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Meeting Highlights

Rule

2008 American Society Clinical Oncology (ASCO), June 1-5, 2008, Chicago, IL

The following summaries of selected colorectal cancer clinical trials were presented at the 2008 ASCO Meeting. The abstracts are available here

Plenary Session

Title: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. (Abstract 2)
Presenter: Eric Van Cutsem, MD, PhD
Trial: Randomized Phase III Study of Irinotecan and 5FU/FA With or Without Cetuximab in the First-Line Treatment in Patients With mCRC: Referred to as the CRYSTAL Trial

  • Primary endpoint: Progression free survival (PFS),
    • Median PFS: 8 months (FOLFIRI alone) vs. 8.9 months (FOLFIRI + cetuximab)
  • Secondary endpoint: Response Rate (RR)
    • RR = Complete Response (CR) + Partial Response (PR): 38.7 months (FOLFIRI) vs. 46.9 months (FOLFIRI + cetuximab)
  • Conclusions:
    • Adding cetuximab to FOLFIRI in mCRC leads to a significant increase in PFS Hazard Ratio (HR) = 0.84; P = 0.048)
    • Relating KRAS status to efficacy - the benefit of cetuximab + FOLFIRI is greater in patients with KRAS wild-type tumors than KRAS mutant
      • mPFS estimate: 8.7 (FOLFIRI)  vs. 9.9 months (FOLFIRI + cetuximab)
      • PFS rate at 1 year: 25% (FOLFIRI) vs. 43% (FOLFIRI + cetuximab)
      • RR (CR + PR): 43.2% (FOLFIRI) vs. 59.3% (FOLFIRI + cetuximab) (P = 0.0025)
    • Patients with KRAS mutant tumors do not benefit from the combination of cetuximab and FOLFIRI
    • In KRAS mutant patients FOLFIRI + cetuximab negatively impacted PFS vs. FOLFIRI alone
      • Median PFS estimate:  8.1 (FOLFIRI)  vs. 7.6 months (FOLFIRI + cetuximab)
      • RR (CR + PR): 40.2% (FOLFIRI) vs. 36.2% (FOLFIRI + cetuximab)
    • The grade 3/4 adverse event profile was similar in the KRAS mutant and wild-type populations
    • KRAS is the first molecular marker for selection of a targeted therapy in combination with a standard chemotherapy in first-line mCRC
    • Patients with KRAS wild-type tumors have a strong benefit from the combination of  cetuximab and FOLFIRI
    • Cetuximab in combination with a standard first-line treatment for mCRC is an important new option for patients with wild-type tumors

Session: The Biomarkers for Colorectal Cancer Management
Title: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. (Abstract 4000)
Presenter: Carsten Bokemeyer, MD
Trial: Phase II Trial of Oxaliplatin and Cetuximab in first line treatment of mCRC:
Referred to as the OPUS Trial

  • Predictive/Prognostic:
    • Predictive: A patient is likely or not to benefit from an intervention
    • Prognostic: A patient is likely or not to do well (“pro” – in the future and “nosis”- knowledge)
  • Conclusions:
    • In patients with KRAS wild-type tumors, addition of cetuximab to FOLFOX resulted in a significant and relevant improvement in:
      • Overall response (OR): 61% vs. 37% (P = 0.0011)
      • Median progression free survival (mPFS): 7.7 vs. 7.2 months ( Hazard Ratio (HR) = 0.57; P = 0.02)
    • In patients with KRAS mutant tumors, the addition of cetuximab to FOLFOX had worse outcome:
      • OR: 33% vs. 49% (P = 0.11)
      • mPFS: 5.5 months vs. 8.6 months (HR 1.83; P = 0.02)
    • The safety profiles of cetuximab and chemotherapy were generally comparable and consistent with their known safety profiles

Session: Gastrointestinal (Colorectal) Cancer

Title: Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). (Abstract 4001)
Presenter: Sabine Sejpar, MD
Trial: Phase I/II Dose-Escalation in Patients With mCRC With No or Slight Skin Reactions on Cetuximab Standard Dose Treatment: Referred to as the EVEREST Trial

  • Conclusions:
    • Higher response rates were seen in the KRAS wild-type patients vs. no clinical response in the KRAS mutant patients
      • Response rates (RR): (including both mutant and wild-type patients): 16% (standard dose cetuximab {arm A}) vs. 30% (dose escalating cetuximab {arm B})
    • Patients with KRAS wild-type tumors benefited from irinotecan plus cetuximab treatment
    • In the dose escalation arm a trend toward increased responses was observed in patients with KRAS wild-type tumors
      • RR: 30.4% (control arm) vs. 41.9% (dose escalation)
    • Dose escalation did not improve the efficacy in KRAS mutant patients
    • Skin toxicity and KRAS status are independent predictors of outcome – KRAS is the stronger predictor
      • Skin toxicity and outcome: KRAS  wild-type progression free survival (PFS) estimated
        • Grade 2 rash - 425 days
        • Grade 3 rash - 725 days
      • Skin toxicity and KRAS mutant PFS estimated
        • Grade 2 rash - 175 days
        • Grade 3 rash - 200 days
    • Predictive markers that act independently of KRAS were identified

Session: Gastrointestinal (Colorectal) Cancer

Title: Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. (Abstract 4003)
Presenter: Fotios Loupakis, MD

