Scientists at Fred Hutchinson Cancer Research Center in Seattle, Washington, successfully tested a mechanism that increases the number of progenitor cells extracted from a unit of human umbilical cord blood. The laboratory method potentially solves the 1- to 2-month delay in myeloid engraftment after cord blood transplantation (CBT). This delay, associated with increased transplant-related morbidity and mortality, currently discourages wider use of CBT for treating patients with leukemia and other hematologic malignancies.

Thirty percent of patients who need a transplant fail to find a donor match. Clinical studies suggest that umbilical cord blood stem cells do not need to match as precisely as stem cells from bone marrow and peripheral blood. Scientists have been unable to exploit this advantage, however, because cord blood contains about one-tenth the number of stem/progenitor cells as traditional transplant sources. This severely delays myeloid engraftment, leaving immune-compromised patients at an increased risk of developing life-threatening infections and death.

The Hutchinson Center scientists expanded the CD34+ hematopoietic stem cell count in units of cord blood to an average of 6 million cells per kilogram of the patient’s body weight. This massive increase over the standard 200,000 stems cells in cord blood brought the graft on par with bone marrow and peripheral blood.

In an ongoing phase I clinical trial, the enhanced cord blood units were administered to 10 patients (aged 3-43 y) with high-risk acute leukemia. Each patient received 1 unit of regular cord blood and 1 manipulated unit with an expanded cell count. The average time to engraftment for the expanded cord blood unit was 14 days after transplantation, which was 2 weeks shorter than the engraftment period for regular units. The expanded units also rapidly enhanced neutrophil recovery in the crucial period following transplantation, and 70% of patients remain alive with no evidence of disease and sustained, complete donor engraftment.

, says further testing and technological improvements are necessary to verify the trial results. The authors said that if the cord blood procedures are approved in the future, minority patients would benefit greatly, because 95% never find suitable donor matches.

Irwin Bernstein, MD, a member of the Hutchinson Center’s Clinical Research Division, developed the method for expanding the stem cell count, which involves activating the Notch signaling pathway in the stem cells. Data were first published in 2000. It took another decade to translate the laboratory findings to patients in a clinical setting.

“The real ground-breaking aspect of this research is that we have shown that you can manipulate stem/progenitor cells in the lab with the goal of increasing their numbers. When given to a person, these cells can rapidly give rise to white blood cells and other components of the blood system,” said Colleen Delaney, MD, assistant member of the Hutchinson Center’s Clinical Research Division and an assistant professor in the Department of Pediatrics at the University of Washington School of Medicine.

Delaney C, Heimfeld S, Brashern-Stein C, et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. 

Articles

Scientists at Fred Hutchinson Cancer Research Center in Seattle, Washington, successfully tested a mechanism that increases the number of progenitor cells extracted from a unit of human umbilical cord blood. The laboratory method potentially solves the 1- to 2-month delay in myeloid engraftment after cord blood transplantation (CBT).

Scientists Closer to Effectively Using Cord Blood to Treat Patients with Cancer

New data suggest that women who take aspirin regularly following a breast cancer diagnosis cut their risk of death and distant metastases by nearly 50%. The prospective observational Nurses’ Health Study (NHS) was conducted in collaboration by researchers from Brigham and Women’s Hospital (BWH), Dana-Farber Cancer Institute, and Harvard Medical School. The investigators said they found no preventative correlation between aspirin use and breast cancer incidence and cautioned that further research is needed before physicians recommend women with breast cancer take aspirin.

The ongoing NHS is designed to examine how lifestyle factors affect women’s health. For this analysis, investigators looked at data for a subset of 4164 women who are registered nurses and received a diagnosis of stage I, II, or III breast cancer between 1976 and 2002. The women were followed until June 2006, and during this period, there were 732 deaths, of which 341 were from breast cancer. Overall, there were 400 distant recurrences.

