In December 2009, the FDA completed its review of final data from the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial and interim data from the SHARP (Study of Heart and Renal Protection) and IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) studies and concluded that the cholesterol-lowering drugs simvastatin (Zocor), ezetimibe (Zetia), and Vytorin (ezetimibe/simvastatin) are not likely to increase cancer risk. In a statement, the FDA said a relationship between these agents and cancer cannot be ruled out, however, and it will continue to assess safety data from the SHARP and IMPROVE-IT trials, which are expected to conclude in 2010 and 2012, respectively.

In August 2008, the FDA warned of a possible association between simvastatin, ezetimibe, and Vytorin and an increased cancer risk based on preliminary data from the SEAS trial. The agency had not identified a causal relationship between the drugs and cancer risk, however, nor did it advise healthcare providers to stop prescribing them.

SEAS was a 4-year, double-blind trial that randomized 1873 patients with mild to moderate asymptomatic aortic stenosis to receive Vytorin (10 mg of ezetimibe and 40 mg of simvastatin) or placebo daily. The study’s primary endpoint was reduction in major cardiovascular events. Investigators observed an increased cancer incidence in the Vytorin cohort, with 105 cases (11.1%) reported compared with 70 (7.5%) in the placebo group (P = .01). The cancers observed in the Vytorin group were not clustered at any particular site. The Vytorin group also experienced an increased number of cancer deaths compared with the placebo group (39 vs 23, respectively).

The SHARP trial is an international, doubleblind, placebo-controlled study that randomized ~9400 patients with chronic kidney disease to Vytorin (10 mg ezetimibe and 20 mg simvastatin) or placebo. The study is seeking to determine whether Vytorin is associated with any major vascular complications in patients with chronic kidney disease.

The IMPROVE-IT trial, which is still accruing patients, is a multisite, randomized double blind trial enrolling up to 18,000 moderate- to high-risk patients with chronic coronary artery disease and acute coronary syndromes. Patients are receiving Vytorin (10 mg of ezetimibe and 40 mg of simvastatin) or 40 mg of simvastatin alone to determine whether adding ezetimibe improves cardiovascular outcomes.

The FDA weighed several factors in evaluating a possible relationship between use of simvastatin, ezetimibe, or Vytorin and cancer risk. The agency cited several reasons for concluding that such a relationship is unlikely, including the fact that most long-term clinical data on simvastatin have shown no increased risk of cancer. The FDA acknowledged that long-term clinical data on ezetimibe is insufficient to rule out an association between the drug and cancer but noted that preclinical animal studies found no increased cancer risk. In addition, longer use of Vytorin in the SEAS trial was not associated with an increased rate of cancer, which would be expected if it caused cancer or promoted the growth of pre-existing cancers. Finally, the cancers were not clustered at a particular point or of a specific type. A single carcinogenic drug rarely increases the risk of multiple cancer types, making a cancer association unlikely.

While analyses of interim cancer data from SHARP and IMPROVE-IT, which enrolled a cumulative 20,617 patients, found no increased risk of cancer with Vytorin, more cancer-related deaths were observed in treatment arms than in the control groups (97 vs 72, respectively). This finding, however, did not reach statistical significance. An assessment of all three trials showed no consistent pattern of increased cancer risk among patients treated with Vytorin. The SEAS trial was not designed to evaluate cancer risk, making the true statistical significance of the cancer imbalance observed in this trial unclear.

The FDA will continue to monitor cancer data from SHARP and IMPROVE-IT. In the meantime, the agency urges healthcare professionals and consumers to report adverse effects from the use of simvastatin, ezetimibe, or Vytorin to the FDA’s MedWatch Adverse Event Reporting program, which can be accessed online at www.fda.gov/safety/MedWatch/default.htm.

US Food and Drug Administration. Early Communication About an Ongoing Safety Review of Ezetimibe/ Simvastatin (marketed as Vytorin), Simvastatin (marketed as Zocor) and Ezetimibe (marketed as Zetia) - FDA Investigates a Report from the SEAS Trial (8/21/08). http://tinyurl.com/yedgfyu. Accessed January 6, 2010.

Articles

The FDA concludes that the cholesterol-lowering drugs simvastatin (Zocor),ezetimibe (Zetia), and Vytorin (ezetimibe/simvastatin)
are not likely to increase cancer risk.