  • Conclusions:
    • Primaries and related mets from CRC differed in terms of  PTEN immunoreactivity in 40% of cases
    • KRAS mutations found on primary tumors are almost always confirmed (95% of cases) on metastasis
    • Loss of PTEN on mets predicted lack of activity of cetuximab plus irinotecan combination treatment in mCRC patients
    • KRAS is confirmed to be a predictor of resistance to cetuximab plus irinotecan combination treatment in mCRC
    • The combination of PTEN immunohistochemistry performed on metastasis and KRAS mutational analysis identified a subgroup of patients with higher chances of benefiting from cetuximab plus irinotecan treatment
  • This abstract highlights the trend of identifying markers that can predict response

Session: Gastrointestinal (Colorectal) Cancer
Title: Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. (Abstract 4008)
Presenter: Daniel J. Sargent, PhD

  • Conclusions:
      • Defective MMR (dMMR) cells are resistant to 5FU
      • dMMR is validated as a prognostic marker in untreated patients
      • No suggestion of benefit from 5FU based treatment in dMMR patients
      • Significant overall survival decrement to 5FU based treatment in stage II patients
      • In a patient being considered for 5FU based therapy (stage II), mismatch repair status by MSI or IHC should be tested to determine whom not to treat
    • This abstract highlights the trend of identifying markers that can predict response

    Session: Gastrointestinal (Colorectal) Cancer
    Title: Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). (Abstract LBA4011[Late Breaking Abstract])
    Trial: CAIRO2 (CApecitabine, IRinotecan and Oxaliplatin)
    Presenter: Cornelis J. Punt, MD, PhD

    • Conclusions:
      • The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab results in a significantly decreased progression free survival (PFS) without affecting overall survival (OS)
    • Median PFS: 10.7 months (arm A, without cetuximab) vs. 9.6 months (arm B, with cetuximab)
    • Median OS: 20.4 months (arm A, without cetuximab) vs. 20.3 months (arm B, with cetuximab)
      • The addition of cetuximab to chemotherapy results in a significant increase of skin toxicity and diarrhea, however the toxicity is acceptable in both treatment arms
      • The grade of cetuximab skin-related toxicity significantly correlates with PFS
        • Grade 0-1shorter PFS vs. grade 3 rash
      • In patients with KRAS mutation the addition of cetuximab to chemotherapy and bevacizumab results in a significant decrease in PFS
        • mPFS KRAS mutant: 12.5 (arm A) vs. 8.6 months (arm B) (P = 0.043)
        • mPFS KRAS wild-type: 10.7 (arm A) vs. 10.5 months (arm B) (P = 0.10)
      • Toxicity as a reason for discontinuation of treatment does not significantly differ between treatment arms, therefore a negative interaction between anti-VEGF and anti-EGFR antibodies cannot be excluded

    Session: Gastrointestinal (Colorectal) Cancer
    Title: Initial safety report of NSABP C-08, a randomized phase III study of modified 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer. (Abstract 4006)
    Presenter: Carmen J. Allegra, MD
    Trial: NSABP CO-8 (National Surgical Adjuvant Breast and Bowel Project)

    Conclusions:

    • The overall safety of adding bevacizumab to mFOLFOX6 in the colon cancer adjuvant setting is acceptable in the selected populations of patients eligible for C-08 with a mean time on study of 28.5 months; however the use of bevacizumab in the colon adjuvant setting cannot currently be recommended in the absence of efficacy data The overall safety of adding bevacizumab to mFOLFOX6 in the colon cancer adjuvant setting is acceptable in the selected populations of patients eligible for C-08 with a mean time on study of 28.5 months; however the use of bevacizumab in the colon adjuvant setting cannot currently be recommended in the absence of efficacy data
    • The cumulative dose and dose intensity of mFOLFOX6 was not decreased by the addition of bevacizumab
    • No increase in arterial or venous thrombotic events, hemorrhage, GI perforations or death from any cause as a result of the addition of bevacizumab to mFOLFOX6
    • Other complications seen at increased frequency (hypertension, wound complications, proteinurea and pain) are important but manageable
    • Sensory neuropathy grade 2 was increased with bevacizmab but may be secondary to an increased cumulative dose of oxaliplatin
    • Long term follow-up to detect any potential increase in delayed side effects associated with bevacizumab continues
      • Rule

    2008 Oncology Nursing Society Congress Highlights, May 15-18, 2008, Philadelphia, PA

    Skin Reactions

    Instructional Session: Dermatologic Toxicities of ChemoBiotherapy

    Coordinator: Pamela Calarese, MS, RN, CS, ANP. Speakers: Mario Lacouture, MD, Susan Newton, RN, MS, AOCN® , AOCNS®

    The objective for this instructional session was to describe the dermatologic toxicities of chemobiotherapy and mechanisms of action of epidermal growth factor receptors (EGFR) and monoclonal antibody (MAb) targeted therapies. The number of publications on this subject has increased dramatically based on the clinical symptoms seen in practice. Dr. Lacouture explained that it takes 28 days to completely renew skin, a reason to see direct effects to these rapidly proliferating cells. It is desirable to target cancer with critical pathways, but not all pathways because some are physiologically necessary for normal hair and skin growth. Dermatologic toxicities can lead to dose decrease, interruption and discontinuation of treatment affecting outcome. These effects appear in skin, paronychia, and hair. It is not unusual to see a slightly different presentation with MAb versus multikinase inhibitors (MKI) with toxicity possibly less severe with MKIs based on their mechanism of action.

