Shan-Qi Guo, Xiao-Jiao Gao, Xiao-Jiang Li, Ying-Jie Jia,*

1Department of Oncology, First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.2Department of pathology, Kunshan First People's Hospital Affiliated to Jiangsu University, Jiangsu, China

Abstract

Keywords:Maxillary sinus carcinoma, Apatinib, Ttraditional Chinese medicine,Hand and foot skin reaction

Introduction

Paranasal sinus carcinomas account for only 3% of head and neck cancers.In advanced maxillary sinus cancer treated with surgery and radiotherapy, poor local control rates, and the potential for organ preservation have prompted interest in the use of systemic therapy [1].Apatinib (Aitan?, brand name in China) is a new anti-antiangiogenic agent mainly acts on VEGFR-2 that has been approved for the treatment of advanced gastric cancer (GC) in China [2].Several clinical studies also showed that curative effects and survival benefits for patients with various types of solid tumor are obviously improved [3-4].As to adverse reaction, apatinib had a relatively higher incidence of hypertension, urine protein, and hand-foot syndrome [5].Traditional Chinese medicine, including herbal medicine, has been used for the prevention, treatment, and cure of disorders or diseases for centuries.TCM has been used directly as therapeutic agents in this case for HFSR amazed demonstrate the good clinical effect and avoid apatinib withdrawal and reduction.

Case report

A 78-year-old woman with no previous disease was admitted to maxillary sinus carcinoma.She was undergone discontinuous left face swelling and painful resection from December 10th，2017, accompanied without bloody discharge, dysosmia, and dysgeusia.Paranasal sinus MRI prompting that malignant tumor originated from the anterior wall of the left maxillary sinus, involved the medial wall of the left maxillary sinus, ethmoid and the left orbital inferior wall (Figure 1A).PET-CT showed that left maxillary sinus masses with abnormally increased metabolism was considered malignancy, protruding into the nasal cavity and ethmoid sinus, no other site metastases were found.Ruled out contraindications for surgery, a left maxillary sinus mass resection and sinus opening were performed at February 6th, 2018.Postoperative pathological findings:(left maxillary sinus mass, left ethmoid sinus,left nasal stenosis) squamous cell carcinoma; The left anterior maxillary sinus posterior lateral wall) skeletal muscle tissue can be seen in cancer tissue.Immunohistochemistry:CK (+), CD68 scattered (+),P63(+), CK5/6(+), Ki-67 40% (Figure 2).Staging:T2N0M0, Phase Ⅱ.

Considering the age of the patient and side effects,she and her family refused local radiotherapy after an operation.Five months later, the swelling was aggravated with the left cheek (Figure 3A), and an MRI showed that the tumor was involved in the left ethmoid sinus and the left side of the frontal sinus.In May 31th 2018 and June 25th, 2018, second-line treatment with cisplatin and 5FU was introduced.The first evaluation after 2 courses showed an unexpected clinical and radiological response and achieved a partial response(PR) (Figure 1B).Then cisplatin and 5FU chemotherapy went on in July 19th and August 14th 2018, while after 4 courses chemotherapy, she felt her left face swelling was slightly less than before (Figure 3B), with a new MRI disappointed read the thickening of soft tissue in the zygomatic arch on the left was more obvious than that on the front, the local mucosa also thickening in the right maxillary sinus and multiple nodules appeared in the neck, efficacy evaluation manifest a progression disease (PD) (Figure 1C).Meanwhile, severe gastrointestinal reaction and asthenia as side effects appeared and she stopped chemotherapy after the four courses of cisplatin and 5FU.

