Abstract
Objectives:
To compare the effects of the Shouzu Ning Decoction (SND) and Halometasone plus Celecoxib (Hal/Cxb) as therapy in patients with grade 2 hand-foot skin reaction (HFSR).
Materials and Methods:
Fifty patients with grade 2 HFSR participated in a randomized, single-center, open-label study. Patients were randomly assigned in a 1:1 ratio to receive the SND or Hal/Cxb treatment, twice daily for 4 weeks, followed by 4 weeks of post-treatment follow-up. The primary endpoint was clinical remission of HFSR at the end of the fourth week (W4). The secondary endpoints were recurrence rate, quality of life (QoL), pain intensity, and safety.
Results:
In this study, 46 patients successfully completed the study, and 4 patients were excluded. There was no statistically significant difference between the 2 groups on demographic and baseline clinical characteristics. In the SND group, 56.52% of patients showed clinical remission at W4, which was significantly superior to that achieved in the Hal/Cxb group (26.09%, P = .036). In addition, the HF-QoL score was statistically lower in the SND group compared to the Hal/Cxb group at W2 (P = .007), W3 (P = .005), and W4 (P = .005), respectively. In line with this, the inter-group difference in NRS score was statistically significant (P = .004).
Conclusion:
In the present study, SND treatment has been observed to be effective and well tolerated for patients with grade 2 HFSR. Thus, SND treatment could be considered a suitable option for HFSR patients.
Trial registration:
Chinese Clinical Trial Registry, ChiCTR1900027518. Registered on 17 Nov 2019.
Keywords: Shouzu Ning Decoction, hand-foot skin reaction, multiple tyrosine kinase inhibitors, randomized controlled trial, quality of life
Introduction
Multiple tyrosine kinase inhibitors (MKIs) have been proven to be powerful in treating cancer in the past 2 decades. More than 20 kinds of MKIs, such as apatinib, lenvatinib, axitinib, cabozantinib, and pazopanib, have been approved by the FDA for the treatment of various types of cancers.1-6 Despite their excellent efficacy for tumor suppression, MKIs usually lead to a dermatological adverse event known as hand-foot skin reaction (HFSR). 7 Although preventive measures such as moisturizers, and urea-based creams are advocated during MKI therapy, 8 the incidence of HFSR remains high, especially for Asians, who experience 41% to 82% of cases. 9 HFSR is classified into 3 stages: grade 1, grade 2, and grade 3, with increasing severity. Among the 3 stages, grade 2 HFSR is generally regarded as the starting point for dose reduction of MKIs, while grade 3 HFSR is generally regarded as the point for termination of MKIs. 10 The appearance of grade 2 HFSR usually leads to a compromised anti-tumor effect of MKIs.
Grade 2 is characterized by erythematous lesions, hyperkeratosis, peeling, and other symptoms. Patients with grade 2 HFSR experience continuous pain and impaired quality of life. However, to date, no clinically approved specific drugs are available to treat the disease, resulting in exacerbation to grade 3 HFSR. Topical steroid hormones and non-steroidal anti-inflammatories (NSAIDs) are commonly used in clinical practice in grade 2 patients but have limited clinical efficacy.10,11 Accordingly, novel agents are needed for providing the opportunity to possibly switch off HFSR progression.