    Ms. Newton noted that targeted therapies are very specific and the EGFR pathway is essential in signal transduction. There are three components of the EGFR

    • Extracellular ligand-binding domain
    • Hydrophobic membrane-spanning domain
    • Intracellular domain where tyrosine kinase inhibition (TKI) occurs

    Hyperactivation of the EGFR and signaling can occur with overexpression of the receptor and overproduction of EGFR ligand. Mutations in EGFR (K-ras) may cause continuous firing of the signaling system. She described the incidence of EGFR skin toxicities including

    • Rash (60% to 80%)
    • Paronychia (6% to 12% or higher) (painful inflammation of tissue around the nails)
    • Hair changes (5% to 6%)
    • Dry skin (4% to 35%)
    • Hypersensitivity reaction (2% to 3%)

    Ms Newton stressed the importance of the oncology nurse to instruct patients on the meaning of the rash (surrogate marker of efficacy) and how to monitor and assess for possible dose reductions and delay. She quoted treatment interventions for rash based on data from the 2007 ASCO Annual Meeting discussing tetracycline1 and the efficacy of minocycline with cetuximab rash.2

    References

    1. Jatoi A, Rowland J, Sloan JA, et al. Does tetracycline prevent/palliate epidermal growth factor receptor (EGFR) inhibitor-induced rash? A phase III trial from the North Central Cancer Treatment Group (N03CB). 2007 ASCO Annual Meeting. June 1-5, 2007. Chicago, IL. Abstract LBA9006. Accessed June 23, 2008.
    2. Scope A, Agero ALC, Dusza S, et al. Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption. J Clin Oncol. 2007;25:5390-5396.

    Podium session #8: Evaluation of Regenecare® Topical Gel for Treatment of Adverse Rash Symptoms Associated with EGFR Inhibitor Drugs

    Patricia Gowland, RN, BSN, OCN®, CCRC, Joy Vlamakis, RN, Julie Koch RN, BSN, et al. Abstract 2980. Oncol Nurs Forum. 2008;35:page 536.

    Epidermal growth factor receptor (EGFR) drugs have become an important part of the armamentarium for various cancers, including metastatic colorectal cancer (mCRC). Ms Gowland remarked that 88% of patients receiving EGFR therapies suffer moderate to severe side effects with skin rash and there are no evidenced-based interventions. Since rash is associated with a positive outcome, it is acknowledged as an important marker. However, Wagner and Lacouture reported in Oncology (2007;21(11 Suppl 5):34-6) that patients identified pain, burning and skin sensitivity as most problematic during treatment. These skin toxicities can result in dose interruption, reduction or cessation.

    The oncology nurse is important in managing patients with rash. The researchers conducted a small single center prospective pilot study with 20 patients (although 3 dropped out due to grade 3 skin reactions). Regenecare® topical gel, containing aloe vera, collagen, vitamin E and 2% lidocaine, was applied when the rash first appeared after cleaning 4 times daily. The primary objective of the pilot study was to assess if the gel relieved pain and itching. The secondary objective was to assess the severity and reduction of the rash symptoms. The researchers were also interested on how the gel felt on the patient’s skin. Patients were assessed weekly and participated in quality of life measurements. Results: The researchers reported that the gel reduced itching and was soothing and noted a moderately reduced appearance of the rash. They concluded that the gel is effective in managing grade 1-2 symptoms. Study participants said they would recommend this treatment to other patients.

    Safety Profile

    Poster: The Safety Profile of Panitumumab Monotherapy in Patients with Metastatic Colorectal Cancer (mCRC) Across 10 Clinical Trials.

    Teresa Knoop, MSN, RN, AOCN®. Abstract 2651. Oncol Nurs Forum. 2008;35:page 491.

    Ms Knoop presented the results of a large study (966 patients from 10 clinical trials) evaluating the clinical safety of panitumumab in mCRC and the evaluation of the incidence of adverse events for both skin and hypersensitivity reactions (HSRs). Results: Of a total of 7,618 infusions, treatment-related adverse events were experienced by 94% of the patients, with 20% having grade 3 or 4 events. There were rare instances of severe infusion reactions (0.4% grade 3, but no grade 4 reactions). None of the patients required premedication. There were two deaths noted in the study, a pulmonary embolism in a patient with a history of coagulopathy and a MI and CVA in a patient with a history of multiple comorbidities

    The author stated that it is important for oncology nurses to know safety data associated with the EGFR inhibitor agents and the poster provided a summary of the crucial safety data associated with panitumumab in mCRC patients.

    Screening

    Poster: Colorectal Screening Initiative: A Model for Kansas.

    Elizabeth Lindal, RN, OCN®. Abstract 2734. Oncol Nurs Forum. 2008;35:page 502.

    Ms Lindal notes that routine colorectal screening can help to reduce the death rate from CRC when the disease is detected earlier and where treatment is known to be more effective. Using 2004 statistics, only 21.7% of the residents in the state of Kansas age 50 years and older had a fecal occult blood test (FOBT) within the past year. A cancer outreach coordinator and an OCN® nurse, partnered with the American Cancer Society and Walgreen pharmacies to launch a community colorectal screening event in low-income areas of Wichita, Kansas for residents age 50 to 65 years.

    Kits were distributed containing FOBT cards, return mail envelopes along with instructions and educational material in both English and Spanish. Results: One-hundred and seventy-nine (179) residents participated with 70 residents never having a colon cancer screening. Eighty-eight (88) kits were processed with 7 positive readings requiring additional testing and follow up. A 28 year old female was tested because of family history. She had positive results and received a follow-up colonoscopy and subsequent polypectomy.

