Study Tests Extension of Anti-Her-2 Therapy Beyond Herceptin for Early Stage Breast Cancer Patients

August 5, 2009

The Wyeth Study 3144A2-3004-WW testing a new oral drug, neratinib, is active and enrolling at CORT.  This study is open to early-stage, her-2 positive patients who have completed adjuvant therapy and one year of trastuzumab (Herceptin), the current standard-of-care.  Such patients are generally followed without further treatment.  The relapse risk of these patients is reduced by the one year of trastuzumab (see Figure 1: Analysis of Relapse Risk over Time, adapted from Herceptin Product Literature).  

Annual Relapse Risk for Her-2 Positive Early-Stage Breast Cancer Patients, Treated with or without Trastuzumab

As can be seen from the figure, the AC>TH arm has a lower risk of annual recurrence that begins during the first year (the time the treatment with trastuzumab is given), and that benefit continues, when compared to patients treated with chemotherapy alone (AC>T).  However, the risk for recurrence does rise in the trastuzumab-treated patients after the therapy is completed at one year, and that risk remains increased for another 2 or 3 years, at approximately 4.9% per year. 

To address that continued risk, studies testing the extension of anti-her-2 therapy are being conducted.  The Wyeth study at CORT tests the oral anti-her-2 drug neratinib (HKI-272).  The study is a randomized comparison of neratinib versus a neratinib placebo, given daily by mouth for one year.  Neratinib may reduce cardiac function (similar to other her-2 blockers), so function must be monitored.  Other risks include rash, diarrhea, and nausea.  Based on experience with the drug to date, these risks can be managed with supportive care medication and/or dose reduction in most circumstances. 

Patients who have completed one year of adjuvant therapy with trastuzumab (Herceptin), and who are within 2 years of completion of that therapy are eligbile for the Wyeth study at CORT. 

For more information about this study, or to schedule a consultation about management of breast cancer, call 972-566-5588, and ask to speak with a Patient Care Coordinator.   Additional information about this study, and directions to the office are located at: www.CORTPA.com.

Prostate Cancer Immunotherapy Study Open at CORT

August 5, 2009

CORT is actively enrolling patients with metastatic hormone-refractory (androgen-independent) prostate cancer in the BMS 184-043 study of ipilimumab (versus placebo).   The study is open to patients who have at least one bone metastasis, and who have progressed after prior therapy with docetaxel (Taxotere).  Other inclusions and exclusions are required.   Ipilimumab is a monoclonal antibody that inhibits the cellular function of CTLA-4.  CTLA-4 inhibits the T-cell immune response to cancer cells, and by blocking this molecule, T-cells are activated.  Ipilimumab is in clinical development in melanoma (also at CORT).  Responses in both metastatic prostate cancer and melanoma have been demonstrated.  The drug is given every 3 weeks IV for four treatments (induction).  Thereafter, for patients with improvement or stability in their disease, the drug is continued every 3 months (maintenance).  The most common risks are rash and diarrhea.  Other risks include changes in pituitary, thyroid, and adrenal function.  Rare auto-immune reactions (some severe and potentially life-threatening) have occurred.

CORT enrolled the first US patient to the prostate cancer study in 6/09. 

To learn more about this study, or to schedule consultation regard this and other treatments for prostate cancer, call 972-566-5588.   Additional information, including directions to the office are located at www.CORTPA.com.

Patients Who Seek Information From Media Sources More Likely to Receive Newer Therapies

February 26, 2009

A study published in the April 1 issue of Cancer shows that colorectal cancer patients who seek out information about their therapy from media sources (internet, TV, etc.) are more likely to receive new therapies that those who do not.  The study was conducted by the Dana Farber Cancer Institute, with lead investigator Dr. Stacey Gray.  The study collected information from 633 patients in the Pennsylvania Cancer Registry.  Those patients who sought information were 2.8 times more likely to have heard about newer treatments for their disease, and they were 3.2 times more likely to receive those therapies.  While the study does not examine outcomes of those patients, outcomes of patients who have received newer treatments for colon cancer are likely to be superior to those who have not. 

