NCI) grading criteria are more commonly used.
1. Grade I: numbness, dullness/abnormal sensation, pins and needles, painless swelling or erythema or discomfort in the hand or foot (but does not affect normal activities), as in Figure (1).
Figure (1): Grade I HFS
2. Grade II: Hand-foot syndrome is defined as the presence of erythema and swelling with pain or/and discomfort in the hands or/and feet that interferes with daily life, as in Figure (2).
Figure (2): Grade II HFS
3. Grade III: Skin peeling, ulceration, blistering or severe pain and/or severe discomfort in the hands and/or feet causing the patient to be unable to work or perform daily activities, as in Figure (3).
Figure (3): Grade III HFS
Pathologic features of hand-foot syndrome
The main pathological features of HFS are vacuolar degeneration of basal keratinocytes, perivascular lymphocytic infiltration of the skin, keratinocyte apoptosis and skin edema. Microscopically, inflammatory changes, vasodilatation, edema and leukocyte infiltration are seen, but no clear markers have been identified.
Pathogenetic features of hand-foot syndrome
Several large-scale national and international studies have shown that the onset of chemotherapy-associated HFS often occurs in the first two cycles after drug administration. the onset of HFS is independent of gender, age and primary tumor size, but may be related to patient characteristics. One study found that the occurrence of HFS was associated with a higher behavioral status (PS). A multivariate Cox regression analysis also showed that combined docetaxel was the only independent risk factor. It was also observed that the occurrence of HFS was associated with chemotherapy-associated stomatitis that appeared earlier than HFS.
Treatment strategies for hand-foot syndrome
1. Vitamin B6: A retrospective study in the United States analyzed the preventive effect of vitamin B6 (Vit B6) on chemotherapy-associated HFS. The results showed that there was no significant difference in the incidence of HFS between the Vit B6 treatment group and the control group (63% vs. 53%), but the treatment benefit rate was significantly higher in the Vit B6 treatment group than in the control group (65% vs. 12%, P<0.001).
2. COX-2 specific inhibitor: COX-2 specific inhibitor (celecoxib) can be used to prevent HFS or reduce the extent of HFS. a retrospective study by Lin et al. analyzed the efficacy and safety of capecitabine combined with celecoxib versus capecitabine monotherapy for colorectal cancer. The results showed that the incidence of HFS (12.5% vs. 34.3%) and grade 3/4 diarrhea (3.1% vs. 28.6%) were significantly lower in the combination group than in the monotherapy group, and the tumor remission rate was improved and the time to disease progression (TTP) was longer than in the monotherapy group (6 months vs. 3 months).
However, the increased risk of death related to cardiovascular events (myocardial infarction, shock, heart failure) associated with the combination of COX-2 inhibitors has forced the discontinuation of many phase I/II studies, so the benefits/risks of their clinical use need to be further investigated.
3.Vit E: Kara et al. gave oral Vit E (300 mg/d) to 5 patients with metastatic breast cancer who developed grade 2/3 HFS after capecitabine combined with docetaxel treatment, and after 1 week, 5 patients did not require dose reduction due to symptom reduction.
Topical topical medication: Pendharkar et al. gave topical urea cream (stratum corneum separator) to 13 patients with grade 2/3 capecitabine-related HFS twice a day, and it was effective after 2-3 days of use.
The study at the 2009 ASCO annual meeting showed that topical topical application of 10% uracil ointment for 5-FU/capecitabine-related HFS (n=84) 2-3 times daily was ineffective in 34% of 68 patients who could be evaluated for efficacy, and 66% had a 1-2 grade decrease in HFS grading after 2-4 weeks of treatment, and one patient had an allergic skin reaction, but no systemic allergic reaction was seen.
5. Traditional Chinese medicine: HFS is a new problem that emerged with the progress of clinical treatment of tumor, and there is no relevant record in the traditional texts. In clinical practice, according to the clinical manifestations of patients, the pathogenesis of HFS is “qi deficiency, blood stasis, cold condensation and ligament blockage”, and the method of “activating blood circulation and removing blood stasis, warming the meridians and opening the ligaments” is used. It can significantly improve the quality of life of patients.