Idaho Medical News

PHILADELPHIA — An old antibiotic — one of the last drugs still active against many bacteria — is facing rapidly developing resistance, a researcher said here.

Polymyxin B, which fell out of favor because of toxicity after it was developed in the 1960s, is becoming the treatment of last resort for some drug-resistant Gram-negative bacteria, according to Jason Kessler, MD, of Columbia University in New York.

But a retrospective analysis of clinical isolates tested at his institution showed that resistance to polymyxin B, while still low, increased 50% between 2006 and 2008, he said at the annual meeting of the Infectious Diseases Society of America.

The drug is an injectable agent and member of a class called polymyxins that also includes colistin, Kessler told reporters. They were left on the shelf because of kidney toxicity.

“Our clinical experience has been that the drug is relatively well-tolerated,” Kessler said, perhaps because several decades of progress have made it easier to manage the kidney issues.

Precisely because it has not been widely used, polymixin B is often still potent against bacteria, such as Klebsiella pneumoniae and Pseudomonas aeruginosa — that are resistant to many other classes of antibiotics. This has led to wider use of the old antibiotic, Kessler said.

In an attempt to measure that use, Kessler and colleagues checked to see how often clinical isolates were tested for resistance to polymyxin B at Columbia University Medical Center from 2005 through 2008.

Such testing, he said, could be considered a proxy for actual use, which is harder to measure. But it also offers information about the change in resistance over time, he said.

In 2005, Kessler said, the hospital tested 239 isolates from 99 patients and found that the vast majority of samples — 223 — were sensitive to the drug.

But in the following years, while the number of patients grew steadily, the proportion of resistant strains also grew sharply: In 2006, 937 isolates from 319 patients were tested, and 66 were resistant. In 2007, 1,210 isolates were tested from 382 patients and 138 were resistant. In 2008, 1,248 were tested, from 416 patients, and 122 were resistant.

Over the study period, Kessler and colleagues reported, 74% of the isolates tested for polymyxin susceptibility were resistant to at least three other classes of drugs and 32% to five classes.

The increasing use of polymyxin is not an isolated phenomenon, according to Neil Fishman, MD, of the University of Pennsylvania, who was not part of the study but who moderated a news conference at which it was discussed.

Fishman said his medical training in the 1980s included almost no mention of the drugs, except for the warning: “they’re toxic and you’ll never have to use them.”

“Starting two years ago, I did have to use them,” he said, adding that he and colleagues are still trying to learn how to use the drugs and to manage the toxicity.

An additional issue, he said, is that some of the drugs are in short supply. “Because they are old antibiotics, there aren’t a lot of companies making them and their use in increasing,” he said, “and it has become increasingly difficult to obtain some of the polymyxins for clinical use.”

The researchers did not report any external support or any conflicts.

ROCKVILLE, Md., June 6 — The FDA has cleared the way for Tysabri (natalizumab), the multiple sclerosis drug, to go back on the market but under a special restricted distribution program.

Tysabri is a monoclonal antibody that was approved in November 2004 for relapsing forms of MS because it demonstrated efficacy in reducing the frequency of exacerbations.

But in February 2005 it was withdrawn by its maker, Biogen Idec, and distributor, Elan, after three patients in clinical trials developed progressive multifocal leukoencephalopathy (PML), a rare viral infection of the brain. Two of the cases were fatal. At the same time, the FDA stopped clinical trials of the drug.

In February of 2006, after an independent safety review of patients who had participated in the previous trials found no additional cases of PML, the FDA permitted a resumption of Tysabri studies.

To decrease the possibility of patients developing PML in the future, while also making Tysabri available to appropriate MS patients, FDA consulted in March 2006 with its Peripheral and Central Nervous Systems Drugs Advisory Committee.

The advisory committee recommended a risk-minimization program with mandatory patient registration and periodic follow-up to identify as early as possible any cases of PML that may occur, and to try to determine the reason the infection occurs. In response, Biogen Idec and Elan submitted to the FDA a risk management plan, called the TOUCH Prescribing Program, to help ensure safe use of the product.

