Hand-foot syndrome induced by chemotherapy drug: Case series study and literature review.

INTRODUCTION: Chemotherapy drugs can be responsible of several side effects such as hand-foot syndrome (HFS). This syndrome is also called "palmar-plantar erythrodysesthesia" and "acral erythema." Without proper management, it can deteriorate the quality of life of a patient, leading to temporary or definitive stop of chemotherapy. AIM OF THIS STUDY: To identify the epidemiological and clinical characteristics of patients, the risk factors for occurrence and worsening of this syndrome, and the drugs most likely to be responsible of HFS.
METHODS: Our study was retrospective, including 42 patients with HFS secondary to a chemotherapy drug. These cases were notified to the National Center of Pharmacovigilance over 7 years. The severity of HFS has been classified according to the NCI-CTCAE v4.0 classification.
RESULTS: Our population was composed of 40 women and 2 men. The mean age was 51 years. Docetaxel was the main drug associated with this adverse effect. Hands were involved in all cases and were sometimes associated with other skin surfaces apart from feet. Erythema of the hands and/or feet was present in all patients; it was associated with edema in more than half of the cases. The distribution of different grades according to the NCI-CTCAE classification among the patients was almost equal: 28% Grade 1, 36% Grade 2, and 36% Grade 3. HFS occurred mainly after the first course of chemotherapy with a mean period of 3-4 days. The regression of HFS occurred more rapidly for Grade 1 and Grade 2 compared with Grade 3, especially when assisted by symptomatic treatment. The recurrence rate of HFS for those patients with decreased doses, spacing of cures, and/or symptomatic and prophylaxis treatment was 25%.
CONCLUSION: An early detection of HFS, associated with preventive measures, enables patients to continue the chemotherapy.

Introduction

The treatment of malignant tumors is usually based on the combination of specific treatments: surgery, radiotherapy, and systemic drugs. The drugs of chemotherapy aim to stop or slow the uncontrolled multiplication of cancer cells. They include cytotoxic chemotherapy, hormone therapy, and targeted molecular therapies. These drugs improve the prognosis of malignant tumors and have a place both in the treatment of advanced cancers and in adjuvant treatment after surgery or radiotherapy in localized tumors. These anticancer drugs may be responsible of adverse effects (AEs). Some of these AEs are well known and almost mandatory, while others are much rare and their mechanism of occurrence is poorly understood.

Hand–foot syndrome (HFS), also known as “acral erythema” or “palmar-plantar erythrodysesthesia” or “toxic erythema of palms and soles” or “Burgdorf syndrome,” is a known and relatively rare side effect of chemotherapy drugs. Even if it is not life-threatening, HFS, without proper management, can cause serious skin lesions and thus deteriorates the life quality of a patient, which often leads to the interruption of the chemotherapy.[12] HFS, at its onset, presents with dysesthesia and/or paresthesia, followed by erythema mainly affecting palmoplantar area. In the absence of adequate management, these lesions evolve into desquamation, ulceration, and blistering and become more painful.[2] Several hypotheses about the mechanism of this syndrome have been advanced, but its exact mechanism remains unknown. Its management remains palliative and discussed.[3]

The Tunisian National Center of Pharmacovigilance (NCPV) has been involved in the collection and analysis of this side effect as a part of chemotherapy monitoring program. The purpose of our work was to study the epidemiological and clinical characteristics of the patients who consulted at the NCPV for HFS secondary to chemotherapy, to identify the risk factors for the occurrence and aggravation of HFS, and to identify the chemotherapy drugs that are the most responsible of HFS.

Methods

Our study was descriptive, cross-sectional, and retrospective in design, performed over a period of 7 years, from January 2011 until December 2018. We collected cases of HFS associated with chemotherapy drugs and notified to the NCPV during this period.

We considered a cutaneous lesion as being a HFS if erythema mainly affected the palmoplantar areas. We included, in our work, patients who presented a HFS associated with chemotherapy drugs having the highest intrinsic imputation score, if associated with other drugs. We did not include the cases where:

The skin involvement was limited to pruritus

The event was a generalized reaction associated with erythema of the hands or feet

The chemotherapy drugs had an intrinsic imputation score lower than the other associated drugs

The information was very limited in the medical file

The signed consent form in the native language (given by the patient or his legal representative) for the use of the data was not provided.