    This project was a model for the Kansas Colorectal Cancer Project 2008 with documentation available in the Kansas Department of Health and Environment.

    Adherence to Oral Cancer Therapies

    Podium Session # 22: Assessment of Current Nursing Practice Associated with Oral Chemotherapy Adherence.

    Karen Schulte MSN, ANP-BC, OCN®, Teresa Mazeika, RN, BSN, OCN®, Elizabeth Tracey PhD, RN, OCN®, et al. Abstract 3074. Oncol Nurs Forum. 2008; 35:page 551.

    Ms Schulte reported on a study conducted at the Dana-Farber Cancer Institute (DFCI) in Boston MA that identified and described the current nursing practice of caring for patients receiving oral chemotherapy. Schulte and her colleagues designed a study evaluating several nurse characteristics of the Synergy Model© currently used at DFCI: clinical judgment, caring practices and systems thinking. 36 participants were invited to participate (66% response rate) and were evaluated through a survey instrument developed following nursing focus group interviews. Results of the study showed that 85% of all surveyed staff care for patients on oral chemotherapy on a daily basis but are primarily involved in symptom management and insurance issues, not initial patient teaching. Written educational materials are utilized 60% of the time. Areas for improvement were identified: standardization of nursing documentation, interdisciplinary communication and educational materials for investigational agents in early drug development.

    Promoting Patient Adherence to Oral Cancer Treatment. Susan Moore, RN, MSN, ANP, AOCN®, Yvette Stoker. Abstract 2728. Oncol Nurs Forum. 2008; 35:page 501.

    Ms Moore reported on behavioral models developed in primary care that may be useful in increasing adherence to oral cancer therapies. The Health Belief Model and the Self-Efficacy Model may be useful tools although validation in an oncology setting has not been reported. Johnson’s Self-Regulation Model has been validated in radiation oncology and may be useful in medical oncology as well. A secondary aim of the project was to broaden the scope of oncology nursing to include a telephone support system for patients on oral capecitabine therapy. Results: Comprehensive patient screening and education, use of adherence tools and early management of adverse events through nurse-run telephone support services resulted in an additional 3 cycles of oral capecitabine for patients with metastatic breast cancer and 5 additional cycles for patients with metastatic colorectal cancer. Patients participating in the telephone support program reported 40% fewer grade 3/4 adverse events than those not enrolled in the program.

     

    Rule

    5-29-08 - More Information…Use of a COX-2 Inhibitor in Prevention of Polyps

    Dr Nadir Arber of Tel Aviv University reported 5-year data from the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial on May 21, 2008 at Digestive Disease Week in San Diego CA. Patients at high risk for adenomas who took celecoxib (Celebrex), a COX-2 inhibitor, daily for 3 years had a 25% lower risk of new colorectal polyps and significantly fewer advanced ones 2 years after cessation of treatment. The cumulative rate of adenoma detection at year five (3 years on drug or placebo and 2 years off) was 51.4% vs 57.5% in the placebo group (RR 0.75, 95% CI 0.65 to 0.86, P<0.0001) and the advanced adenoma detection rate was 10% vs 13.8% (RR 0.64, 95% CI 0.457 to 0.887, P = 0.0072).

    There were more cardiovascular events in the Cox-2 inhibitor arm, including myocardial infarctions, stroke, and at least one sudden death.

    • Cardiovascular event rate:10.4% in the celecoxib arm vs 6.5% in the placebo arm
    • Serious adverse event rate: 23.9% in the Cox-2 inhibitor arm vs 20.6% in the placebo group

    PreSAP was designed as a three-year randomized, placebo-controlled, double blind study of 1,561 adenoma-prone patients. Patients had colonoscopies at year one and year three. On Sept. 24, 2004, a chemoprevention trial of rofecoxib (Vioxx), another Cox-2 inhibitor, was stopped when an analysis revealed an increased risk of cardiovascular events in the rofecoxib arm. Dr Arber stated that the PreSAP study was stopped soon after, but 1,043 of the original cohort agreed to continued safety assessments for at least two years after treatment ended and/or a follow-up colonoscopy at year five.

    Preliminary reports of PreSAP data through 3 years of study data showed

    • At year 1, the adenoma rate was 20.8% in the celecoxib arm versus 32.5% in controls
    • At year 3, the rate was 16.1% in the celecoxib arm vs 24.9%
    • After 3 years, there was a 36% reduction in the relative risk of new adenomas favoring celecoxib and a 51% reduction in the relative risk of advanced adenomas (RR 0.49, 95% CI 0.33 to 0.73, P <0.001)

    Dr. Arber suggested the following teaching points for patients interested in celecoxib for risk reduction:

    • Study suggests a cumulative benefit for celecoxib in reducting the risk of adenomas
    • NSAIDs, including celecoxib, may increase the risk of cardiovascular events
    • Information on the PreSAP study has been presented as an abstract, which is a preliminary reporting of data and conclusions; the information has not yet been published in a peer-reviewed journal.

    Reference

    1. MedPage Today: http://www.medpagetoday.com/MeetingCoverage/DDW/tb/9532

    Rule

    5-6-08 – Celecoxib for CRC Chemoprevention May Not be Safe for Everyone

    Monica Bertagnolli MD, principal investigator of the Adenoma Prevention with Celecoxib (APC) study, an international randomized, placebo-controlled trial, reported on 5-year efficacy and safety results at the American Association of Cancer Research (AACR) annual meeting in San Diego, CA. Results indicate that CRC chemoprevention with the COX-2 inhibitor celecoxib is effective and can be safe for patients without any underlying cardiovascular risk factors. Celecoxib at low doses protects against high-risk lesions that can lead to colon cancer; however, it does not appear to be safe for patients with cardiovascular risk factors.

