Successful treatment of advanced pancreatic liposarcoma with apatinib: A case report and literature review

ABSTRACT

Pancreatic liposarcoma is a malignant tumor originated from the pancreas mesenchymal tissue and mostly presented in skin, subcutaneous, periosteum, and long bone on both sides. Both conventional chemotherapy and radiotherapy have limited efficacy and poor prognosis for advanced pancreatic liposarcoma. Here, we reported a case of advanced pancreatic liposarcoma and reviewed the literature specific for liposarcoma of the pancreas and discuss the emerging options of treatment. The patient was treated with apatinib and a cross-line rescue therapy combined with paclitaxel after progressive disease. The therapeutic effect of the combination regimen has been evaluated. Apatinib is an oral tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor-2 (VEGFR-2), which has dual effects of anti-angiogenesis and anti-tumor cell proliferation. To our knowledge, this is the first case to report the successful use of apatinib for advanced pancreatic liposarcoma.

KEYWORDS:

• Apatinib
• liposarcoma
• pancreatic cancer
• paclitaxel
• prognosis

Abbreviations

VEGFR-2	=	vascular endothelial growth factor receptor-2
STS	=	Soft tissue sarcoma
SD	=	stable disease
CT	=	computed tomography
PR	=	partial response
DP	=	distal pancreatectomy
MRI	=	magnetic resonance imaging
PD	=	progressive disease
TKIs	=	tyrosine kinase inhibitors
OS	=	overall survival
IHC	=	immunohistochemistry

Introduction

Soft tissue sarcoma (STS) is rare malignancy of mesenchymal origin with high incidence of 2.4/10 million to 5/10 million, accounting for approximately 1% of adult malignancies and 15% of children.^1,2 With distinct heterogeneity, STS frequently occurs in adolescents and middle-aged adults.³ The 5-year survival rate is 40–60%, varies with the prognostic factors as age, tumor location, size, histological grade, and tumor metastasis. As STS mostly occurs in a concealed position and progresses slowly without any symptoms, it causes delayed detection of the disease until the tumor is oppressed by the adjacent tissue and causes clinical symptoms.⁴ Surgical resection of the primary tumor remains the main treatment. Unfortunately, considerable numbers of patients will develop local recurrences or distant metastase. Effective systemic therapies for this broad range of rare disease have been lacking, consequently leading to poor prognosis for patients with advanced disease, especially for malignant dedifferentiated liposarcoma. Thus it is crucial to find out a newer, safer, and more effective treatments of the disease.

Apatinib is an orally small-molecule tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptor-2 (VEGFR-2), it can inhibit tumor neovascularization by blocking downstream signal transduction.⁵ Wide potential efficacy of anti-angiogenic agent also showed in a variety of solid tumors including metastatic lung, colon, and breast cancer.

A case of pancreatic liposarcoma on the left upper quadrant with stable disease (SD) and was treated with apatinib was reported here. We found related literature indicated that orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib showed effective in combination with paclitaxel and carboplatin in advanced cancer.⁶ And we found that there was a case report about successful treatment of apatinib in malignant fibrous histiocytoma in relevant report.⁷ Consequently, after disease progressed with adriamycin and ifosfamide combination treatment, the patient was treated with apatinib and paclitaxel combination chemotherapy. Chest CT (CT) images showed a significant reduction in abdominal mass than before, and the efficacy was evaluated as partial response (PR) (Fig. 2, A-C). To the best of our knowledge, this is the first case of pancreatic liposarcoma that responded to apatinib and paclitaxel combination chemotherapy.

Case report

In December 2015, a 29-year-old female patient visited our hospital because of left upper abdominal discomfort without any obvious incentive. The abdominal distension can be eased after vomiting. The patient was initially found the abdominal mass in June 2015. The CT image revealed that occupying lesions in left abdomen and the left side of the lesion connected with the tail of pancreas (Fig. 1A). Then the patient received the operation of tumor excision. The tumor was observed located behind the stomach and on the upper border of the pancreas, with a volume of approximately 20cm × 15cm × 10cm during the operation, the left segment reached the splenic hilum and the border was basically clear. The tumor capsule was basically complete and the blood was rich. The left edge of the tumor connected with the tail of the pancreas. Intraoperative pathological results suggest malignant mesenchymal tumor, which was considered as dedifferentiated liposarcoma. In the surgery the whole piece of tumor and parts of the spleen as well as the pancreas has been removed, there is no visible lesions existed (Fig. 1B).