We noted the following parameters from each selected case: age, sex, medical history, nature of the cancer requiring chemotherapy, nature of lesions, grade of the HFS (according to NCI-CTCAE v4.0 classification), the delay of the onset and the regression of the symptoms, symptomatic treatment, most suspected drug, beginning of chemotherapy, dose, time of appearance compared to the first and the last cure, intrinsic and extrinsic imputation score of the drug,[4] recurrence of the event, or not if possible reintroduction.

We tried to contact patients for evolution, and we were able to reach 20 of the 42. For the other 22 patients, 17 of them were unreachable and the remaining 5 patients died and the family could not provide us with the required information.

These cases were analyzed and validated according to the French method of causality assessment.[4] The severity of the HFS was classified according to the NCI-CTCAE v4.0 classification. The statistical study was carried out by Kruskal–Wallis and Mann–Whitney tests.

Ethical clearance was obtained from the institutional ethics committee.

Results

The study included 42 patients [Table 1]. Twenty-nine patients had no chronic pathology other than their cancerous pathology (69%), 8 patients had one chronic pathology (19%), and 5 patients had more than one (12%). Two patients had a history of hypersensitivity reaction to drugs: one of them was allergic to penicillin and the other to vibramycin. The tumor pathology requiring chemotherapy was breast cancer in 96% of the cases [Table 1].

Table 1

Main characteristics of the patients

Main characteristics	Effective
Age (years): Median (extremes)	51 (35-75)
Sex: Female/male	40/2
Chronic pathology
HTA	10
Diabetes	1
Hypothyroidism	1
Dyslipidemia	1
Anxiety	1
Tumor pathology
Breast cancer	40
Colon cancer	1
Acute myeloid leukemia	1

HTA=Human tissue authority

The chemotherapy drugs were docetaxel, 5-fluorouracil (5-FU, bolus in the context of FEC protocol: FU, epirubicin and cyclophosphamide), hydroxycarbamide, and capecitabine [Table 2]. Among the 37 cases where docetaxel was incriminated, 29 patients (78%) received 3–6 cures of FEC in advance. For the other patients, the prior administration of FEC was not specified.

Table 2

Culprit chemotherapy drugs in hand-foot syndrome

Drug (INN)	Brand name	Number of cases	Original/generic	Total (%)
Docetaxel	Taxotere®	14	Original	37 (89)
	Eriox®	8	Generic
	Docetaxel®	4	Generic
	Hospira®	4	Generic
	Doxetal®	3	Generic
	Unspecified	4	Unspecified
5-fluorouracil	5-FU	3	Generic	3 (7)
Hydroxycarbamide	Hydrea	1	Original	1 (2)
Capecitabine	Xeloda®	1	Original	1 (2)
Total	-	42	-	42 (100)

INN=International Nonproprietary Names

The manifestations of HFS appeared after the first cure of the chemotherapy in 30 patients (71%) and after the second cure in 5 patients (12%).

The dose was specified in 11 patients over the 42 of our study. Among these 11 cases, 9 patients received docetaxel: 7 patients had the dose of 100 mg/m2 and the two others had 80 mg/m2. Concerning the two other patients, one received capecitabine at the dose of 4.5 g/day and the other received hydroxycarbamide at the dose of 1.5 g/day.

The involvement of the hands was found in all the patients of our population. Nobody developed isolated foot involvement. Thirty-one patients developed simultaneous hand and foot involvement, and the remaining 11 patients developed hand injury with no skin damage on the feet [Table 3]. Erythema was reported in all patients. Edema of the hands and feet was reported in 24 patients (57%) [Table 4]. Twenty-six patients (62%) developed pruritus: generalized in 5 cases, localized in the hands and feet or the other affected areas, if existing, in 15 cases, and not specified in 6 cases. Nail involvement was noted in 6 cases (14%), without precision of its type. In these six notifications, the HFS was classified Grade 2 and Grade 3 NCI. Thirteen patients had mucosal involvement (31%): 10 had mucositis, 2 had glossitis, and one patient had dry mouth. Eight patients had peripheral neurological impairment, with paresthesia in the hands and feet in 7 patients (17%) and Grade 3 neuropathy (without further details) in one patient.

