Archive for November, 2008

BRiTE Study: Improved Survival in Metastatic Colorectal Cancer

November 19, 2008

The BRiTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety) Study was published in the Journal of Clinical Oncology in the November 20, 2008 issue (Journal of Clinical Oncology, Vol 26, No 33 (November 20), 2008: pp. 5326-5334).  This study was a large registry study conducted at 248 sites in the US, enrolling 1953 patients.  CORT was a participating research site for this study.  The study was observational, collecting survival information for patients with metastatic colorectal cancer who had not received previous therapy for their metastatic disease, and who received bevacizumab (Avastin) as a component of therapy in their first-line treatment.  Bevacizumab is a monoclonal antibody against the vascular endothelial growth factor (VEGF), a major contributor to cancer angiogenesis.  The study analyzed the outcomes of patients according to the types of treatment that they received after the first evidence of progressive disease (PD): no-post PD therapy, post-PD therapy without bevacizumab (no “bevacizumab beyond progression”=no BBP), and post-PD therapy with bevacizumab (“bevacizumab beyond progression”=BBP).  At a median follow-up of 19.6 months, the overall survival (OS) of the entire group was 25.1 months, with a median time-to-progression (TTP) of 10 months.  The study demonstrated major differences in OS for patients in the three groups analyzed: 12.6, 19.9, and 31.8 months in the no post-PD treatment, no-BBP, and BBP groups, respectively.  Hypertension that required medication was the only bevacizumab-related safety event that occurred more frequently in the BBP group (24.6% v 19.2%). 

This study was not a randomized, prospective study.  It does serve to provide a “real world” experience based on a large set of patients with characteristics typical of those encountered in private practice settings.  The results suggest that the addition of bevacizumab to ongoing therapy of metastatic colon cancer after the first progression event may improve outcome and extend survival in these patients.  The study does not answer the question of whether the use of “maintenance” bevacizumab (used alone after completion of planned initial therapy) versus second-line integration of bevacizumab (bevacizumab used in conjunction with a second therapy at the time of progression) is advantageous.  That question is an important one, because bevacizumab is costly. 

This study did not directly compare bevacizumab-containing secondary therapy to directly to any other secondary therapy directly.  For example, the study did not report bevacizumab-continaing second-line chemotherapy compared to therapy such as cetuximab (anti-epidermal growth factor receptor antibody)-containing second-line therapy which did not include bevacizuamb.  Cetuximab (Erbitux) and Panitumumab (Vectibix) are both hold substantial prospect for subsets of metastatic colorectal cancer patients whose tumors have non-mutated k-ras oncogene.  For such patients, other studies have demonstrated that EGFR inhibitors improve outcomes when added to chemotherapy.  The BRiTE study therefore cannot be construed to show that bevacizumab-containing second-line therapy is superior to anti-EGFR-containing second-line therapy.  That question is a subject of ongoing study.  In addition, a direct comparison of bevacizumab-containing first-line therapy with anti-EGFR containing first-line therapy remains an important research question for patients with non-mutant k-ras tumors.

The good news for patients is that the BRiTE study confirms what practicing oncologists have already been noting for some time in the clinic: survival for metastatic colorectal patients is improving substantially, as the use of these “targeted” antibodies is integrated into various “lines” of therapy.  The number of regimens and combinations of agents are expanding. The safety and tolerability of these outpatient programs allow  oncologists to select therapy based upon the patients overall health and individual disease status (or molecular features), resulting in better survival for the patients.  CORT staff thanks our patients who participated in the BRiTE study for their contributions to the work. 

For more information about ongoing research at CORT, visit our website at www.CORTPA.com, or contact a research coordinator at 972-566-5588. 

CORT Study Tests Addition of Avastin (Bevacizumab) in Adjuvant Therapy for Non-Small Cell Lung Cancer

November 12, 2008

Post-operative chemotherapy for Stage IB-IIIA Non-Small Cell Lung Cancer (NSCLC) has become standard-of-care, improving survival modestly.  Commonly utilized chemotherapy regimens include cisplatin-vinorelbine (Navelbine), cisplatin-docetaxel (Taxotere), or cisplatin-gemcitabine (Gemzar).  Although carboplatin has also been commonly employed in treatment for lung cancer, meta-analysis comparing carboplatin and cisplatin has suggested a possible modest advantage to cisplatin therapy, so cisplatin is often the platinum analogue chosen in potentially curative (adjuvant therapy) patients.

