FDA Activities/Clinical Trials
7-11-08 – Oxaliplatin Gives a Small 5-year Survival Advantage
Findings from the large, randomized National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial were reported at the Annual Meeting of the American Society of Clinical Oncology (ASCO) in June. Norman Wolmark, M.D. and colleagues presented information suggesting that oxaliplatin should be part of a standard chemotherapy regimen for stage II or III colon cancer. Adding oxaliplatin may provide a small five-year survival advantage, according to C-07 researchers.
The NSABP C-07 trial included 2409 patients with stage II or III colon cancer who were randomized to three 8-week cycles of 500 mg/m2 of fluorouracil(FU) bolus and 500 mg/m2 of leucovorin weekly with or without the addition of 85 mg/m2 of IV oxaliplatin
Outcome
- Together with 5-FU and leucovorin, oxaliplatin improved the relative odds of disease-free survival (DFS) by 19% at five years, with a trend for improved overall survival (OS) (P=0.06)
- With oxaliplatin, the absolute DFS at five years was 69.4% versus 64.2% without it
Endpoints
- Primary endpoint of DFS at three years showed a significant 4.6% absolute benefit from the addition of oxaliplatin (76.1% versus 71.5%)
- Secondary endpoint of DFS at five years showed a larger 5.2% absolute advantage with oxaliplatin over standard therapy (69.4% versus 64.2%, hazard ratio 0.81, P=0.002)
- All the subgroup analyses showed at least a trend for better DFS
For OS, the findings showed a similar pattern of increasing benefit over time but still did not reach statistical significance. The difference between chemotherapy with oxaliplatin and without was
- 2.0% at five years (80.3% versus 78.3%, HR 0.85, P=0.06)
- 4.2% at six years (77.7% versus 73.5%)
- Longer follow-up is likely needed to find a significant benefit for OS
Conclusions
The trial left unanswered questions about how best to manage stage II colon cancer patients, who in a subgroup analysis appeared to benefit less from the addition of oxaliplatin, and why survival after recurrence appeared lower with oxaliplatin despite better OS. Dr. Wolmark cautioned that while some have claimed there is no benefit for stage II patients, there is danger in misinterpreting unplanned subgroup analyses and the wide confidence intervals argued against a real disadvantage.
Reference
Wolmark N, et al. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07. ASCO Annual Meeting 2008; Abstract LBA4005. Available online here
06-10-08 – Fluoropyrimidine Tolerability Differences Among Regions
Haller and colleagues recently published results of a retrospective analysis of three randomized single-agent fluoropyrimidine clinical trials to explore the hypothesis that there are regional tolerability differences. This was prompted by the controversy surrounding tolerability of labeled-doses of capecitabine in Europe and the concerns that labeled dosing in the United States (US) is too high. Additionally, there were observations that patients receiving adjuvant bolus flurouracil have shown regional tolerability differences.
The investigators analyzed two identical phase III trials (S014796 and S014695) of patients with metastatic colorectal cancer (mCRC). Patients (n = 1,189) were randomized to capecitabine (Xeloda®) or 5FU/LV. A third phase III adjuvant trial (NO16968) analyzed stage III patients (n = 1,864) randomized to either capecitabine + oxaliplatin (XELOX) or 5FU/LV. The US was compared to non-US in all three studies. The US was compared to the rest of the world (RoW) and East Asia in the adjuvant study.
In the mCRC studies of treatment parameters of US patients vs non-US patients the relative risk (RR) at a 95% confidence interval (CI) was
- Grade 3/4 adverse events (AEs) –1.77 (1.35-2.31)
- Dose reduction –1.72 (1.32 - 2.25)
- Discontinuation –1.83 (1.27 - 2.65)
In the adjuvant study more grade 3/4 AEs and discontinuations were reported in US patients vs non-US patients. Further subdivision of non-US patients into East Asian and RoW, show lower RR of grade 3/4 and serious AEs with East Asians and higher RR in the US. The following table shows the different rates of treatment-related adverse events.
Treatment-Related Adverse Events in Adjuvant Colon Cancer Study:
US vs. RoW and East Asia
Potential factors influencing these differences include:
- Method of reporting in clinical trials
- Baseline prognostic and predictive factors
- Dietary intake of folate
- Effect of culture on drug adherence/persistence
- Genetic polymorphisms affecting drug metabolism
The authors conclude that individual dosing for different regions cannot be made. Data support differences in regional tolerability profiles suggesting further phase 1 and 2 drug development.