Following a thorough review of the risk management plan and proposed changes to the drug’s original marketing application, the FDA determined that Tysabri can be made available under the TOUCH Program with the following main features:

The drug will only be prescribed, distributed, and infused by prescribers, infusion centers, and pharmacies registered with the program.
Tysabri will only be administered to patients who are enrolled in the program.
Prior to initiating the therapy, health care professionals are to obtain the patient’s MRI scan to help differentiate potential future multiple sclerosis symptoms from PML.
Patients taking Tysabri are to be evaluated at three and six months after the first infusion and every six months after that, and their status will be reported regularly to Biogen Idec and Elan.

In addition to its activity in MS, Tysabri is being studied for Crohn’s disease. Last month in a study reported at Digestive Disease Week, researchers said that 51% of patients with moderate to severe Crohn’s receiving Tysabri responded to the initial infusion versus 37% of patients in a placebo group (P=0.001). At eight weeks the difference was still significant, with 48% of Tysabri patients showing a response versus 32% of the placebo group (P

RESEARCH TRIANGLE PARK, N.C., Sept. 20 — More aggressive management of pregnancies with preeclampsia has appeared to have a big payoff for fetal survival, as shown by registry data in Norway.

In a review of more than 800,000 births in Norway from 1967 to 2003, investigators here and in Norway found that the likelihood of a stillbirth from a preeclamptic pregnancy had become barely higher than that of non-preeclamptic pregnancies.

This compared with the likelihood of a stillbirth from a preeclamptic pregnancy in the late 1960s that was four times greater than normal pregnancies, they reported in the Sept. 20 issue of Journal of the American Medical Association.

Although their findings apply specifically to Norway, they would likely apply to other industrialized nations with similar facilities and medical practices, noted Olga Basso, Ph.D., of the National Institute of Environmental Health Sciences here, and colleagues at the University of Bergen and Norwegian Institute of Public Health.

Much of the improvement appears to have come from advances in medical management of preeclampsia, the investigators wrote.

Yet they also found that while there was a large reduction in stillbirths and a significant increase in induced pregnancies before 37 weeks gestation, the relative risk of neonatal death following a preeclamptic pregnancy was largely unchanged, suggesting that the increase in presumably risky preterm births was offset by improvements in care of extremely premature neonates.

“Preeclampsia still carries a twofold increased risk of neonatal death, which has changed little over time,” they wrote. “This stability in neonatal risk is remarkable, considering the increasing number of very preterm deliveries in recent years resulting from aggressive obstetric management of preeclampsia. Modern medical management of preeclampsia appears to have been effective in preventing fetal death without causing an increase in infant or maternal death.”

The investigators drew on the comprehensive Medical Birth Registry of Norway for their data, focusing on the effect of early delivery of preeclamptic pregnancies on fetal and infant survival.

They reviewed registry data on 804,448 singleton first-born infants born in the period spanning 1967 to 2003. The main study outcome was the odds ratio for fetal and early childhood death in relation to preeclampsia.

They found that among the 33,835 pregnancies with preeclampsia, inductions before 37 weeks of gestation increased from 8% in the 1967-1978 period to nearly 20% in 1991-2003.

The increase in planned preterm births accompanied a drop in the odds ratio for stillbirth in preeclamptic pregnancies from 4.2 (95% confidence interval 3.8-4.7) in 1967-1978, to 1.3 (95% CI, 1.1-1.7) in 1991-2003.

During the same time spans, however, the odds ratio for neonatal death (days 1-28 of life) were virtually unchanged, at 1.74 (95% CI, 1.44-2.11) in 1967-1978, and 1.98 (85% CI 1.50-2.61) from 1991-2003. Rates of later infant and childhood mortality also showed little change, the authors noted.

“While our data strongly suggest that medical interventions in the management of preeclampsia have benefited the fetus (and, presumably, the mother),” the authors wrote, “these results do not per se imply that early interruption of pregnancy is justified; factors other than early termination have probably contributed as well.”

They acknowledged that physicians must balance the risks to the fetus of preterm delivery against the risks to the mother from preeclampsia.

“Our data suggest that, in Norway at least, all these decisions have worked to the net advantage of the child, while achieving a low maternal mortality rate,” the investigators wrote.