FDA Says Simvastatin & Ezetimibe Unlikely to Cause Cancer

Patients with unresectable metastatic colorectal cancer who experience a chemotherapy-free interval (CFI) following first-line chemotherapy have shorter durations of disease control (DDC) and progression-free survival (PFS) compared with patients who begin maintenance therapy immediately, according to data from a French study. Conducted by Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR), the OPTIMOX (Optimized Leucovorin [LV]-Fluorouracil [FU]-Oxaliplatin) 2 trial is a follow-up to GERCOR OPTIMOX1. The OPTIMOX1 study demonstrated that discontinuing a FOLFOX7 regimen after 6 cycles and starting on a simplified maintenance regimen of LV plus bolus and infusional FU (LV5FU2) resulted in lower toxicity but was as effective as continuing FOLFOX4 until disease progression or unacceptable toxicity.

In OPTIMOX2, investigators enrolled 202 patients with colorectal cancer at 12 treatment centers in France between February 2004 and April 2006. Over ~3 months, all patients received induction chemotherapy with 6 cycles of a modified FOLFOX7 regimen that used a reduced dose of oxaliplatin and an increased dose of FU. Following chemotherapy, patients were randomized to receive maintenance therapy with the simplified LV5FU2 regimen (n = 98) or no treatment until evidence of disease progression (n = 104). In addition, patients in the LV arm who experienced progression on maintenance therapy could start second-line treatment.

In all, 24 patients experienced disease progression or death during the induction phase of the trial, 24 had salvage surgery of metastases, and 8 discontinued treatment, making them ineligible for the second phase of the trial. Only 63% (n = 62) of patients assigned to receive maintenance therapy with the simplified LV5FU2 regimen continued on to the investigational phase of the trial compared with 81% (n = 84) assigned to a CFI. Patients in the LV arm received maintenance therapy for a median of 4.8 months, and the median CFI lasted 3.9 months.

Patients were assessed at baseline, again after 4 and 6 cycles of treatment, and then every 2 months or every 4 cycles, with tumor response evaluated according to RECIST. The trial’s primary endpoint was median DDC, which was 13.1 months in the maintenance arm versus only 9.2 months in the CFI arm (P = .046). Patients who received maintenance therapy also had a longer median PFS, at 8.6 months compared with 6.6 months for those in the CFI arm (P = .0017). Median overall survival in the LV arm was 23.8 months compared with 19.5 months for the CFI arm (P = .42). The 2-year survival rate was also higher in the LV arm, at 50.0% versus 39.4% for the CFI group.

Following disease progression, 54 patients (81.8%) in the LV arm and 66 patients in the CFI arm (84.6%) were reintroduced to FOLFOX chemotherapy. Patients whose disease progressed on FOLFOX or those with limiting sensory neuropathy were not eligible for reintroduction. Reintroduction occurred at a median of 9 days for patients on maintenance therapy and 8 days for those in the CFI arm. Overall response rate after the initial reintroduction of FOLFOX was 20.4% in the LV group and 30.3% in the CFI group, with the vast majority of patients (90%) who responded to induction FOLFOX responding to treatment. More than half the patients in both arms (59.3% in the LV arm and 57.6% in the CFI arm) achieved partial response plus stable disease.

The majority of patients in each arm who received second-line therapy after progression were given an irinotecan-based regimen: 62 in the LV arm and 53 in the CFI arm. In the LV arm, 15% of patients received bevacizumab (Avastin) in addition to chemotherapy compared with 11% in the CFI arm. Cetuximab (Erbitux) was administered to 6% of patients in the maintenance arm and 2% of patients in the CFI arm. Patients in the LV arm started second-line therapy at a median of 11.7 months after diagnosis compared with 9.4 months for patients in the CFI arm.

The researchers concluded that “maintenance therapy with simplified LV5FU2 after modified FOLFOX7 is an active strategy for treatment of patients with previously untreated metastatic colorectal cancer.” They cautioned that although maintenance therapy was associated with improvement in DDC and PFS, the duration of chemotherapy prior to the CFI was relatively short, at ~3 months. Up to 20% of patients in the CFI arm would likely have continued on induction therapy outside of the trial setting.