Reference:
Haller, DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol. 2008;26;2118- 2123.
5-16-08 – No Benefit with Use of Cisplatin in Treatment for Anal Cancer
A paper published by Ajani and colleagues in the April 23, 2008 issue of the Journal of the American Medical Association (JAMA) reports results of the US Gastrointestinal Intergroup trial RTOG 98-11. This multicenter, phase 3, randomized controlled trial compared the standard treatment of 5-FU, mitomycin and radiation vs treatment with 5-FU, cisplatin and radiation for anal cancer. Researchers found that the addition of cisplatin to 5-FU and radiation may not improve outcomes for patients with anal cancer.
The standard therapy for anal cancer is 5-FU, mitomycin, and radiation with a 5-year survival rate of 65% following standard treatment. Ajani and colleagues sought to determine if the addition of cisplatin to 5-FU and radiotherapy could improve outcomes of patients with anal cancer.
Study Design
- 682 patients diagnosed with anal cancer between 1998 and 2005
- Categorized according to gender and tumor features
- Received either standard care of 5-FU, mitomycin and radiation, or 5-FU, cisplatin and radiation.
- Goals of the study: measure 5-year survival rates, overall survival and time to relapse
- Results were evaluated from 644 (95%) patients
- Average patient age–55 years
- 444 (69%) women
- 174 (27%) had tumors greater than 5cm
- 168 (26%) had positive lymph node involvement
Results
- The 5-year disease-free survival rate was
- 60% (95% confidence interval [CI], 53%-67%) in the mitomycin-based group
- 54% (95% CI, 46%-60%) in the cisplatin-based group (P = .17)
- The 5-year overall survival rate was
- 75% (95% CI, 67%-81%) in the mitomycin-based group
- 70% (95% CI, 63%-76%) in the cisplatin-based group (P = .10)
- The 5-year local-regional recurrence and distant metastasis rates were
- 25% (95% CI, 20%-30%) and 15% (95% CI, 10%-20%), respectively, for mitomycin-based treatment
- 33% (95% CI, 27%-40%) and 19% (95% CI, 14%-24%), respectively, for cisplatin-based treatment
- The cumulative rate of colostomy was significantly better for mitomycin-based than cisplatin-based treatment (10% vs 19%; (P = .02)
- Severe hematologic toxicity was worse with mitomycin-based treatment (P < .001)
Researchers concluded that cisplatin-based therapy failed to improve DFS and contributed to significantly higher colostomy rates. These findings do not support the use of cisplatin in place of mitomycin in the treatment of anal cancer.
Reference:
Ajani J, Winter K, Gunderson L, et al. Fluorouracil, mitomycin and radiotherapy vs. fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal. JAMA. 2008;299:1914-1921. Full text is available to subscribers.
5-6-08 - Relistor Approved to Treat Opioid-Induced Constipation
Relistor (methylnaltrexone bromide) was approved by the US Food & Drug Administration (FDA) on April 24, 2008 to help restore bowel function in patients with late-stage, advanced illness who are receiving opioids on a continuous basis to help alleviate their pain. Such patients include those with a diagnosis of incurable cancer and other advanced illnesses. Opioids can interfere with normal bowel elimination function by relaxing the intestinal smooth muscles and preventing them from functioning. Relistor acts by blocking opioid entrance into the cells thus allowing the bowels to continue to function normally and is administered by subcutaneous injection Further information on the FDA approval of Relistor can be found at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01826.html. Full prescribing information and healthcare provider information can be found at http://www.wyeth.com/hcp/relistor/landing. Relistor will be available commercially beginning in June 2008.
3-12-08 – Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption
Epidermal growth factor receptor (EGFR) inhibitor therapy has become an integral part of metastatic colorectal cancer (mCRC) treatment. Oncology nurses have utilized anecdotal strategies to manage the inflammation, discomfort, and/or pain that are hallmarks of the EGFR inhibitor therapy macular-papular rash. The results of a randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption by Scope & colleagues1 are important in the care of those patients with EGFR-inhibitor associated rash.