    In the APC trial, 2,035 polypectomy patients at very high risk for developing colorectal adenomas and CRC were randomly assigned to: (1) placebo or (2) celecoxib 200 mg twice daily (bid), roughly twice the usual dose now recommended for arthritis, or (3) celecoxib 400 mg bid.

    After 3 years of treatment

    • Patients taking 200 mg celecoxib bid had 33% fewer adenomas and 57% fewer advanced adenomas than patients on placebo
    • Patients taking 400 mg celecoxib bid had 45% fewer adenomas and 66% fewer advanced adenomas
    • Colonoscopies performed in 639 patients at 5 years (3 years on celecoxib and 2 years of observation) showed the rate of advanced adenomas was reduced by 41% in patients receiving the lower celecoxib dose (200mg) and 26% among those who took the higher celecoxib dose (400mg)

    At 33 months

    • Celecoxib was stopped when the APC study found 2 to 3 times increase in serious adverse cardiovascular events
    • A similar study conducted in Israel, Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP), reported data at the time of the APC announcement indicating a hazard ratio of 1.2 for those taking celecoxib compared with placebo for death from cardiovascular events and nonfatal heart attack or stroke. (Arber N. et al, AACR Abstract CP-3)
    • Three years of celecoxib was associated with a "small but significant" increase in cardiovascular risk, according to the APC investigators

    The overall rate of cardiovascular events reported in the APC trials was:

    • 3.8% in the placebo group
    • 6% in the low-dose (200mg) celecoxib group
    • 7.5% in the high-dose (400 mg) celecoxib group

    For patients with no cardiovascular risk factors before initiating celecoxib, the rate of cardiovascular events was lower:

    • 0.9% in the placebo group
    • 3.9% in the low-dose celecoxib group
    • 1.9% in the high-dose celecoxib group

    For patients with one cardiovascular risk factor at study entry, the rate of cardiovascular events was:

    • 2.2% in the placebo group
    • 3.7% with low-dose celecoxib
    • 4.9% with high-dose celecoxib

    For patients with two or more cardiovascular risk factors at the outset, the overall risk of having cardiovascular events was:

    • 5.9% in the placebo group
    • 8.2% in the low-dose celecoxib group
    • 11.2% in the high-dose celecoxib group

    Dr. Bertagnolli noted that 84% of patients in the APC study had at least one risk factor for cardiovascular disease, because at the time the study was designed, the cardiotoxicity of COX-2 inhibitors had not been recognized, so no exclusion criteria were included for cardiac risk.

    In summary, the study confirms a high level of efficacy of celecoxib for CRC chemoprevention but further stated that celecoxib should not be used in patients with any cardiovascular risk factors. The new data allow investigators to carefully select patients who can benefit from celecoxib.

    A summary of the Betragnolli and Arber AACR abstracts presented in 2006 can be found here http://www.aacr.org/home/public--media/news-releases/news-archives-2006.aspx?d=845 Arber, et al published their results in the New England Journal of Medicine. The abstract can be found here http://content.nejm.org/cgi/content/abstract/355/9/885

    Dr. Betragnolli’s follow-up data presented in 2008 can be found here http://www.aacr.org/home/scientists/meetings--workshops/annual-meeting-2008.aspx Click on On-line Proceedings, Advance Search and Abstract # LB-141.

    Rule

    4-15-08 – K-ras: A Biomarker for Treating Metastatic Colorectal Cancer (mCRC)

    Identifying biomarkers for treating CRC continues to evolve. The intent of biomarkers is either to

    • Prognosticate if a patient is likely to respond to treatment, or
    • Predict if a patient is likely to benefit from a specific intervention

    A recent scientific discovery in CRC is the relationship of the proto-oncogene* K-ras, and sensitivity to epidermal growth factor receptor (EGFR) inhibitors in metastatic disease. Two current monoclonal antibodies (mAb) that inhibit EGFR are approved by the US Food and Drug Administration (FDA) for treatment of CRC. Cetuximab, approved in 2004, is a chimeric mAb (mouse and human) and panitumumab, approved in 2006, is a fully-human mAb.

    These drugs were initially indicated for patients whose tumors over expressed EGFR suggesting a correlation between EGFR expression and response. It is now known that there is no correlation between the degree of EGFR expression and clinical response to anti-EGFR therapy.1

    Researchers began to investigate other predictive and prognostic variables of anti-EGFR agents. It was known that binding at the EGFR should halt activation of downstream pathways, preventing signals to stop apoptosis and promote cellular proliferation. Based on the hypothesis that presence of a mutation in the K-ras oncogene may be associated with resistance to anti-EGFR agents, researchers moved forward.

    Pivotal data on K-ras were presented at the 2007 European CanCer Organisation (ECCO) by Amado and colleagues.2 These data represent the largest population of patients in whom
    K-ras was studied as a predictive marker for anti-EGFR therapy. Tumor samples were analyzed from patients treated with panitumumab vs best supportive care (BSC) to identify mutant or wild-type (naturally occurring gene) K-ras.