Table 3

Location of the hand-foot syndrome

Location	Number of cases	Total (%)
Hands only
Palm of the hands	2	11 (26)
Back of the hands	1
Unspecified	8
Feet only	0	0
Hands and feet
Plant of the feet + palm of the hands	7	31 (74)
Back of the feet + back of the hands	1
Back of the feet + palm of the hands	1
Unspecified	22
Total	42	42 (100)

Table 4

Type of the cutaneous lesions of hand-foot syndrome

Nature of lesions	Number of cases (%)	Total (%)
Erythema
With edema	10 (24)	22 (52)
Without edema	12 (28)
Erythema + maculopapules
With edema	3 (7)	4 (10)
Without edema	1 (3)
Erythema + desquamation
With edema	8 (19)	11 (26)
Without edema	3 (7)
Erythema + bubbles/detachment
With edema	3 (7)	5 (12)
Without edema	2 (5)
Total	42 (100)	42 (100)

Twenty-three patients had pain in the hands and feet associated with injuries (55%). Among these patients, 18 had a functional impairment (43%) ranging from a restriction of the daily activities and difficulty in performing daily actions to the impossibility of achieving them and therefore a limitation of the autonomy such as the impossibility of walking or holding objects.

We classified the clinical manifestations of the HFS according to the NCI-CTCAE classification [Table 5]. The delay of the onset of the HFS compared to the last chemotherapy cure varied from 1 to 10 days [Tables 5 and 6].

Table 5

Delay of occurrence and regression of hand-foot syndrome according to National Cancer Institute grade

NCI grade	Delay of occurrence of HFS					Regression of HFS
	Number of cases	Extreme (days)	Average (days)	Median (days)	SD (days)	Number of cases	Extreme (days)	Average (days)	Median (days)	SD (days)
Grade 1	12	1-10	3.70	3	2.425	7	6-15	8	7	3.094
Grade 2	15	1-8	4	3	2.236	10	7-10	7.5	7	1.354
Grade 3	15	1-8	3.70	3	2.017	10	10-21	14	14	3.9
P	0.778*					<0.001*

*Kruskal-Wallis test. SD=Standard deviation, HFS=Hand-foot syndrome, NCI=National Cancer Institute

Table 6

Delay of occurrence and regression of hand-foot syndrome according to the drugs (original and generics)

Drug (INN)	Brand name	Delay of occurrence of HFS					Regression of HFS
		Number of cases	Extreme (days)	Average (days)	Median (days)	SD (days)	Number of cases	Extreme (days)	Average (days)	Median (days)	SD (days)
Docetaxel	Taxotere®	14	1-8	4.40	3.50	2.341	11	7-21	10	9	4.290
	Eriox®	8	3-10	4.90	3.50	2.588	4	6-15	8.75	7	4.193
	Docetaxel®	4	2-3	2.75	3	0.5	2	7-14	10.5	10.5	4.95
	Hospira®	4	1-3	2	2	0.816	4	7-15	10.5	10	3.317
	Doxetal®	3	1-3	1.70	1	1.155	1	20	20	20	-
5-fluorouracil	5-FU®	3	3-4	3.40	3	0.707	0	0	0	0	-
Hydroxycarbamide	Hydrea®	1	5	5	5	-	1	11	11	11	-
Capecitabine	Xeloda®	1	8	8	8	-	1	15	15	15	-
P		0.155*					0.812*

*Kruskal-Wallis test. SD=Standard deviation, HFS=Hand-foot syndrome, INN=International Nonproprietary Names

The healing time was mentioned only in 27 cases (64%). Its average varies from 9 days, for patients who received symptomatic treatment, to 13 days for patients who did not. Twenty-six patients received symptomatic treatment for hand–foot injuries (62%). These symptomatic treatments were specified in 20 cases: topical treatment (topical corticosteroids and moisturizers) (13 cases), systemic corticosteroids (7 cases), and antihistamines in association with corticosteroids (5 cases). Among the 27 patients whose healing time was specified, 20 received symptomatic treatment [Tables 5 and 6].