Minocycline
Scope et al1 randomized 48 eligible patients to receive either minocycline (100 mg/d) or placebo starting on the first day of cetuximab and continued for eight weeks. Minocycline is a member of the tetracycline class of antibiotics, which has a role as an anti-inflammatory agent for many different diseases; minocycline seems to have a more potent anti-inflammatory effect versus first-generation tetracyclines.1
Patients had facial photographs taken at week 4, which were reviewed for global rash severity. The results of the trial showed:
- Total facial lesion counts were significantly lower in patients receiving minocycline at week 1 through week 4.
- A lower proportion of patients receiving minocycline reported moderate to severe itch at week 4 versus the patients receiving placebo (20% versus 50%).
- Patients receiving minocycline also showed a smaller number of moderate to severe rashes versus the placebo patients (20% versus 42%).
Patients with grade 3 skin rash are recommended to stop therapy until improvement of symptoms while receiving cetuximab. In this trial, none of the patients on minocycline interrupted therapy versus four patients who interrupted therapy while on placebo.
Tazarotene
A second agent, topical tazarotene (0.05%), was applied to either the left or right side of the face for this trial. This therapy was associated with considerable irritation of the skin, which caused 1/3 of the patients to stop tazarotene treatment. The researchers concluded that topical tazarotene is not recommended for the management of rash related to administration of cetuximab. Based on the positive results with minocycline, the authors of the study reported that oral minocycline may be helpful in decreasing the severity of rash associated with cetuximab during the first month of therapy. The study results confirm the role of minocycline in the treatment algorithm as detailed by Lynch & colleagues.2
Reference:
Scope A, Agero ALC, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;34:5390-5396.
11-12-07 – Detecting Advanced Neoplasia:Traditional Colonoscopy or Computed Tomographic Colonography (CTC)?
An article recently published in the New England Journal of Medicine reported that virtual colonoscopy, referred to as computed tomographic colonography (CTC), is an effective initial screening measure for the detection of CRC. Traditional endoscopic or optical colonoscopy (OC) has been the gold standard of screening for CRC for many years. Many patients view traditional colonoscopy as invasive and potentially uncomfortable, resulting in a low compliance rate. Researchers are hopeful the use of a less invasive procedure will increase CRC screening compliance.
Researchers from the University of Wisconsin recently conducted a phase III, randomized, prospective clinical trial to compare traditional colonoscopy to CTC for the detection of CRC. This trial included approximately 3,300 adults with an average age of 57 years. Patients underwent either initial screening with CTC or initial screening with traditional colonoscopy. Patients initially screened with CTC in whom polyps at least 6mm in size were detected were offered a polypectomy with traditional colonoscopy. As well, patients with one or two polyps between 6mm and 9mm were offered the option of CTC surveillance (repeated scans at specified intervals to detect growth).
- Among patients initially receiving CTC, nearly 8% were referred to undergo a subsequent traditional or optical colonoscopy (OC)
- Advanced neoplasia (abnormal cellular growth often considered precancerous) was detected in 3.2% of patients who underwent an initial CTC and 3.4% of patients who underwent an initial traditional colonoscopy
- 25% of the polyps were removed among patients who underwent a CTC compared with those who underwent an initial OC
The researchers concluded that primary CTC and OC screening strategies resulted in similar detection rates for advanced neoplasia, although the numbers of polypectomies and complications were considerably smaller in the CTC group. They further stated, "These findings support the use of CTC as a primary screening test before therapeutic traditional colonoscopy. Individuals may wish to speak with their healthcare provider about screening schedules for CRC."
Reference:
Kim D, Pickhardt P, Taylor A, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med. 2007;357:1403-1412.
10-10-07 – ALERT - New labeling for Cetuximab (Erbitux®)
New labeling was approved for cetuximab in response to data showing activity as a monotherapy in epidermal growth factor (EGFR) inhibitor-expression in patients with metastatic colorectal cancer (mCRC) after failing both irinotecan- and oxaliplatin-based regimens.
The previous indication for cetuximab was for patients with mCRC in combination with the chemotherapy drug irinotecan after progression of tumor following treatment with irinotecan, or as a single agent in patients who are unable to tolerate chemotherapy treatment with irinotecan.
The new label reflects updated data showing prolonged overall survival data from a randomized, multicenter Phase III trial in which 572 EGFR-positive mCRC patients (after failure of irinotecan- and oxaliplatin-based regimens) received cetuximab plus best supportive care (BSC) compared with BSC alone, (defined as all approved palliative therapies that relieve pain and treat mCRC-related effects).