Primary source: Journal of the American Medical Association

Source reference:
Basso O et al. “Trends in Fetal and Infant Survival Following Preeclampsia.” JAMA. 2006;296:1357-1362

Medicare patients had shorter hospital stays after hip replacement surgery but higher rates of discharge to post-acute care and readmission, 17 years of claims data showed.
The mean length of stay after total hip arthroplasty declined by more than 50%, from more than nine days in 1991 to 1992 to fewer than four days in 2007 to 2008. During the same time period, the proportion of patients discharged to home decreased from 68% to 48% (P=0.002), whereas the proportion discharged to intermediate- and skilled-care facilities doubled.
The mixed results also showed that the 30-day all-cause readmission rate increased from 5.9% to 8.5% (P<0.001), as reported in the April 20 issue of the Journal of the American Medical Association.

Similarly, clinical outcomes reflected a combination of good and not-so-good news.

Mortality following primary total-hip arthroplasty declined significantly over time, but mortality associated with revision procedures did not improve and might have increased slightly, Peter Cram, MD, of the University of Iowa in Iowa City, and co-authors reported.

The length of stay, discharge, and readmission data have potentially major policy implications.

“These findings reinforce the potential wisdom of moving to bundled payments, reimbursing for episodes of care, or a combination of both as a way for incentivizing the correct length of stay, rather than perpetual reductions in length of stay that seem to be occurring,” Cram and co-authors wrote.

As the volume of total-hip arthroplasty has increased in recent years, many observers have assumed improved outcomes accompanied the accumulation of of experience. In fact, rigorous empirical data to document the improvement are lacking, the authors wrote.

The lack of data is particularly surprising in light of ongoing efforts to regionalize surgical procedures to higher-volume and higher-quality hospitals, they continued. As an elective surgery in most instances, total hip arthroplasty should be well suited for regionalization.

Since the introduction of Medicare’s prospective payment system in 1983, reducing length of stay has emerged as a major cost-control mechanism. However, concern has arisen that the reductions in length of stay might reflect premature discharge, which could lead to increased use of skilled-care facilities and more frequent readmission, offsetting in cost savings for shorter length of stay.

To address some of the uncertainty, Cram and colleagues analyzed Medicare Part A data to identify beneficiaries who underwent primary or revision total-hip arthroplasty during 1991 to 2008. Outcomes of interest included hospital length of stay; inhospital, 30-day, and 90-day mortality; discharge disposition; and 30- and 90-day all-cause readmission rates.

The final analysis included 1,453,493 elective primary total-hip arthroplasty procedures and 348,596 revision procedures. Patient risk and procedure complexity increased over time for primary and revision procedures. Patient age increased, prevalence of diabetes doubled, and the proportion of patients who were obese tripled.

Mean length of stay for primary total-hip replacement decreased from 9.1 days during the first two years of the review period to 3.7 days during the last two years (P<0.001). Inhospital mortality declined from 0.5% to 0.2% (P<0.001), 30-day mortality from 0.7% to 0.4% (P=0.004), and 90-day mortality from 1.2% to 0.8% (P<0.001). Results were similar after adjustment for baseline characteristics.

The 20% absolute decrease in the proportion of patients discharged to home was accompanied by an increase in discharges to skilled or intermediate care from 17.8% to 34.4% (P<0.001). The 30-day all-cause readmission rate declined from the first two years to 2001 to 2002 (5.9% versus 4.6%, P<0.001) before increasing significantly to 8.5% by 2007 to 2008 (P<0.001).

For revision procedures, length of stay declined from an average of 12.3 days to 6.0 days (P<0.001). Inhospital mortality declined from 1.8% to 1.2% (P<0.001), but 30-day mortality increased from 2.0% to 2.4% (P=0.004) and 90-day mortality from 4.0% to 5.2% (P<0.001). After adjustment, both 30-day and 90-day mortality remained stable.

The proportion of patients discharged to home after revision procedures decreased from 57.4% to 35.4% (P<0.001), which was accompanied by an increase in the rate of discharge to intermediate or skilled care from 26.7% to 42.4% (P<0.001). The 30- and 90-day all-cause readmission rates initially declined but then increased toward the latter part of the review period (P<0.001).

Since the study was limited to a Medicare population, the authors cautioned that extrapolating the findings to a general population was problematic. Moreover, they relied on an administrative database so were unable to assess functional status and quality of life.

The authors had no relevant disclosures.

The consumer group Public Citizen has asked the FDA not to approve rivaroxaban (Xarelto) for use in patients with atrial fibrillation because of safety and efficacy concerns.