Bevacizumab (Avastin) is a monoclonal antibody against vascular endothelial growth factor (VEGF).  The anti-VEGF action of bevacizumab leads to blockade in angiogenesis (new blood vessel formation).  Because VEGF acts to promote tumor growth by a number of mechanisms, bevacizumab probably has a number of other anti-tumor actions as well.  Bevacizumab has been studied in metastatic lung cancer in several trials, most notably, ECOG 4599.  That study showed a significant improvement in progression free survival (PFS) and response rate in first-line treatment of metastatic NSCLC.  Toxicities of bevacizumab have included bleeding, thrombosis, hypertension, proteinuria, delayed wound healing, infusion reactions, and rare bowel perforation or death.  Bevacizumab use in patients with metastatic NSCLC is modestly restricted, to avoid enrollment of patients with higher risk for serious bleeding, such as large, centrally-located tumors, and tumors of squamous histology.  Such a restriction is not necessary in the setting of resected disease.  

Bevacizumab is approved for use in metastatic lung, breast, and colorectal cancer.  Bevacizumab is not currently approved for use in adjvuant lung cancer treatment.  Therefore, because bevacizumab is not likely to be covered by insurers for adjuvant therapy, access to bevacizumab for adjuvant treatment is likely to be limited to patients who choose to participate in a clinical trial. 

The use of chemotherapy with or without bevacizumab for adjuvant therapy is being tested in the EGOG 1505 study.  Patients with good performance status, resected disease, no metastases, and adequate liver, lung, kidney, and marrow function are potentially eligible.   For more information about this study, visit the CORT website at www.CORTPA.com, or contact a Study Coordinator at 972-566-5588 (Dallas) or 972-981-4012 (Plano).

Adjuvant Therapy of Melanoma: BMS CA184-029/EORTC 18071 Study at CORT

November 12, 2008

Melanoma, malignant cancer of the pigmented cells (melanocytes), has increased in incidence.  This cancer is the most serious form of skin cancer, with a higher likelihood of recurrence or metastatic spread than other forms of skin cancer.  Other less common sites for origination of melanoma include the pigmented layer of the retina, or mucosal areas such as the rectum.  Principle treatment is surgical, with wide excision.  The extent of local disease is defined by the T stage (tumor depth of invasion), and the N stage (presence of nodal involvement).  TNM staging for melanoma may be found at http://en.wikipedia.org/wiki/Melanoma.  Nodal staging is important in defining overall stage, so resection of lymph nodes to determine involvement has become a standard practice, in patients other than the shallowest depths of invasion (with more significant chances of nodal involvement).  The risk of lymph node sampling may include lymphedema, so sampling of nodes by selective means (sentinel lymph node dissection) is often employed first, with full regional lymphadenectomy reserved for cases with initially positive sentinel lymph nodes.  Patients with positive lymph nodes and no other evidence of metastatic disease spread are Stage III in overall stage.  The 5-year survival for Stage III disease ranges from 25-60%, depending on the extent of involvement. 

Efforts to improve the outcome of Stage III melanoma patients have focused on immunotherapy, because adjuvant radiation or chemotherapy have not improved outcome.  High dose Interferon-alpha-2b (Intron-A) has been studied in large, randomized placebo-controlled adjuvant Phase III studies (ECOG 1684, ECOG 1690).  Lower doses have also been studied in other randomized clinical trials.  An overview of the results of those randomized studies has been published (http://jco.ascopubs.org/cgi/content/full/20/7/1818).  The ECOG studies reported improvement in disease free survival (DFS), and the ECOG 1684 study reported an overall survival (OS) improvement that was not confirmed in other studies.  Interferon therapy has potentially serious toxicities, including abnormal liver functions, rash, fatigue, anemia, thrombocytopenia, leukopenia, abnormal thyroid function, and exacerbation of autoimmune phenomena.  Many patients are unable to complete interferon therapy at high dose, and the value of low dose therapy is not as certain.  In the ECOG interferon protocol, continuation of lower dose interferon continues for up to one year, and many patients are unable to complete the duration of therapy.  Studies utlizing a newer form of interferon (pegylated interferon alpha, the EORTC Trial 18991) have been reported more recently (ASCO 2007 Annual Meeting, Abstract 8504).  That study demonstrated reduced relapse, but again, survival was not improved.  Overall, the conclusion can be reached that Stage III melanoma patients should be offered interferon therapy, or a clinical trial of new treatment. 