Among the 20 patients who were contacted by phone, 16 patients received chemotherapy again with the same incriminated drugs: 12 did not have recurrence of the symptoms and 4 presented a recurrence of HFS (25%). Information on the dose and the conditions of recovery (symptomatic treatment, premedication) was not provided by the patients. One patient has changed the trade name (from Taxotere® to Taxol®) without recurrence of HFS. The remaining three patients had not received chemotherapy anymore.

Discussion

HFS due to cancer chemotherapy is quite challenging as it impacts not only the quality of life of patients but also the oncologists who manage such cases. In Tunisia, in spite of having trained medical professional, HFS remains under-reported. In the current study, we assessed cases of HFS induced by chemotherapy drugs notified to the Tunisian Pharmacovigilance Center over a period of 7 years. This allowed us to detect some particularities concerning the epidemiologic features of patients, the clinical aspects of HFS, and the drugs most involved.

In our study, we found that majority of HFS occurred in females. According to Nagore et al., in a review of literature, women have a higher risk of developing HFS.[5] This hypothesis has been supported by other authors, notably Miller et al. and Lassere and Hoff.[16] Other authors have found no significant difference between the sexes for the prevalence of HFS in their studies.[789] On the other hand, pharmacovigilance studies have shown a predominance of women in the occurrence of drug-related adverse events (65%–70%) compared to 30%–35% in men, as shown by Demoly and Bousquet.[10]

Majority of HFS collected in our study occurred in adults. Similar results were found with some authors, including Hofheinz et al. and Palaniappan et al.[811] The role of age in the occurrence of HFS is discussed in the literature. According to Karol et al., HFS is rare in pediatrics and is more common in adultsThe incidence of HFS in patients aged from 4 to 18 years receiving either high doses of methotrexate or high doses of cytarabine was 1.3%.[7] In the study by Lassere and Hoff, in a literature review on HFS with capecitabine, advanced age is a risk factor.[1] Similarly, Ajgal et al., in a 10-year descriptive retrospective study of HFS with liposomal doxorubicin, found that the frequency of HFS for patients aged over 70 years was higher than those under 70 years of age.[12] According to other authors, age was not a risk factor for the occurrence of HFS.[8]

Sixty-nine percent of our patients had no history of significant chronic disease. A prospective study conducted in 2015 on the risk factors of capecitabine-induced HFS had identified preexisting inflammatory pathology as a risk factor for HFS.[9] These pathologies have not been found in our study.

Breast cancer was the reason for prescribing chemotherapy in 96% of our patients. These results match with those of the literature. Palaniappan et al. have studied a population treated with different chemotherapy drugs for several indications of cancer. Breast cancer was the most common indication for patients developing HFS (32%) followed by colorectal cancer.[11] In Law et al.'s study about HFS risk factors, colorectal cancer and breast cancer were, respectively, the reasons for prescribing chemotherapy in their studies.[9]

Docetaxel was the most incriminated drug in the genesis of HFS in our series (89%). In literature, the most common chemotherapy drugs associated with HFS are capecitabine, cytarabine, liposomal doxorubicin, FU, and docetaxel.[513141516] Other drugs may give a lower frequency of HFS, such as paclitaxel, methotrexate, hydroxyurea, and mitotane.[14]