This new indication gives patients with mCRC another possible treatment option.
8-31-07 – Higher Intake of a Western Diet Pattern May Be Linked to Adverse Outcomes in Colon Cancer Patients
Numerous studies have demonstrated that diet and life style factors have an influence on the risk of developing colon cancer; however, their influence on the outcomes of patients with colon cancer has been unclear.
Research recently published in the August 15, 2007 issue of the Journal of the American Medical Association (JAMA) suggest that consumption of a Western diet was associated with a higher risk of colon cancer recurrence and death.
Dr. Jeffrey Meyerhardt and colleagues conducted a prospective observational study of 1,009 patients with stage III disease enrolled in a randomized adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB 89803]) from April 1999 through May 2001. Patients were asked to complete a semi-quantitative food questionnaire during, and 6 months after chemotherapy. By factor analysis, the researchers identified 2 major dietary patterns, the Western and prudent patterns.
- The prudent diet was characterized by high intakes of fruits, vegetables, whole grains, legumes, poultry, and fish
- The Western diet was characterized by intake of red and processed meats, desserts, French fries, high fat dairy products and refined grains
During a median follow up of 5.3 years for the overall cohort, findings included:
- 324 patients had cancer recurrence
- 223 patients died with recurrence
- 28 patients died without an apparent cause
- Patients in the highest quintile of adherence to the Western pattern were 3.25 times more likely to have colon cancer recurrence or death than those in the lowest quintile
- In contrast, there was no relationship seen for risk of recurrence or overall survival in those patients adhering to a prudent diet.
Additional characteristics reported:
- Higher prudent scores were detected in patients who were physically active, had lower body mass index 6 months after adjuvant therapy (second questionnaire) and less likely to currently smoke. Females tended to have a more prudent dietary pattern
- Higher Western scores were seen in men, whites and past or current smokers
The authors concluded that as this was an observational study, causality cannot and should not be drawn from the data. Further studies are needed to identify specific nutrients or food groupings that may show the strongest association.
Meyerhardt J, Niedzwiecki D, Hollis M, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007;298:754-764. Subscription required for the full text article.
A summary of the article can be found here: http://www.medpagetoday.com/HematologyOncology/ColonCancer/tb/6412
7-24-07 – Gefitinib and FOLFOX6: First Clinical Use Of Combination Therapy for Metastatic Colorectal Cancer (mCRC)
The first use of an oral inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase combined with simplified FOLFOX6 for patients with metastatic colorectal cancer mCRC was reported by Zampino and colleagues, ahead of print (June 26) in Cancer. Although the use of EGFR agents are now common in patients with mCRC, current therapy is monoclonal antibody agents (specifically cetuximab and panitumumab), requiring intravenous administration (IV).
Monoclonal antibodies
- Large molecule agents given IV
- Active in the extracellular region
- Prevent ligand binding and subsequent cell signaling activation
Tyrosine kinase inhibitors
- Small molecule agents given orally
- Active in the intracellular region
- Prevent phosphorylation and subsequent cell signaling activation
This phase 2 Italian study examined the use of gefitinib combined with the simplified (modified) FOLFOX6 regimen in 56 patients with mCRC. The simplified FOLFOX6 IV regimen was given on day 1 and repeated 14 days later
- Oxaliplatin 100 mg/m2 over 2 hours, day 1
- Leucovorin 200 mg/m2 over 2 hours, day 1
- 5-FU 400 mg/m2 bolus, day 1, followed by 5-FU infusion over 46 hours 2400 mg/m2
Gefitinib 250mg/d was given on day 1 and continued throughout the course of therapy.
All patients had cancers that showed overexpression of EGFR and had not been treated for metastatic disease. The majority of patients had Stage IV disease at diagnosis (69.6%), with 92.9% having liver disease and 46.4% with > 2 metastatic sites.
- 53 patients (95%) were evaluated for response using the RECIST (Response Evaluation Criteria in Solid Tumors) criteria
- 40 patients (71.4%) achieved a complete or partial response
- 11 patients (19.6%) had stable disease
- The most common toxicity noted was gastrointestinal, followed by
- Neurologic, associated with oxaliplatin administration
- Hematologic and fatigue
- Dermatologic, as expected with EGFR agents
The researchers concluded that the median time to progression was 7 months and the regimen was delivered with manageable toxicity as a first-line therapy.