This study finding is somewhat intuitive.  At the CORT research center, we have observed the influence of patient education on treatment selection for quite some time.  Patients who have sought out more information about their therapy have come for consultation have in many instances been offered new cancer therapy agents or trial participation options that were not initially suggested in their initial consultatons.   The evidence that new agents (cetuximab, bevacizumab, panitumumab) have improved the outcomes of survival in colon cancer is now unequivocal.   Information-seeking patients will continue to be more apt to receive the next generation of new agents. 

CORT is currently investigating the use of genetic and molecular markers to select patients for adjuvant therapy of Stage II colon cancer (ECOG 5202 Study), the use of cetuximab (Erbitux) in combination with FOLFOX therapy in Stage III colon cancer patients with wild-type k-ras mutation status (N0147 Study), and the comparison of the relative benefit of bevacizumab (Avastin) versus panitumumab (Vectibix) in combination with FOLFOX therapy as first-line treatment of metastatic colon cancer patients with wild-type k-ras mutations status.  The thrust of the investigations at CORT is to seek more information that will allow treatments to be more individualized to the patient disease characteristics, since colon cancers are not all the same, even though they may have similar appearances when analyzed by conventional methods. 

For more information about colon cancer therapy, visit out website at www.CORTPA.com.  For  requests for consultation, contact CORT at 972-566-5588 (Dallas) or 972-981-4012 (Plano).

FDA Approves Use of Imatinib (Gleevec) for Adjuvant Therapy of Resected GIST

January 31, 2009

On December 19, 2008, the FDA approved use of imatinib (Gleevec) for adjuvant therapy of resected adult GIST (GI Stromal Tumor). 

GISTs are tumors of the bowel wall that originate in the interstitial cells of Cajal, part of the autonomic cell network that control movement of food and fluids through the bowel.  GIST occurs in 5000-6000 patients per year in the US.  The tumors have an appearance often confused with other bowel wall smooth muscle tumors, known as leiomyomas or sarcomas.  GISTs have mutations of cell surface proteins that activate cell proliferation, primarily in the cellular gene c-kit, but also in PDGFRA (platelet derived growth factor receptor-A).  Common mutations are in exon 11 and exon 9 of the c-kit gene.  Imatinib was found to inhibit the activation of c-kit in patients (those with imatinib-sensitive mutations), and it was approved in 2001 by the FDA for treatment of metastatic GIST, after clinically-meaningful responses (overall approximately 40% of patients have radiographic responses by CT scan, compared to historical responses seen in only 0-5% of chemotherapy-treated GIST)  and disease control was demonstrated in early studies.  Further investigation has shown that imatinib improves progression-free survival (PFS).  The PFS has ranged between 17-24 months in metastatic GIST, depending on the dose of imatinib.  Significant differences in response and PFS with imatinib therapy have been established for differing mutations in c-kit (and PDGFRA). 

The use of imatinib for adjuvant therapy (post-resection treatment) after complete resection of GIST tumors (when patients have no other apparent disease) was studied in the ACSOG Z9001 study.  This was a randomized, double-blind study of imatinib for patients with GIST at high risk for recurrence after resection.  The study enrolled 644 patients, and it was stopped in 2007, after a significant improvement in PFS was determined for patients receiving adjuvant imatinib therapy (400 mg/d x 12 months).  After 18 months of median follow-up, PFS was 97% in the imatinib group versus 83% in the placebo group.  The improvement in PFS was seen across a broad range of tumor size. 

Therefore, patients who have had surgery for GIST should now receive at least one year of adjuvant imatinib therapy.  The duration of imatinib therapy continues to be studied in other ongoing investigations.   It is very important for patients with GIST tumors to be correctly identified when resection occurs, so the benefit of adjuvant therapy is not potentially missed.  The CD117 stain may help to differentiate GIST from other soft tissue tumors of the bowel.  However, there have been reports of CD117-negative GISTs.  PDGFRA staining may also prove helpful.  Molecular genetic analysis of c-kit and PDGFRA may not only help to  identify patients with GIST, but because certain mutations in these genes is associated with imatinib resistance, testing may serve to help assess the potential benefit of therapy, as other drugs have been developed that have activity in imatinib-resistant forms of GIST.  These specialized tests may be obtained by consultation and specimen referral to specialized pathology labs.  Such testing can be done on archival tumor tissue.   For example, tumor tissue may be sent for analysis at MD Anderson Pathology Lab.  A requistion form and instruction is here in the attachment:

MD Anderson Pathology Requisition

Other labs that have experience in testing GISTs:

A review of expanding information about GIST therapy is beyond the scope of this brief post.  Additional information is available through GIST support groups (www.liferaftgroup.org, www.gistsupport.org, www.gistinfo.org). Patients who are interesting on medical oncology consultation at CORT may call 972-566-5588.  Information about CORT is available at our website: www.CORTPA.com.

Lung Cancer Study of Novel Oral Drug Sapacitabine at CORT

January 28, 2009

CORT has opened a phase I-II study of sapacitabine for second-line therapy of unresectable advanced or metastatic non-small cell lung cancer (NSCLC). Sapacitabine is an oral nucleoside analog prodrug that acts through a dual mechanism. The compound interferes with DNA synthesis by causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase.

Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in both blood and solid tumors in preclinical studies. In a liver metastatic mouse model, sapacitabine was shown to be superior to gemcitabine (Gemzar®; Lilly) or 5-FU, two widely used nucleoside analogs, in delaying the onset and growth of liver metastasis.

A number of clinical trials are evaluating sapacitabine in both solid and hematological tumors to establish a foundation for future Phase 2 studies and combination studies with other anti-cancer agents. Three Phase 1 studies have been completed, which evaluated safety and pharmacokinetics of a variety of dosing schedules in approximately 120 patients with solid tumors. Sapacitabine is currently being evaluated in Phase 2 trials in patients with advanced cutaneous T-cell lymphoma (CTCL), in elderly patients with acute myeloid leukemias (AML), and in therapy of NSCLC.

For more information about the CORT study in NSCLC, contact a CORT Research Coordinator at 972-566-5588 (Dallas), or 972-981-4012 (Plano).  Addtional information may be found at the CORT website: www.CORTPA.com.

Sequential Therapies and Integration of Investigational Agents in Treatment of Metastatic Cancer

January 16, 2009

Broad advances in patient outcomes for patients with metastatic cancers have been noted in the past five years.  These improvements have occurred for a number of reasons.  Non-oncology physicians have been more active in encouraging patients to engage in therapy for advanced disease.  Oncologists have been armed with improved agents that boost response and improve disease control for longer periods, with reduced toxicity of the agents in most cases.  Supportive care efforts to minimize treatment risks and toxicities have reduced complications of therapy.  Treatment has nearly completely shifted to outpatient oncology infusion centers, improving convenience and lowering costs for treatment delivery. 

Clinical trial participation has also contributed to improving care and patient outcomes.  While a specific therapy may not always have an evident benefit in survival for an individual patient, the integration of new therapies by clinical trial participation may extend survival compared to sequential therapy with standard approved therapies alone.  That may be conceptually understood by the example below, where integration of trial agents X, Y, and Z to existing standard therapy with agents A, B, and C have improved survival expectations.   In this hypothetical example, the trial agents have had benefit.  However, even if an individual agent does not produce improvement, the sequential integration of such agents into the existing standard treatment paradigm gives the patient an expanded opportunity for having meaningful control of disease and improved survival. 

Hypothetical Example of Improved Survival by Integration of Investigational Drugs (X,Y,Z) to Existing Standard Therapy (A,B,C)

Hypothetical Example of Improved Survival by Integration of Investigational Drugs (X,Y,Z) to Existing Standard Therapy (A,B,C)

Such an approach has been the overlying theme of treatment at the Center for Oncology Research & Treatment (CORT) for over a decade.  At CORT, we plan our participation in clinical investigations with the premise that a patient may have a sequence of standard and investigational programs, such that failure of an individual treatment can be followed by another treatment option with cutting-edge new agents that have a significant chance to improve survival for our patients.