Starting in 1980, frequency of aspirin use was assessed every 2 years via a self-reported questionnaire. Usage categories included never, past, and current, and options for frequency of aspirin use included 1 day per week, 2 to 5 days per week, and 6 to 7 days per week. Women who never provided an aspirin assessment after diagnosis or for whom no baseline assessment was available were excluded from the analyses.

Most women (35%) who reported taking aspirin regularly did so to prevent heart disease. The exact dosage was not recorded, but the investigators said the typical dose used for heart disease prevention is ~81 mg per day. Other more commonly reported reasons included muscle or joint pain (16%), headache (13%), backache (7%), and menstrual cramps (1%).

The primary endpoints of the analyses included death from breast cancer, distant recurrence, and death from any cause. The study authors said aspirin use was associated with a reduced risk of death relative to never-aspirin users. Adjusted relative risk (RR) for 1 day of aspirin use per week compared with no use was 1.07 (95% CI, 0.70-1.63); for 2 to 5 days of use per week, RR was 0.29 (95% CI, 0.16- 0.52), and for 6 to 7 days of aspirin use per week, RR was 0.36 (95% CI, 0.24-0.54). Metastasis results were similar, with an adjusted RR of 0.91 (95% CI, 0.62-1.33) for 1 day of use compared to none; 0.40 (95% CI, 0.24-0.65) for 2 to 5 days of use; and 0.57 (95% CI, 0.39-0.82; test for trend, P = .03) for 6 to 7 days of aspirin use. When adjusting the analyses for variables associated with an increased risk of breast cancer death, such as stage, menopausal status, body mass index, and estrogen receptor status, results were similar.

NHS found no association between aspirin use and breast cancer incidence. In addition, women who had used aspirin for at least 5 years had a modest reduction in the risk of death from breast cancer. The investigators also looked for any relationship between breast cancer survival and distant metastasis with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and found indications of a protective effect from NSAIDs but none from acetaminophen.

Previous studies of the effect of aspirin and other NSAIDs on breast cancer survival rates and metastasis have produced mixed results. Although this inherently limited observational study did not conclusively determine the mechanism of aspirin’s action, investigators said one possible explanation for the risk reduction is that by inhibiting the enzyme cyclooxygenase, NSAIDs may suppress estrogen synthesis, thereby stunting breast cancer proliferation. Unique among NSAIDs, aspirin irreversibly inhibits cyclooxygenase. Another theory maintains aspirin’s anti-inflammatory effects may inhibit cancer growth.

“More research is needed to determine how aspirin, which is an NSAID, may work to prohibit the recurrence of breast cancer,” said Michelle Holmes, MD, DrPH, lead author of the paper and a researcher and associate professor of medicine at the Channing Laboratory at BWH, in a BWH press release.

The study’s authors urge women with breast cancer to discuss the risks and benefits of regular aspirin use with their physician before starting an aspirin regimen. Aspirin is known to interact with other medications, and it is associated with adverse effects, including gastrointestinal bleeding. They noted, however, that “aspirin has relatively benign adverse effects compared with cancer chemotherapeutic drugs and may also prevent colon cancer, cardiovascular disease, and stroke” and said it appears to affect estrogen receptor—positive and –negative tumors.

The investigators said further studies, possibly including a randomized trial of aspirin use after breast cancer diagnosis, were needed to confirm their findings and establish aspirin’s mechanism of action in breast cancer. Still, they remained optimistic about the study’s findings. “The ability to affect length and quality of life after breast cancer by a common medication would be welcome,” they wrote, concluding, “If confirmed, our results may broaden the scope of interventions available to reduce breast cancer—related morbidity and mortality.” The article was published online ahead of print in the 

New data suggest that women who take aspirin regularly following a breast cancer diagnosis cut their risk of death and distant metastases by nearly 50%.