Zampino MG, Magni E, Massacesi C, et al. First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first-line treatment for metastatic colorectal cancer. Cancer. 2007; June 26: [Epub ahead of print].
The abstract for this article is available here
6-25-07 – Sanofi-aventis issues the following ALERT – Preliminary Results of CONCEPT Trial
The CONCEPT Trial is a randomized trial comparing conventional versus intermittent schedules of FOLFOX, plus bevacizumab, administered to previously-untreated patients with advanced colorectal cancer. At initiation, the trial contained a secondary randomization to calcium and magnesium infusions or placebo as prophylaxis against neurological adverse events. After 140 patients had been enrolled, the trial was amended to administer calcium and magnesium infusions to all patients.
An unplanned interim analysis of data by the Data Management Committee (DMC) indicates that calcium/magnesium infusions, administered to reduce or prevent oxaliplatin-associated neurological adverse events in the CONCEPT study, may be associated with a reduced response rate to FOLFOX treatment in the pooled population of patients receiving either the conventional (FOLFOX4) or the intermittent (IO) schedule of oxaliplatin in combination with 5-FU/LV. Sanofi-aventis intends to promptly analyze the study data and to present the findings when the analysis is complete. In the meantime, based on the recommendations of the DMC, the trial has been closed.
Therefore, sanofi-aventis is taking a proactive stance to communicate this information as quickly as possible.
6-27-07 – Comparing Capecitabine + Oxaliplatin (CAPOX)(XELOX) With FU/LV + Oxaliplatin (FUFOX) As First-Line Therapy for Metastatic Colorectal Cancer (mCRC)
Final Results of 2 Trials: AIO Colorectal Study Group (German) and Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. Both trials were reported on-line ahead of print in the Journal of Clinical Oncology on June 4, 2007
Porschen and colleagues reported in the final results of the phase III randomized trial of the AIO Colorectal Study Group comparing
- Capecitabine (1000 mg/m2 BID given day 1 - 14) plus oxaliplatin (70 mg/m2 given day 1 and 8) repeated every 22 days (CAPOX), with
- Infusional 5-fluorouracil (2000 mg/m2 as a 22 hour infusion with leucovorin 500 mg/m2) and oxaliplatin (50 mg/m2) (FUFOX) given day 1, 8, 15, 22, repeated every 36 days.
Oral capecitabine is an oral fluorouracil pro-drug that has shown similar efficacy with reduced toxicity compared to bolus FU for patients with mCRC.
The study population included 474 patients with mCRC being treated in the first-line setting. The trial design was to determine
- Noninferiority for CAPOX (new treatment is equivalent to standard treatment)
- Primary end point was progression-free survival (PFS)
- Secondary end points of response rate (RR), overall survival (OS), time to treatment failure, and toxicity
The findings showed the
- Median PFS was 7.1 months in the CAPOX arms versus 8.0 months in the FUFOX arm
- Median OS of 16.8 months for CAPOX versus 18.8 months with FUFOX
- Overall RR were 48% for CAPOX and 54% for FUFOX
Although both arms were tolerated well, the CAPOX arm had a significantly higher incidence of grades 2/3 hand-foot syndrome.
The researchers concluded that the regimen of CAPOX had a slightly inferior efficacy than the use of FUFOX, with a significantly higher incidence of grade 2/3 HFS with CAPOX as well.
Subscription required for full text article. The abstract may be viewed at the following link: http://jco.ascopubs.org/cgi/content/abstract/JCO.2006.09.2684v1
The Spanish phase III randomized trial trial, led by Diaz-Rubio, et al., compared the efficacy and safety of capecitabine + oxaliplatin (XELOX) versus continuous-infusion high-dose 5-fluorouracil (5-FU) + oxaliplatin as first-line therapy for mCRC . The regimens used in this study were:
- XELOX 1000mg/m2 capecitabine BID for 14 days plus oxaliplatin 130mg/m2 on day 1 every 3 weeks; or
- FUOX continuous-infusion 5-FU 2250mg/m2 during 48 hours on days 1,8,15,22,29 and 36 plus oxaliplatin 85g/m2 on day 1, 15, and 29 every 6 weeks.
