pazopanib and Peritoneal-Neoplasms

Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC.. An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m. 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%).. The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial; Deoxycytidine; Fallopian Tube Neoplasms; Female; Gemcitabine; Humans; Indazoles; Middle Aged; Peritoneal Neoplasms; Pyrimidines; Sulfonamides

AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS.. Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS.. Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non-significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82).. Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Fallopian Tube Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genome-Wide Association Study; Germ-Line Mutation; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Pyrimidines; Sulfonamides; White People; Young Adult

Analysis of progression-free survival (PFS) as the primary endpoint in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer (AEOC) trials may be confounded by the difficulty of radiologic evaluation of disease progression and the potential for discrepancy between investigator and blinded independent central assessments. PFS as assessed by local investigator (INV) was the primary endpoint of AGO-OVAR16, a randomized, double-blind trial of pazopanib maintenance therapy in AEOC. To confirm the robustness of the primary analysis, PFS was also evaluated by blinded independent central review (BICR).. Patients with histologically confirmed AEOC (N = 940) were randomized 1:1 to receive pazopanib 800 mg/day or placebo for up to 24 months. Tumor response in the intent-to-treat population was evaluated by CT/MRI every 6 months and analyzed per RECIST 1.0.. Pazopanib prolonged PFS versus placebo by INV (median 17.9 vs 12.3 months; hazard ratio [HR] = 0.766, 95% confidence interval [CI]: 0.643-0.911; P = 0.0021). Results for PFS by BICR were similar (median 15.4 vs 11.8 months; HR = 0.802, 95% CI: 0.678-0.949; P = 0.0084). Progression events were recorded later by INV in 23% of pazopanib-treated patients and 17% of placebo-treated patients. The overall concordance between INV and BICR assessments was 84% and 86% in the pazopanib and placebo arms, respectively.. By INV and BICR assessments, maintenance therapy with pazopanib in AEOC provided a significantly longer PFS than placebo. The good overall concordance between INV and BICR assessments, as well as HR and P value consistency, supports the reliability of investigator-assessed PFS as the primary endpoint in AGO-OVAR16.

Topics: Angiogenesis Inhibitors; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Double-Blind Method; Endpoint Determination; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Pyrimidines; Sulfonamides

The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer.. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (> 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green-Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation).. Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported.. Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other small-molecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing.

Topics: Adult; Aged; Aged, 80 and over; CA-125 Antigen; Disease-Free Survival; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Pyrimidines; Sulfonamides; Survival Rate

Peritoneal angiosarcoma is an extremely rare sarcoma (0.01287% incidence per 100,000) with an aggressive course and a poor prognosis. In this case, the manifestation of peritoneal angiosarcoma was ascites, which caused difficulty in early diagnosis and the diagnosis of peritoneal angiosarcoma, was made only after the surgery.. A 61-year-old man working in Mainland China presented with a 1-month history of abdominal distension. A contrast-enhanced abdominal computed tomography (CT) scan revealed peritoneal carcinomatosis with massive ascites. However, his tuberculosis (TB) polymerase chain reaction was negative. The ascites cell block and cytology also revealed negative for malignant cells. The patient underwent intra-abdominal tumor excision. After the operation, the patient's blood pressure (BP) dropped. Due to the state of shock, he was transferred to an intensive care unit (ICU).. According to the pathology report, the neoplastic cells were positive for cytokeratin, cluster of differentiation 31 (CD31), cluster of differentiation 34 (CD34), and negative for cytokeratin 7 (CK7), cytokeratin 7 (CK20). Therefore, the diagnosis of epithelioid angiosarcoma was made.. The patient took 400 mg of Pazopanib once a day.. Even though vasopresser was used, the patient's BP was still low. Finally, he expired.. Initialy, the patient presented with abdominal distension and large amount of ascites in the beginning. TB peritonitis was highly suspected after the abdominal CT scan. Therefore, surgical procedures would be essential in the identification of proper diagnosis. In the future, the diagnosis of peritoneal epithelioid angiosarcoma should also be taken into consideration for patients with abnormal ascites besides the common diagnoses of TB, liver cirrhosis, and infection.

Topics: Ascites; Hemangiosarcoma; Humans; Hypotension; Indazoles; Male; Middle Aged; Peritoneal Neoplasms; Postoperative Complications; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Tomography, X-Ray Computed

Pazopanib, an oral tyrosine kinase inhibitor, is the first molecular-targeted agent approved for the treatment of advanced soft tissue sarcoma(STS). Rhabdomyosarcoma in adults is rare, accounting for less than 3%of all adult STS cases. A 57-year old woman presented with cervical lymphadenopathy. Computed tomography revealed a heterogeneous mass in the retroperitoneum, replacing the entire right kidney. On the basis of the above findings, the patient was diagnosed with alveolar rhabdomyosarcoma. She was first treated with 4 courses of vincristine, actinomycin D, and cyclophosphamide(VAC), which resulted in a partial response. Dose reduction and delay occurred owing to hematological toxicity and febrile neutropenia. As second-line chemotherapy, the patient was administered a single daily dose of 800 mg of pazopanib. Because of an episode of hand-foot syndrome and hepatic impairment, the 800-mg daily dose of pazopanib was reduced to a daily dose of 600 mg, which had to be further reduced to a daily dose of 400 mg owing to fatigue and anorexia. The patient maintained a partial response for a total of 4.3 months when treated with pazopanib. Therefore, this drug may be a new treatment option for patients showing metastatic STS after previous chemotherapy.

Topics: Angiogenesis Inhibitors; Biopsy, Needle; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Middle Aged; Peritoneal Neoplasms; Pyrimidines; Rhabdomyosarcoma; Sulfonamides

Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was the first angiogenesis inhibitor approved for the first-line treatment of metastatic colorectal cancer in combination with intravenous fluorouracil-based chemotherapy. Two major cohort studies--BRiTE and BEAT--reported a 2% incidence of bowel perforation, which remains a rare, but serious, complication of bevacizumab treatment. Late anastomotic complications, arising > 3 months after surgery, are emerging occurrences that may be associated with bowel perforation. We report here on such a case caused by pazopanib, a new antiangiogenic agent, and also include a review of the published cases in the literature (n = 23) and an analysis of their management. Proctectomy was the initial surgery in 17 patients (74%) with rectal cancer, and 13 of these patients had undergone adjuvant radiation prior to surgery. The majority (84%) of the complications occurred with antiangiogenic treatment after a mean number of four cycles. Patients' management was invariably associated with withdrawal of the antiangiogenic agent, together with conservative treatment in 14 patients (66%).

Topics: Anastomosis, Surgical; Angiogenesis Inhibitors; Anti-Bacterial Agents; Carcinoma; Colectomy; Female; Humans; Hysterectomy; Indazoles; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Ovarian Neoplasms; Ovariectomy; Peritoneal Neoplasms; Pyrimidines; Salpingectomy; Sulfonamides; Surgical Wound Dehiscence; Treatment Outcome