For more information about clinical trials at CORT, contact a Clinical Care Coordinator or Research Nurse at 972-566-5588 (Dallas), or 972-981-4012 (Plano), or visit our website at www.CORTPA.com.

First-Line Chemotherapy for Her-2 Negative Metastatic Breast Cancer

January 12, 2009

Paclitaxel (Taxol) chemotherapy in combination with Bevacizumab (Avastin) has become a standard treatment regimen for her-2 negative patients with metastatic breast cancer, based on findings of improved outcomes with the combination in the ECOG 2100 study.  That trial  compared paclitaxel alone to paclitaxel and bevacizumab combination therapy.  For the combination, response rate was improved (30% vs. 14%, p<0.0001) and progression-free survival was improved (11.4 mos. vs. 6.1 mos; HR=0.51, p<0.0001).  Bevacizumab was approved for treatment of metastatic breast cancer based on these results. 

Many patients may not be appropriate for the combination of paclitaxel and bevacizumab therapy.  Patients who have received prior taxane therapy in the adjuvant setting (particularly with a short disease-free interval to the time of metastatic disease) may increased risk for resistance to taxane therapy.  Patients who are diabetic may have exacerbation of diabetes because of corticosteroid premedication required before taxane therapy.  Patients with neuropathy may have worsening of neuropathy with taxane therapy.  

For these patients,  therapy with another chemotherapy agent in combination with bevacizumab may be considered.    However, clinical trial data supporting the combination of other chemotherapy agents with bevacizumab is limited, and insurer coverage may be restrictive.   An example of an alternative regimen would be gemcitabine (Gemzar) and bevacizumab.   No corticosteriod premedications are required for gemcitabine therapy, and there is no risk of neuropathy. 

Other important clinical circumstances may make the use of bevacizumab unattractive, such as severe hypertension, angina or recent ischemic events from coronary or cerebrovascular disease, thrombosis risk, bleeding, or the presence of CNS metastatic disease.  Bevacizumab may cause proteinuria, increased blood pressure, bleeding, thrombosis, infusion reactions, delayed wound healing, or other rare toxicities (bowel perforation). 

For more information about breast cancer therapy and clinical trial information, contact a CORT Research Coordinator at 972-566-5588 (Dallas) or 972-981-4012 (Plano), or visit our website at www.CORTPA.com.

Rare Cancer Presentations: Intraspinal Metastasis of Lung Cancer

January 7, 2009

Author: Barry C. Mirtsching, MD  (Center for Oncology Research & Treatment, PA, Dallas, TX)

Spinal column metastasis of solid tumors are not uncommon.  Most of these tumors are extrdural in location.  However, intradural metastases are rare, comprising only  6% of all spinal metastases, involving the subarachnoid space, filum terminale, or spinal cord.  Reports of such cases in the English literature are rare.  This report reviews a case of a patient with non-small cell lung cancer (NSCLC)  who progressed with disease involving the filum terminale.  A similar case was reported previously (Su, J-H et al., Tzu Chi Med J; 2005. 17: 421-423.)

Case Description:

A 62 year old white male smoker presented in 6/2007 with cough and was found to have a 4 cm right upper lobe (RUL) tumor, with associated ipsilateral mediastinal lymph node enlargement and right supraclavicular lymphadenopathy.  A biopsy of the RUL tumor revealed bronchogenic adenocarcinoma.  He was treated with weekly carboplatin +paclitaxel, and concurrent radiotherapy to the involved regions.  He then had 4 cycles of full-dose carboplatin and paclitaxel chemotherapy.  He had partial respone in his disease by CT scans, but his supraclavicular nodal disease progressed within three months of completion of therapy.  He was then treated with pemetrexed for 4 cycles, but his disease continued to progress in the right supraclavicular area.  The patient was then treated on an investigational protocol of sunitinib and erlotinib for two months, with further progression of his supraclavicular nodal disease.  He developed severe pain in the lumbar area, with radiation to his bilateral lower extremities.  He did not have bowel or bladder disturbance.  He had mild hypoaesthesia in his pelvis and lower extremities, and subjective weakness.  The patient was moderately debilitated (ECOG performance status 2) and was losing weight.  At this time, the patient came to our Center  for evaluation and further care in 7/2008.

