Archive for October, 2007

Ixabepilone (Ixempra) Approved for Metastatic Breast Cancer

October 20, 2007

Ixabepilone (Ixempra) was approved on 10/16/07 for treatment of metastatic breast cancer.  The specific approval is: (1) Ixebepilone in combination with capecitabine (Xeloda) for treatment of metastatic or locally advanced breast cancer patients who have become resistant to anthracycline (such as Adriamycin) and taxane therapy (such as Taxotere or Taxol), or for patients who are resistant to taxane therapy, in whom further anthracycline therapy is contraindicated, and (2) Ixebepilone as monotherapy for treatment of metastatic or locally advanced breast cancer patients whose tumors are resistant to anthracyclines, taxanes, and capecitabine.

CORT was part of the multicenter study that established the efficacy of ixabepilone, and our physicians and nurses are experienced in management of this treatment.  CORT applauds the FDA decision to approve this drug, which should expand the treatment choices for these patients who have limited other treatment options.  For more information about treatment with ixabepilone, contact the CORT office at 972-566-5588 (Dallas), or at 972-981-4012 (Plano).  Information about CORT and the innovative treatments and studies offered can be found at our website: www.CORTPA.com.

Who Benefits from Taxanes: Controversy in Breast Cancer Management

October 13, 2007

The benefit of adjuvant paclitaxel (Taxol), in addition to anthracycline-based chemotherapy was evaluated in the CALGB 9344 study, which has previously been reported.  CALGB 9344 evaluated 4 cycles of escalating doses of doxorubicin (Adriamycin) combined with a fixed dose of cyclophosphamide (AC) with or without 4 cycles of sequential Taxol in 3170 women with node-positive primary breast cancer. After 52 months of follow-up, important changes were noted when compared with earlier interim analyses at 21 and 30 months follow-up.  Specifically, the addition of sequential paclitaxel to AC significantly improved the disease-free survival (P = .0324), but not overall survival (P = .0745). The disease-free survival rates for patients treated with sequential AC and Taxol versus those treated with AC alone at 48 months follow-up were 73% vs 70%, respectively. Overall survival rates for the 2 groups at 48 months were 84% vs 81%, respectively.

Molecular subtypes of breast cancer are now better defined.  Her-2 positive breast cancer (about 15% of all breast cancer) is an aggressive subtype, with growth driven by the over-expression of her-2 growth regulating receptors on the cancer cells.  Older studies, such as CALGB 9344 did not include the use of adjuvant anti-her-2 treatment, trastuzumab (Herceptin), in addition to chemotherapy, which is now the standard-of-care for her-2 positive disease.  It has been hypothesized that her-2 positive cancers benefit more from chemotherapy than other cancers, possibly because of increased levels of intracellular topoisomerase II (topo II), or because of a higher proliferation rate.  The question of whether her-2 positive breast cancer patients (when compared to her-2 negative patients) benefit to a greater degree by the addition of Taxol to AC was analyzed in a retrospective analysis of the CALGB 9344 study, which was published in the New England Journal of Medicine, October 11, 2007. 

In this analysis, Her-2 positivity was associated with a significant benefit from paclitaxel. The interaction between Her-2 positivity and the addition of Taxol to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01), a 41% reduction in risk. Patients with a Her-2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status.  Taxol did not benefit patients with HER2-negative, estrogen-receptor–positive cancers.   However, Her-2 negative, estrogen-receptor negative patients did have a significant reduction in the hazard ratio for recurrence (P=0.002), indicating that Taxol has benefit for some patients who are not Her-2 positive. 

Oncologists have been cautioned about premature interpretation and possible clinical practice changes until further study can confirm these results.  The CALGB analysis was retrospective, and the aggregate results of the study did show general benefit of Taxol adjuvant therapy for breast cancer patients.  Similar findings of benefit have been reported for adjuvant use of docetaxel (Taxotere) for adjuvant treatment of node-positive patients.  In addition, the use of taxol in the CALGB study (every 3 weeks) was not optimal, based on more recent studies that have demonstrated that Taxol is more effective when given on a more frequent schedule (weekly).  Therefore, the conclusion that adjuvant addition of weekly Taxol to AC might not be beneficial to estrogen-receptor positive patients requires confirmation.  Newer taxanes have been developed (for example, Abraxane, a nanoparticle of taxol in albumin protein), which may be more effective that Taxol.  A US Oncology study suggests that a more intensive taxane therapy and schedule may be a significant addition for her-2 negative and estrogen-receptor negative patients. Further study of taxanes in all molecularly-defined groups of patients is warranted, to determine what the degrees of benefits may be.  Finally, the substitution of taxane therapy for anthracycline-based treatment in the adjuvant setting appears to be a promising strategy in reducing possible cardiac toxicity of treatment. 

