ONE DOSE OF H1N1 VACCINE IS ENOUGH AND SAFE

September 11, 2009 — Two studies reported online September 10 in the New England Journal of Medicine suggest that monovalent 2009 influenza A (H1N1) vaccines appear to be immunogenic in adults, with mild to moderate vaccine-associated reactions.

"A novel influenza A (2009 H1N1) virus is responsible for the first influenza pandemic in 41 years," write Michael E. Greenberg, MD, MPH, from CSL, Parkville, Victoria, Australia, and colleagues. "A safe and effective vaccine is urgently needed. A randomized, observer-blind, parallel-group trial evaluating two doses of an inactivated, split-virus 2009 H1N1 vaccine in healthy adults between the ages of 18 and 64 years is ongoing at a single site in Australia."

In this preliminary report, the investigators describe the immunogenicity and safety of the vaccine at 21 days after the first of 2 scheduled doses among 240 participants, who were equally divided into 2 age groups (<50>

At baseline and 21 days after vaccination, antibody titers were measured with hemagglutination-inhibition and microneutralization assays. Outcomes reflecting immunogenicity were the proportion of subjects with antibody titers of 1:40 or more on hemagglutination-inhibition assay, the proportion of participants with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer.

Antibody titers of 1:40 or more by day 21 after vaccination were documented in 116 (96.7%) of 120 participants vaccinated with 15-μg hemagglutinin antigen and in 112 (93.3%) of 120 participants vaccinated with 30-μg.

First Study: Immunogenic and Mild Adverse Events

Nearly all adverse events were mild to moderate in intensity, including injection-site tenderness or pain in 46.3% of participants and systemic symptoms such as headache in 45.0% of participants. There were no reported deaths, serious adverse events, or adverse events of special interest.

"A single 15-mcg dose of 2009 H1N1 vaccine was immunogenic in adults, with mild to moderate vaccine-associated reactions," the study authors write. "Estimates of the true effect of the vaccine when used in mass immunization programs will come from vaccine-effectiveness studies."

Limitations of this study include its lack of generalizability to groups other than healthy adults or to other geographic locations.

The second study, by Tristan W. Clark, MRCP, from the University of Leicester, United Kingdom, and colleagues, was a single-center study designed to test the monovalent influenza A/California/2009 (H1N1) surface-antigen vaccine in both MF59-adjuvanted and nonadjuvanted forms. Age range of the participants (n = 175) was 18 to 50 years.

Participants were randomly assigned to receive 2 intramuscular injections of vaccine containing 7.5 μg of hemagglutinin on day 0 in each arm or 1 injection on day 0 and the other on day 7, 14, or 21; or two 3.75-μg doses of MF59-adjuvanted vaccine or 7.5- or 15-μg doses of nonadjuvanted vaccine, given 21 days apart. Hemagglutination-inhibition assay and a microneutralization assay on days 0,14, 21, and 42 after injection of the first dose allowed determination of antibody responses.

An interim analysis of the responses to the 7.5-μg dose of MF59-adjuvanted vaccine by days 14 and 21 used data from 100 participants in 4 of the 7 groups studied.

Pain at the injection site was the most frequent local reaction, occurring in 70% of the participants. The most frequent systemic reaction was muscle aches, occurring in 42% of the participants. Fever (temperature, 38°C or higher) occurred in 2 patients after the first dosing.

Second Study: Protection Likely After 14 Days

At day 14, antibody titers, expressed as geometric means, were generally higher in participants who had received two 7.5-μg doses of MF59-adjuvanted vaccine than in those who had received only 1 dose by this time (P = .04 by the hemagglutination-inhibition assay and P < .001 by the microneutralization assay).

Rates of seroconversion by 21 days after vaccination with the first dose of 7.5 μg of MF59-adjuvanted vaccine, as measured with hemagglutination-inhibition assay and microneutralization assay, were 76% and 92% of participants, respectively, who had received only 1 dose to date (with the second dose scheduled for day 21) and 88% to 92% and 92% to 96% of participants, respectively, who had already received both doses (P = .11 and P = .64, respectively).

"In preliminary analyses, the monovalent influenza A (H1N1) 2009 MF59-adjuvanted vaccine generates antibody responses likely to be associated with protection within 14 days after a single dose is administered," the study authors write.

Study limitations include lack of recognized immune correlates for immunogenicity data and the inability to rule out asymptomatic infection with H1N1.