Si-Miao-Yong-An decoction (SMYAD), a heat-clearing agent in Traditional Chinese medicine (TCM), is comprised of Lonicerae Japonicae Flos (Jinyinhua), Scrophularia ningpoensis Hemsl. (Xuanshen), Angelica sinensis (Oliv.) Diels (Danggui), and Glycyrrhiza glabra L. (Gancao) at a mass ratio of 3:3:2:1. Due to its medical properties, SMYAD has been traditionally used for treating sores and carbuncles for centuries. Pharmacologically, SMYAD exhibits anti-inflammatory, anti-oxidative stress, and anti-thrombosis activity.12-14 Clinically, it has been used to treat peripheral vascular diseases, such as thromboangiitis obliterans, diabetic ulcers, and venous stasis ulcers.15-18 The clinical characteristics of these diseases are similar to those of HFSR. Thus, SMYAD had been investigated in clinical setting to prevent HFSR in our previous research. 19 Clinical data confirmed that patients with SMYAD treatment showed a lower incidence of apatinib-induced HFSR than the Western medicine treatment alone. 19
To improve the treatment efficacy of HFSR, we added 2 herbs [Lonicerae japonicae Caulis (Rendongteng), Spatholobus suberectus Dunn (Jixueteng)] into the SMYAD to create the Shouzu Ning Decoction (SND). Lonicerae japonicae Caulis (Rendongteng) extracts were reported to possess favorable antioxidant activity, which remedies inflammation related disorders. 20 Spatholobus suberectus Dunn (Jixueteng) extracts were reported to possess various medicinal activities such as anti-inflammatory, anti-platelet, anti-rheumatic, and antioxidant activity.21,22 Thus, the compatibility formula (SND) of the above 6 herbs carries out the effect to clear heat and detoxify, active blood circulation, and relieve pain. In a previous study, we prospectively demonstrated that the SND treatment could alleviate symptoms, relieve pain and improve the quality of life in patients with grade 3 HFSR. 23 HPLC approach was also applied for the quality consistency assessment of SND. Despite its robust efficacy, only 35% of the patients recovered to grade 1. 23 Generally, grade ≤1 HFSR is considered a safe stage for tolerating adequate dosage.
We wonder if earlier therapeutic intervention with the SND treatment at grade 2 stage would bring better therapeutic outcomes. Thereof, we test the efficacy and safety of SND as a new first-line treatment for grade 2 HFSR in a randomized controlled trial. In this trial, the traditional first-line treatment (a combination of halometasone and celecoxib) was selected as the control.
Materials and Methods
Study Design
This was a single-center, open-label, randomized controlled clinical trial designed to assess the relative efficacy of 2 therapeutic options: Shouzu Ning Decoction (SND) treatment, or Halometasone plus Celecoxib (Hal/Cxb) treatment. The primary endpoint was clinical remission, and the secondary endpoints were recurrence rate, quality of life (QoL), pain intensity, and safety.
Participants
All participants had received MKIs treatment and developed grade 2 HFSR. Inclusion criteria were as follows: patients had to be aged 18 years or older; continuously administered with MKIs (apatinib, sorafenib, lenvatinib, axitinib); defined as grade 2 HFSR according to National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0, Supplemental Table 1); and having a Karnofsky performance status (KPS) of at least 60. The following exclusion criteria were also applied: patients with skin disease other than HFSR in hand or foot; received capecitabine, docetaxel, liposomal doxorubicin, paclitaxel, or other agents within 4 weeks, which may lead to hand-foot syndrome (HFS) or peripheral neuropathy, as well as patients receiving pain medicines within 1 week before the study; received prior dermatologic treatment for HFSR.
Intervention
Eligible patients were randomly assigned in a 1:1 ratio to receive the SND (25 patients) or Hal/Cxb (25 patients) treatment. The randomization was generated using an interactive web response system. In Hal/Cxb group, participants were instructed to use the topical halometasone on their lesion sites, concomitant taking celecoxib 0.2 g orally, twice a day. In the SND group, the lesion sites were soaked in a solution of 200 ml SND and 800 ml water at 35°C to 40°C for 20 minutes, twice daily. All the participants were instructed to use a provided moisturizing cream (petrolatum) 3 times a day. The SND was manufactured in accordance with Chinese Pharmacopoeia (2015) standards by the Preparation Room of the Zhejiang Chinese Medical University (Zhejiang, China). The SND herbs (180 g) consisted of 30 g Lonicerae Japonicae Flos (Jinyinhua), 30 g Scrophularia ningpoensis Hemsl. (Xuanshen), 30 g Angelica sinensis (Oliv.) Diels (Danggui), 30 g Glycyrrhiza glabra L. (Gancao), 30 g Lonicerae japonicae Caulis (Rendongteng), and 30 g Spatholobus suberectus Dunn (Jixueteng) (plant names have been checked with http://www.theplantlist.org on the date of October 18th, 2022). And the detailed fabrication process of the SND was shown in our previous study. 23 Halometasone cream and Celecoxib capsules were purchased from Bright Future Pharmaceuticals Factory (Hongkong, China, LOT:6201340) and Pfizer Pharmaceuticals LLC (Puerto Rico, America, LOT:DX7406), respectively. The main ingredient of halometasone cream is halometasone-hydrate, and its specification is 1 g: 0.5 mg. Treatment was continued until unacceptable toxicity, withdrawal of consent, or investigator decision. At the completion of 4 weeks of active treatment, patients underwent 4 weeks of observation. Meanwhile, the optimal dosage of MKIs administered at baseline was maintained throughout the study.