In summary, the CALGB study analysis is provacative, but not unexpected. Not all patients derive the same benefit from adjuvant treatments with different agents.  Taxane therapy should not be an immediate addition to every patient, but it should be considered based on a careful and individualized basis of each patient’s breast tumor characteristics, stage, and recurrence risk.  Additional study of taxane treatment in clinical trials, such as those offered at CORT, will be important in helping to improve treatment selection for patients.  In the meantime, it is premature to routinely deny patients with estrogen-receptor positive cancers the addition of a taxane in adjuvant therapy, without additional confirmatory study.

Screening for Colon Cancer: CT Colography (“Virtual Colonoscopy”) Compared to Traditional Colonoscopy

October 9, 2007

Software may  construct a three-dimensional CT scan image of the colon, which is termed CT colography, or “virtual” colonoscopy.  A report from the University of Wisconsin in the New England Journal of Medicine in October, 2007 compared virtual colonscopy (VC) to standard colonoscopy (SC) screening in approximately 6000 patients who were involved in parallel screening programs.  Prior studies of VC have shown that it can detect polyps of greater than or equal to 10 mm 90% of the time.  However, these prior reports have urged caution in the adoption of VC for screening.  The technique may miss smaller polyps, flat growths, or have diminished sensitivity for lesions in the right colon.  The preparation for VC is simpler and perhaps causes less distress.  However, at least 10% of VC studies were judged technically inadequate in prior studies, in some cases because of inadequate bowel cleansing.  The technique of VC is safe, and because it is non-invasive, the risk of bowel perforation is absent.  VC facilities are not widespread, software is potentially expensive, and radiologists are not all trained or experienced in VC interpretation.  When VC demonstrates a significant lesion requiring biopsy, then SC is required, which increases the cost (since both studies would be done) in such a patient.

The NEJM report demonstrated that the number of advanced neoplasms (polyps >=10 mm and/or cancers) found was the same for VC (3.2%) or SC (3.4%) screening, in a average risk population of patients.  The number of polypectomy procedures was significantly lower in the VC group (561) vs. the SC group (2434).  That finding is easily understood, since patients with 1-5 mm lesions found at VC were not further evaluated, and patients with 6-9 mm lesions found at VC were offered either observation or SC.  Only lesions >=10 mm at VC were referred for SC and biopsy.  Therefore, the referral rate for SC from the VC group was 7.9% (246/3120 patients).  7/3163 patients in the SC group experienced procedure-related bowel perforations. 

The potential drawback of VC noted by the authors is the possibility that failure to remove smaller lesions (<10 mm) might result in interval cancer development and progression, before the next planned VC follow-up.  The data does support that polyp size is a reasonable surrogate for histologically-advanced (pre-malignant or malignant) lesions, the ones that really should be removed.  In the study, lesions <10 mm were histologically advanced in only 20 polyps (15/6283 patients, prevalence 0.2%).  In the <=5 mm category of polyps (diminuative), only 4 polyps were histologically advanced. 

This study shows the promise of VC as a screening tool for average risk populations of patients.  The technique may help “filter” patients who require SC screening, which may improve resource-utilization and reduce costs.  The acceptance of VC be the general population might be superior as well.  The study supports that VC can be used by experienced centers to achieve screening outcomes that are equivalent to SC.  The risk of progression of small lesions that would be observed by serial VC (without biopsy) appears to be very small in this study.  Patients who may consider VC as an alternative to SC should do so with caution, investigating the experience of the center, and with attention to following a protocol for re-evaluations such as the one described in this study. 

Other methods of initial screening (to target patients who might require SC interventions) are under investigation, such as protein- or gene-based stool sample screening.   The use of these methods to identify patients who have cancer-related protein or gene products in the stool might serve as another non-invasive tool to identify patients who need SC.  However, these methods are not yet available or sufficiently validated.  Therefore, the prudent advice for patients is to continue with regular SC screening methods at intervals outlined in available accepted guidelines.