          Mutant K-ras

    • Of 427 patients evaluated, 184 had a K-ras mutation (43%)
    • Median progression-free survival (PFS) was 7.4 weeks in the panitumumab arm vs 7.3 weeks for the BSC arm
    • No patients with mutant K-ras responded to panitumumab therapy

          Wild-type K-ras

    • 17% had a partial response to panitumumab
    • Median PFS for the panitumumab arm was 12.3 weeks vs 7.3 weeks for BSC
    • Patients treated with panitumumab, had a median overall survival of 8.1 months vs 4.9 months in those with mutant K-ras.3

    Researchers are now retrospectively evaluating data from completed combination therapy trials. Based on the available data in single agent panitumumab treatment, K-ras status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

    *proto-oncogene— proto meaning first or original that could become an oncogene. oncogene—a gene in the DNA that causes normal cells to develop cancer either by mutation or expression at the wrong time in development.

    References

    1. Abbruzzese, JL. K-Ras and sensitivity to EGFR inhibitors in metastatic colorectal cancer. Clin Adv Hematol Oncol. 2008;6:174-175.
    2. Amado RG, Wolf M, Peeters M, et al. Wild-type K-Ras is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. A link to the abstract is available at http://jco.ascopubs.org/cgi/content/abstract/26/10/1626 Full text is limited to subscribers.
    3. Amado RG, Wolf M, Freeman D, et al. Panitumumab (pmab) efficacy and patient –reported outcomes (PRO) in metastatic colorectal cancer (mCRC) patients with wild-type (WT) KRAS tumor status. Abstract No: 278. ASCO Gastrointestinal Cancers Symposium. Retrieved on April 4, 2008 here.

    Rule

    2008 ASCO Gastrointestinal Cancers Symposium

    Go-Ahead Given To Resume Calcium and Magnesium For Neurotoxicity Associated With Oxaliplatin

    CONcePT (Combined Oxaliplatin Neurotoxicity Prevention Trial) was a randomized study comparing conventional vs intermittent schedules of FOLFOX with bevacizumab in patients with advanced colorectal cancer. There was a secondary randomization for calcium and magnesium infusions or placebo for neurotoxicity associated with oxaliplatin.

    After an unplanned interim analysis, a warning was issued in the spring of 2007 that a preliminary finding suggests that calcium and magnesium infusions may be associated with a reduced response rate to FOLFOX in those patients receiving the treatment, which led to the closing of the trial.1 (see http://www.managecrc.com/html/breaking-news-fda-ct.asp 6/25/07)

    Hochster et al1 recommended at that time that clinicians consider the perceived benefit of calcium/magnesium treatments against the possible reduction of the efficacy of therapy. Further analysis was expected and in January, 2008, an update of the study data was presented at the ASCO Gastrointestinal Cancers Symposium.2,3

    Dr. Hochster reported

    • The independent data monitoring committee “got it wrong.”
    • A new analysis showed that based on the central radiology review, the response rate favored the addition of calcium and magnesium, but was not statistically significant.3
    • He planned to treat patients with calcium and magnesium to reduce the neurotoxicity associated with oxaliplatin.
    • Dr. Charles Blanke, another discussant, agreed with Dr. Hochster’s report, however, he felt that the calcium and magnesium should not be used in clinical trials because its efficacy in the reduction of neurotoxicity has not been proven.

    The above conclusions have not yet been reviewed or published in a peer-reviewed publication, and should be considered preliminary at this point in time.3 More data will be presented at the annual ASCO meeting in June, 2008.

    Addendum: Correspondence regarding the study and emphasis on following the research protocol of infusing calcium and magnesium sequentially and not concurrently is found in JCO Mar 1 2008: 1188–1189. Available at: http://jco.ascopubs.org/current.shtml#CORRESPONDENCE

    References

    1. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007;25:4028-4029.
    2. Hochster HS, Grothey A, Shpilsky A, Childs BH. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on response to FOLFOX+bevacizumab (BEV) in the CONcePT trial. Presented at the ASCO Gastrointestinal Cancers Symposium; January 28-29, 2008; Orlando, FL. Abstract 280. Available here. Accessed February 20, 2008.
    3. Peck P. ASCO GI: Green light re-issued for neurotoxicity-limiting ploy for oxaliplatin in colon cancer. MedPage Today, January 28, 2008. Available at: http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/8122. Accessed February 20, 2008.

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    Poster Presentations ASCO 2006

    Treating mCRC: Oxaliplatin, Capecitabine, and Bevacizumab

    Capecitabine, which bypasses the need for an infusion pump, provides a convenient alternative for delivering fluoropyrimidine treatment. Bendell et al evaluated the combination of capecitabine, oxaliplatin, and bevacizumab (CapOX-BV) for activity in patients with untreated metastatic CRC (mCRC). The capecitabine dose, originally 1,000 mg/m2, was decreased to 850 mg/m2 because of excessive toxicity. Common grade 3 toxicities for all patients included diarrhea (24%), neuropathy (14%), and nausea or vomiting (10%); no grade 4 events occurred. Antitumor activity was evident in 2% of patients with complete responses, 51% with partial responses, and 43% with stable disease. Median progression-free survival was 10.7 months, comparable to results of similar studies. CapOX-BV is effective and generally well tolerated in mCRC patients.