Ipilimumab (MDX-010, Anti-CTLA4) is an antibody therapy that activate the immune response against melanoma.  Ipilimumab has been studied in patients with metastatic melanoma, and responses have been seen in 13% of patients treated, some of which were fairly durable.  The response rate appears to be somewhat higher than that of interferon in metastatic patients. 

Therefore, ipilimumab has entered testing for adjuvant therapy of Stage III melanoma.  This study is the BMS CA184-029/EORTC 18071 study http://clinicaltrials.gov/ct2/show/NCT00636168 Patients with completely resected melanoma, with adequate lymph node dissection staging, good performance status, and absence of autoimmune disease are potential candidates.  Patients may not have received other adjuvant therapy for disease, and they must enter the study and be randomized within 12 weeks of surgery.  Other inclusion and exclusion criteria do apply.  The study is placebo controlled.  CORT has been selected as a participating site in this trial.  For more information on the study, visit the CORT website (www.CORTPA.com), or contact a Research Coordinator at 972-566-5588.  

ALLTO Study Evaluates the Role of Lapatinib (Tykerb) in Adjuvant Therapy of Her-2 Positive Breast Cancer

November 10, 2008

CORT has opened the NCCTG N063D (BIG 2-06) study for adjuvant therapy of her-2 positive breast cancer.  This study is a worldwide study funded by the National Cancer Institute Cooperative Group (NCCTG).  It is known as the ALLTO study

Her-2 (ErbB-2) is a protein which can drive the growth of breast cancer.   It is overexpressed on the cancer cell surface in as many as 25% of breast cancers.  That expression is a result of amplification of the Her-2 gene in those cases.  Standard adjuvant therapy for her-2 positive breast cancer includes treatment with chemotherapy and trastuzumab (Herceptin).  Trastuzumab is a monoclonal antibody that blocks her-2 protein on the cancer cell surface.  Several studies (NSABP B-31, NCCTG N9831, FinHer, BCIRG 006) established the role of adding trastuzumab to adjuvant chemotherapy, with significant (50%) relative risk reduction in the recurrence risk of disease recurrence.  At the present time, standard therapy may consist of a sequence of doxorubicin (Adriamycin) and cyclophosphamide (AC), followed by taxane therapy, with trastuzumab given during the taxane portion of that treatment.  In addition, trastuzumab therapy is given as maintenance for a duration of one year. 

The ALLTO study compares the effectiveness of another anti-her-2 drug, either alone or in combination with trastuzumab.  That drug is lapatinib (Tykerb).  Lapatinib is an oral drug.  Lapatinib has a different mode of blocking the her-2 protein.  Lapatinib binds the intracellular (inside the cell) portion of the her-2 molecule, stopping the action her-2 from activating other signaling proteins in the cell.  Lapatinib is approved in combination with chemotherapy (capecitabine=Xeloda) for treating metastatic breast cancer that has progresed after at least one trastuzumab-chemotherapy combination therapy.  The ALLTO study is moving lapatinib therapy into the adjuvant treatment setting.

There are two treatment designs in the ALLTO study.  The physician will select the treatment design that he feels most appropriate for the patient’s care.  Patients in group 1 (design 1) will complete all of their chemotherapy before starting anti-her-2 therapy.  Patients in group 2 (design 2) will complete standard AC therapy, and then have standard weekly paclitaxel (Taxol) therapy.  In group 2, the anti-her-2 therapy will begin at the same time as the initiation of paclitaxel therapy.  In both groups, the patients will be randomized between four anti-her-2 treatments: 1) lapatinib daily for one year, 2) trastuzumab for one year, 3) trastuzumab for 12 weeks, followed by 6 weeks of no therapy, then lapatinib for 34 weeks, and 4) lapatinib and trastuzumab for 52 weeks.  The schema for design 2 is depicted below.

altto-study-schema-design-2

Efficacy, safety, and tolerability will be evaluated.