Aspirin May Reduce Breast Cancer Metastasis and Mortality Rates

In a phase III study of 1052 patients, nanoparticle albumin-bound (nab) paclitaxel (Abraxane) produced significant improvement in the overall response rate compared with standard paclitaxel in the first-line treatment of patients with advanced non—small cell lung cancer (NSCLC). Both treatments were administered in combination with carboplatin. Investigators believe one reason why the trial met its primary endpoint is that the proprietary “nab” delivery system allows higher doses of paclitaxel to reach tumor locations than the standard formulation. Results of the randomized trial were submitted as a possible late-breaking abstract for the June annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.

The multicenter study included 102 sites worldwide, and its researchers consider it one of the largest NSCLC studies conducted to date. Said principal investigator Mark Socinski, MD, University of North Carolina Lineberger Comprehensive Cancer Center, in a press release, “This is exciting news for lung cancer patients and has important implications not only in late-stage cancer but also in earlier stages of the disease.”

In an interview with Socinski, he suggested the study might lead to practice changes down the road. “Given this data show superiority in response compared to the established treatment regime, these results show the potential for a new option for patients with NSCLC.” While exact details regarding trial outcomes will not be available until the June ASCO meeting, Socinski said, “The trial reached its primary endpoint… with regard to response rates.”

The prospects for FDA approval of Abraxane in NSCLC are enhanced by the trial’s special protocol assessment (SPA) status. SPA classification means that the FDA considers a trial’s design, clinical endpoints, and statistical analyses acceptable for approval provided the trial has a successful outcome. In this case, the FDA determined the demonstration of a statistically superior response rate to be a sufficient standard for submission of a supplemental new drug application (sNDA). With nab-paclitaxel outperforming paclitaxel, the path is clear for Abraxis to seek approval of nab-paclitaxel in combination with carboplatin as an initial treatment for NSCLC. Dr Socinski told

, “Abraxis BioScience is planning to file an sNDA for Abraxane in this indication in early 2011.”

The treatment of lung malignancies would be the second FDA-approved indication for nab-paclitaxel. In 2005, the FDA approved the drug as an injectable treatment for metastatic breast cancer after failure of combination chemotherapy that has spread or relapsed within 6 months of adjuvant chemotherapy with a combination regiment. Other indications for nab-paclitaxel currently being considered include malignant melanoma, pancreatic cancer, gastric cancer, and expanded applications for metastatic breast cancer.

In a phase III study of 1052 patients, nanoparticle albumin-bound (nab) paclitaxel (Abraxane)produced significant improvement in the overall response rate compared with standard paclitaxel in the first-line treatment of patients with advanced nonâ€“small cell lung cancer (NSCLC).

Nab-Paclitaxel Outperforms Paclitaxel in NSCLC

In a new report, published in the March issue of the 

, investigators led by Harold J. Burstein, MD, PhD, associate professor of medicine, Harvard Medical School, Cambridge, Massachusetts, say monotherapy with neratinib, an investigational tyrosine kinase inhibitor, demonstrated substantial clinical activity in patients with HER2-positive breast cancer with manageable toxicity (

). Burstein said the researchers studied neratinib in two groups of women with advanced HER2 positive breast cancer. “The first group [consisted of] women who had not previously received trastuzumab; neratinib made the cancer shrink in over half of these patients. In a group of women who previously had had trastuzumab, over one-quarter responded to neratinib,” said Burstein.

The open-label, multicenter, phase II trial administered 240 mg of neratinib once daily to 136 patients with advanced HER2-positive breast cancer. Patients were divided into two cohorts; 66 had prior treatment with trastuzumab (Herceptin) and 70 were trastuzumab-naive. The trial’s primary endpoint was 16-week progression-free survival, and at the end of this period, 63 patients in the prior-trastuzumab arm and 64 patients in the trastuzumab- naive arm were evaluable.