In an accompanying editorial, Kathleen M. Neuzil, MD, MPH, from PATH, Seattle, Washington, notes that "the robustness and consistency of the antibody response, and the use of internationally standardized reagents and controls, are reassuring and lend credibility to the results of Greenberg et al. and Clark et al.

"In our current global situation, in which demand for influenza vaccine greatly exceeds supply, dose-sparing strategies are needed," Dr. Neuzil writes. "Fewer or partial doses and the use of adjuvants can all contribute to increased global vaccine supply. The studies by Greenberg et al. and Clark et al. provide evidence that such strategies may be successful for the current pandemic."

CSL supported the first study, with funding from the Department of Health and Aging of the Australian government, and employs all of its authors. The second study was supported by grants from University Hospitals Leicester and Novartis; some of the study authors have disclosed various financial relationships with Illumina, Novartis, GlaxoSmithKline, Baxter, Sanofi Pasteur, and/or Hoffmann-LaRoche. Dr. Neuzil has disclosed no relevant financial relationships.

N Engl J Med. Published online September 10, 2009.

HORMONE THERAPY AND DEATH RISK IN PROSTATE CANCER PATIENTS WITH HEART DISEASE

September 1, 2009 — In localized or locally advanced prostate cancer, the use of neoadjuvant hormone therapy was associated with a nearly 2-fold risk for death in men who also had a history of coronary artery disease.

This finding comes from a retrospective study of 5077 men who were treated with brachytherapy for their cancer, 30% of whom received neoadjuvant hormone therapy for a median treatment duration of 4 months.

The hormone therapy consisted of both a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) and a nonsteroidal antiandrogen (bicalutamide or flutamide).

On the bright side of the data, there was no increase in all-cause mortality among men treated with hormone therapy who had either no cardiovascular comorbidity or a single coronary artery disease risk factor, such as diabetes mellitus, hypercholesterolemia, or hypertension. Smoking and a family history of heart disease were not evaluated as risk factors.

The study was published in the August 26 issue of the Journal of the American Medical Association.

In an interview with Medscape Oncology, the study's lead author stressed that only 5% of the men in the study — a "small subgroup" — had coronary artery disease (congestive heart failure or past heart attack).

"Our results suggest that for these men, either hormonal therapy not be used in the treatment of their prostate cancer or their underlying heart disease be addressed by a primary-care physician and/or a cardiologist before they are considered for hormonal therapy," said Akash Nanda, MD, PhD, from Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr. Nanda acknowledged that it is not known if treatment for heart disease would improve outcome. "The study does not address whether or not treatment for coronary artery disease potentially changes the risk for these patients," he said.

Dr. Nanda and his coauthors concluded that "this study should heighten awareness about the potential for harm with neoadjuvant hormone therapy in select men."

Study Details

Several clinical trials have shown that adding hormonal therapy to radiation therapy in the treatment of aggressive prostate cancer leads to an increase in survival, observed Dr. Nanda. However, a recent analysis (JAMA. 2008:299:289-295) indicated that "this may not be the case for men with coexisting illnesses," according to Dr. Nanda. The purpose of the new study was to identify comorbidities that might affect survival.

To that end, the investigators looked at 5077 men with clinical stage T1 to T3 N0 M0 prostate cancer treated between 1997 and 2006 at the Chicago Prostate Cancer Center, a community practice in Westmont, Illinois. Men were referred to this center on the basis of their interest in or candidacy for brachytherapy.

Among the men, 2653 (52.3%) had no history of a cardiovascular comorbidity, 2168 (42.7%) had a coronary artery disease risk factor, and 256 (5%) had coronary artery disease. The median age of the men was 69.5 years, and 555 (10.9%) had received supplemental external-beam radiation.

Most of the men in the study (70%) did not receive neoadjuvant hormone therapy and served as comparators for the men who did.

Neoadjuvant hormone therapy use was not significantly associated with an increased risk for all-cause mortality in men with no comorbidity (9.6% vs 6.7%; adjusted hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.72 - 1.32; P = .86) or a single coronary artery disease risk factor (10.7% vs 7.0%; adjusted HR, 1.04; 95% CI, 0.75 - 1.43; P = .82) after median follow-ups of 5.0 and 4.4 years, respectively.

However, for men with coronary artery disease, the therapy was significantly associated with an increased risk for all-cause mortality (26.3% vs 11.2%; adjusted HR, 1.96; 95% CI, 1.04 - 3.71; P = .04). These men had a median follow-up of 5.1 years.