Galiximab for Low-Grade B-cell Lymphoma

October 3, 2007

CD80 (B7.1) is a membrane-bound molecule that is known for its role in regulating immune T-cell activity. Several studies have suggested that CD80 may also play a role in the regulation of normal and malignant B cells. CD80 is continuously expressed on a variety of lymphomas, including low grade B-cell lymphoma, making it an attractive target for lymphoma therapy. In lab studies, cross linking CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation, to induce cell death regulating (pro-apoptotic) molecules, and to induce antibody-dependent cell mediated cytotoxicity (ADCC). These observations constitute the rationale for development of an anti-CD80 therapy for B-cell lymphoma. Galiximab is a monoclonal antibody that binds and inhibits CD80. In a phase II study of single-agent galiximab in refractory low grade B-cell lymphoma, 11% of patients had response, with two complete responses. The most common side effects were fatigue, nausea, and headache. Low blood counts were rare.

The TARGET NHL Trial (Targeted Antibody Therapy with RITUXAN and Galiximab Efficacy Trial), continuing enrollment at CORT, is a randomized, double-blind, global multi-center study (114-NH-301) of galiximab in combination with rituximab compared with rituximab in combination with placebo. The primary study objective is to compare the clinical benefit of each treatment arm in subjects with relapsed or refractory, follicular NHL. Progression-free survival (PFS) is the primary study endpoint. An open-label retreatment study (114-NH-302) with galiximab in combination with rituximab, will be available to subjects who progress on 114-NH-301 after experiencing at least a partial response (PR) with a time to progression (TTP) of six months or greater in either arm of the study.


For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

Anti-Angiogenic Therapy in Testing for Diffuse Large B-Cell Lymphoma

October 3, 2007

Bevacizumab (Avastin) is a new agent that “targets” tumor blood vessels by the inhibition of VEGF (vascular endothelial growth factor). It has been tested in combination with chemotherapy in a variety of tumor types, with significant improvements in survival, leading to approval of Avastin in the treatment of colon cancer, and general practice use for treatment of breast and lung cancer.

Avastin is being tested in the treatment of advanced stage diffuse large B-cell lymphoma in a study at CORT. The study compares standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R-CHOP plus Avastin. The goal of the study is to determine if the addition of Avastin improves the cure rate and survival after treatment.

The risks of treatment with standard therapy include fever, infection, hair loss, nausea, vomiting, mouth sores, low blood counts, fatigue, sensory nerve injury, and cardiac dysfunction. The risks of Avastin include high blood pressure, protein in the urine, infusion reactions, allergy, bleeding, blood clots, and rare central nervous system vascular injury or bowel perforations. Most Avastin risks are mild-moderate, and tolerable.

For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

Belinostat (PXD101) for Refractory Aggressive Lymphoma: A Novel New Drug

October 3, 2007

Belinostat (PXD101) is a promising small molecule histone deacetylase (HDAC) inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents. HDAC inhibitors represent a new class of anti-cancer therapeutics that target HDAC enzymes and have been shown to arrest growth of cancer cells (including drug resistant subtypes), induce cell death, inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.


Intravenous belinostat is currently being evaluated in the SWOG S0520 Study at CORT for treatment of refractory aggressive B-cell lymphoma, including large cell lymphoma, Burkitt’s-like lymphoma, and primary mediastinal lymphoma. Patients may have had up to three prior treatment regimens. Risks of belinostat include rash, edema, constipation, low platelet blood count, fatigue, and dehydration. A potential for changes in the electrocardiogram or arrhythmia exists for this class of drugs.

For more information on these studies, visit www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

Vectibix and Chemotherapy, E7389 (Eribulin) for Treatment of Head & Neck Cancer

October 3, 2007

Advances in the management of patients with head & neck cancer (HNC) were presented at the Multidisciplinary Head and Neck Cancer Symposium, cosponsored by the American Society for Therapeutic Radiology and Oncology (ASTRO) and the American Society of Clinical Oncology(ASCO), January 18-20, 2007. Despite increasing awareness of the cancer-causing effects of tobacco, the incidence of HNC has not decreased worldwide. Efforts to prevent these tumors through drugs or treatments have largely failed, and early detection strategies have not been successful. Therefore, most patients with HNC continue to present with advanced (stages III and IV) disease.

Oral cavity tumors are treated primarily with surgical resection because of the high toxicity of radiation in this region (eg, osteoradionecrosis of the jaw). Advanced tumors of the throat and larynx are usually treated with combined modality therapy (chemoradiation [CRT]).  Surgery is often reserved for neck dissection, to manage advanced neck disease (N2 or N3 node staging) and/or to manage the neck nodes after an incomplete response in the neck to CRT. The major advance in the management of HNC was the integration of targeted new agents into current treatment regimens.