After discussion in the multidisciplinary team, the patient was advised to treat with oral apatinib mesylate 250mg per day from September 29th, 2018.Ten days later, the ultrasound result showed the irregular hypoechoic mass in the left maxillary sinus was much smaller than before.Nevertheless, the skin of patient's palms appeared peeling, blistering and accompanied with local edema, and unbearable pain also occurred which sometimes need morphine to relieve, all the above symptoms more or less affected her daily life and activities.We concluded that she had GradeⅡ hand and foot skin reaction (HFSR).Then apatinib was stopped given.Simultaneously, traditional Chinese medicine (TCM) including comfrey cream two grams each time, twice a day (The main components are comfrey and angelica.It has the function of transforming saprophytic muscle and relieving pain),Guicao moisturizing two grams each time, twice a day(mainly composed of angelica and licorice, which has the effect of astringing and protecting the skin) cream for external use.Beyond that, the herbal decoction aimed to promote blood circulation and relieve the pain was used to wash her hands twice a day.Four days later,the swelling of her hands was significantly better than before and began to peel from the center of her palms(Figure 4).Then she was resumed oral administration of apatinib 250mg per day from the fifth day, at the same time, TCM was also synchronous treatment.To our surprise, a cycle of treatment for 28 days, accompanied by the treatment of TCM, apatinib highlights good efficacy without withdrawal and reduction(Figure 1D,3C).

Discussion

Paranasal sinus malignancies are rare neoplasms that present an ominous prognosis.Among them, sinonasal squamous cell carcinoma represents about 3% of all malignancies of the head and neck region.It predominantly occurs within the maxillary sinus and less frequently in the nasal cavity, ethmoid, and sphenoid/frontal sinuses[6].Surgery is the gold-standard approach to improve significantly the overall survival and local-regional control for paranasal sinus malignancies patients, radiotherapy associated or not with chemotherapy is also recommended postoperation based on the staging of disease.What cannot be ignored is that patients with radiotherapy always suffer from some complications such as visual impairment, superficial necrosis, cerebrovascular accidentet al.Marcello Roter M Santoset al.concluded that patients who were treated by tri-modal therapy achieved the highest survival rate[7].In this case, the patient did a left maxillary sinus mass resection and sinus opening surgery, then four courses of cisplatin and 5FU chemotherapy were introduced, no good results were achieved and serious adverse reactions were reported.Then targeted drug therapy was performed.

Apatinib is a new type of small molecule tyrosine kinase inhibitor that has been approved by the CFDA for patients with metastatic gastric adenocarcinoma or gastroesophageal conjunctive adenocarcinoma after the failure of second-line therapy mainly acts on VEGFR-2.Additionally, several clinical studies have shown that short-term curative effects and survival benefits for patients with various types of middle-late solid tumor such as lung cancer, hepatocellular carcinoma, and sarcoma are improved.Xueet al.analyzed short-term acute adverse reactions, such as myelosuppression,nausea and vomiting, hypertension, proteinuria,hand-foot syndrome, and gastrointestinal reactions[8].

Apatinib-related HFSR is similar to that seen with other multikinase inhibitors (e.g.sunitinib, cabozantinib,sorafenib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies.The mechanism of the occurrence of HFSR is unclear.It may be related to blocking the VEGR/VEGFR pathway, which damages the vascular vessels of the dermis and affects its repair process.Residues in skin tissue are associated with toxicity.The goal of management is to control hyperkeratosis, cushion callused areas, moisturize skin,and relieve discomfort.Tianet al.demonstrated a randomized, double-blind, placebo-controlled trial showed that topical use of Danxiong Granules(CDG),as an instant herbal powder, was significantly effective in minimizing dermatologic toxicities induced by targeted anticancer therapies, the total effective rate in the CDG group was significantly higher than that of the placebo group (77.61% versus 27.27%, resp.)[9]. In the current case, the patient uses Chinese herbal medicines as an external application plus external washing, and the syndrome was relieved earlier, which ensured the therapeutic effect.To our knowledge, there are no systematic and multicenter clinical trials have been reported, we concluded that TCM has a certain effect in improving the adverse reactions of apatinb, and it can be used clinically.

Figure 1 Imaging findings of maxillary sinus carcinoma.

Figure 2 Immunohistochemical results of postoperative pathology (200×).

Figure 3 (A) The patient left face after surgery for five months, (B) finished four courses of chemotherapy, (C)treat with apatinib for 28 days.

Figure 4 Pictures of TCM treated for HFSR of Day1, 4, 8 and 12.