In arriving at these findings, the investigators adjusted for age, treatment year, supplemental external-beam radiation therapy, treatment propensity score, and known prostate cancer prognostic factors (such as Gleason score).

The authors also noted that, in other research in different settings, hormone therapy has been associated with a variety of adverse effects, including increased risk for cardiovascular death.

More on Clinical Significance

Dr. Nanda and his colleagues recommend that, in men with favorable-risk prostate cancer and a history of coronary artery disease, alternative strategies to brachytherapy and hormone therapy be considered. These include active surveillance, treatment with external-beam radiation alone, and prostatectomy. In such men, hormone therapy is not really needed to "maximize outcome" anyway, explained Dr. Nanda. Instead, hormone therapy is used to reduce the size of the gland, ensuring that brachytherapy is not obstructed by the arch of the pubic bone.

However, in men with unfavorable-risk prostate cancer, hormone therapy offers a survival benefit. "This is a tougher decision because hormone therapy is needed to maximize outcome," said Dr. Nanda. The risks and benefits of hormone therapy must be balanced; as noted above, appropriate medical evaluation or treatment is needed before hormone therapy is used in this setting, Dr. Nanda said.

Dr. Nanda also pointed out that the findings were limited to brachytherapy and, as a result, not necessarily generalizable to men with prostate cancer who are treated with external-beam radiation. "Other investigators will want to validate these findings in other settings," he said.

The authors also note that the duration and extent of hormone therapy are variables in need of study. "Men with locally advanced prostate cancer are frequently treated with 2 to 3 years of hormone therapy in combination with external-beam radiation therapy," they write.

The researchers have disclosed no relevant financial relationships.

JAMA. 2009;302:866-873.

HPV VACCINES APPROVED FOR BOYS

September 11, 2009 — A second vaccine against human papillomavirus (HPV) for the prevention of cervical cancer — GlaxoSmithKline's Cervarix — has been recommended for approval in the United States; the extended use of Merck & Co's Gardasil, the first vaccine, was recommended for boys and men for the prevention of genital warts.

The recommendations came from the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee. In both cases, the voting was almost unanimously in favor, with only 1 abstention or no vote, but the meeting heard concerns about the safety of the vaccines and questions about the public-health value of the extended indication.

The voting on Cervarix was carried out by 13 members of the committee. There were 12 votes in favor of and 1 vote against the data supporting its efficacy in preventing precancerous lesions and cervical cancer in females in the 15 to 25 year age group and, from immunobridging studies, the 10 to 14 year age group. One member left the meeting before the vote on safety, but 11 of the remaining members voted in favor of the data supporting the safety of Cervarix in this population; there was 1 vote against.

Eight members of the committee voted on Gardasil use in boys and men. The vote was 7 in favor of the efficacy data supporting the use of Gardasil in males 9 to 25 years of age for the indication of preventing genital warts; there was 1 abstention. The vote was also 7 in favor of the data supporting the safety of Gardasil in this population; there was 1 vote against.

The FDA usually — but not always — follows the recommendations of its advisory committees.

Second Vaccine for Cervical Cancer

If approved, Cervarix would be the second HPV vaccine available in the United States. It is already marketed in more than 100 countries worldwide, including the 27 member states of the European Union. This product has been used in nationwide vaccination programs in the United Kingdom and Australia since it was first approved in 2007. At the meeting, the manufacturer estimated that around 7 million doses have been distributed worldwide.

Ceravix is a bivalent vaccine, active against HPV types 16 and 18, which together are thought to be responsible for about 70% of all cervical cancer cases. However, data from clinical trials presented at the committee meeting suggested that the vaccine also offers protection against other virus types responsible for causing cervical cancer, including HPV types 31, 33, and 45, the next most common cancer-causing strains. In addition, the data presented showed a duration of immunity of 6.4 years.

In contrast, Gardasil is a quadrivalent vaccine with activity against 4 HPV types: HPV types 16 and 18, which cause cervical cancer, and HPV types 6 and 11, which cause genital warts. This extra activity means that this vaccine is also indicated for the prevention of genital warts in girls and women, and it has now been recommended for that same indication for boys and men. However, the current data on Gardasil in males extends only out 2 to 3 years, and in women extends only out 5 years.

Is Cervarix Better at Protecting Against Cervical Cancer?

The main purpose behind the development of these HPV vaccines was to prevent cervical cancer, and for this indication, Cervarix is the better of the 2 vaccines, said Diane Harper, MD, from the University of Missouri–Kansas City School of Medicine. She has been involved in clinical trials with both vaccines, and was approached by Medscape Oncology for comment.