A total of 348 mCRC patients were treated in this study. There were no statistically significant differences between the two treatment groups. The safety profile of the two regimens was similar, although the XELOX arm showed
- Lower rates of grade 3/4 diarrhea and grade 1/2 stomatitis and
- Higher rates of grade 1/2 hyperbilirubinemia and grade 1/2 hand-foot syndrome
The investigators in this Spanish trial concluded that
- XELOX is an active and safe regimen for first-line treatment of mCRC
- XELOX was not inferior to a continuous infusion FUOX regimen
- Median time to progression in both arms of the study was consistent with that observed in other studies using approved oxaliplatin combination regimens in first-line treatment
- XELOX regimen offers advantages over infusional therapy in terms of simplicity and convenience, reducing patient travel and clinic or hospitalization time.
The abstract is available at http://jco.ascopubs.org/cgi/content/abstract/JCO.2006.09.8467v1
5-31-07 – FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images
So many cancer patients are evaluated using MRIs. The U.S. Food and Drug Administration (FDA) has asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents which are used to enhance the quality of magnetic resonance imaging (MRI). The following link is to the FDA Digest concerning a safety warning about the use of gadolinium contrast for MRIs.
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html
5-24-07 – Phase III Trial of Panitumumab vs Best Supportive Care
A phase III open-label trial of panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, vs best supportive care (BSC) showed significant improvement in progression-free survival (PFS) according to a report published in the May 1, 2007 issue of the Journal of Clinical Oncology.
The researchers chose BSC as the control group because none of the phase II trials of EGFR-inhibitor therapy included a BSC control group. BSC in both arms was defined as the best palliative care per investigator, excluding antineoplastic agents.
A total of 463 patients were enrolled and randomly assigned to the two arms. The study was not blinded due to the expected skin toxicity related to EGFR-inhibitors. Panitumumab was dosed at 6mg/kg every 2 weeks plus BSC.
Results
- A statistically significant improvement in PFS was observed favoring the panitutumab group (P<.0001)
- Median and mean PFS times, respectively
- 8.0 and 13.8 weeks for panitumumab
- 8.5 and 7.3 weeks for BSC
- In a subset analysis
- PFS for patients in the panitumumab group appeared to favor patients with a worst severity of grade 2-4 vs grade 1skin toxicity, a finding that is consistent with previous reports of other EGFR-inhibitor studies
- Skin-related toxicity occurred in 90% of patients in the panitumumab group and 9% of patients in the BSC group
The abstract can be found at http://jco.ascopubs.org/cgi/content/abstract/25/13/1658
2-27-07 – FDA Alert: Use of Erythropoiesis-Stimulating Agents (ESA) in Cancer Patients Not Receiving Chemotherapy
An FDA alert was issued on February 16, 2007 by the Office of Oncology Drug Products regarding erythropoiesis-stimulating agents (ESA), specifically Aranesp (darbopoietin alfa, Amgen, Thousand Oaks CA). A recent study of Aranesp vs placebo in anemic cancer patients not currently receiving chemotherapy demonstrated a lack of efficacy as well as increased mortality in the patients receiving aranesp . The target hemoglobin in this study was 12g/dl. The FDA has previously noted increased mortality, possible tumor promotion and thromboembolic events in patients receiving ESA (including Aranesp, Procrit and Epogen) when the target hemoglobin level was >12g/dl. FDA is planning to review and discuss the safety and efficacy of ESA at an upcoming Oncology Drug Advisory Committee (ODAC) meeting. Additional information is available on the FDA website at http://www.fda.gov/cder/drug/infopage/rhe/default.htm
2-23-07 – Use of Complementary and Alternative Medicine (CAM) in Cancer Clinical Trials
Use of CAM is well documented in the general population. Use of CAM in cancer patients is reported as high as 83%. However, use of CAM among patients in cancer trials, especially Phase I trials, has not been examined. Phase 1 trials are designed to test drug toxicity and determine best dosages.
Dr. Christopher Daugherty and colleagues from the University of Chicago studied the use of CAM is patients with advanced cancer who are participating in Phase 1 clinical trials. 212 patients were surveyed regarding their use of biologically based CAM compounds. These include vitamins, minerals, herbal remedies, and diet according to the National Center for Complementary and Alternative Medicine.
Thirty-four percent (34%) or 72 patients reported using CAM. About 50% stated they used herbals drugs and about 50% said they used vitamins or minerals. The researchers found that some patients were taking high-dose vitamin C and St. John’s wort, which are known to interfere with chemotherapy drugs. See Drug Interactions.