Clinical Evaluation
The primary endpoint was clinical remission of HFSR from the SND or Hal/Cxb treatment at the end of the fourth week. Clinical remission was defined as follows: clinical symptoms of HFSR remitted from grade 2 to grade ≤1 according to NCI-CTCAE v5.0. The grading of HFSR was assessed at the first week after the treatment and every 1 week thereafter (W1, W2, W3, W4). If a patient used the treatment for less than 1 week, the case was unavailable for the evaluation of the efficacy of HFSR treatment. If the grading of HFSR was assessed as ≤2, treatments were administered until the end point of the study at 4 weeks. If the grading of HFSR developed to grade 3 persisting for 1 week, the treatments were stopped.
The secondary endpoints were recurrence rate, quality of life (QoL), pain intensity, and safety. Recurrence rate was defined as the proportion of patients who recurred grade ≥2 HFSR during 4 weeks of follow-up (week 5-8) after completion of the treatment phase (week 1-4). Previous studies indicated that both the Hand-Foot Quality of Life Scale (HF-QoL) and Numerical Rating Scale (NRS) have good reliability and validity in the assessment of QoL and pain intensity in HFSR patients, respectively.24,25 HF-QoL consists of 4 subscales: physical, self-care, social, and psychological. Each item is scored on a scale of 0 to 4, with a higher score indicating greater difficulty in daily activities affecting HFSR-related quality of life. Pain intensity was defined by the NRS from 0 (no pain) to 10 (most severe pain). Safety evaluations included assessments of adverse events (AEs), laboratory safety evaluations, vital signs, and physical examinations. Adverse events were graded using NCI-CTCAE version 5.0.
The clinical evaluation procedures were conducted in a standardized manner by 2 well-trained oncologists, who had experience previously in the diagnosis of MKIs-induced HFSR and were blind to the treatment interventions.
Statistical Analysis
Sample size calculation
The clinical effective rate of the SND treatment for HFSR was 85% in our previous studies. For the Hal/Cxb group, the intervention of steroid hormone and celecoxib is based on expert consensus and lacks reliable clinical studies data. So we estimated the effective rate of 30% according to the clinical observation. We set a one-sided 0.025 alpha and 0.90 power. The group allocation was equal. After calculating a total of 24 patients were required considering the dropout rate and the capacity of our center, we finally set the sample size as 50 patients.
Analysis
Statistical analyses were conducted by SPSS Statistics version 26. Descriptive statistics were presented, quantitative indicators were performed by mean ± standard deviation (SD) or median (second and fourth quartile), and qualitative indicators were performed by frequency and percentage. Qualitative indicators were assessed by chi-square test, while quantitative variables were by assessed Student’s t-test or Mann-Whitney U test. All data were assessed in the full analysis set (FAS), and modified Intention-to-treat (mITT) was used for statistical analysis, so all patients with at least one recorded evaluation were included in the analysis, and the missing data of patients who discontinued the treatment prematurely due to HFSR grade aggravation were dealt by using the last observation carried forward (LOCF) method, whereby the last available measurement for each individual at the time point before withdrawal from the study was retained in the analysis.