Evaluation of his CT scans revealed scar-like density in the RUL and ipsilateral mediastinum and a 2 cm nodule in the left lower lobe.  MRI of the spine revealed a mass in the lumbar area below the terminus of the cord, involving the filum terminale.  The mass extended in the spinal sac from T2 to T4, without extension into the extradural tissue.  The mass was enhancing on T1 imaging with gadolinium (Figure 1, T1 with gadolinium sagital images), and it was easily recognized on T2 images (Figure 2, T2 sagital images).   The patient was also found to have a 1 cm right cerebellar metastasis.

Figure 1:

MRI images T1 with gadolinium
MRI images T1 with gadolinium
Figure 2:
MRI image T2

MRI image T2

 The patient obtained pain control with narcotic therapy and radiotherapy to the spinal lesion.  His cerebellar metastasis was treated with stereotactic radiosurgery and whole brain radiation.  These areas were symptomatically completely controlled (sensory function normalized, no appearance of objective motor weakness) and did not progress for 5 months following completion of treatment.

The patient continued with systemic therapy for his cancer, with stable disease in the supraclavicular region and left lung for 5  months.  He sequentially received single-agent docetaxel and single-agent gemcitabine.  His disease in the supraclavicular area and lung progressed, and he declined further therapy.

Discussion:

This case illustrates the MRI appearance of an usual intraspinal metastasis of lung cancer involving the filum terminale.   Symptoms of pain, hypoaesthesia below the level of the lesion, lower extremity weakness, and bowel or bladder contractile disturbance may be associated with such disease.  Treatment with surgical decompresion could be considered for relief of acute neurologic compromise, such as paralysis.  However, in this case the lesion was treated with radiotherapy, because of the patient’s poor performance status, progressive systemic disease at other sites requiring chemotherapy, absence of significant motor impairment, and  poor predicted short-term prognosis.   Radiotherapy was effective for prevention of progressive neural impairment and for pain relief.

Study Testing Anti-Angiogenic Drug Therapy for Metastatic Renal Cancer

December 25, 2008

CORT has initiated the SWOG S0717 Study for treatment of metastatic renal cancer that has progressed after prior sunitinib (Sutent) or sorafenib (Nexavar) therapy.   These treatments are standard first-line treatments.  After failure of sunitinib or sorafenib, currently, there is no standard therapy for this disease.  The study will evaluate anti-angiogenic drug therapy. 

Bevacizumab (Avastin) is a monoclonal antibody against VEGF (vascular endothelial growth factor).  VEGF is a key protein that stimulates angiogenesis (new blood vessel growth), when binding to endothelial cell VEGF-receptors (VEGF-R).  Inhibition of VEGF by bevacizumab has proven successful in metastatic breast, lung, and colon cancer, settings where bevacizumab has already been FDA-approved for use.   MEDI-522 (Etaracizumab, Abegrin) is a monoclonal antibody against integrin molecules (av,b3).  Intregins are structural signaling molecules that direct cell movement and attachment, and these are required for new blood vessel growth.  Early phase studies have shown that disruption of vascular growth by anti-integrin molecules results in tumor growth arrest. 

In the S0717 study, patients with metastatic renal cancer will receive either bevacizumab in combination with a placeo MEDI-522 (inactive), or bevacizuamb in combination with active MEDI-522.  All patients will receive active bevacizumab.   This study evaluates whether the combination of anti-angiogenic drug therapy is more active than anti-angiogenic therapy with bevacizumab alone.

For more information about this study, call a CORT Research Coordinator at 972-566-5588, or visit our website at www.CORTPA.com.

CORT Clinical Trials Brochure: PDF Version

December 20, 2008

CORT offers a broad array of oncology clinical phase II-III studies for solid tumors and lymphomas.  The attached PDF lists our current or pending studies. For more information about our studies, visit the CORT website at www.CORTPA.com, or contact a Reseach Coordinator at 972-566-5588. 

CORT Clinical Trials March 2010