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    Preliminary Results of First BEAT Study: Treatment With Bevacizumab in First-Line mCRC

    Michael et al analyzed the First BEAT trial to determine the feasibility of metastasectomy after treatment with bevacizumab and chemotherapy. The First BEAT study was designed to evaluate bevacizumab’s safety in combination with various chemotherapy regimens. Of 43 patients (2.4%) who underwent metastasectomy after receiving treatment for mCRC, 60% had received oxaliplatin-based chemotherapy, 37% irinotecan-based chemotherapy, and 2% fluorouracil monotherapy. By design, bevacizumab was stopped 6 to 8 weeks before surgery and resumed 28 days after surgery. In 67% of patients, no complications were seen following metastasectomy; the most common complication, operative site infection (12%), was unrelated to bevacizumab. When bevacizumab is stopped 6 to 8 before surgery, metastasectomy is safe and effective for patients receiving chemotherapy in combination with that agent.

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    Cost Variations in Treating CRC

    Ferro et al examined the variation in chemotherapy costs for CRC patients, finding that newer agents (oxaliplatin and irinotecan), as well as supportive drugs, substantially increased the cost of treatment, especially in late-stage disease. The variation in per-patient cost was as high as $36,799; excluding treatment with fluorouracil plus leucovorin for early disease, the cost differential was as high as $26,434. However, further research is necessary to establish whether increased cost provides increased clinical benefit.

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    BRiTE Results: Safety of Bevacizumab Plus Chemotherapy in Treating Patients With mCRC

    The BRiTE (Bevacizumab Regimens Investigation of Treatment Effects and Safety) observational study, following about 2,000 patients for 3 years, tracks the safety and efficacy of bevacizumab in combination with first-line metastatic CRC chemotherapy. Hedrick et al concluded that the incidence of selected serious adverse events linked to bevacizumab use in the BRiTE population was comparable to that in the pivotal phase 3 study leading to FDA approval. Only 1.5% of patients permanently discontinued bevacizumab because of toxicity. The incidence of hypertension (HTN) requiring medication was 16.4% (similar to the 11.0% reported in phase 3), and the majority of cases were manageable, with patients requiring 2 or fewer changes to their antihypertensive regimen. Additionally, bevacizumab–associated HTN was not dependent on preexisting HTN. Follow-up of patients continues.

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    Meta-Analysis: Adjuvant Treatment Following Curative Resection of mCRC

    Mitry et al conducted a pooled analysis of results of previous studies assessing whether adjuvant chemotherapy could improve survival and reduce recurrence in patients undergoing surgical resection of CRC metastases with curative intent. Two phase 3 trials investigating similar regimens of bolus fluorouracil plus leucovorin (dosing differed slightly between these studies) for treatment of liver or lung metastases were included; both studies had closed early because of slow patient accrual. Although the numbers did not reach significance, adjuvant chemotherapy with bolus fluorouracil-based regimens showed improvement in median progression-free survival (P= .059) and overall survival (P = .125). Thus, adjuvant chemotherapy after resection of CRC metastases may be warranted.

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    Phase 2 Study of First–Line Treatment for mCRC: Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI)

    The efficacy and tolerability of FOLFIRI plus bevacizumab in the first-line treatment of mCRC were examined by Kopetz et al. Of 23 patients assessed for response to therapy, 17 had a partial response and 6 did not respond (74% response rate). Median progression-free survival (PFS) was 12.5 months, superior to the PFS reported for FOLFIRI alone (8.5 months) and irinotecan, fluorouracil, and leucovorin plus bevacizumab (IFL + BV) (10.6 months). The median time to response was 4 months, indicating late response to treatment. The most common adverse event was neutropenia (12 patients, grade 3; 2 patients, grade 4); other events possibly related to bevacizumab therapy included hypertension, gastrointestinal perforation, bleeding, and proteinuria. The rate of adverse events was similar to the rate reported for IFL + BV, yet only 5% of patients in this study required hospitalization, compared with 45% of patients in the previous study. The addition of bevacizumab to FOLFIRI is well tolerated and efficacious in the first-line treatment of mCRC.

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    Preliminary Data: Dose-Escalation Study of Skin Reactions in Patients Receiving Cetuximab for mCRC

    Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, was studied by Tejpar et al in EGFR-expressing patients with metastatic CRC (mCRC) failing irinotecan monotherapy. Because skin reaction seems to correlate with response to cetuximab, patients with no or only slight skin reactions were randomized to either the standard cetuximab treatment (250 mg/m2 per week; arm A) or a dose-escalation arm (50-mg/m2 step increases to 500 mg/m2, toxicity, or tumor response; arm B). In the dose-escalation arm, 55% of patients tolerated the 500-mg/m2 maximum dose. Common grade 3/4 adverse events were diarrhea (18%) and fatigue (16%) and were present in both arms. No grade 3/4 skin reactions occurred in arm A; 7% of patients in arm B reported skin reactions, most commonly acnelike rash. Including all grades, skin reactions were slightly higher in arm B. Forthcoming data on efficacy and pharmacodynamic analysis will clarify the usefulness of cetuximab in the treatment of mCRC.

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    Selected abstracts from oral presentations at ASCO 2006 are available through the ASCO Web site at www.asco.org. All GI (colorectal) abstracts can be accessed there.

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    OPTIMOX2: Maintenance LV5FU Versus Chemotherapy Stop

    Maindrault-Goebel et al. reported results of the OPTIMOX2 study, designed to compare maintenance chemotherapy with LV5FU versus a complete stop of chemotherapy after 6 cycles of FOLFOX7 treatment in patients with metastatic colorectal cancer. Overall, maintenance LV5FU prolonged progression-free survival (PFS; 36 vs 28 weeks; P = .01). PFS was significant in responders (41 vs 30 weeks; P = .001) but not in stable patients (34 vs 26 weeks; P = .23). There was a small but not significant increase in the duration of disease control (41 vs 36 weeks; P = .17) in patients receiving maintenance therapy. Therefore, the survival advantage may be outweighed by the improvement in quality of life (25 weeks, median chemotherapy-free interval) for patients in these circumstances.

