Posts Tagged ‘phase 1 sarcoma trial’

Prognostic algorithm for retroperitoneal sarcoma

Larry H. Bernstein, MD, FCAP, Curator




Prognostic Nomogram for Retroperitoneal Sarcoma Validated in Large Cohort

Cancer Network  By


A new study validated a prognostic nomogram for retroperitoneal sarcoma (RPS) using a large, external cohort. The nomogram incorporates six variables, and provided strong concordance with observed disease-free survival (DFS) and overall survival (OS).
RPS account for about 15% of all soft-tissue sarcomas, and their unique characteristics make traditional staging difficult, according to study authors led by Chandrajit P. Raut, MD, of Brigham and Women’s Hospital in Boston. A multi-institutional nomogram was developed previously based on a 523-patient cohort who underwent surgical resection for RPS between 1999 and 2009.

The nomogram included six clinical characteristics and variables: age at the time of diagnosis; tumor size; FNCLCC tumor grade; histologic subtype; multifocality at the time of initial presentation; and extent of surgical resection. Because the American Joint Committee on Cancer (AJCC) is considering including this tool in its forthcoming revised staging system, the study authors decided to validate it in an external cohort of 631 RPS patients who underwent surgery at one of six centers. The results were published online ahead of print in Cancer.

The 7-year DFS rate in the validation cohort was 38.4%, and the 7-year OS rate was 58%. This was similar to the development cohort’s outcomes, at 35.7% and 50.5%, respectively. All six of the nomogram’s included variables were found to be independently prognostic.

The researchers used a Harrell C-statistic to measure the nomogram’s discriminative ability. For DFS, the result was 0.69, while for OS it was 0.73. These were very similar to the concordance rates found in the development cohort (0.71 and 0.74, respectively).

“Correlation between observed and nomogram-predicted DFS and OS rates suggest good calibration of the multi-institutional RPS nomogram in a larger, independent validation cohort,” the authors wrote. “External validation of the…nomogram established its broad applicability in predicting outcomes in patients with primary RPS who were treated at experienced centers, and supports its inclusion in the 8th edition of the AJCC classification.”

Study Details
The median age in the validation cohort was 59 years, and the median tumor size was 21 cm. There were similar numbers of patients with FNCLCC grade 1 (32.7%), 2 (39.8%), and 3 (27.5%) tumors.

The most common histologic subtype was dedifferentiated liposarcoma (36.6%), followed by well-differentiated liposarcoma (25%), leiomyosarcoma (21.7%), and other subtypes. Almost all patients (94.8%) had a complete resection. Most patients (91%) did not receive chemotherapy or radiotherapy (68.3%).



Panobinostat Shows Promise in Phase I Sarcoma Trial



Ball-and-stick model of panobinostat; image © molekuul.be / Shuttersto…


A phase I trial found that panobinostat combined with epirubicin is well tolerated and could offer benefit in patients with refractory sarcoma.
“More than half of patients treated for localized soft tissue sarcoma will experience relapse,” wrote study authors led by Pamela N. Munster, MD, of the University of California, San Francisco. Histone deacetylase (HDAC) inhibitors have shown some promise in other early phase I studies with anthracyclines. “Furthermore, HDAC inhibition was shown to promote differentiation and apoptosis in sarcoma.”

The new phase I trial combined the HDAC inhibitor panobinostat—which was approved in February 2015 for the treatment of multiple myeloma—with epirubicin. It began as a 3 + 3 dose escalation trial in patients with advanced solid tumors, followed by an expansion cohort at the maximum tolerated dose in 20 sarcoma patients. The results were published in Annals of Oncology.

In total, 40 patients received 20- to 60-mg panobinostat; 17 patients had previous exposure to topoisomerase II inhibitors. The study drug was administered on days 1, 3, and 5, followed by 75-mg/m2 epirubicin on day 5, in 21-day cycles. Dose-limiting toxicities were seen at 50 mg (one patient) and 60 mg (two patients); these included atrial fibrillation, grade 4 thrombocytopenia and febrile neutropenia, and grade 3 fatigue. The recommended phase II dose was set at 50 mg, and the 20 sarcoma patients in the expansion cohort received this dose.

Of 37 total evaluable patients, a partial response was seen in four of them (11%), and 17 patients (46%) had stable disease.

In only the 20-patient sarcoma expansion cohort, 12 patients were deemed to have received benefit from panobinostat. There was one response in those patients, and 11 patients had stable disease for longer than 3 months. The median progression-free survival in these patients was 3.4 months, and the median overall survival was 8.3 months. The authors noted that acquired topoisomerase resistance was reversed in 8 of 14 patients.

“A major challenge in HDAC inhibitor therapy is the absence of biomarkers,” wrote the authors. In this study, they showed that patients with a “pronounced degree” of peripheral blood mononucleocyte histone acetylation were more likely to derive benefit from the therapy. A decrease in neutrophil count over the first 5 days of the first cycle of therapy also was correlated with clinical benefit.

“This study suggests that further investigation of HDAC inhibition in combination with DNA-damaging agents in defined advanced sarcoma subtypes to validate these preliminary findings is warranted,” concluded the authors.

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