In a letter sent Thursday, the group expressed four concerns about the phase III ROCKET-AF trial: The control arm was suboptimal There was a possible rebound excess in stroke occurrence following discontinuation of rivaroxaban The sponsor tested a once-daily 20-mg dose of the drug, when previous studies had tested twice-daily 10-mg doses There are possible ethical concerns related to study protocol and conduct

At the American Heart Association meeting last year, researchers reported that rivaroxaban, an oral direct factor Xa inhibitor, was noninferior to warfarin, but not superior.

In September, the FDA’s Cardiovascular and Renal Drugs Advisory Committee recommended approval of rivaroxaban for stroke prevention in those with atrial fibrillation. But clinical staff reviewers for the FDA said that the drug should not be approved and that more tests needed to be conducted to clarify safety and efficacy issues.

The letter from Public Citizen highlighted the discrepancy between the committee’s recommendation and the reviewers’ concerns.

Public Citizen also noted a negative Perspective piece in the Oct. 6 New England Journal of Medicine by a member of the FDA advisory committee, Thomas Fleming, PhD. Fleming wrote that some members of the advisory committee voted for approval of rivaroxaban in the hopes that postmarketing trials would resolve unanswered safety and efficacy questions.

“Given the uncertainty surrounding the efficacy and safety of this drug, and the fact that there are already two existing therapies for the same indication [dabigatran and warfarin], rivaroxaban should not be approved until appropriate clinical studies are performed,” the letter concluded.

Dabigatran (Pradaxa), a direct thrombin inhibitor, was approved for stroke prevention last year.

Public Citizen’s letter detailed the concerns expressed by the FDA reviewers. In particular, it noted that only 55% of the patients in the warfarin arm of ROCKET-AF were in optimal therapeutic range. This contrasts with the 63% to 73% who maintain optimal therapeutic range in other “modern warfarin-controlled studies.”

“We agree with the FDA reviewers” that the evidence is “insufficient to support approval of rivaroxaban … and that another clinical trial must be first performed in which warfarin is used at least as skillfully and appropriately” as in previous studies, the watchdog group said.

Another complaint about the trial was that there was not a sufficient “bridge” for patients transitioning from the study drug to warfarin. The sponsor, Johnson & Johnson, had provided a bridging protocol, but not until after the trial was over. Public Citizen argued that this protocol needs to be tested as “part of the preapproval clinical study.”

The letter to the FDA also asked that additional testing be done prior to approval “to ensure that the tested dose is, in fact, the optimal dose.” It cited an FDA reviewer who questioned why the trial chose a once-daily 20-mg dose rather than the previously used twice-daily 10-mg dose.

Aside from the FDA reviewers’ concerns, Public Citizen said it was unethical that more than 40% of patients who discontinued the study early and nearly 8% of those who completed the study were followed for 30 days with no anticoagulation administered.

The group also said it was unethical that many patients, particularly those at international sites, “were insufficiently treated with warfarin throughout the trial, with no indication that the sponsor intervened at any point to address this dangerous situation.”

The FDA is expected to make a decision regarding rivaroxaban by November.

From the American Heart Association:

2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation

AHA Rocket-AF Summary Page (video interviews and summary slide)

BOSTON — Updates of key clinical guidelines highlight the program for the American Academy of Pediatrics National Conference and Exhibition, which begins here on Friday and continues through Oct. 18.

The AAP will unveil new recommendations for attention deficit/hyperactivity disorder and sudden infant death syndrome (SIDS) and sleep safety in infants during the conference. Both guidelines will be discussed during plenary sessions at the AAP meeting and will be published in the Nov. 11 issue of Pediatrics.

Additionally, the AAP will post new parent information on ADHD and SIDS on the academy’s Healthy Children website.

The plenary sessions will provide a setting for many of the major presentations at the conference, according to Pittsburgh neonatologist Robert Cicco, MD, chair of the conference’s planning group.

“The topics that will be covered during the plenary sessions run the gamut from basic science research to new algorithms on how to manage mental health problems in the office to public health and advocacy,” Cicco told MedPage Today.

Pediatric specialists and generalists will find presentations to meet their scientific and educational needs, he continued. As examples he cited presentations on robotics and bariatric surgery in children and far-reaching discussions of the growing obesity epidemic among children.

A number of pediatric specialty organizations will have their own meetings-within-a-meeting, which will include scientific presentations and discussions of topics of particular interest to pediatricians with specialty practices.