Dr. Harper outlined the following reasons for her opinion:

• Cervarix and Gardasil are equally effective for HPV types 16 and 18 in women with no previous HPV, but Cervarix has proven to have a longer duration than Gardasil (6.4 vs 5 years); there are still no data on how long the protection will ultimately last, and whether booster shots will be needed.
• Cervarix offers cross protection for 5 cervical-cancer-causing types of HPV, whereas Gardasil offers cross protection for 3. In addition, Cervarix offers protection against the 3 most common types of HPV that cause adenocarcinoma, which is very difficult to detect with Pap testing; Gardasil is deficient in 1 of those types.
• Cervarix prevents nearly twice the number of excisional therapies as does Gardasil (70% vs 40%), which is one of the harms that Pap screening can cause (excisional therapies lead to reproductive morbidity).
• The antibody titers induced by Cervarix are superior to those for Gardasil, and are superior for women older than 25 years, should there come a time when the vaccines are approved for optional use by women in this age group. The antibody titers in the cervical mucous are also superior with Cervarix, and it is in the mucous on the epithelial surface that "half the action happens."

"I realize that this may sound like an advertisement for Cervarix, but these are the facts" Dr. Harper explained. "If you bother to vaccinate in countries with screening, then you want to vaccinate with the vaccine that will offer you the greatest cancer protection," she said.

Voting Against the Vaccines

The votes against both vaccines came from the consumer representative on the committee, Vicky Debold, PhD, RN, director of patient safety at the National Vaccine Information Center. She told Medscape Oncology that she has concerns about the safety of these vaccines, and acknowledged that her view is colored by listening to reports of adverse events from members of the public, in particular parents whose daughters who have suffered after vaccination with Gardasil.

"I'm not quite sure what is going on, but there have been too many patients with problems," she said. "There have been reports of demyelinating conditions and also deaths, and I wonder if there is a tendency toward a hyperstimulating of the immune system that results in such catastrophic outcomes." She suspects that there are individuals who might be particularly susceptible to adverse effects, maybe because of pre-existing conditions or genetic vulnerability.

It is very difficult to assess the safety of vaccines, Dr. Debold noted. At the meeting, she pointed out that, in many cases, the trials of both vaccines did not use a true placebo, such as a saline injection. The trials of Gardasil used an adjuvant control, and some of the Cervarix studies used hepatitis A vaccine as the control. "This makes the data very confusing," she said.

In addition, Dr. Debold had an issue with the way the question on the efficacy of Cervarix was worded. She felt the data showed that the vaccine did prevent precancerous lesions (and she would have voted yes for that), but the question also included wording about the prevention of cervical cancer, "and the data do not show this, not yet. The implication is that by preventing the earlier lesions, you prevent cervical cancer, but that is an implication, it has not been shown," she said.

At the meeting, specific questions about the safety of Cervarix focused on an "imbalance" of reports of spontaneous abortions and autoimmune adverse effects, but experts at the meeting were not convinced that these reports were related to the vaccine, with 1 commenting that "there are quirks in the collection of data."

Other Benefits From the Vaccines

Another potential benefit from a vaccine such as Gardasil that is active against HPV types 6 and 11 is that it might also offer protection against other "warty" diseases, including juvenile respiratory papillomatosis. Speaking during the open part of the meeting, Craig Derkay, MD, pediatric otolaryngologistat the Eastern Virginia Medical School in Norfolk, noted that there are about 1500 new cases each year of laryngeal papilloma caused by HPV 6 and 11, with the infection usually acquired from the mother during passage through the birth canal. There are no adjuvant therapies for this disease, and surgery is often not curative, he said. A vaccine that targets HPV 6 and 11 could "substantially reduce" this disease burden, and might also prevent HPV-associated head and neck cancer. If an HPV vaccine is to be used, it is preferable to use one with the broader spectrum so as to also prevent these types of diseases, he said.

Also speaking in the open part of the meeting was Dianne Zuckerman, PhD, president of the National Research Center for Women and Families. She expressed concern about the lack of long-term efficacy data for Gardasil in boys and men. The trial data that were presented were for 2 years, but some of the seroconversion data were for only 7 months, she pointed out.

The whole point of vaccinating boys 9 to 11 years old is to protect them from genital warts once they become sexually active, but some of the data showed that the antibody titers dropped off during the 2 years of the trial, which raises the concern that any protection offered by the vaccine could have worn off by the time these boys become sexually active. "The boys of America are not facing an epidemic of genital warts and we have time to wait for efficacy data," she said.

