pazopanib and Skin-Neoplasms

Topics: Aged; Antineoplastic Agents, Immunological; Axons; Carcinoma, Renal Cell; Drug Substitution; Fatal Outcome; Humans; Indazoles; Kidney Neoplasms; Lymphatic Metastasis; Male; Motor Neurons; Nivolumab; Paraparesis; Polyneuropathies; Pyrimidines; Skin Neoplasms; Sulfonamides

Merkel cell carcinoma is an aggressive neuroendocrine tumor with a high incidence of local recurrence, regional nodal and distant metastasis, and a high mortality rate. It has been linked to a polyomavirus in addition to immune suppression. Traditionally, treatment options have been limited to surgery and radiation therapy. Better understanding of the molecular pathways of infection and carcinogenesis has provided potential molecular targets and potential immunotherapies which are discussed in this review.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Benzamides; Biomarkers; Carcinoma, Merkel Cell; CD56 Antigen; Electrochemotherapy; Hepatitis A Virus Cellular Receptor 2; Humans; Imatinib Mesylate; Immunotherapy; Immunotherapy, Adoptive; Indazoles; Inhibitor of Apoptosis Proteins; Interferons; Interleukin-12; Interleukin-2; Ipilimumab; Lymphatic Metastasis; Membrane Proteins; Merkel cell polyomavirus; Oligonucleotides, Antisense; Piperazines; Polyomavirus Infections; Prognosis; Programmed Cell Death 1 Receptor; Pyrimidines; Receptors, Somatomedin; Skin Neoplasms; Somatostatin; Sulfonamides; Survivin; Thionucleotides; TOR Serine-Threonine Kinases

Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.

Topics: Adult; Aged; Biomarkers, Tumor; Dermatofibrosarcoma; Drug Resistance, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Skin; Skin Neoplasms; Sulfonamides; Tumor Burden

There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity.. The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings.. Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m. Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17).. In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Cytokines; Drug Administration Schedule; Female; Humans; Indazoles; Infusions, Intravenous; Male; Melanoma; Paclitaxel; Pyrimidines; Skin Neoplasms; Sulfonamides; Treatment Outcome; Up-Regulation

Cutaneous angiosarcoma (CAS) is a rare and highly aggressive type of vascular tumor. Although chemoradiotherapy with taxanes is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial. From the above findings, the efficacy and safety profiles of taxane-switch (change paclitaxel to docetaxel or vise), eribulin methylate, and pazopanib regimens in second-line chemotherapy were evaluated retrospectively in 50 Japanese taxane-resistant CAS patients. Although there was no significant difference in progression-free survival (P = 0.3528) among the regimens, the incidence of all adverse events (AEs) (P = 0.0386), as well as severe G3 or more AEs (P = 0.0477) was significantly higher in the eribulin methylate group and pazopanib group than in the taxane-switch group. The present data suggest that switching to another taxane should be considered for the treatment of taxane-resistant CAS in second-line therapy based on the safety profiles.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; East Asian People; Female; Hemangiosarcoma; Humans; Paclitaxel; Retrospective Studies; Skin Neoplasms; Taxoids

Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated.. We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions.. Among the patients evaluated, 51 patients (68%) were male and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression-free survival (mPFS) of 4.0 months (95% confidence interval [CI], 3.0 to 6.1), and a median overall survival (mOS) of 10.2 months (95% CI, 7.0 to 14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 months vs. 3.2 months, respectively; p=0.014) with a tendency for prolonged mOS (13.8 months vs. 11.6 months, respectively; p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI, 1.8 to 4.3) and a mOS of 5.4 months (95% CI, 3.5 to not available).. Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Hemangiosarcoma; Humans; Indazoles; Liver Neoplasms; Male; Middle Aged; Paclitaxel; Prognosis; Pyrimidines; Retrospective Studies; Skin Neoplasms; Sulfonamides; Survival Rate

Topics: Hemangiosarcoma; Humans; Indazoles; Pyrimidines; Skin Neoplasms; Sulfonamides

Topics: Hemangiosarcoma; Humans; Indazoles; Interleukin-2; Pyrimidines; Scalp; Skin Neoplasms; Sulfonamides

Paclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial.. In February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute.. If the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established.. Registry number: UMIN000031438 [ http://www.umin.ac.jp/ctr/index.htm ]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Hemangiosarcoma; Humans; Indazoles; Male; Middle Aged; Paclitaxel; Prognosis; Pyrimidines; Research Design; Salvage Therapy; Skin Neoplasms; Sulfonamides; Young Adult

Topics: Adult; Aged; Bone and Bones; Bone Neoplasms; Humans; Indazoles; Magnetic Resonance Imaging; Middle Aged; Neoplasms, Second Primary; Nerve Sheath Neoplasms; Neurofibromatosis 1; Pyrimidines; Radiotherapy, Adjuvant; Skin; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

Topics: Aged; Amputation Stumps; Amputation, Surgical; Biopsy; Chemoradiotherapy; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hemangiosarcoma; Humans; Indazoles; Leg; Lymphangiosarcoma; Neoplasm Recurrence, Local; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Skin; Skin Neoplasms; Sulfonamides

