pazopanib and Uterine-Neoplasms

Uterine leiomyosarcomas (ULMS) account for 1% of all uterine malignancies and for 30% of all uterine sarcomas. The preoperative diagnosis of ULMS is challenging for the physicians, as the symptoms of these tumors are often vague and nonspecific. Moreover, as ULMS have an aggressive biologic behavior, affected women frequently have very poor prognosis.. The aim of this review is to describe the current pharmacotherapy for ULMS, including the ongoing clinical trials.. Surgery is the standard treatment for patients with early-stage ULMS. In this setting, the role of adjuvant therapies is still unclear. In the case of advanced, persistent, or recurrent ULMS, chemotherapy is the standard care with the most frequently used drug being doxorubicin. As the outcomes for patients with the currently available conventional single or combined regimens are far from being satisfactory, new alternative and innovative medical compounds have or are being evaluated. Recently, pazopanib, and olaratumab, two innovative targeted drugs, have been approved by the Food and Drug Administration (FDA) for treating advanced soft-tissue sarcoma, including ULMS. However, further clinical investigations into new and innovation therapeutic options are warranted.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Combined Modality Therapy; Doxorubicin; Female; Humans; Indazoles; Leiomyosarcoma; Prognosis; Pyrimidines; Sulfonamides; Uterine Neoplasms

Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy. Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS. Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.

Topics: Angiogenesis Inhibitors; Female; Humans; Indazoles; Leiomyosarcoma; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Uterine Neoplasms

Leiomyosarcoma, a rare tumor subtype, accounts for 1% of all uterine malignancies, but contributes to a significant proportion of uterine cancer deaths. Surgery is considered the mainstay of treatment for all soft tissue sarcomas, including uterine variants. However, uterine leiomyosarcoma is challenging to diagnose preoperatively and can mimic the appearance of benign uterine leiomyomas. Recently, concerns have grown in this regard, as surgeons have utilized uterine morcellation and myomectomy procedures unknowingly in the setting of occult uterine sarcoma. Because of aggressive tumor biology and relative chemotherapy and radiotherapy resistance, efficacious therapies to achieve prolonged survival or cure in those with both early and advanced-stage uterine leiomyosarcoma have been elusive. The strongest determinant of survival remains stage at diagnosis, though prediction models may provide a more accurate prognosis. Given the aggressive nature of this sarcoma subtype, novel early detection strategies and targeted therapies are the focus of several recently published and ongoing studies. While gemcitabine/docetaxel and doxorubicin remain the most active regimens in the treatment of advanced or recurrent disease, currently available cytotoxic regimens remain inadequate, with 5-year disease-specific survival of <30%. Pazopanib, trabectedin and olaratumab, are FDA-approved, targeted therapies with activity in uterine and other leiomyosarcomas, while aromatase inhibitors and immunotherapies are under active investigation. This review provides a critical appraisal of the literature regarding the contemporary surgical and medical management of uterine leiomyosarcoma, the role of targeted therapies, and the implications of uterine morcellation on gynecologic surgical practice.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Chemotherapy, Adjuvant; Deoxycytidine; Diagnostic Errors; Dioxoles; Docetaxel; Doxorubicin; Female; Gemcitabine; Humans; Hysterectomy; Indazoles; Laparoscopy; Leiomyoma; Leiomyosarcoma; Morcellation; Neoplasm Staging; Pyrimidines; Sulfonamides; Taxoids; Tetrahydroisoquinolines; Trabectedin; Uterine Myomectomy; Uterine Neoplasms

Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas.. Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared.. Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352).. Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Indazoles; Leiomyosarcoma; Middle Aged; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoma; Sulfonamides; Survival Rate; Uterine Neoplasms; Young Adult

Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus.. Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0-2. Pazopanib was administered orally at 800mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0.. Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥6months (90% CI: 4.4%, 35.9%). The median PFS was 2.0months (first and third quartiles were 1.6 and 4.0months, respectively). The median overall survival was 8.7months (first and third quartiles were 2.6 and 14.0months, respectively).. Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients.

Topics: Aged; Angiogenesis Inhibitors; Carcinosarcoma; Disease-Free Survival; Female; Humans; Indazoles; Middle Aged; Mixed Tumor, Mullerian; Neoplasm Recurrence, Local; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome; Uterine Neoplasms

Our objective is to report on a case of posterior reversible encephalopathy syndrome associated with pazopanib.. A 64-year-old patient with uterine sarcoma developed PRES 3 days after pazopanib was initiated. After the discontinuation of pazopanib, the symptoms of PRES improved.. The first report worldwide to describe a patient with uterine sarcoma experiencing PRES caused by pazopanib. Patients with uterine sarcoma may experience PRES, even in the early phase of pazopanib therapy.

Topics: Angiogenesis Inhibitors; Diagnosis, Differential; Female; Humans; Indazoles; Magnetic Resonance Imaging; Middle Aged; Posterior Leukoencephalopathy Syndrome; Pyrimidines; Sarcoma; Sulfonamides; Uterine Neoplasms

Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy.. To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma.. We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated.. Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8-107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2-7.5) months and 12.9 (95% CI, 7.8-16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1-10.5) months in the <180 days group and 16.4 (95% CI, 13.1-130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10-0.66), respectively.. The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinosarcoma; Docetaxel; Doxorubicin; Female; Humans; Ifosfamide; Indazoles; Middle Aged; Ovarian Neoplasms; Paclitaxel; Prognosis; Progression-Free Survival; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome; Uterine Neoplasms