Those enrolled in the study who reported using CAM believed they would die within one year. These users were found to have a lesser quality of life than non-users. Those reporting use of CAM were younger (average age of 55) than those who did not report using CAM (average age of 65).
The outcome of this study suggests that CAM use is more common than expected. It was associated with age, stated life expectancy based on diagnosis and quality of life. The results are reported in the February 10 issue of the Journal of Clinical Oncology, concluding that patients in early-phase trials should be questioned about their use of CAM.
10-17-06–Drug Warning - Bevacizumab
In September 2006, the Food and Drug Administration (FDA) added the following black box warnings to the prescribing information for Avastin (bevacizumab). Reversible posterior leukoencephalopathy (RPLS) syndrome has been reported to occur with the use of bevacizumab, and may be characterized by the appearance of lethargy, confusion or even visual loss. Prompt recognition of this syndrome is essential; once it occurs, the agent should not be restarted as the safety of this practice has not been established. Although rare, this syndrome is a brain-capillary leak condition related to hypertension, fluid retention and cytotoxic effects of certain agents, and has been linked with bevacizumab. Magnetic Resonance Imaging (MRI) is necessary to confirm the diagnosis of RPLS. Click here for more information regarding this warning.
Glusker P, et al. Reversible posterior leukoencephalopathy sydrome and bevacizumab. NEJM. 2006;354:980-981.
Ozcan C, et al. Reversible posterior leukoencephalopathy sydrome and bevacizumab. NEJM. 2006;354:981-982. http://content.nejm.org/cgi/content/extract/354/9/980
An additional new warning has been issued for nasal septum perforation, a condition occurring with bevacizumab patients as well. A small series of patients have been reported to have developed nasal septum perforation while receiving this agent. This condition does not require treatment modification, and is generally considered self-limiting; although patients should be encouraged to minimize manipulation of affected tissue. Click here for more information regarding this new warning.
Fakih M and Lombardo J. Bevacizumab-induced nasal septum perforation. The Oncologist. 2006;11:85-86. Available at: http://theoncologist.alphamedpress.org/cgi/reprint/11/1/85
10-16-06–Clinical Trial for Hand Foot Syndrome
NCCTG-N05C5: (North Central Cancer Treatment Group-National Cancer Institute) Phase III Randomized Study of Pyridoxine and Topical Urea in Preventing Palmar-Plantar Erythrodysesthesia in Patients Receiving Capecitabine for Colorectal and/or Breast Cancer.
This 4-arm randomized phase III trial is studying giving pyridoxine (Vitamin B6) together with topical urea to see how well they work compared with giving pyridoxine together with a placebo, giving topical urea together with a placebo, or giving two placebos in preventing hand-foot syndrome in patients who are receiving capecitabine for colorectal or breast cancer.
Objectives
- Compare the efficacy of pyridoxine and/or topical urea vs placebo in preventing PPE in patients receiving capecitabine for colorectal and/or breast cancer
- Compare the incidence/severity of PPE in patients treated with pyridoxine and/or topical urea vs placebo
- Evaluate the toxicity of pyridoxine and urea
Eligibility criteria and additional information about the study can be found on the NCI website. Click here.
9-28-06 – New Drug Approved for Metastatic Colorectal Cancer
Vectibix (panitumumab), a monoclonal antibody, for the treatment of patients with colorectal cancer that has metastasized following standard chemotherapy, received accelerated approval after showing effectiveness in slowing tumor growth and, in some cases, reducing the size of the tumor. The FDA states that “Under the accelerated approval program, drugs for serious and life-threatening diseases can be made available earlier in the development process if a promising effect of the drug is observed.” The manufacturer agreed to conduct a postmarketing trial to determine improvement in survival in patients with fewer prior chemotherapies.
The drug was approved following a randomized, controlled clinical trial of 463 patients with metastatic cancer of the colon and the rectum after undergoing treatment with chemotherapy drugs, fluoropyrimidine, oxaliplatin and irinotecan. The most common adverse events associated with the drug included skin rash, fatigue, abdominal pain, nausea, and diarrhea.
More details are available on the FDA Web site. Click here.
9-22-06 – 10,000 Volunteers –> 500+ Meetings with Member of Congress –> 300+ Signers of the Congressional Cancer Promise
Nearly 10,000 cancer patients, survivors and their families from every Congressional District in the country gathered today, Sept. 20, on the National Mall for Celebration on the Hill 2006, a unique grassroots event celebrating cancer survivorship and urging Congress to make cancer a national priority.
