Author: RR

Oncoprescribe Blog VEGF In Brain Tumors

RR

It appears that VEGF (Vascular Endothelial Growth Factor) is the main driver for low and high grade malignant gliomas. These tumors, as one would expect, also harbor high concentrations of VEGF receptors. In fact, tumor VEGF receptor concentration appears to be directly related to poor clinical outcomes. This would make perfect sense as VEGF development was based on Glioblastoma Multiforme xenograft models.

No wonder, Bevacizumab (AVASTIN), a humanized antibody targeting VEGF in combination with chemotherapy, improved response rates, progression free survival and overall survival.

Oncoprescribe Blog Prostate Cancer – Androgen Independent or Castrate Resistant

RR

It is not semantics anymore. Prostate Cancer is a heterogeneous disease. It appears that in patients touted to have Hormone Refractory Prostate Cancer (HRPC), the cells continue to produce androgen receptor message even in the absence of androgens. The tumor cells are therefore not androgen independent. On the contrary, they continue to  thrive, having access to androgens or androgen precursors, by various different mechanisms. It is for this reason imperative that one continue chemical castration with LHRH agonists concurrently with other lines of treatment including chemotherapy.

So the appropriate term should be Castrate Resistant Prostate Cancer rather than Androgen Independent Prostate Cancer.

Oncoprescribe Blog Pazopanib in Thyroid Cancer

RR

Pazopanib (Votrient) is a Tyrosine Kinase Inhibitor (TKI) that  targets Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), c-kit and Ret. This drug is presently approved by the FDA for the treatment of metastatic renal cell carcinoma. Data presented at the ASCO 2010 demonstrated impressive responses using Pazopanib (Votrient) in advanced radioiodine-refractory Follicular, Papillary and even Hurthle cell thyroid carcinomas.

This is an important step forward, in addressing this malignancy, as the benefit seen with chemotherapy is at best marginal, in the subset of patients studied. VEGF (Vascular Endothelial Growth Factor) appears to play a very important role in the pathogenesis of Thyroid Carcinomas. Learning and targeting the molecular mechanism of a malignancy is clearly the wave of the future.

Oncoprescribe Blog Vandetanib (Zactima) in Medullary Thyroid Cancer

RR

Medullary Thyroid Cancer accounts for about 6% of all thyroid cancers. This cancer originates from the parafollicular cells, also called C cells, of the thyroid. Calcitonin is a hormone produced by the C cells. For this reason, measuring serum calcitonin following complete resection of Medullary Thyroid Carcinoma can be helpful in diagnosing recurrent disease.

There is presently no active treatment approved by the FDA,  for the treatment of advanced Medullary Thyroid Carcinoma (MTC). A new oral Tyrosine Kinase Inhibitor (Vandetanib) has shown promising results and may soon become available. This agent is a dual inhibitor and targets the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). It also appears to inhibit RET-tyrosine kinase activity, an important  driver of cell growth in MTC.

Results from a double blind phase III trial (ZETA study) presented at ASCO 2010, showed that treatment with Vandetanib significantly extended progression free survival with a 54% reduction in the rate of disease progression compared to placebo.

Vandetanib (Zactima) is very likely to be studied in other solid tumors given its ability to target multiple receptors. Stay Tuned.

Oncoprescribe Blog Improving Progression Free Survival with Bevacizumab in Ovarian Cancer patients

RR

Taxanes were first introduced in the mid 1990’s for the first line treatment of ovarian cancer. There has since been no real progress made. However recent data presented at ESMO (European Society for Medical Oncology) 2010, shed light on the benefit of adding Bevacizumab to standard chemotherapy. In the ICON 7 trial, 1,528 women with high risk, early or advanced stage ovarian cancer were randomized to receive either 6 cycles of standard chemotherapy with Carboplatin and Paclitaxel or Carboplatin and Paclitaxel given along with Bevacizumab, followed by maintenance Bevacizumab for an additional 12 cycles.

There was a significant improvement in the median progression free survival in the Bevacizumab group. Patients with poor risk features benefited the most. So, after over 15 years of drought, we are now seeing progress made, in the treatment of ovarian cancer. It is not clear at this time however, if this three drug combination will improve Overall Survival.

Oncoprescribe Blog Denosumab approved for bone metastases in solid tumors

RR

Denosumab (Xgeva) was approved by the FDA for the prevention of  Skeletal Related Events (SRE’s) in patients with bone metastases from solid tumors. Denosumab is a monoclonal antibody targeting a protein called RANKL (Receptor Activator for Nuclear Factor kappa B Ligand). RANKL also known as  ODF (osteoclast differentiation factor) is an important molecule necessary for maintaining bone homeostasis. Overproduction of RANKL leads to increased osteoclastic activity resulting in bone resorption. Accelerated bone resorption can not only result in osteoporosis, but has also been implicated in the development of tumor related bone metastases. Denosumab binds to RANKL negating the formation, function and survival of osteoclasts.