Figure 1. CT image of initial diagnosis (A); CT image of post resection(B).

The immunohistochemical results also showed that: CK(−), Vimentin(+), CD34(+), CD117( ± ), S-100(+), Dog-1 ( ± ), CD68(Scattered+), Desmin(−), MyoD1 (Foci+), Bcl⁻2 (+), β-Catenin(–), and Ki67(25%). Then the spindle cell malignancy was revealed with the immunohistochemical results of VEGF (+), VEGFR (+), EGFR (+), CD34 (+), and overexpression of VEGFR-2 protein in tumor cells (Fig. 2). However, the result indicated that the nonspecific biomarker for dedifferentiated liposarcoma MDM2 has no obvious amplification. (The distance between the red and green signals in our testing is 0.8)(Fig. 3). Then we retrieved the relevant literature in the Pubmed database and we found that although MDM2 amplification is a very important biomarker for dedifferentiated liposarcoma, it cannot be the absolute standard for diagnosis.⁸

Figure 2. Hematoxylin and eosin staining of a tumor section(scale bar 100μm).

Figure 3. FISH detection result of MDM2 amplification.

In July 2015, the patient was treated with a postoperative adjuvant chemotherapy using epirubicin in combination with ifosfamide for soft tissue sarcoma, for 4 cycles outside the hospital. However, the patient experienced severe chemotherapy-related adverse reactions such as marrow suppression and mucosal ulceration, which resulted the hesitation of the medication use. But the patient refused to change the first-line chemotherapy. Six months after the surgery, multiple nodules appeared around the operation area, the CT scan demonstrated another left abdominal neoplasm, diameter of approximately 112 × 76mm, which was consistent with liposarcoma recurrence. After the patient was hospitalized in our hospital, the physical examination showed elevated CRP of 265.4mg/L, elevated PCTQ of 0.185ng/ml, as well as an ion disorder. The patient received effective symptomatic treatments can her condition became stable.

As epirubicin in combination with ifosfamide showed insufficient effectiveness, after the patient provided written informed content, apatinib was administered at a dose of 500 mg/day. The size of tumors in abdominal cavity was significantly reduced after 6 months treatment (Fig. 4). Patients taking regular application of apatinib and regular review of CT during February to June 2016, the efficacy was evaluated as stable disease (SD). In July 2016, the disease progressed with new abdominal lesions by CT and was considered to be progressive disease (PD). Related studies indicated that orally small-molecule tyrosine kinase inhibitor showed effective in combination with paclitaxel and carboplatin in advancedcancer.⁶ Thus, a cross-line rescue therapy of apatinib combined with paclitaxel was administered with a dose of apatinib 500 (PO) mg/d and paclitaxel (Ivdrip, VD) 210 mg at the first day, 21days/cycle. Following 4 cycles of treatment, the size of tumor was reduced significantly. The CT indicated that tumor size was 27.61% less than that in September 2016 and 32.9% less than that in July 2016, which was considered as a PR. In addition, there were no severe adverse reactions appeared during the treatment. To our knowledge, it is the first time to report the successful use of apatinib in combination with paclitaxel in advanced pancreatic liposarcoma with a PR. At present, surgical pathologic biopsy was to be performed for whole genome sequencing and VEGFR gene amplification detection to clarify the effective mechanism of drug action and drug resistance of apatinib.

Figure 4. Chest CT images showed abdominal mass before (A) and after treatment with apatinib (B&C); new increased lesions before (D) and after treatment with apatinibin combination with paclitaxel (E and F).