Perhaps not surprisingly, healthcare reform and its potential impact on pediatricians and their patients will take center stage in several presentations, said Cicco. Attendees will also have an opportunity to get the latest information on the status of various immunization programs.

Although many presentations will reflect the current hot topics in pediatrics and medicine in general, attendees can also stay abreast of developments related to “more mundane” aspects of pediatrics, such as management of urinary tract infections.

“Urinary tract infections are nothing new, but the guidelines for managing them in pediatric patients are new,” said Cicco. “Pediatricians need to know which patients are likely to have uncomplicated infections and which patients might require renal ultrasound and more in-depth evaluations.”

Other topics expected to attract considerable interest include: Seat-belt safety Sports injuries Firearms injuries and safety Media use and appropriateness in young children Use of Internet-based medical information Healthcare disparities Palliative care Surgical emergencies

In recent years, the conference planning group has made a concerted effort to make the program broadly applicable to specialists and generalists. In the past, some specialists might have found programs of interest on only one day, said Cicco. The meeting now has programs and presentations that “cross the primary care-specialty boundary.”

Endovascular repair for abdominal aortic aneurysm produced a lower 30-day mortality rate than the more invasive open procedure, an interim report from a multicenter, randomized trial showed.
Perioperative death occurred in 0.5% of those who received the endovascular procedure and 2.3% of those who had an open repair (P=0.006), according to Frank Lederle, MD, of the Veterans Affairs Medical Center in Minneapolis, and colleagues.
The number needed to treat was about 48.
However, the mortality rate at two years did not differ significantly between the two groups (7% versus 9.8%, P=0.13), the researchers reported in the Oct. 14 issue of the Journal of the American Medical Association.

The early difference in mortality “was not offset by increased morbidity or mortality in the endovascular group in the first two years after repair,” they said.

But, they said, “longer-term data are needed to fully assess the relative merits of the two procedures.”

The trial is ongoing and will follow patients for nine years.

According to the researchers, about 45,000 U.S. patients with unruptured abdominal aortic aneurysm undergo elective repair each year, and about 1,400 die in the first 30 days.

There have been reports that endovascular repair, performed transluminally through the femoral or iliac arteries, reduces perioperative mortality and time spent in the hospital and intensive care unit, compared with the traditional, open procedure. But little data existed to compare the short-term outcomes of the procedures, they said.

At 42 VA medical centers, Lederle and his colleagues randomized 881 veterans (99% male; 87% white) to receive endovascular or open repair. All were at least 49 years old (mean age 70).

Baseline characteristics were generally similar in each group. The only difference was that a higher percentage of patients in the open group were using aspirin (63.4% versus 55%, P=0.01).

In addition to the early survival advantage, patients who underwent the endovascular procedure had reduced procedure time (2.9 versus 3.7 hours), reduced blood loss (200 versus 1,000 mL), reduced duration of mechanical ventilation (3.6 versus five hours), shorter hospital stay (three versus seven days), shorter ICU stay (one versus four days), and lower transfusion requirements (0 versus 1.0 units) (P<0.001 for all).

However, the endovascular procedure, unlike open repair, required substantial exposure to fluoroscopy (average of 23 minutes) and contrast (average of 132.5 mL).

There were no significant differences between the two groups in major morbidity — including myocardial infarction, stroke, amputation, and renal failure requiring dialysis. Nor were there significant differences in procedure failures, secondary therapeutic procedures, aneurysm-related hospitalizations, health-related quality of life, or erectile function.

The study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. Study nurses were compensated directly by the VA study grant.

Lederle reported no conflicts of interest. One of his co-authors reported receiving research support, consultant fees, or training director fees from Abbott/Guidant, Abraxis, Bard, Cook, Cordis, ev3, Lumen, Medtronic, Sanofi, and WL Gore. Another study author reported receiving research support as an investigator for the Medtronic AneuRx Phase III clinical trial.

ROCKVILLE, Md., Aug. 10 — The FDA has warned consumers against using three brands of red yeast rice, a product marketed as a natural remedy for high cholesterol, because they may contain lovastatin, the active ingredient in Mevacor.