Two international randomized studies demonstrated the superiority of Denosumab over Zoledronic acid in patients  with bone metastases, secondary to Breast Cancer and Castrate Resistant Prostate Cancer. In a third study involving patients with other solid tumors with bone metastases, Denosumab was found to be non-inferior to Zoledronic acid.

Denosumab, a RANK ligand inhibitor is a welcome addition to IV bisphosphonates, Pamidronate (Aredia) and Zoledronic acid (Zometa).

Oncoprescribe Blog Eribulin improves survival in metastatic Breast Cancer

RR

Eribulin is a non taxane inhibitor of microtubule dynamics and is a synthetic analog of halichondrin B, a product derived from a a sea sponge Halichodria okadai. The EMBRACE trial is a randomized open label phase III study involving 762 heavily pretreated patients with locally recurrent or metastatic breast cancer. Patients were randomized to either Eribulin (508 patients) or to an approved treatment of their physician’s choice and this could be single agent chemotherapy, hormonal therapy, biological therapy or palliative radiation therapy (254 patients). There was a statistically significant improvement in overall survival in the Eribulin group 13.12 months compared to 10.65 months in the control group. This statistically significant benefit was also seen in the overall response rates.

We now have another agent with a distinct survival advantage for heavily pretreated metastatic breast cancer patients.

Oncoprescribe Blog Nab-Paclitaxel in Non Small Cell Lung Cancer

RR

A randomized phase III trial data was presented at ASCO 2010 by Dr. Socinski and colleagues, involving chemonaïve patients with stage IIIb and stage IV non small cell lung cancer patients. Five hundred and twenty five (525) patients received Nab-Paclitaxel (Abraxane) without any pre medications at 100 mg/m2 on days 1, 8 and 15 along with Carboplatin given on day 1 at an AUC of 6. The control group of 525 patients received standard Paclitaxel 200mg/m2 and Carboplatin at an AUC of 6 on day 1. The major end point was response rate. The Nab-Paclitaxel group had a response rate of 33% compared to 25% for the standard Paclitaxel group. When broken down by histology, the response rates in those with squamous cell carcinoma was 41% in the Nab-Paclitaxel group versus 24% in the standard Paclitaxel arm whereas the non squamous subtypes had a response rate of 26% versus 25% in the Nab-Paclitaxel and Paclitaxel group respectively. It is hypothesized that the superior response rates in squamous cell histology may be due to the overexpression by this sub type of Caveolin–1, which is a protein which may facilitate a higher intratumoral drug concentration.

So, here is something for squamous cell histology. Choosing therapy based on histology is here to stay.

Oncoprescribe Blog Anticancer therapy with bisphosphonates

RR

Parenteral therapy with bisphosphonates in patients with skeletal metastases has significantly decreased the risk of skeletal related events and need for radiation therapy. Evolving data suggests that bisphosphonates in general and one of the more commonly used bisphosphonates Zoledronic acid (Zometa) has been shown to induce apoptosis, inhibit angiogensis, inhibit tumor metastases and exhibit synergy with certain anticancer agents in early stage Breast Cancer.

In the Z-FAST and ZO-FAST trials, Zoledronic acid improved disease free survival in hormone receptor positive early stage breast cancer. This intriguing data regarding the benefits of bisphosphonates in early stage breast cancer is likely to move this class of agents into the adjuvant setting, to become a part of adjuvant therapy.

Oncoprescribe Blog Newer agents for hard-to-treat cancers. Sorafenib to the rescue

RR

It was once Renal Cell Carcinoma and then Malignant Melanoma, but now we are about to conquer Hepatocellular carcinoma (HCC). In the SHARP trial published in the NEJM, patients with Hepatocellular carcinoma were randomized to receive either Sorafenib, a raf-kinase inhibitor or placebo. The outcomes were quite striking. Sorafenib significantly improved overall survival with a 31% reduction in the risk of death.

It is important to realize that patients with HCC already have a damaged liver secondary to cirrhosis and the patients in this study predominantly belonged to  Child-Pugh category A .  Sorafenib is presently being studied in combination with Doxorubicin for the treatment of HCC. As we learn more about the pathobiology of a malignancy, drug development to target the molecular mechanism of the disease is becoming a reality.