For more information about the ALTTO study, visit the CORT website at www.CORTPA.com, or speak with a Study Coordinator at 972-566-5588 (Dallas), or 972-981-4012 (Plano).

ABCSG-12: Zoledronic Acid (Zometa) Reduces Recurrence of Early Breast Cancer

November 5, 2008

The Austrian Breast and Colorectal Cancer Study Group Trial 12 results were reported at the American Society of Clinical Oncology (ASCO) 2008 Annual Meeting.  The study compared treatment with zoledronic acid (Zometa) with placeo in premenopausal women who were treated with anti-estrogen therapy following surgery. 

Between 1999 and 2006, over 1800 women participated in the study. All were premenopausal, had estrogen receptor (ER)- and/or progesterone receptor (PR)-positive stage I or II (<10 positive nodes) breast cancer, and have received no chemotherapy other than neo-adjuvant (pre-operative) treatment.

Following completion of surgery (with radiotherapy in breast conservation cases), women were treated with 3.6 mg of goserelin (an ovarian suppression LHRH drug) and then randomized to one of four treatment arms: tamoxifen 20 mg/day; tamoxifen 20 mg/day plus zoledronic acid 4 mg given intravenously every 6 months; anastrozole 1 mg/day; or the AI plus the bisphosphonate at the same doses and schedule.

Dr. Gnant of the University of Vienna reported that the disease-free (DFS) and overall survival (OS) rates were very good for the whole cohort, at 94.0% and 98.2%, respectively.

A total of 137 first DFS events were reported. Of these, 72 occurred in patients treated with anastrozole, and the remaining 65 occurred in those treated with tamoxifen. Statistical analysis showed no significant difference in the primary endpoint of DFS according to the type of endocrine treatment used, but there was a significant difference according to whether or not patients had been given the bisphosphonate. Of the 137 DFS events, 54 occurred in women who had received zoledronic acid, with the remaining 83 in those who had not received the drug. This gave a hazard ratio of 0.643 (95% confidence interval: 0.46-0.91), with a p value of 0.011, in favor of bisphosphonate use over no bisphosphonate use.  This is a 35% reduction in the number of events. 

The reduction in events were not limited to bone metastasis reduction.  Reduction in other distant metastases, local recurrence, and contralateral breast cancer events was established. 

Zoledronic acid is a bisphosphonate drug which reduces bone resorption and thereby increases bone mineral density.  Bisphosphonates are approved therapies for treatment of osteoporosis.   The anticancer effect of bisphosphonates has been suggested in prior studies of other bisphosphonate drugs, e.g., oral clodronate (NSABP).  The mechanism of the anticancer effect is not known. 

These results have been called “practice changing” by some observers, but not all.  However, if the effect is confirmed in other large ongoing studies (AZURE, BIG 1-04, NATAN, GAIN, NSABP B-34), then the use of bisphosphonate therapy is likely to have a large impact on practice, as well as the design of future studies. 

Access to bisphosphonate therapy for adjuvant therapy of early breast cancer in the US is limited, because the drugs are not FDA-approved yet for breast cancer treatment.  For example, Medicare does not pay for coverage for zoledronic acid for breast cancer.  Private payors may not pay for zoledronic acid for breast cancer either, since their treatment algorithms heavily rely upon national guideline groups and current FDA approvals.  While zoledronic acid is approved for osteoporosis, the dosing of the drug at the approved frequency is yearly, and the dosing that was shown to be effective in the ABCSG study was more frequent, so therapy was more intensive. 

