Archive for the ‘Colorectal Cancer’ Category

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).

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. 

Erbitux (Cetuximab) in First-Line Treatment Colorectal Cancer Mangement

October 30, 2008

CORT has conducted research and treatment studies with the monoclonal anti-EGFR (anti-epidermal growth factor) antibody cetuximab (Erbitux) since 2002.  Early cetuximab studies focused on treatment of disease that was refractory (resistant) to other available chemotherapy agent.  Those agents included fluropyrimidines (5FU), oxaliplatin (Eloxatin), and irinotecan (Camptosar).  Responses to Erbitux monotherapy were seen in 11.6% of patients, with a median duration of response of 4.2 months.  The median progression free survival was 1.5 months, and the median overall survival was 6.6 months. 

The CORT data on response predictors was reported at the same time several other major cancer centers released their results.  Certain baseline clinical characteristics (performance status, number of metastatic sites) and the appearance of skin rash after therapy were strong predictors of response and outcome.  Interestingly, the intensity of tumor tissue staining for EGFR protein did not correlate to response to cetuximab.  CORT data demonstrated that 25% of such refractory patients treated with cetuximab monotherapy had stable disease for longer than 6 months.  Certain patients had exceptional responses, including complete responses (CR).  One heavily pre-treated patient at CORT had a CR and continued maintenance cetuximab for 18 months, then continued in unmaintained remission for over one year.  This patient relapsed and again entered CR with cetuximab monotherapy retreatment, again lasting one year.  The patient stopped therapy, relapsed a third time, and then had only partial response to cetuximab therapy for a third time.  She continues to be alive on other investigational therapy.  Additional studies in patients refractory to irinotecan therapy demonstrated that cetuximab therapy combined with irinotecan was superior to cetuximab therapy alone (BOND-1), and cetuximab + irinotecan + bevacizumab (Avastin) was superior to cetuximab + irinotecan (BOND-2).  It must be noted that in BOND-2, these patients had not previously received bevacizumab in any earlier line of therapy. 

Multiple investigators have reported that mutated k-ras protein confers resistance to cetuximab therapy.  This is mechanistically explained by the activation of intracellular signaling “downstream” of the EGFR protein.   Commercial testing for k-ras protein mutation status is now available, and clinical use of this response prediction test is being widely adopted. 

Based on such promising data seen in the refractory colorectal patient population, cetuximab has been studied in first line treatment of metastatic colorectal cancer.  The 1198 patient Crystal Study was a randomized comparison of the FOLFIRI (irinotecan, 5-FU, leucovorin) and FOLFIRI-cetuximab.  The results were initially reported in 2007.  The study met its primary endpoint of increasing progression-free survival (PFS) (15% improvment: 8.9 months vs. 8.0 months, p=0.048). The study also demonstrated a 21% improvement in the response rate (46.9% vs. 38.7%, p=0.004).

In the analysis of the total treatment population, not sorted by k-ras status, the study did not demonstrate a statistically significant prolongation of overall survival (OS), compared to chemotherapy alone. The OS of all ERBITUX-treated patients was 19.9 months compared to 18.6 months for FOLFIRI alone (Hazard Ratio [HR]=0.931, p=0.305).

However, the study results were further analyzed by k-ras mutational status. 540 of the patients had tumor samples evaluable for k-ras. The k-rase mutation was detected in 192 of those patients (36%). Patients with k-Ras wild-type (non-mutated) tumors had the greatest benefit from cetuximab treatment. The OS for patients with the non-mutated, or “wild-type,” form of the K-Ras oncogene, which is noted in about 65% of patients with mCRC, was 24.9 months, 4 months difference, compared to 21 months for FOLFIRI alone (HR=0.844, p=0.217). These survival times are among the longest seen in first line treatment studies.

Furthermore, for patients with k-ras wild-type tumors, there was a 32% decrease in risk of progression (9.9 months vs. 8.7 months, HR=0.68, p=0.017) and a significant increase in response rate up to 59% (59.3% vs. 35%, p=0.003).

How will these results change therapy?  Until recently, oxaliplatin-based regimens with bevacizumab (Avastin) have been the most widely utilized first line treatments.  In April, 2008, a large study evaluating oxaliplatin-containing therapies (either Xelox or FOLFOX) with or without bevacizumab was reported in the Journal of Clinical Oncology.  This study of 1401 patients showed that the PFS was 9.4 months in the bevacizumab + chemotherapy group, versus 8.0 months in the placebo + chemotherapy group (harzard ratio (HR) 0.83; 97.5% CL: 0.72-0.95, p=0.00213).  The OS for the bevacizumab + chemotherapy group was 21.3 months, versus 19.9 months in the placebo + chemotherapy group (HR) 0.89; 97.5% CL, 0.76-1.03, p=0.077).   The response rates were similar in both arms.  Therefore, despite the significant longer progression time, the response rate and overall survival was not significantly improved by the addition of bevacizumab.  k-ras is not a factor that predicts bevacizumab response. 

The treatment paradigm for first line treatment of metastatic colorectal cancer is shifting based on the Crystal results.  FOLFIRI-cetuximab first-line treatment is expanding (in k-ras wild type patients).  In addition, the benefit of adding bevacizumab to oxaliplatin-based regimens appears to have limited benefits.  Another factor in reduced use of oxaliplatin regimens in the first line metastatic setting is the increased use of oxaliplatin-based adjuvant therapy.  For patients who received prior oxaliplatin-based adjuvant therapy, the risk of developing peripheral neuropathy with oxaliplatin regimens for relapsed disease is increased.  Cumulative marrow suppression of oxaliplatin (e.g, thrombocytopenia) is also problematic.  These toxicities limit retreatment with oxaliplatin regimens.  In addition, retreatment with oxaliplatin regimens after pior oxaliplatin adjuvant therapy may be less effective in some patients, becasue of disease resistance.  FOLFIRI is well tolerated, and neuropathy is not an expected toxicity of this regimen.

Cetuximab is also being studied in the colon cancer adjuvant therapy setting.  The NCCTG N0147 Study is comparing oxaliplatin-based therapy alone to oxaliplatin-based therapy wtih cetuximab for patients with Stage III disease. This study is opening at CORT.  

CORT is conducting other colon cancer studies, including the ECOG E5202 Study that evaluates adjuvant therapy for Stage II patients with bevacizumab + oxaliplatin-based therapy in tumor defined by high risk tumor genetic characteristics.  The role of adjuvant bevacizumab + oxaliplatin-based therapy versus oxaliplatin-based therapy alone for Stage III patients has been studied in the NSABP C-08 study, also conducted at CORT. That study has completed accrual, and results are eagerly anticipated. 

For consultation requests or more information about colon cancer treatment studies at CORT, visit our website at www.cortpa.com, or call and speak with a Research Coordinator at: 972-566-5588 (Dallas), or 972-981-4012 (Plano). 

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.