In addition, she pointed out that genital warts are not life-threatening, and the male genital cancers that the vaccine offers protection against, such as penile and anal cancer, are very rare in heterosexual men.

One of the committee members highlighted the natural history of genital warts, which he felt was important for the discussion. "While they are ugly and a nuisance, they are also self-limiting and will go away on their own in individuals with a normal immune system," he said.

Approached for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas MD Anderson Cancer Center in Houston, who is an editorial advisor for Medscape Oncology, said: "I suspect evidence supporting the protection of males from genital warts will need to be very strong for the FDA to approve [this indication]. There is a very strong theoretical rationale to support vaccination of males to prevent cervix cancer in women, but considering the current cost of vaccination, I would seriously question the cost-effectiveness of this approach, at least in the United States. Further, there may be genuine protection of males against the risk of head and neck and other uncommon cancers, but again, this will need to be demonstrated in the clinical-trials setting."

Also during the open part of the meeting, there were testimonials from 2 mothers whose daughters had suffered adverse effects after vaccination with Gardasil, one of whom died shortly after her third dose. One of these mothers suggested that there was a link between niacin deficiency and adverse reactions to the HPV vaccine, and that individuals with pyruvate kinase deficiency might be particularly susceptible.

Paradigm-Shifting Prevention Strategy

Speaking out in favor of HPV vaccination — indeed, describing it as a "paradigm-shifting prevention strategy for cervical cancer" — was Mark Einstein, MD, MS, director of clinical research for women's health and gynecologic oncology at the Albert Einstein College of Medicine, in the Bronx, New York; he was representing the Society of Gynecologic Oncologists.

Cervical cancer remains a clinically relevant problem with in the United States, he told the meeting, with 11,000 new cases diagnosed annually, and about half a million women affected annually by precancerous lesions that could affect their reproductive health.

"The public-health value of the protection afforded by HPV vaccination overwhelmingly outweighs the self-limiting local side effects and even the rare but more serious effects that may or may not be vaccine-related," he told the meeting.

ESCALATED BEACOPP FOR ADVANCED STAGE HODGKIN LYMPHOMA

NEW YORK (Reuters Health) Sep 03 - A new, escalated-dose chemotherapy regimen improves long-term freedom from treatment failure and overall survival in patients with advanced-stage Hodgkin's disease, according to a report in the August 24th Journal of Clinical Oncology.

"(This) more efficient regimen should be the standard of care for patients with advanced Hodgkin lymphoma," Dr. Andreas Engert from Universitatsklinik Koln, Germany, told Reuters Health by email.

Dr. Engert and colleagues in the German Hodgkin Study Group evaluated 10-year follow-up results of the HD9 trial, which compared 2 different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1196 patients with advanced-stage Hodgkin's lymphoma.

Complete remission occurred at a higher frequency with BEACOPP escalated (96%) than with BEACOPP baseline (88%). It was also superior to the 85% achieved with COPP/ABVD (COPP alternated with doxorubicin, bleomycin, vinblastine, and dacarbazine), the authors report.

Freedom from treatment failure at 10 years was significantly higher after BEACOPP escalated (82%) than after BEACOPP baseline (70%) or COPP/ABVD (64%). Results were similar for overall survival at 10 years (86%, 80%, and 75%, respectively).

BEACOPP escalated caused more acute hematologic toxicity (leukopenia, thrombocytopenia, and anemia) and more grade 3/4 infections than did BEACOPP baseline, the researchers note.

The estimated 10-year cumulative incidence of secondary acute myeloid leukemia and myelodysplastic syndrome was significantly higher after BEACOPP escalated (3.2%) than after BEACOPP baseline (2.2%).

"(BEACOPP escalated) is somewhat more toxic compared to ABVD," Dr. Engert said. "However, with adequate management (i.e., growth factors, prophylactic antibiotics) and adaptation of the dose level given to patients' individual tolerability, this regimen is safe also in the outpatient setting."

J Clin Oncol 2009.

MORE EVIDENCE FOR HIGH DOSE FASLODEX

NEW YORK (Reuters Health) Sep 04 - For first-line endocrine therapy in advanced hormone receptor-positive breast cancer in postmenopausal women, double the approved dose of fulvestrant does at least as well as anastrozole, researchers report in the August 24th issue of the Journal of Clinical Oncology.

