A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib.

BACKGROUND: Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (-1, -2, and -3), and PDGFR (-α and-ß) in patients with advanced GIST following failure of at least imatinib and sunitinib. METHODS: Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. RESULTS: Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2-7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5-37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6-5.2), and the median OS was 10.7 months (95% CI 3.9-NR). CONCLUSIONS: Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST.

Germ cell tumor associated primitive neuroectodermal tumors.

PURPOSE: This retrospective review was done to assess the prognosis and response in patients presenting with primitive neuroectodermal tumor admixed with germ cell tumor. MATERIALS AND METHODS: Of the 40 patients treated at our institution from 1984 to 1999, 15 had initial stage I and 25 had initial metastatic disease. Median followup after the diagnosis was 25 months (range 4 to 142). RESULTS: Of the 40 patients 15 presented with clinical stage I disease, including 9 treated with retroperitoneal lymph node dissection and 6 who elected surveillance. Seven of the 9 patients had normal lymph nodes and all continuously had no evidence of disease. Two of the 9 patients had lymph nodes involved with teratoma with or without primitive neuroectodermal tumor. Retroperitoneal relapse in 5 of the 6 patients on surveillance was treated with cisplatin based chemotherapy followed by post-chemotherapy retroperitoneal lymph node dissection. Residual primitive neuroectodermal tumor was noted in 4 of the 5 patients and only 3 of 6 are currently without disease at a median followup of 17 months (range 15 to 69). A total of 25 patients presented with metastatic disease, of whom 23 underwent cisplatin based chemotherapy. Only 3 patients achieved complete remission with chemotherapy alone and 2 of the 3 subsequently relapsed. Of the remaining 20 patients 16 underwent post-chemotherapy retroperitoneal lymph node dissection, including 11 with primitive neuroectodermal tumor in the resected specimen. Two of these 11 patients have continuously had no evidence of disease, while an additional 3 currently have no evidence of disease after further therapy. Teratoma was present in the resected specimen in 5 of 16 patients, of whom 2 have continuously had no evidence of disease, while an additional 2 currently have no evidence of disease after further surgical resection. Therefore, 11 of 25 patients who presented with metastatic disease currently have no evidence of disease at a median followup of 19 months (range 2 to 111). CONCLUSIONS: Primitive neuroectodermal tumor in the orchiectomy specimen has adverse prognostic significance. This condition in the retroperitoneum is potentially curable by retroperitoneal lymph node dissection but rarely eradicated by chemotherapy. Therefore, we recommend retroperitoneal lymph node dissection for all clinical stage I cases with primitive neuroectodermal tumor in the orchiectomy specimen. Patients who present with metastatic primitive neuroectodermal tumor should be treated aggressively with surgical resection as an integral part of the therapeutic strategy.

Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors.

BACKGROUND: The aim of this study was to determine the effects of independent prognostic variables, such as prechemotherapy tumor markers, the extent of disease at diagnosis, the tumor markers postchemotherapy (PC), and the pathology of the PC residual mass on the overall survival of patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCT). METHODS: The authors undertook a retrospective review of 39 patients with PMNSGCT between 1983 and 1997 who received their initial chemotherapy at Indiana University and 36 additional patients referred for PC resection. All patients received chemotherapy based on the combination of cisplatin and etoposide. The median follow-up was 22 months (range, 12-144 months). RESULTS: The prechemotherapy tumor markers did not affect overall survival. Extent of disease (mediastinal only vs. visceral metastases) was an important prognostic factor for survival in univariate analysis (P = 0.042). Sixty-two of 75 patients underwent PC resection of residual disease. Fifteen of the 62 patients achieved a CR with chemotherapy alone, as the PC resection revealed only necrosis. Fourteen of these 15 patients continuously had no evidence of disease (NED). Forty-seven of the 62 patients had NED with chemotherapy and PC resection, including 31 with teratoma and 16 with carcinoma. However, 11 of 31 with teratoma and 11 of 16 with carcinoma subsequently relapsed. Although 18 patients had elevated tumor markers at the time of PC resection, 6 of 18 had only necrosis and 4 had teratoma. The PC tumor markers did not affect survival. The pathology of the resected specimen was the most significant predictor of survival in multivariate analysis (P < 0.001). CONCLUSIONS: Twenty-eight of 39 patients (71.8%) with PMNSGCT treated at Indiana University achieved NED status, but only 16 (41%) continuously had NED. Twenty of 36 (55.5%) referred for resection continuously had NED. Disease confined to the mediastinum and necrosis in the PC specimen were important prognostic factors for survival.

Positron emission tomography scans in the evaluation of postchemotherapy residual masses in patients with seminoma.

PURPOSE: To assess the ability of positron emission tomography (PET) scans in differentiating between necrosis and viable seminoma in postchemotherapy (PC) residual disease. PATIENTS AND METHODS: We conducted a prospective study of 29 patients with seminoma at Indiana University. All patients had PC residual disease. Computed tomography and PET scans were performed for 19 patients after primary chemotherapy (group A) and for 10 patients after salvage chemotherapy (group B). RESULTS: In group A, the PC masses were >/= 3 cm in 14 patients, less than 3 cm in three patients, and not quantified in two patients. All of the patients in group A had negative PET scan results and have had stable or decreasing residual mass size (median follow-up duration, 11.5 months; range, 6 to 26 months). In group B, the PC masses were >/= 3 cm in four patients, less than 3 cm in five patients, and not quantified in one patient. One patient had a positive PET scan result for a posterior mediastinal mass. Pathologic diagnosis of the PET-positive mass showed only necrotic tissue. The same patient had a negative PET scan of the retroperitoneal mass but relapsed in that area. Overall, of patients in group B, five have stable or decreasing mass (median follow-up duration, 8 months; range, 7 to 22 months), and five had relapsed disease. CONCLUSION: PET scans have no apparent benefit in PC evaluation of residual masses in bulky seminoma.

Primary mediastinal nonseminomatous germ cell tumors: the influence of postchemotherapy pathology on long-term survival after surgery.

OBJECTIVES: The treatment of nonseminomatous germ cell tumors with cisplatin-based chemotherapy followed by aggressive surgical resection of residual disease is one of the most successful models for multimodality cancer therapy. We reviewed the case histories of 91 patients treated at our institution from 1981 to 1998 with primary mediastinal nonseminomatous germ cell tumors to evaluate variables that may influence survival after surgery. METHODS: Twelve of the 91 patients did not undergo postchemotherapy resection because of progressive disease. Seventy-nine of them underwent 82 thoracic surgical procedures and are the basis of this review. The majority (71/75) had elevated serum tumor markers, 75% (n = 50) of which returned to normal levels after first- or second-line chemotherapy. RESULTS: There were 3 operative deaths and 1 late death, attributed to pulmonary complications. Twenty-four patients died of recurrent disease and 3 of leukemia, for an overall survival of 61% after an average follow-up of 48 months. The pathologic findings of complete tumor necrosis (n = 19) and benign teratoma (n = 28) in the surgical specimen predicted excellent and good long-term survival, respectively, which was statistically better than that of patients having persistent nonseminomatous germ cell tumors (n = 24) or carcinomatous/sarcomatous degeneration (n = 8). CONCLUSIONS: Primary nonseminomatous germ cell tumors of the mediastinum can be cured with a multimodality therapy, particularly in the subset of patients with postchemotherapy pathologic findings of tumor necrosis and teratoma. Survival is poor but possible in patients with unfavorable pathologic findings after chemotherapy, currently justifying an aggressive surgical approach in patients with otherwise operable disease.