The frequency of HFS depends on the drug administered and the dose. Several results have been found in the literature according to the modification of these two variables. Degen et al. found that 30% of patients treated with docetaxel at the dose of 100 mg/m2/21 days developed HFS.[15] With capecitabine, the frequency of occurrence of HFS would be the largest.[17] The second drug most frequently responsible of HFS is liposomal doxorubicin. Several studies have found that 40% of patients, treated with this molecule, presented HFS.[1318] The frequency of HFS with liposomal doxorubicin, especially the pegylated form, is much higher than with conventional doxorubicin.[19] For 5-FU, continuous infusion gives considerably more HFS than bolus administration.[1314] These studies also reported that the frequency of HFS varied with the different combinations of chemotherapy agents. Dhanraj et al. found that 52% of patients, who received doxorubicin then docetaxel, had developed HFS and 24% of patients, who received FEC and docetaxel, had developed a HFS. However, for both groups, the appearance of HFS was observed in all cases during the courses of docetaxel.[20] Wardley found that 5% of patients who received herceptin with docetaxel developed HFS versus 46% of patients who received herceptin with docetaxel in combination with capecitabine.[21] Heo et al. reported that the combination of docetaxel with capecitabine is a risk factor for HFS compared to its use alone or in combination with other molecules.[22] In our study, in the 78% of cases where docetaxel was incriminated, patients had previously received between 3 and 6 cures of FEC. According to Mavroudis et al., HFS was more common in patients who received FEC then docetaxel than patients who received docetaxel plus cyclophosphamide.[23] The administration of FEC before the docetaxel cures would promote the occurrence of HFS.

Taxotere® was the brand name of docetaxel that provided the most cases of HFS in our series. A Japanese study conducted by Tagawa et al. in 2017 showed that the frequency of HFS differed between the brand and the different generics of docetaxel: the frequency of HFS with Docetaxel Hospira® and Docetaxel Sandoz® was higher than with Taxotere®.[24] The nature and concentration of the solubilizing agents would be the cause of this difference in frequency.

In our study, 71% of patients developed HFS after the first chemotherapy cure, 12% after the second, and only 12% after the fourth. In the literature, HFS occurs mostly after the first cure. Abushullaih et al. reported that half of the patients developed HFS during the first cure of capecitabine and that most severe cases were observed after the second cure.[25] According to Heo et al., 86% of patients treated with capecitabine developed HFS during the first three cycles.[22] Hofheinz et al. found that 51% of patients developed HFS with capecitabine during the first two cures and 75% of patients during the first four courses.[8] As for doxorubicin, several studies have shown that HFS usually develops after the second and third cures.[12] According to Templeton et al., 52% of patients on liposomal doxorubicin developed HFS after the first chemotherapy cure and only 14% at the fourth cure or more.[26]

Chemotherapy dosage was specified in only 11 cases in our study. Among these patients, seven received 100 mg/m2/21 days of docetaxel and two received 80 mg/m2/21 days. HFS is reported to be dose-dependent. It depends on the dose administered during each cure as well as the total administered dose.[2] According to Gilbar, HFS in chemotherapy is seen especially with high dosage or after repeated exposures (as for 5-FU or cytarabine) or continuous exposure (as for capecitabine). All these situations lead to drug high plasma concentration.[14] In addition, with large doses and close courses, the time of the onset is shorter and injuries are more severe. There is also a cumulative effect. Nagore et al. found that for 5-FU, HFS appears from a median cumulative dose of 18.5 g.[5] Several studies have shown that decreasing the dosage decreases the frequency of HFS. Taking the example of Zimmerman, he showed that at the dose of 100 mg/m2, docetaxel has considerably more skin-related adverse effects than at the dose of 85 mg/m2.[27] Vincent et al. found that 46% of patients, on capecitabine at the dose of 2000 mg/m2/day, developed HFS, compared with 30% of patients at the dose of 1500 mg/m2/day.[28] Al-Batran et al. and Ajgal et al. showed that doxorubicin-associated HFS is dose-dependent, with cumulative effect. They found in their respective work a net decrease in the frequency and the severity of HFS by decreasing dosage.[1218] However, even if the HFS is dose-dependent, it can appear at any dose. However, its frequency and its severity remain lower with low doses and spaced cures. Indeed, some cases of HFS with docetaxel at a dose of 60 mg/m2 have been reported, some of them were even classified Grade 2 NCI. Some authors have explained the occurrence of these cases by the existence of hepatic insufficiency, due to hepatic metastases.[29] Moreover, Childress and Lokich insists on the cumulative effect of dosage for docetaxel.[21] The HFS is seen more often with cures spaced a week than cures spaced 3 weeks.[21] The frequency of the HFS also depends on the modality of the administration. In the Hueso et al.'s study, the frequency of HFS for patients on continuous infusion with 5-FU was 24% versus 0.7% for patients on 5-FU bolus.[13] According to Karol et al., the frequency of HFS was higher in patients who received methotrexate as a fast infusion than those who received it as a slow infusion.[7]