The products, marketed in stores or on the Web, are Red Yeast Rice and Red Yeast Rice/Policosonal Complex, sold by Swanson Healthcare Products, and manufactured by Nature’s Value, and Kabco, respectively; and Cholestrix, sold by Sunburst Biorganics.

FDA investigators conducting routine testing of the supplement detected lovastatin, which was the first statin approved by the FDA. It has been available as a generic drug since 2002.

Steven Galson, M.D., M.P.H., director of FDA’s Center for Drug Evaluation and Research, said consumers may be unaware of side effects associated with lovastatin. These include rhabdomyolysis, especially when lovastatin is combined with the antidepressant nefazodone, certain antibiotics, drugs for fungal infections and HIV infections, and other cholesterol-lowering medications.

The FDA recommended that consumers who use any red yeast rice product obtain medical advice if they have muscle pain or other problems that may be associated with the red yeast.

The agency issued warning letters advising Swanson and Sunburst Biorganics to stop promoting and selling the products.

The FDA’s warning letters said that the products Red Yeast Rice, Red Yeast Rice/Policosonal Complex, and Cholestrix represent unapproved new drugs that are marketed in violation of the Federal Food, Drug, and Cosmetic Act.

BOSTON, March 25 — A whiff of the rotten-egg scented hydrogen sulfide gas may make people hold their breath, but longer, controlled doses could be used to put the lungs, heart, and metabolism into hibernation, researchers found.

Low doses of hydrogen sulfide dropped the respiratory, metabolic, and heart rate of mice without reducing oxygen levels or blood pressure, reported Warren M. Zapol, M.D., of Massachusetts General Hospital, and colleagues in the April 2008 issue of the journal Anesthesiology.

Hydrogen sulfide, emitted by sewers, volcanoes, sulfur springs, and various sulfur-containing products, can be toxic at high concentrations.

However, these findings suggest controlled doses could be used to preserve organ function when oxygen supply is limited, such as after a traumatic injury or cardiac arrest, the researchers said.

Previous animal studies showed hydrogen sulfide lowered body temperature and metabolic rate and improved survival of mice with acute hypoxia.

To determine the cardiovascular impact and whether reduced body temperature was responsible for the other effects, the researchers exposed conscious mice to normal air or 80 ppm hydrogen sulfide and 17.5% oxygen under different temperature conditions.

As in the previous study, breathing the gas at room temperature progressively dropped body temperature of the mice. It fell from an average 37.4?° C (about 99?° F) before exposure down to 33.8?° C (about 91?° F) after two hours and stabilized at 29.3?° C ( about 84?° F) after six hours, which was significant at P

MADRID, June 1-Substituting Taxotere (docetaxel) for fluorouracil in a common adjuvant chemotherapy regimen showed improved outcomes for women with node-positive breast cancer.

So found the Breast Cancer International Research Group, which reported in the June 2 New England Journal of Medicine that Taxotere, Adriamycin (doxorubicin), and Cytoxan (cyclophosphamide) (TAC) is superior to fluorouracil, Adriamycin and Cytoxan (FAC).

The study randomized 1,491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. With a median follow-up of 55 months, 76.9% (573 of 745) of women randomized to the Taxotere regimen were disease-free, compared with 69.6% (519 of 746) in the fluorouracil arm, reported Miguel Martin, M.D., of the Hospital Universitario San Carlos and colleagues.

The estimated five-year disease free survival rates were 75% and 68% (p = 0.001), respectively. The difference in the relapse rate was due primarily to a higher number of patients with distant disease in the control arm. Subgroup analysis showed that TAC patients had improved disease-free survival regardless of hormone receptor status, HER2/neu status, or menopausal status. For patients with one to three positive nodes, there was improved survival (HR 0.61; 95% CI 0.46, 0.82). For patients with four or more nodes, the results were not significant (HR 0.83; 95% CI 0.63, 1.08).

Patients in the Taxotere arm also had a 30% reduction in the risk of death, compared to those in the fluorouracil arm (hazard ratio = 0.70, 95% CI 0.53-0.91). Estimated five-year survival was 87% in the Taxotere arm and 81% in the control arm.

The clinical improvement, however, comes “at the expense of increased toxic effects,” wrote Dr. Martin and colleagues. Significantly more patients in the Taxotere arm had Grade 3 or 4 hematologic side effects or serious non-hematologic adverse events than did patients treated with the fluorouracil combination (36.3% versus 26.6%, p