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    Efficacy of Xaliproden for FOLFOX4-Induced Peripheral Sensory Neuropathy

    Patients given oxaliplatin-based therapy often develop peripheral sensory neuropathy (PSN). Cassidy et al reported that xaliproden, an orally active agent with neuroprotective abilities, could reduce the risk of grade 3 PSN by 39% in patients receiving the FOLFOX4 regimen for first-line treatment of metastatic CRC. However, xaliproden did not aid recovery from grades 2 and 3 PSN. The addition of xaliproden did not affect FOLFOX4 antitumor activity. Xaliproden may aid some patients’ ability to tolerate oxaliplatin-based therapy.

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    Cetuximab Increases Rate of Response to FOLFOX and FOLFIRI

    Venook et al. examined the effects of adding cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), to either FOLFOX or FOLFIRI regimens for first-line metastatic colorectal cancer (mCRC) treatment. Preliminary data indicate similar efficacies for FOLFOX and FOLFIRI regimens, but the addition of cetuximab increased the rate of response to either treatment without additional toxicity. Inadequate data on EGFR status in tumors prevented conclusions about the receptors feasibility as a predictor of response to treatment. The analysis of critical endpoints, such as progression-free survival, duration of response, and overall survival, was not reported. Results of planned follow-up studies will determine whether cetuximab will be incorporated into first-line treatment of mCRC.

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    TREE Study: Safety and Efficacy of 3 Oxaliplatin/Fluoropyrimidine Regimens With or Without Bevacizumab

    Because bevacizumab combined with 5-FU-based chemotherapy increases survival in patients with metastatic CRC, Hochster et al. assessed safety, tolerability, and efficacy of bevacizumab in combination with oxaliplatin-based chemotherapeutic regimens. The 3 regimens examined—FOLFOX, bolus FOL, and CAPOX—all appeared tolerable and effective. Adding bevacizumab increased the incidence of grade 3/4 hypertension, impaired wound healing, and bowel perforation. In all regimens, the bevacizumab addition conferred an advantage in overall response rate, time to progression, and probability of survival at 18 months. The addition of bevacizumab to oxaliplatin-based therapy appears promising for patients with metastatic CRC.

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    Safety and Efficacy of FOLFOX4 in Elderly Versus Younger Patients

    Sargent et al. conducted a retrospective analysis to compare safety and efficacy of the FOLFOX4 regimens in elderly (≥ 70) versus younger (< 70) patients receiving FOLFOX4 in various settings (adjuvant therapy, first- or second-line therapy in advanced disease). Advanced age was associated with a significantly higher rate of neutropenia and thrombocytopenia, but no other grade 3/4 events. No difference was observed in any measurement of therapeutic value: progression-free survival, overall survival, response rate, or dose intensity. Thus, age should not limit the use of FOLFOX4 in elderly patients.

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    Efficacy of Bevacizumab Plus Chemotherapy in mCRC: Updated BRiTE Results

    The BRiTE registry collects safety and efficacy information in unselected with metastatic CRC (mCRC) patients who are receiving bevacizumab plus first-line chemotherapy. In an interim analysis, Kozloff et al. report that median progression-free survival (PFS; 11.3 months) in their study compares favorably to that in the trial leading to FDA approval. The BRiTE patient population largely reflects the demographics of mCRC patients in bevacizumab trials, with some differences in baseline patient characteristics. Bevacizumab increased median PFS, independent of the type of selected chemotherapy (ie, oxaliplatin- or irinotecan-based). This community-based observational registry will continue to track about 2,000 patients for 3 years.

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    Neurotoxicity With FULV Versus FLOX: NSAB Protocol C-07

    In patients with stage II or III colon cancer, FLOX gives a significant increase in 3- year disease-free survival over FULV (76.5% vs 71.6%, P = .004). Land et al. compared patient-reported neurotoxicity between the 2 groups, using the Functional Assessment of Cancer Therapy–Gynecologica Oncology Group (FACT/GOG) Oxaliplatin-Specific Neurotoxicity Scale (NTX-12). Neurotoxicity was higher in the FLOX arm during the study period (P < .0001) and at 18 months (P = .009). Specifically, FLOX patients had significantly increased hand-foot neuropathy (including foot and hand numbness or tingling and pain in response to cold, and hand discomfort) and overall weakness, although they had significantly less trouble hearing than did patients in the FULV arm during chemotherapy. At 18 months, hand neurotoxicity resolved, but foot discomfort persisted and patients experienced ringing in the ears. Patients should weigh the survival advantage of FLOX against the increased neurotoxicity of this treatment.

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    Safety of XELOX Versus Bolus 5FU/LV

    Final safety evaluation of XELOX (a modified CAPOX regimen) compared with bolus 5FU/LV as adjuvant therapy for patients with stage III colon cancer was presented by Schmoll et al. Hematologic safety findings were similar between regimens; relative to 5FU/LV, XELOX reduced neutropenia, likely leading to the observed decrease in grade 3/4 febrile neutropenia, but it increased thrombocytopenia. XELOX led to increased neurosensory toxicity and hand-foot syndrome, similar to results with other common regimens utilizing oxaliplatin. 5FU/LV increased the incidence of stomatitis. The decision to incorporate XELOX into treatment awaits efficacy data scheduled to be available in 2007.

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