In our study, the involvement of the hands was found in all patients. This injury was exclusive in the hands without touching the feet in 26% of the cases, while an associated involvement of the hands and feet was found in 74% of cases. Several studies have found that hands are more often affected than feet and may be the only affected area[2513] and that hand involvement usually precedes the feet.[3] Some authors have found that this involvement is bilateral and symmetrical.[1430]

Palms of the hands and plants of the feet were found the most affected area. Hueso et al. found that 84% of patients had limited injuries on both palms and plants.[13] According to Karol et al., in a descriptive study of HFS with cytarabine and methotrexate, 68% of patients developed injuries on palms of the hands and soles of the feet, 18% in the palms only, and 14% in the soles only.[7] These injuries are therefore located mainly at the palmoplantar level, but injuries on the back of the hands and feet can be found, too.[15] In a review of literature, Gilbar found that the symptomatology is usually more pronounced at the distal phalanxes.[14]

Nail injury was found in 14% of cases. For these patients, the HFS was graded Grade 2 and Grade 3 NCI. Nail damage is an adverse effect of chemotherapy whose frequency depends on the drug used. It is more common with docetaxel, 5-FU, or doxorubicin.[21] Several studies have highlighted the frequency of nail involvement with docetaxel and described different types: onycholysis, subungual hemorrhage, hyperpigmentation, presence of mucous membranes, and paronychia.[3631] According to Baker et al., the resolution of these symptoms takes an average of 6 months for the nails of the fingers and 1 year for the nails of the feet.[31]

All our patients had skin erythema. This erythema was macular in 52% of the cases, maculopapular in 10%, desquamative in 26%, and bullous in 12%. Swelling of hands and feet was reported in 57% of patients. Hueso et al. found that for Grades 1 and 2 NCI, patients developed only erythema or macules with significant late desquamation and re-epithelialization and a little edema or cervices.[13] For Grade 3, the lesions were more severe in palms and plants with increased erythema and edema, early and severe desquamation, and crevices (3 out of 44).[13] HFS lesions are often preceded by warning signs such as dysesthesia and tingle of the palms and plants for 3–4 days followed by erythema and edema, with probable evolution in desquamation, blisters, and ulcerations, which exacerbates pain and functional prognosis.[6]

Histologically, lesions are characterized by syringometaplasia, apoptosis and atypia of keratinocytes, vascular degeneration of the basal layer of the epidermis, and cutaneous edema.[3]

On the other hand, the nature of the lesions depends on the chemotherapy drug used. With docetaxel, lesions are mostly erythema and desquamation. Blisters are seen mainly with 5-FU or doxorubicin.[21] Bullous lesions are mainly seen with methotrexate and cytosine arabinoside.[14] The loss of fingerprints is seen mainly with capecitabine by destruction of the epithelium.[3]

Paresthesia was found in 17% of patients of our series. One case of Grade 3 neuropathy was also reported. Paresthesia in the palms and plants is a common sign of HFS and is usually part of the prodromes.[11] Peripheral neurologic impairment is a known adverse effect of chemotherapy drugs, is dose-dependent, cumulative, predominantly sensitive, and is manifested mainly by paresthesia, heaviness and sensitive, and motor loss in the most severe cases.[31]

Pain was found in 55% of patients. It was without functional discomfort in 12% of the cases and with a functional discomfort, limitation, or even impossibility to perform daily actions in 43% of the cases. At the beginning, even before the appearance of the erythema, the sensation of dysesthesia and tingling is felt by almost all patients, then appears a burning sensation.[12] If the lesions evolve and the HFS passes Stage 2 NCI, the pain in the hands and plants began limiting the daily activities of the patients. Moreover, for Stage 3, it will be impossible to perform daily tasks such as walking or holding objects.[214] This pain generally appears 3 days after the warning signs.[1117]