Pazopanib-a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects-has shown promise in the treatment of soft-tissue sarcomas. Hyperthermia has been also applied as an adjunctive treatment to chemotherapy for these malignancies. Here, we show that pazopanib and hyperthermia act synergistically in inhibiting uterine leiomyosarcoma (LMS) cell growth. Compared with either treatment alone, the combination of pazopanib and hyperthermia exerted the highest antitumor activity in a xenograft model. Mechanistically, we found that combined treatment with pazopanib and hyperthermia inhibited histone acetyltransferase 1 (HAT1) expression in LMS cells. The Clock element on the HAT1 promoter was critical for pazopanib- and hyperthermia-induced HAT1 downregulation. Inhibition of HAT1-either by pazopanib and hyperthermia or through HAT1 silencing-was mediated by suppression of Clock. Accordingly, Clock protein reconstitution rescued both HAT1 levels and HAT1-mediated histone acetylation. Immunohistochemistry revealed a higher expression of HAT1 in uterine LMS than in leiomyomas (p = 0.007), with high HAT1 expression levels being associated with poor clinical outcomes (p = 0.007). We conclude that pazopanib and hyperthermia exert synergistic effects against LMS growth by inhibiting HAT1. Further preclinical studies on HAT1 as a potential drug target in uterine LMS are warranted, especially in combination with hyperthermia. KEY MESSAGES: Pazopanib and hyperthermia inhibit the growth of leiomyosarcoma. Their combined use inhibits HAT1 expression in leiomyosarcoma cells. The promoter Clock element is required for HAT1 downregulation. HAT1 expression is higher in leiomyosarcoma than in leiomyomas. An increased HAT1 expression is associated with poor clinical outcomes.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Biomarkers; CLOCK Proteins; Female; Gene Expression Regulation, Neoplastic; Histone Acetyltransferases; Humans; Hyperthermia, Induced; Indazoles; Leiomyosarcoma; Pyrimidines; Sulfonamides; Uterine Neoplasms

In the treatment of metastatic soft tissue sarcoma (STS), pazopanib is considered a standard treatment after failure of chemotherapy. We retrospectively investigated outcomes of pazopanib in patients with metastatic uterine STS.. A retrospective study was performed on 35 consecutive patients with uterine STS treated with oral pazopanib 800 mg daily as salvage therapy for metastatic disease between September 2013 and December 2015. Endpoints included response rate, survival, and safety.. Among 35 patients, 27 (77%) had a histologic diagnosis of leiomyosarcoma (LMS) and the median age was 57 years (range, 36-70). Median number of metastatic sites was one (range, 1-5) with lung as the most frequently involved site. Pazopanib was generally well-tolerated: the major hematologic toxicity was grade 1/2 anemia (14%). Among the non-hematologic toxicities, grade 1/2 stomatitis was most commonly observed (22%), followed by fatigue and hypertension. Objective response and stable disease were observed in 10 (29%) and 11 (31%) patients, respectively. However, most cases of clinical response were observed in patients with LMS: 33% for LMS, 20% for undifferentiated pleomorphic sarcoma, and 0% for endometrial stromal sarcoma. Median progression-free and overall survivals were 5.8 months (95% confidence interval [CI]=3.6-8.1) and 20.0 months (95% CI=11.6-28.4), respectively.. In this "real-world" retrospective study, salvage therapy with pazopanib demonstrated clinically relevant efficacy and tolerability in unselected patients with uterine STS. Although it is encouraging that outcomes for Korean patients with uterine STS were similar to those reported in the phase III trial, the clinical benefit was limited to LMS.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Female; Humans; Indazoles; Middle Aged; Neoplasm Metastasis; Pyrimidines; Retrospective Studies; Salvage Therapy; Sarcoma; Sulfonamides; Survival Analysis; Uterine Neoplasms

A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients.. Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation.. A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs.. The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

Topics: Angiogenesis Inhibitors; Compassionate Use Trials; Disease-Free Survival; Female; Hemangiosarcoma; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Solitary Fibrous Tumors; Sulfonamides; Survival Rate; Time Factors; Uterine Neoplasms

Topics: Aged; Antineoplastic Agents; Carcinosarcoma; Female; Humans; Indazoles; Middle Aged; Ovarian Neoplasms; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Uterine Neoplasms

Uterine leiomyosarcoma (ULMS) is an aggressive tumor associated with high rates of progression, recurrence, and mortality. Pazopanib is the only approved molecular targeted drug for advanced soft tissue sarcoma, and it has been proven to prolong progression-free survival relative to placebo. We herein report a case of ULMS with multiple lung metastases treated with pazopanib, which led to sustained disease control for 44 weeks. A 53-year-old woman was referred to our hospital due to massive uterine bleeding from a uterine corpus tumor mass. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed as emergency surgery. The final histopathological diagnosis was uterine leiomyosarcoma, and computed tomography revealed multiple lung metastases. After chemotherapy with 17 cycles of gemcitabine and docetaxel and two cycles of doxorubicin, the lung metastases had increased in size and new lesions had appeared. Pazopanib administration at 800 mg/day was started as third-line therapy. Ten weeks later, the dose of pazopanib was reduced to 600 mg/day because of hepatic impairment and hypertension. However, lung metastases of ULMS were stabilized by pazopanib administration for about 44 weeks without a decline in the patient's quality of life. After 44 weeks of therapy, pazopanib administration was discontinued because of progressive disease and worsening of the patient's respiratory status. Pazopanib is an oral multityrosine kinase inhibitor of vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor-α and -β; and c-Kit receptor. The role of pazopanib may be clinically significant in the treatment of advanced ULMS.

Topics: Antineoplastic Agents; Female; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Salvage Therapy; Sulfonamides; Tomography, X-Ray Computed; Uterine Neoplasms