The study, lead investigator Dr. John F. R. Robertson told Reuters Health, "suggests that a higher dose of fulvestrant -- 500 mg -- is more effective than a third generation aromatase inhibitor, although I think the data are not yet sufficient to change clinical practice."

Dr. Robertson of the University of Nottingham, UK, and colleagues came to this conclusion after an open-label study of 205 patients who were randomized to treatment with the pure antiestrogen fulvestrant or anastrozole. Those in the fulvestrant group were given 500 mg on day 14 of the first month and 500 mg per month thereafter. Anastrozole patients received 1 mg per day.

The proportion of patients experiencing an objective response or stable disease for at least 24 weeks was 72.5% in the fulvestrant group and 67.0% in the anastrozole group. The corresponding objective response rates were 36.0% and 35.5%. The duration of these responses also favored fulvestrant.

The time to progression was significantly greater for fulvestrant than anastrozole. In fact, the median time to progression was not reached for fulvestrant but was 12.5 months for anastrozole. Both treatments were well tolerated.

"Combined with other data," concluded Dr. Robertson, "it now appears that fulvestrant 500 mg is more effective than the current 250 mg dose, with no apparent difference in tolerability. Other studies to be reported later this year should provide a definitive answer on the clinical value of fulvestrant 500 mg."

J Clin Oncol 2009;27.

KRAS MUTATION AND AGGRESIVENESS OF HEPATIC METASTASES

Ann Surg Oncol. 2009 Sep 1. [Epub ahead of print]

Related Articles, LinkOut

KRAS Mutation Correlates With Accelerated Metastatic Progression in Patients With Colorectal Liver Metastases.

Nash GM, Gimbel M, Shia J, Nathanson DR, Ndubuisi MI, Zeng ZS, Kemeny N, Paty PB.

Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

BACKGROUND: Observational studies of patients with primary colorectal cancer have identified KRAS mutation as a marker of poor prognosis. To examine more directly whether KRAS mutations are associated with accelerated metastatic progression, we evaluated KRAS mutation as well as Ki-67 expression in patients with colorectal liver metastases not treated with cetuximab. METHODS: KRAS mutation status was assessed in a series of resected or sampled colorectal liver metastases. In a subset of these tumors, Ki-67 antigen expression was assessed by immunohistochemical stains. Median follow-up after liver resection or biopsy was 2.3 years. RESULTS: KRAS mutation in the liver metastasis was detected in 27% of the 188 patients. High Ki-67 expression in the liver metastasis was identified in 62% of 124 patients analyzed. Both markers were associated with multiple liver metastases and shorter time interval to their detection. KRAS mutation and high Ki-67 expression were independent predictors of poor survival after colon resection (hazard ratio [HR] 1.9 [95% confidence interval (95% CI), 1.1-3.4], HR 2.6 [95% CI, 1.4-4.8], respectively). Tumors with high Ki-67 expression were less likely to be selected for liver resection, and KRAS mutation was independently associated with poor survival after liver resection (HR 2.4 [95% CI, 1.4-4.0]). CONCLUSIONS: KRAS mutation is associated with more rapid and aggressive metastatic behavior of colorectal liver metastases. These data suggest an important role for KRAS activation in colorectal cancer progression and support continued efforts to develop KRAS pathway inhibitors for this disease.

ZEVALIN APPROVED FOR FIRST LINE USE IN FOLLICULAR LYMPHOMA

September 9, 2009 — The FDA has approved an expanded indication for ibritumomab tiuxetan intravenous infusion (Zevalin, Spectrum Pharmaceuticals) for the first-line treatment of follicular non-Hodgkin's lymphoma in patients who achieve a partial or complete response to chemotherapy.

The approval was based on 3.5-year data from the First-line Indolent Therapy multicenter, randomized, open-label, phase 3 study (n = 414), showing that progression-free survival was significantly prolonged among ibritumomab-treated patients compared with those who received no further treatment (38 months vs 18 months; P < .0001).

"We believe the approval of Zevalin as an effective treatment option following a first-line regimen represents a notable advance in the treatment of non-Hodgkin's Lymphoma, and significantly expands the addressable population for Zevalin," said Rajesh C. Shrotriya, MD, chairman, chief executive officer, and president of Spectrum Pharmaceuticals in a company news release, adding, "We are confident that the strategic and tactical initiatives we have implemented will overcome the clinical, logistical, and reimbursement challenges that have previously hindered physician and patient access to Zevalin."

Ibritumomab tiuxetan previously was approved for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma.