Posts Tagged ‘disease-free survival’

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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Treatment for Metastatic HER2 Breast Cancer

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Word Cloud By Danielle Smolyar

Reporter: Larry H Bernstein, MD, FCAP
Leaders in Pharmaceutical Innovation
http://pharmaceuticalintelligence.com/2013/03/03/9680/Treatment for Metastatic HER2 Breast Cancer 

FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)
T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.
T-DM1 is indicated for patients who were previously treated with

  • the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the

  • HER2-targeted antibody trastuzumab
  • is chemically linked to the cytotoxin mertansine (DM1).

The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.  According to Richard Pazdur, MD, at the FDA Center for Drug Evaluation and Research, T-DM1 carries the drug-conjugate

  • directly to the cancer site
  • to shrink the tumor,
  • slow disease progression, and
  • prolong survival .

It is the fourth drug approved that targets the HER2 protein. Apart from lapatinib, which is marketed by GlaxoSmithKline, all the other HER2-targeted products have been developed and are marketed by Genentech/Roche. For T-DM1, the proprietary technology involved in the DM1 portion of the product was developed by ImmunoGen, working in collaboration with Genentech/Roche.

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of

  • lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months).

There were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy

  • 43.1% vs. 59.2%)

The approval represents a “momentous” day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

  • HER2-positive patients with metastatic disease have a therapy that offers prolonged disease control with less toxicity

 T-DM1 was more effective in EMILIA than standard therapy on every outcome:

  • overall response rate,
  • disease-free survival,
  • progression-free survival, and
  • overall survival.
Herceptin Fab (antibody) - light and heavy chains

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Ribbon diagram of the Fab fragment of , a , bo...

Ribbon diagram of the Fab fragment of , a , bound to the extracellular domain of HER2. Created using Accelrys DS Visualizer Pro 1.6 and . ; Legend Trastuzumab Fab fragment, Trastuzumab Fab fragment, HER2, extracellular domain (Photo credit: Wikipedia)

Breast cancer (Infiltrating ductal carcinoma o...

Breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody. (Photo credit: Wikipedia)

English: Breast cancer incidence by age in wom...

English: Breast cancer incidence by age in women in the United Kingdom 2006-2008. Reference: Excel chart for Figure 1.1: Breast Cancer (C50), Average Number of New Cases per Year and Age-Specific Incidence Rates, UK, 2006-2008 at Breast cancer – UK incidence statistics at Cancer Research UK. Section updated 18/07/11. (Photo credit: Wikipedia)

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