HNC cells express EGFR (epidermal growth factor receptor) at high levels compared to neighboring normal tissue cells.  High EGFR protein on the HNC cells correlate with reduced survival.  The EGFR blocking monoclonal antibody cetuximab (Erbitux) was studed in combination with radiation therapy (RT) versus RT alone in a large multicenter study.  The combination demonstrated improved disease control and survival, and this finding led to approval of this agent by the US Food and Drug Administration (FDA) in 2006 for the treatment of HNC.  Panitumumab (Vectibix)  is a fully humanized anti-EGFR monoclonal antibody.  It is also under study for treatment of HNC.   Vectibix and Erbitux have had comparable activity in metastatic colon cancer, where both are already FDA-approved.  The risks of EGFR blocking monoclonal antibodies also appear to be comparable for both cetuximab and panitumumab, including infusion reactions, rash, diarrhea, or rare drug-induced lung inflammation. 

When patients have progressed after initial CRT or surgery, they often have unresectable local disease or distant metastatic disease, such as in the lung.  Chemotherapy has been the mainstay of treatment for such patients.  Until recently, the combination of cisplatin and 5-fluorouracil (5-FU) was the most common treatment regimen.  Recently, docetaxel (Taxotere) was approved for the treatment of HNC.   Research on the integration of EGFR inhibitors with chemotherapy is now underway at CORT. 

CORT is conducting a phase II study of chemotherapy (Platinol and Taxotere) with or without Vectibix in patients with locally recurrent or metastatic HNC.  The study is a cross-over design.  Patients who do not initially receive Vectibix will be able to receive it if they progress with initial therapy. 

CORT is also participating in the SWOG S0618 study for recurrent or metastatic HNC patients, a phase II  evaluation of E7389, Eribulin.  This drug is a new chemotherapy drug that blocks cell division.  The risks of treatment are fatigue, nausea, vomiting, sensory neuropathy, and low blood counts. 

For more information on these studies, visit http://www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588.

FDA Approves Docetaxel (Taxotere) for Induction Chemotherapy in Head & Neck Cancer

October 1, 2007

On September 28, 2007, the U. S. Food and Drug Administration (FDA) approved docetaxel (Taxotere® Injection Concentrate, Sanofi-Aventis) for use in combination with cisplatin and fluorouracil (5-FU) for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

The safety and efficacy of Taxotere® for the above indication were evaluated in a multi-center, open-label, randomized trial.  In this study, 501 patients with previously untreated locally advanced SCCHN, and performance status 0 or 1, received either Taxotere® 75 mg/m2  followed by cisplatin 100 mg/m2 on day 1, followed by 5-FU 1000 mg/m2/day as a continuous infusion on days 1-4 (TPF regimen) or cisplatin 100 mg/m2 on day 1, followed by 5-FU 1000 mg/m2 /day as a continuous infusion on days 1-5 (PF regimen).  These regimens were administered every 3 weeks for 3 cycles.  All patients in both treatment arms who did not have progressive disease following induction chemotherapy received 7 weeks of chemoradiotherapy (CRT).  During radiotherapy, carboplatin (AUC 1.5) was administered weekly as a 1-hour infusion for a maximum of 7 doses.  Surgery could be considered at anytime following completion of CRT.

Overall survival was significantly prolonged with the Taxotere®-containing regimen (TPF) compared to the PF regimen (log‑rank test, p=0.0058).  The median survival was 70.6 months in the TPF group compared to 30.1 months in the PF group (hazard ratio = 0.70, 95% confidence interval:  0.54, 0.90).

The most frequent adverse events (>40%, any grade) on the TPF arm were neutropenia, anemia, nausea, alopecia, stomatitis, lethargy, vomiting, diarrhea, and anorexia. Neutropenic fever with or without infection occurred in greater than 5% of patients on the TPF arm. Grade 3 or 4 adverse events with a greater than 5% frequency in patients on the TPF arm were neutropenia, infection, stomatitis, nausea, esophagitis/dysphagia/odynophagia, anorexia, vomiting, and anemia. Neutropenia, alopecia, diarrhea, and anorexia were more frequently seen in the TPF arm.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at www.fda.gov/cder/foi/label/2007/020449s045lbl.pdf.