Results
Patient Demographics and Baseline Characteristics
The study was performed from December 2019 to June 2022 at the First Affiliated Hospital of Zhejiang Chinese Medical University. Fifty patients with grade 2 HFSR were enrolled and randomized in the trial (25 to the Hal/Cxb group and 25 to the SND group) (Figure 1). Forty-six patients successfully completed the study, and 4 patients were excluded due to protocol violation (n = 2), or withdrawal of informed consent (n = 2). There was no statistically significant difference between the 2 groups on demographic and baseline clinical characteristics (Table 1).
Figure 1.
Flow diagram of the study.
Table 1.
Baseline Demographic and Clinical Characteristics.
| Hal/Cxb (n = 23) | SND (n = 23) | P | |
|---|---|---|---|
| Gender, male, n (%) | 16 (69.57) | 17 (73.91) | .743 |
| Age, ‾x ± ΣΔ, y | 64.65 ± 9.40 | 63.52 ± 11.82 | .721 |
| BMI, ‾x ± ΣΔ, kg/m2 | 22.15 ± 2.64 | 21.78 ± 4.04 | .717 |
| Cancer, n (%) | .608 | ||
| Hepatocellular carcinoma | 17 (73.91) | 17 (73.91) | |
| Renal carcinoma | 3 (13.04) | 4 (17.39) | |
| Gastric cancer | 2 (8.70) | 0 | |
| Ovarian cancer | 1 (4.35) | 0 | |
| Ileocecal carcinoma | 0 | 1 (4.35) | |
| Thyroid cancer | 0 | 1 (4.35) | |
| MKIs type/dose (mg/d), n (%) | .618 | ||
| Sorafenib /800 | 11 (47.83) | 12 (52.17) | |
| Lenvatinib/8 | 7 (30.43) | 6 (26.09) | |
| Apatinib /500 | 4 (17.39) | 2 (8.70) | |
| Axitinib/10 | 1 (4.35) | 3 (13.04) | |
| KPS, n (%) | .952 | ||
| 90 | 2 (8.70) | 2 (8.70) | |
| 80 | 9 (39.13) | 8 (34.78) | |
| 70 | 12 (52.17) | 13 (56.52) | |
| Time to HFSR onset, d | 18.30 ± 9.29 | 16.13 ± 9.19 | .429 |
Abbreviations: SND, Shouzu Ning Decoction; Hal/Cxb, Halometasone plus Celecoxib; BMI, body mass index; MKIs, Multiple tyrosine kinase inhibitors; KPS, Karnofsky performance status.
Clinical Efficacy
The proportion of patients with clinical remission in both groups at each time point is displayed in Figure 2. Regarding the primary endpoint, 6 of 23 patients (26.09%) in the Hal/Cxb group and 13 of 23 patients (56.52%) in the SND group showed clinical remission at the W4 (P = .036), respectively. Among those patients with clinical remission, 19 were remitted to grade 1, no patient was remitted to grade 0. Representative photographs of patients were shown in Figure 3. The median time from the initiation of treatment to the remission timepoint was 10.46 days in the SND group and 13.17 days in the Hal/Cxb group respectively, which showed no significant difference (P = .122). In the remaining 27 patients with no remission, 21 patients maintained grade 2 (9 in the SND group, 12 in the Hal/Cxb group), and 6 patients developed to grade 3 (1 in the SND group, 5 in the Hal/Cxb group). Notably, the remission rate did not show a significant association with clinical characteristics such as age, sex, body mass index (BMI), cancer type, and type of MKIs. In addition, the remission rates at early visits (W1, W2, and W3) were higher with the SND group than the Hal/Cxb group (Table 2).
Figure 2.
Line graphs showing the remission rate of grade 2 HFSR in both treatment groups.
Figure 3.
A 64-year-old male patient with hepatocellular carcinoma treated with SND. (A): Yellowish hyperkeratosis with surrounding erythema with moderate pain (NRS score 3), limiting instrumental activities of daily living. (B): Improved skin lesions and complete relief of pain following 4 weeks of SND treatment.
Table 2.