The mucosal involvement associated with HFS was found in 31% of our patients, including cases of mucositis and glossitis. Several studies had reported such effect, but its frequency differed according to the drug and the dose administered. According to Al-Batran et al., 48% of patients on liposomal doxorubicin developed mucositis.[18] Some authors reported a correlation between mucosal injury and HFS and pointed out that the risk of developing stomatitis or mucositis has been higher in patients with HFS than chemotherapy patients who have not developed HFS.[891222]

In our study, we have chosen NCI-CTCAE v4.0 because it was the most used classification in the literature. We found that 28% of cases were classified Grade 1, 36% Grade 2, and 36% Grade 3. In the literature, the results varied a lot concerning the rates of each grade of HFS.[81325] This variation is explained by the use of different chemotherapy drugs, different doses, and different treatments for both prophylaxis and treatment of HFS.

The delay on the onset of HFS compared to the last cure of chemotherapy varied in our study from 1 to 10 days, with an average of 4 days and a median of 3 days. These results correspond to those found in the literature.[13] This delay is shorter with large doses and closer cures and longer for low-dose drugs and continuous exposure.[16]

The onset of symptoms, regarding NCI grade, was almost identical. This delay corresponds to the beginning of the symptomatology, so regardless of the severity of the HFS, the clinical signs begin to settle at the same time.[23]

The healing time, when it was specified in our study, ranged from 6 to 21 days, with an average and a median of 10 days each. These results are similar to those found in the literature. According to Nagore et al. and Gilbar, after stopping the drug in question, the healing is obtained in 14 days on average, usually without sequelae,[514] and according to Degen et al. and Hueso et al., the delay has varied from 1 to 2 weeks.[1315]

For patients who received symptomatic treatment, the average and the median of the healing time were shorter than those without symptomatic treatment, but the difference was not statistically significant. Several studies have shown that the use of topical corticosteroids and moisturizers provides faster regression.[23] In addition, patients who received 200 mg/day of pyridoxine had better control of the lesions and a faster healing compared to those who did not receive or received a lower dose than 200 mg/day.[17] Moreover, patients who were treated were able to continue the chemotherapy cures, while for others, injuries worsened after the following cures and the chemotherapy was interrupted.

Sixteen patients in our study received again the incriminated drug in the HFS. The recurrence rate of HFS for these patients (with probably decreased doses, spacing cures, and/or symptomatic treatment and prophylaxis) was 25%. These results, although related to a reduced number, are close to the results found in other studies such as that of Karol et al. where HFS recurred in 50% of cases during the reintroduction of the chemotherapy drug incriminated.[7] According to Nagore et al., the reintroduction of the drug at the same doses led to recurrence in the majority of cases.[5] Hueso et al. confirmed these results. The reintroduction of the drug without any reduction in doses or spacing of cures was accompanied in all cases by recurrence.[13] Thereby, changing the culprit chemotherapy drug to another less harmful may be an alternative for severe HFS cases. However, this measure depends on the risk/benefit balance for each patient.

Several studies have focused on the treatment and prevention of HFS, but none provided any tangible evidence on the efficiency of one treatment versus another, if chemotherapy continued at the same doses.[3] All agree that for Grade 1 NCI, treat HFS by symptomatic treatment (emollient creams, Vitamin B6, topical corticosteroids, cooling) without changing the dose. For NCI Grade 2, in addition to symptomatic treatment, discontinue chemotherapy until the healing or the regression of the injuries to Grade 1, and 25% decrease on the dosage of the next cure. For Grade 3, the same attitude as Grade 2 but decreasing doses by 50%. For recurrent Grade 2 and 3 NCI, the drug in question must be permanently discontinued.[1] Nagore et al. advocate stopping the drug or reducing the dose by 25%–50% for Stage 3 NCI or Stage 2 recidivism, which must be decided, according to the benefit/risk contribution, by the attending oncologist.[5]

Conclusion

The diagnosis of HFS may be easy in the case of typical lesions, but cases associating other localizations or other lesions should not rule out the diagnosis. The identification of risk factors is an important step for prevention. Prior use of FEC, prescription of drugs known to give HFS, and chemotherapy associations are all factors that may lead oncologist to use preventive measures. These actions would prevent not only the deterioration of the quality of life of the patient but especially the interruption of chemotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.