pazopanib and Liposarcoma

A 68-year-old man underwent an inguinal orchiectomy for a right testicular tumor and the pathological diagnosis was atypical lipomatous tumor. Nine years later, a resection procedure was performed for local recurrence. Five years after that second surgery, abdominal computed tomography (CT) findings revealed a low density mass 40 mm in size on the back side of the right kidney and enlarged fat in the retroperitoneal space. We performed a laparoscopic tumor resection under a diagnosis of lipoma or liposarcoma recurrence, and the pathological diagnosis was well differentiated liposarcoma. Treatment with pazopanib was started, as a CT examination showed that the tumor remained, after which we performed an open nephroureterectomy and resected the remaining tumor portion. Pazopanib treatment was continued and no obvious signs of recurrence were seen at 8 months after the most recent surgery. Although well differentiated liposarcoma usually recurs in the original tumor region, multicentric recurrence in other parts is possible.

Topics: Aged; Angiogenesis Inhibitors; Chemotherapy, Adjuvant; Humans; Indazoles; Liposarcoma; Male; Orchiectomy; Pyrimidines; Recurrence; Retroperitoneal Neoplasms; Sulfonamides; Testicular Neoplasms; Time Factors; Tomography, X-Ray Computed

This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma.. Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12).. Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy.. The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Female; Follow-Up Studies; Humans; Indazoles; Liposarcoma; Male; Middle Aged; Neoplasm Grading; Prospective Studies; Pyrimidines; Sulfonamides; Survival Rate; Young Adult

Soft tissue sarcomas (STS) are heterogenous cancers encompassing more than 100 histological and molecular subtypes. Their extreme rarity underscores the need for international collaboration to identify specific treatment protocols. Increasing knowledge of STS complexity as defined by molecular biology has led to the introduction of targeted therapies for several sarcoma subtypes, which is an encouraging start. In advanced STS, doxorubicin-based regimens are standard first-line chemotherapy. Options for second and later lines include ifosfamide, trabectedin, pazopanib, eribulin and gemcitabine-based regimens. Histological subtype has become a key factor when selecting best options to treat advanced sarcoma; however, the challenges of identifying optimal treatments for all STS histotypes are undeniably formidable. Fortunately, the sarcoma community shares the common goal of seeking greater knowledge about the characteristics of each subtype in order to improve diagnosis and outcomes. Progress made to date in this regard suggests that the vision to treat by subtype is achievable.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Doxorubicin; Female; Furans; Gemcitabine; Humans; Ifosfamide; Indazoles; Ketones; Liposarcoma; Middle Aged; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Trabectedin

Liposarcoma (LS) is a chemotherapy-resistant disease. The aim of the present study was to find precise therapy for a recurrent dedifferentiated liposarcoma (DDLS) in a patient-derived orthotopic xenograft (PDOX) model. The DDLS PDOX models were established orthotopically in the right inguinal area of nude mice. The DDLS PDOX models were randomized into five groups: untreated; doxorubicin (DOX); gemcitabine (GEM) combined with docetaxel (DOC); pazopanib (PAZ); and yondelis (YON). On day 15, all mice were sacrificed. Measurement of tumor volume and body weight were done two times a week. The DDLS PDOX was resistant to DOX (P > 0.184). YON suppressed tumor growth significantly compared to control group (P < 0.027). However, only GEM combined with DOC arrested the tumor growth (P < 0.001). These findings suggest that GEM combined with DOC has clinical potential for this and possibly other DDLS patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Models, Animal; Docetaxel; Doxorubicin; Drug Resistance, Neoplasm; Gemcitabine; Heterografts; Humans; Indazoles; Liposarcoma; Male; Mice; Mice, Nude; Neoplasm Recurrence, Local; Pyrimidines; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays

Pazopanib was administered to a 44-year-old man with local recurrence of retroperitoneal liposarcoma. Computed tomography showed an intestinal edema, which gradually progressed 15 months after pazopanib administration although he had no clinical symptoms. Upper gastrointestinal endoscopy implicated marked edematous hypertrophy of the Kerkling's fold. Pathological findings showed crystal deposition and fat accumulation, without a malignant component. All these abnormal findings resolved after pazopanib discontinuation.

Topics: Adult; Antineoplastic Agents; Edema; Endoscopy, Gastrointestinal; Humans; Indazoles; Intestinal Diseases; Intestinal Mucosa; Kidney Neoplasms; Liposarcoma; Male; Neoplasm Recurrence, Local; Pyrimidines; Retroperitoneal Neoplasms; Sulfonamides; Tomography, X-Ray Computed

Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise individualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ± 2.6, p = 0.8087); PAZ (1.29 ± 0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ± 0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX-treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line.

Topics: Aged; Animals; Doxorubicin; Gene Amplification; Humans; Indazoles; Liposarcoma; Male; Mice; Mice, Nude; Neoplasm Proteins; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Disease Progression; Disease-Free Survival; Humans; Indazoles; Liposarcoma; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome

Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data.. Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.. The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.. There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Chemical and Drug Induced Liver Injury; Disease-Free Survival; Female; Fibrosarcoma; Humans; Hypertension; Indazoles; Japan; Leiomyosarcoma; Liposarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Neurilemmoma; Pneumothorax; Product Surveillance, Postmarketing; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Sulfonamides; Survival Analysis; Thrombocytopenia

Pazopanib, a novel tyrosine kinase inhibitor, is an effective therapeutic agent for patients with advanced soft tissue sarcoma. Here we report three patients with recurrent retroperitoneal liposarcoma who were treated with pazopanib. Case 1: A 54-year-old male received three courses of combined chemotherapy consisting of doxorubicin and ifosfamide for recurrent left retroperitoneal dedifferentiated liposarcoma and liver metastasis following tumor excision. Because of the lack of response to chemotherapy, 400 mg/day of pazopanib was subsequently administered for two weeks. The patient died 3 weeks after the initiation of pazopznib therapy. Case 2: A 78-year-old male with right retroperitoneal dedifferentiated liposarcoma underwent irradiation for a recurrent tumor 16 months after the initial tumor excision. Pazopanib (600 mg/day) was partially effective for 2 months. Pazopanib was administered for 7 months, but the patient died 8 months after the initiation of pazopanib therapy. Case 3 : An 80-year-old male with locally recurrent right retroperitoneal myxoid liposacroma was treated with 600 mg/day of pazopanib from 5 months after tumor excision. He remains alive and has had stable disease for 17 months to date. In conclusion, pazopanib may be effective in a subset of patients with recurrent retroperitoneal liposarcoma.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Humans; Indazoles; Liposarcoma; Male; Middle Aged; Neoplasm Staging; Pyrimidines; Recurrence; Retroperitoneal Neoplasms; Sulfonamides; Tomography, X-Ray Computed