Topics: Angiogenesis Inhibitors; Apoptosis; Cell Line, Tumor; Cell Survival; Dermis; Endothelium, Vascular; Fibroblasts; Hemangiosarcoma; Human Umbilical Vein Endothelial Cells; Humans; Indazoles; Pyrimidines; Skin Neoplasms; Sulfonamides; Toxicity Tests

BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. The estimated 5-year survival of patients with metastatic disease is approximately 14%. Cytotoxic chemotherapy is associated with a modest median progression-free survival (PFS) of only 3 months. In recent studies, immunotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated a high response rate in immunocompetent patients (>50% in chemotherapy-naïve patients) and responses are typically durable. However, approximately 50% of immunocompetent patients do not respond to immunotherapy. In addition, immunosuppressed patients have limited therapeutic options. Hence, there is a significant unmet need for effective treatments in these subpopulations. CASE REPORT We describe 5 patients (out of 24 total) with metastatic MCC who were treated with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), either pazopanib (n=4) or cabozantinib (n=1), with clinical benefit. One patient had a complete response to pazopanib after 3 months of therapy. Four patients had stabilization of disease that lasted from 5 months to 3.5 years. In an immunosuppressed patient with psoriatic arthritis, stabilization of MCC was also associated with improvement in his arthritis that allowed cessation of immunosuppression. Patients did not develop any unusual toxicities from VEGFR-TKIs. CONCLUSIONS Treatment with VEGFR-TKIs demonstrated clinical benefit in this selected small group of patients with metastatic MCC. Prospective investigation of VEGFR-TKIs is warranted in this population, especially in patients with disease refractory to immunotherapy.

Topics: Aged; Angiogenesis Inhibitors; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Merkel Cell; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Skin Neoplasms; Sulfonamides

Topics: Carcinoma, Basal Cell; DNA Mutational Analysis; DNA, Neoplasm; Humans; Indazoles; Male; Middle Aged; Mutation; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2

A 63-year-old man presented with a pulsatile cutaneous horn on the nose and multiple angiomatous nodules on the gingiva and scalp, which appeared over 2 months. He had severe hypercalcaemia, lytic lesions in multiple bones and acute kidney injury. Excision biopsy from the gingival nodule showed a clear cell neoplasm. The bone marrow showed atypical cells with similar morphology. Imaging showed a 7 cmx7.5 cm mass at the upper pole of the left kidney with metastases to the bones, liver and lung. Immunohistochemistry was consistent with metastatic renal cell carcinoma. Renal cell carcinoma presenting as a cutaneous horn is extremely rare and to the best of our knowledge only one other case was found in the literature. There was visible regression in the size of the cutaneous horn and nodules following initiation of pazopanib therapy. However, he succumbed to his illness a month later.

Topics: Acute Kidney Injury; Angiogenesis Inhibitors; Carcinoma, Renal Cell; Diagnosis, Differential; Fatal Outcome; Gingiva; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Pyrimidines; Scalp; Skin Neoplasms; Sulfonamides

Topics: Aged; Angiogenesis Inhibitors; Disease Progression; Head and Neck Neoplasms; Hemangiosarcoma; Humans; Indazoles; Male; Pyrimidines; Skin Neoplasms; Sulfonamides

Topics: Abdomen; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Deoxycytidine; Dermatofibrosarcoma; Docetaxel; Doxorubicin; Drug Resistance, Neoplasm; Fatal Outcome; Gemcitabine; Humans; Ifosfamide; Indazoles; Male; Mesna; Middle Aged; Pyrimidines; Skin Neoplasms; Sulfonamides

Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Bridged-Ring Compounds; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Hemangiosarcoma; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Retrospective Studies; Skin Neoplasms; Sulfonamides; Taxoids

Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Female; Hemangiosarcoma; Humans; Indazoles; Male; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Skin Neoplasms; Sulfonamides; Treatment Outcome

Topics: Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Female; Head and Neck Neoplasms; Hemangiosarcoma; Humans; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Scalp; Skin Neoplasms; Sulfonamides

Topics: Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Biopsy; Carcinoma, Renal Cell; Fatal Outcome; Humans; Immunohistochemistry; Indazoles; Kidney Neoplasms; Male; Neoplasm Recurrence, Local; Nose Neoplasms; Pyrimidines; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome

Topics: Angiogenesis Inhibitors; Head and Neck Neoplasms; Hemangiosarcoma; Humans; Indazoles; Male; Middle Aged; Pyrimidines; Scalp; Skin Neoplasms; Sulfonamides

Topics: Aged; Base Sequence; Biomarkers; Carcinoma, Merkel Cell; DNA Mutational Analysis; Fatal Outcome; Female; Humans; Indazoles; Keratins; Mutation; Neoplasm Metastasis; Phosphopyruvate Hydratase; Protein Kinase Inhibitors; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Scalp; Skin Neoplasms; Sulfonamides