The authors also stated that while a CFI might be appropriate for some patients, the decision should be made on an individual basis. “The optimal strategy in patients with metastatic colorectal cancer remains to be defined in a heterogeneous population for whom different goals must be pursued,” the authors wrote. The DREAM (Double Inhibition Reintroduction Erlotinib Avastin Metastatic Colorectal Cancer) GERCOR study (OPTIMOX3) is evaluating monotherapy with targeted drugs as maintenance therapy following a chemotherapy regimen that includes bevacizumab.

Chibaudel B, Maindrault-Goebel F, Lledo G. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. 

According to data from a French study, patients with unresectable metastatic colorectal cancer who experience a chemotherapy-free interval (CFI) following first-line chemotherapy have shorter durations of disease control(DDC)and progression-free survival (PFS) compared with patients who begin maintenance therapy immediately.


Maintenance Therapy Prolongs Disease Control in Metastatic Colorectal Cancer

Terminally ill cancer patients are more likely to seek hospice care and less likely to pursue aggressive end-of-life (EOL) treatment if the medical team supports their spiritual needs, according to a multi-institutional study led by Tracy Anne Balboni, MD, MPH, of the Center for Psycho-Oncology and Palliative Care Research at Dana-Farber Cancer Institute, Boston, Massachusetts. Balboni and colleagues also found that spiritual care helps improve quality of life (QOL) for patients near death.

From September 1, 2002, to August 28, 2008, the team interviewed 343 patients with various types of advanced cancer. The patients were observed until death (median, 116 days) at the following facilities: Dana-Farber; Massachusetts General Hospital; New Hampshire Oncology Hematology; Parkland Hospital, Simmons Comprehensive Cancer Center, Dallas; Veterans’ Affairs Connecticut Comprehensive Cancer Clinics; and Yale University Cancer Center.

Patients rated spiritual care from 0 to 4 for both the medical team and clergy visits at baseline and during follow-up visits. Positive and negative religious coping was assessed using the 14-question Pargament’s Brief Religious Coping Scale. The researchers sought to determine whether a relationship existed between spiritual needs, spiritual care received, and the reliance on hospice care or aggressive treatment in the last week of life. Hospice care was defined as receipt of inpatient or outpatient hospice care versus no hospice care in the last week of life. Aggressive EOL care was considered a need for ventilation, resuscitation, or an intensive care unit stay in the last week of life. Following each patient’s death, the researchers interviewed his or her caregivers regarding the patient’s psychological and physical distress and overall QOL just prior to death.

The study found that patients whose spiritual needs were largely or completely supported by the medical team received more hospice care compared with patients who did not receive spiritual support from the medical team (P = .003). Patients who relied heavily on religion for coping and whose spiritual needs were largely or completely supported were more likely to request hospice care (P = .004) and less likely to receive aggressive care (P = .02) compared with those who felt their needs were not supported. Spiritual support from the medical team and pastoral care visits were also associated with higher QOL scores near death (P = .003).

The study is the first to “prospectively evaluate the impact of spiritual care from the medical system on advanced cancer patients’ medical care and quality of life at the end of life,” said Balboni in an interview with 

. “This study demonstrated that spiritual support from the medical team is significantly associated with greater adoption of hospice care, and among high religious coping patients, less aggressive care at the end of life. Additionally, spiritual care was prospectively associated with better patient quality of life near death.”

Balboni said the findings highlight the relevance of incorporating existing national spiritual care guidelines, such as those provided by the National Consensus Project for Quality Palliative Care. Balboni noted that spiritual care is not frequently provided in the medical setting, and the study’s findings “underscore the importance of training medical practitioners, particularly those caring for those facing life-threatening illness, in recognizing the frequent role of spirituality in illness, such as in taking spiritual histories and in assessing for spiritual needs.” She also recommended integrating pastoral care into multidisciplinary medical teams. The article was published online ahead of print at the 

Balboni TA, Paulk ME, Balboni MJ, et al. Provision of spiritual care to patients with advanced cancer: associations with medical care and quality of life near death. 

According to a multi-institutional study, terminally ill cancer patients are more likely to seek hospice care and less likely to pursue aggressive end-of-life (EOL) treatment if the medical team supports their spiritual needs.

By Nadine M. Hasenecz

Articles

FDA Says Simvastatin & Ezetimibe Unlikely to Cause Cancer

Maintenance Therapy Prolongs Disease Control in Metastatic Colorectal Cancer

Spiritual Support Improves Quality of Life for Oncology Patients Near Death