Read More...
9-20-06 – Featured Clinical Trial
The featured clinical trial in the September 19 issue of the NCI Cancer Bulletin is a Phase III Randomized Study of Cetuximab and/or Bevacizumab in Combination with Either FOLFOX or FOLFIRI in Patients with Previously Untreated Metastatic Adenocarcinoma of the Colon or Rectum (CALGB-C80405).
The bulletin can be accessed by clicking here. Click on Featured Clinical Trial in the left margin.
6-27-06 – 17,500 Participants Needed for CRC Clinical Trials
With the support of The Coalition of Cancer Cooperative Groups, experts from various oncology arenas identified ten trials as high priority colorectal clinical studies. Collectively, these ten studies require more than 17,500 participants.
Following is a list of priority colorectal cancer clinical trials beginning with screening and detection in healthy participants. The listings that follow are treatment trials for colorectal cancer patients. Click here to view the list.
6-20-06 – FDA Approves Avastin for 2nd-Line Treatment
On June 20, 2006, The US Food and Drug Administration (FDA) approved AvastinÆ (bevacizumab) in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy for second-line metastatic colorectal cancer. Avastin is also approved as a first-line treatment of metastatic colorectal cancer (CRC) in combination with intravenous 5-FU-based chemotherapy. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving Avastin plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.
For more information click here.
4-1-06 – Disclosing Study Outcomes to Participants May Backfire
This commentary, due to be published in April's issue of Cancer, suggests that while participants in clinical trials may be very interested in learning the trial outcomes, investigators may serve their patients best by providing participants only the study data that will directly benefit their future care. Pre-study education about how clinical trials work and how statistical models do not necessarily predict individual outcomes may also be helpful.
Source: Click Here
3-22-06 – Colonoscopy: More Gentle Prep Routine
Scripps Howard News Service reported on March 22 that the FDA approved a next-generation tablet to “make colonscopies simple for both the physician and the patient. It is an alternative for patients who cannot tolerate large volume preparations.” For more details, visit www.shns.com and type "colonoscopy" in the search field.
3-1-06 – Survey Suggests Three Out Of Four Americans Are Not Being Screened Regularly For Colon Cancer
Although it is recommended that people get screened for colon cancer starting at age 50, a Harris Interactive poll taken in February 2006 suggests that only 25% of people in that age group are having colonoscopies.
Source: Click Here
2-27-06 – Chemotherapy given directly to the liver improves survival for patients with colorectal cancer
A study of 135 patients who received their chemotherapy via hepatic arterial infusion (HAI)-- directly to the liver through a pump in the abdomen-- appear to have better outcomes and fewer side effects than those who received traditional, intravenous chemotherapy.
Source: Click Here
2-15-06 – Calcium and Vitamin D Supplements Offer Modest Bone Improvements, No Benefits for Colorectal Cancer
Calcium and vitamin D supplements in healthy, postmenopausal women provide a modest benefit in preserving bone mass and prevent hip fractures in certain groups, including older women, but do not prevent other types of fractures or colorectal cancer, according to the results of a major clinical trial, part of the Women's Health Initiative (WHI). While generally well tolerated, the supplements were associated with an increased risk of kidney stones.
The study results are published in the February 16 issue of The New England Journal of Medicine. The WHI is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health.
To read the full release, please go to http://www.nhlbi.nih.gov/new/press/06-02-15.htm.
2-7-06 – News from the Women's Health Initiative: Reducing Total Fat Intake May Have Small Effect on Risk of Breast Cancer, No Effect on Risk of Colorectal Cancer, Heart Disease, or Stroke
Following an eating pattern lower in total fat did not significantly reduce the incidence of breast cancer, heart disease, or stroke, and did not reduce the risk of colorectal cancer in healthy postmenopausal women, according to the latest clinical trial results from the National Institutes of Health's Women's Health Initiative (WHI).
The study was designed to evaluate a low-fat dietary pattern's effect on the risk of cancer. However, investigators also evaluated the data to review the effect on cardiovascular disease. The results from the largest ever clinical trial of low-fat diet are reported in three papers in the February 8 edition of the Journal of the American Medical Association.
To read the full release, please go to: http://www.nih.gov/news/pr/feb2006/nhlbi-07.htm.
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