Patients may gain access to bisphosphonate therapy for early breast cancer by enrolling in clinical studies, such as the SWOG S0307 Study which is open at CORT.  This study compares the efficacy of three different bisphosphonate drugs (IV zoledronic acid, oral clodronate, oral ibandronate) in a randomized fashion.  All patients will receive one of the bisphosphonate therapies.  Three is no placebo group.  This study will also include a broader range of patients, including pre- and post-menopausal women, ER- and ER+ disease, and those who have receive either pre- or post-operative chemotherapy.  In addition, the use of adjuvant biologic therapy such as trastuzumab (Herceptin) or bevacizumab (Avastin) is allowed.  For more information about this study, visit the CORT website (www.CORTPA.com), or call 972-566-5588 to speak with a Study Coordinator.

Addendum (2/12/09):  The ABCSG-12 Study Results were published in the New England Journal of Medicine today.  The reference is: Gnant, M. et al., NEJM 2009; 360 (7): 679-691. 

Advances in First-Line Treatment of Unresectable Non-Small Cell Lung Cancer: Pemetrexed Maintenance Therapy

November 3, 2008

Chemotherapy is the initial standard-of-care treatment for unresectable (stage IIIB/IV) non-small cell lung cancer (NSCLC).  Based upon historical information, the optimal duration of initial therapy with a platinum doublet (two-drug regimen) is 4-6 cycles.  The addition of bevacizumab (Avastin) to the carboplatin and paclitaxel first-line treatment regimen has improved progression free survival (PFS) from 4.5 (placebo) to 6.2 months (bevacizumab) (ECOG 4599, Sandler et al NEJM 355: 2542-2550, 2006).  Longer therapy initial therapy has, in some cases, improved progression free survival (PFS), without improvement in overall survival (OS).  That may be a result of the benefit of second-line treatment (at the time of progression), which may also extend overall survival (OS).  

The benefit of maintenance therapy, after initial treatment, was examined by a group of international investigators, reported by Dr. Ciuleanu (Romania) at the 2008 ASCO Annual Meeting  (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8011)).  Patients received initial chemotherapy, and then the patients were randomly assigned to maintenance therapy with pemetrexed (Alimta) or placebo.  The study demonstrated a significant improvement in PFS for the patients who received maintenance pemetrexed therapy, with PFS of 4 months (versus 2 months for placebo).  In the subset analysis, patients with non-squamous cell histology benefited, while squamous cancers did not.  The observation that response to pemetrexed was superior in non-squamous histology lung cancer has been observed in two previous investigations.  This study also demonstrated a strong trend (nearing statistical significance) for improved overall survival (OS) in patients with non-squamous histology who received pemetrexed maintenance therapy.  The final results of OS in this study have not yet been reported.

The use of maintenance pemetrexed with bevacizumab was also reported at the ASCO 2008 Annual Meeting (J Clin Oncol 26: 2008 (May 20 suppl; abstr 8044)).  Dr. Patel reported the results of a study in which all patients received carboplatin and pemetrexed with bevacizumab as initial therapy x 6 cycles.  Patients without progression continued on pemetrexed and bevacizumab for maintenance therapy every 3 weeks.   This was a single arm study.  The PFS was 9.2 months, and the OS was 13.5 months.  Treatment with maintenance pemetrexed and bevacizumab was very well tolerated, and 60% of patients had >6 cycles, 18% had >18 cycles, and 14% had >24 cycles. 

The PFS of the study reported by Patel et al are favorable.  If one expects a PFS with a platinum doublet + bevacizumab of 6 months, and an additional 4 months of PFS with pemetrexed maintenance therapy, the the results of the Patel study are in line with those reporte by Ciuleanu et al.  The study of Patel did give bevacizumab until progression, as was done in the ECOG 4599 study. 

These studies mark continued progress in treatment of unresectable and metastatic NSCLC.  Integration of anti-angiogenic therapy (bevacizumab) and less toxic treatment with new agents like pemetrexed have incrementally extended PFS.  Overall survival may also be impacted. 

Additional improvements may come with the integration of other sorts of maintenance treatment, for example, anti-tumor vaccine therapy.  CORT is testing the anti-MUC-1 tumor vaccine, Stimuvax, as part of the START study, for patients who have completed initial chemotherapy and radiation therapy for unresectable Stage III NSCLC.  Information about that study is available in another post.  For further information about lung cancer therapy at CORT, including the START study, visit our webpage at www.cortpa.com, or contact a Research Coordinator at 972-566-5588.