Discussion

Soft tissue sarcoma (STS) represents an extremely rare and heterogeneous group of malignant tumors of mesenchymal origin, which accounts for approximately 1% of all adult malignancies. Liposarcomas appear to originate from precursors of adipocytes and are the most common type of malignant soft tissue sarcomas representing at least 20% of all sarcomas in adults.^1,2 Histologically they can beclassified into well differentiated (WD), myxoid, round cell poorly differentiated myxoid and pleomorphic.^9,10 At present, the process of dedifferented liposarcoma is remain unclear, and it has a approximately 15–20% risk of distant metastasis and 15–30% 5-year survival rate.^11,12,13 Specifically, Carefully performed CT or magnetic resonance imaging (MRI) can be pathognomonic for well- and dedifferentiated liposarcoma and in many cases can be highly suggestive of histologic diagnosis.^14,15 Although liposarcoma is the most common retroperitoneal soft tissue tumor, it still has some difficulties pertaining to diagnosis and treatment,¹⁶ because of its concealed location combined with its unconspicuous incipient symptom. Therefore, aggressive surgical resection had indeed provided a productive opportunity for curing the local lesions. Other adverse prognostic factors include giant liposarcoma volume (maximum diameter >10 cm) and tumor cells existence in surgical edge.^17,18 For soft tissue sarcoma, it was recommend that adriamycin and ifosfamide are the first-line treatment, other antineoplastic agents such as dacarbazine, gemcitabine, liposomal doxorubicin, and vinorelbine are also available.¹⁹ Moreover, anti-tumor angiogenesis agents can be used as appropriate.²⁰ Currently, no definite treatment can be provided for pancreatic liposarcoma, merely few patients with sarcoma can get benefit from radiation therapy, which is much less than chemotherapy. During the progression of soft tissue tumor, conventional radiotherapy and cytotoxic chemotherapy are still controversial for metastases or unresectable lesions. Therefore, on the basis of pathological classification of liposarcoma, more effective systemic treatment regimens are required. In recent years, targeted therapy of liposarcoma has been widely concerned.^21,22 At present, several ongoing clinical trials have evaluated the efficacy of different tyrosine kinase inhibitors (TKIs) in the treatment of STS. In one clinical trial of sunitinib, the treatment of liposarcoma was evaluated as SD after 28 weeks.^23,24 Pazopanib, a new multi-target TKI, was administered in a Phase III clinical trial in patients with metastatic and non-adipose tissue soft tissue sarcoma.²⁵ The results showed that overall survival (OS) in treatment group was 1.8 months, which was longer than placebo. However, the specific treatment of liposarcoma treatment was not mentioned. The related Phase II clinical trial of advanced liposarcoma is ongoing, more clinical data need to be collected.^23,24,25 Apatinib is a specific antagonist of epidermal growth factor VEGFR. It has the dual effects of anti-angiogenesis and anti-tumor cell proliferation.²⁶ It is also reported that sarcoma is a kind of tumor with abundant blood supply, and anti-angiogenic therapy is effective for the sarcoma.²⁷ In addition, apatinib is the first small-molecule anti-tumor angiogenesis target drug which is proved to be effective in advanced gastric cancer.^28,29 Apatinib is the TKI targeting the intracellular domain of VEGFR-2, by targeting the ATP binding sites of VEGFR-2 in highly competitive cells, then blocking downstream signal transduction and inhibiting neovascularization in tumor tissue.

In this case, the patient refused to receive genome-wide sequencing and rejected chemotherapy. Meanwhile, immunohistochemistry (IHC) showed VEGFR (+) and apatinib was selected as first-line treatment. After 2 months' treatment, the efficacy was evaluated by CT and PR was confirmed according to the RECIST criteria. The general condition and the quality of life of the patient were significantly improved. However, CT results in September 2016 indicated PD. After some investigations, we found that tyrosine kinase inhibitors showed effective in some advanced diseases, hence apatinib combined with paclitaxel was recommended to obtain a better prognosis with PR. To our best knowledge, it is the first case to report the successful use of apatinib and a cross-line therapy with paclitaxel in advanced pancreatic liposarcoma. Currently, the patient has been treated for 12 months with a significant remission. Meanwhile, the administration of apatinib did not cause major toxic profiles except for mild hand-foot syndrome.

Conclusion

Nowadays, there is no definite protocol for the treatment of advanced metastatic sarcoma, both conventional chemotherapy and radiotherapy have limited efficacy and poor prognosis for advanced pancreatic liposarcoma. Although we know that sarcoma is a kind of tumor with abundant blood supply, and anti-angiogenic therapy is effective for the sarcoma. Our case report provide a potential benefit and effective protocol for progressive liposarcomas. These indicated that the anti-angiogenic effect of apatinib would be a new effective protocol for treatment of advanced sarcoma. In a word, the successful use of apatinib in this case showed significant efficacy on advanced pancreatic liposarcoma. Meanwhile, it can provide reference for the treatment of clinical-related cases. At present, the concept of accurate treatment is widely recognized. Apatinib, as a domestic-made target drug, its importance in the accurate treatment of cancer will be interpreted deeply.

This work was supported by grants from the Postdoctoral Science Foundation of China (No. 2015M582822) and the Doctor Scientific Research Foundation of Liaoning Province (No. 201501022). No additional external funding received for this study.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.