Efficacy Endpoints in Both Groups at Each Time Point.
| HF-QoL, x̄ ± SD |
NRS, median (second and fourth
quartile) |
Remission, n (%) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Hal/Cxb | SND | P | Hal/Cxb | SND | P | Hal/Cxb | SND | P | |
| W0 | 47.09 ± 10.36 | 45.83 ± 10.20 | .679 | 4.0 (4.0, 5.0) | 4.0 (3.0, 5.0) | .658 | 0 | 0 | / |
| W1 | 44.70 ± 13.99 | 36.96 ± 12.54 | .055 | 4.0 (3.0, 5.0) | 3.0 (2.0, 4.0) | .011 | 0 | 2 (8.70) | .470 |
| W2 | 40.78 ± 16.41 | 28.39 ± 13.01 | .007 | 4.0 (2.0, 5.0) | 1.0 (0.0, 3.0) | .001 | 3 (13.04) | 11 (47.83) | .010 |
| W3 | 37.00 ± 17.57 | 23.48 ± 13.06 | .005 | 3.0 (0.0, 4.0) | 0.0 (0.0, 3.0) | .006 | 6 (26.09) | 13 (56.52) | .036 |
| W4 | 32.87 ± 19.09 | 18.57 ± 13.01 | .005 | 3.0 (0.0, 3.0) | 0.0 (0.0, 2.0) | .002 | 6 (26.09) | 13 (56.52) | .036 |
Abbreviations: HF-QoL, Hand-Foot Quality of Life Scale; NRS, Numerical Rating Scale; SND, Shouzu Ning Decoction; Hal/Cxb, Halometasone plus Celecoxib.
The secondary endpoints of the study were presented in Table 2. The mean HF-QoL score fell to 36.96, 28.39, 23.48, and 18.57 at the end of W1, W2, W3, and W4, respectively, from a baseline score of 45.83 in the SND group. Similarly, in the Hal/Cxb group, from a baseline score of 47.09, the mean HF-QoL score fell to 44.70, 40.78, 37.00, 32.87 at the end of W1, W2, W3, and W4, respectively. The decrease of HF-QoL score was statistically significant between the 2 groups (P = .001). Of note, the HF-QoL score was statistically lower in the SND group compared to the Hal/Cxb group at W2 (P = .007), W3 (P = .005) and W4 (P = .005), respectively. In line with this, the inter-group difference in NRS score was statistically significant (P = .002).
In addition, 12/19 patients who had achieved clinical remission showed recurrence of HFSR (8/13 in the SND group, 4/6 in the Hal/Cxb group), with no significant difference between the 2 groups (P > 0.999).
Safety
During the study period, no significant adverse effects of treatment were observed. Nonetheless, 4 patients from the SND group experienced skin discoloration in their hands and feet, which disappeared within 1 week after the end of treatment. Three patients from the Hal/Cxb group had mild indigestion or acidity.
Discussion
HFSR is one of the most intractable and frequent side effects of MKI treatment, and therefore a major barrier to effective cancer therapy with MKI treatment. This study was the first randomized trial to demonstrate the efficacy of the TCM treatment versus the Western medicine treatment for initial therapy of grade 2 HFSR. Our study showed statistically significant improvement in the SND group at the first, second, third, and fourth week in comparison with the Hal/Cxb group, suggesting that treatment with SND had a better response than Halometasone plus Celecoxib in treating grade 2 HFSR.
Grade 2 HFSR are generally managed with topical corticosteroids and NSAIDs. However, this recommendation is solely based on expert opinion with no controlled clinical trial evidence.10,26 Our data showed that the remission rate was 26.09% for Halometasone plus Celecoxib for 4 weeks in grade 2 HFSR patients, which is consistent with the clinical practice. Furthermore, SIRT1 inhibitor nicotinamide was found to be effective in treating sorafenib-induced HFSR, 27 but with low case numbers, which needed to be further investigated. In addition, a number of randomized controlled studies evaluated that prophylactic strategies using 1% bis-glyceryl ascorbate cream, 28 urea-based cream,8,29 or hydrocolloid dressing containing ceramide could decrease the incidence of HFSR. 30 Despite advances in prophylactic management, a significant number of patients progressed to grade 2 HFSR, leading to modification of MKIs dosage.
TCM treatment has long been considered a safe and effective treatment for HFSR patients. SND, an empirical prescription, was used for treating HFSR patients for a decade via clearing heat and activating blood circulation, according to the traditional Chinese medicine theory. The present study indicated that topical SND treatment for 4 weeks revealed a remission rate of 56.52%, which was significantly superior to that achieved by Halometasone plus Celecoxib treatment. 23 Furthermore, patients with SND treatment had better-alleviated symptoms of HFSR and better-improved quality of life compared to that in the Hal/Cxb group. In addition, the time to HFSR degradation was similar in both groups (10.46 days vs 13.17 days), indicating that a 2-week treatment is likely needed to be efficacious. Regrettably, our study also observed a high rate of recurrence rate in 4 weeks of post-treatment follow-up, which reminded us that long-term HFSR treatment was necessary.
There are some limitations of this study as well. First, this study was a single-center trial with a relatively small number of patients and a short follow-up duration. Nevertheless, these facts do not hinder the identification of the efficacy and tolerability of the treatment. Second, the lack of blinding of participants and physicians may have affected questionnaire responses. On the other hand, independent evaluators were blind to the treatment interventions and statisticians performed an external blind analysis of the deidentified collected data, which might have reduced the bias to the greatest extent possible in this open-label trial. Third, further research to understand the mechanisms by which HFSR occurs and by which SND is not absorbed into the circulation to impair the activity of the MKIs is needed.
Conclusions
In the present study, SND treatment has been observed to be effective and well tolerated for patients with grade 2 HFSR. Thus, SND treatment could be considered a suitable option for HFSR patients. In addition, further studies are needed to establish the optimum dose and duration of SND treatment.
Supplemental Material
Supplemental material, sj-doc-1-ict-10.1177_15347354231168796 for The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial by Liumei Shou, Tianyu Shao, Jialu Chen, Yao Zhang and Qijin Shu in Integrative Cancer Therapies
Supplemental material, sj-docx-2-ict-10.1177_15347354231168796 for The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial by Liumei Shou, Tianyu Shao, Jialu Chen, Yao Zhang and Qijin Shu in Integrative Cancer Therapies
Acknowledgments
The authors acknowledge all the participants in this study.
Footnotes
Author Contributions: Qijin Shu: Conceptualization, edited the manuscript, and provided the funding. Liumei Shou: Designed the clinical trial, edited the manuscript, and provided the funding. Tianyu Shao: Writing—original draft, conducted statistical analysis. Jialu Chen: Writing—original draft, recruited subjects, and collected samples. Yao Zhang: Prepared the SND, supervised the clinical trial. All authors read and approved the final manuscript.
Availability of Data and Materials: The datasets will be available from the corresponding author on reasonable request.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by the Project of Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2020ZB076, 2022ZB113), the Scientific Research Fund of Zhejiang Provincial Education Department (Y202145970), and “the Postgraduate Scientific Research Fund” of Zhejiang Chinese Medical University (2021YKJ03).
Ethics Approval and Consent to Participate: The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (approval No.2019-KL-080-01), and trial was conducted in accordance with the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. Written informed consent was obtained from all the study participants.
Consent for Publication: All authors had read the manuscript and consented of its pubulication.
ORCID iD: Qijin Shu 
https://orcid.org/0000-0002-3338-3269
Supplemental Material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, sj-doc-1-ict-10.1177_15347354231168796 for The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial by Liumei Shou, Tianyu Shao, Jialu Chen, Yao Zhang and Qijin Shu in Integrative Cancer Therapies
Supplemental material, sj-docx-2-ict-10.1177_15347354231168796 for The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial by Liumei Shou, Tianyu Shao, Jialu Chen, Yao Zhang and Qijin Shu in Integrative Cancer Therapies