Based on an independent radiologic assessment, investigators reported a much higher rate and duration of PFS for patients that had not received trastuzumab previously and a higher objective response rate (ORR). In the trastuzumab-treated group, 59% of patients experienced 16-week PFS and PFS persisted a median of 22.3 weeks. Patients not treated previously with trastuzumab had a 16-week PFS rate of 78% and a median PFS of 39.6 weeks. ORR for prior trastuzumab patients was 24% (95% confidence interval [CI], 14%-36%) compared with 56% (95% CI, 43%-69%) for trastuzumab-naive patients.

Median onset of first complete response or partial response was 7.1 weeks in both groups, with 39 patients treated previously with trastuzumab experiencing tumor shrinkage compared with 52 that did not get trastuzumab therapy. Median duration of objective tumor response for the trastuzumab-treated cohort was 39.3 weeks (95% CI, 32.3 weeks-93.7 weeks) versus 52.4 weeks (95% CI, 33.1 weeks to not estimable) for the trastuzumabnaive cohort. In total, 14 patients (6 in the prior-trastuzumab arm and 8 in the trastuzumab-naive arm) achieved stable disease lasting ≥24 weeks. The clinical benefit rate was 33% for patients treated with trastuzumab and 69% for patients that were not.

The most common grade 3-4 adverse event was diarrhea, experienced by 30% of patients in the prior-trastuzumab cohort and 13% in the trastuzumab- naive cohort. Diarrhea occurred almost immediately, with a median time to onset of 2 to 3 days. Each episode lasted a median of 5 to 7 days. The diarrhea resulted in dose reductions for 29% of patients with prior trastuzumab treatment and 4% of patients with no prior trastuzumab treatment. Management with dose adjustment and antidiarrheal agents allowed 99% of patients to continue on neratinib, with 22 receiving neratinib for >1 year. Only 1 patient discontinued prior to 16 weeks. Additional adverse events included nausea, vomiting, and fatigue; and approximately 25% of patients developed mild skin rash. No incidents of grade 3-4 neratinib-related cardiotoxicity were reported. Burstein said, “Neratinib is quite well tolerated,” adding that “many patients develop mild diarrhea that is controlled with over-the-counter medications.”

Burstein noted that the distinct subset of HER2- positive tumors “have a more aggressive natural history than other kinds of breast cancers.” He described trastuzumab as an antibody against HER2 that is effective for HER2-positive cancers and explained that neratinib “is a different kind of anti-HER2 therapy” known as a dual-kinase inhibitor. “It is an oral medication that targets both the HER2 protein and a related protein, EGFR,” Burstein said.

“These results suggest that neratinib may be a potent drug for women with HER2-positive breast cancer,” said Burstein. He said the study’s findings “set the stage for ongoing trials that will compare neratinib against other dual-kinase inhibitors, or separately, study whether adding neratinib to trastuzumab is clinically valuable.”

Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. 

In a new report, published in the March issue of the Journal of Clinical Oncology, investigators led by Harold J. Burstein, MD, PhD, associate professor of medicine, Harvard Medical School, Cambridge,
Massachusetts, say monotherapy with neratinib, an investigational tyrosine kinase inhibitor, demonstrated substantial clinical activity in patients with HER2-positive breast cancer with manageable toxicity.

Neratinib in Patients with Advanced HER2-Positive Breast Cancer

Early-stage diagnosis gives patients their best chance against lung cancer. The rush to adopt lung cancer screening seems premature, however, because no randomized trials have definitively demonstrated that it improves survival outcomes. The National Lung Screening Trial (NLST), sponsored by the National Cancer Institute, aims to supply this data, with final results expected in ~1 year. In an ominous preview of what the trial might find, the NLST feasibility study, recently published in the 

, concluded that screening smokers for lung cancer using low-dose computed tomography (CT) scanning and chest radiography produced significant rates of false positives. The authors note that an incorrect screening result has physical, psychological, and economic consequences and warn clinicians to exercise caution in responding to a patient’s request for lung cancer screening.

From September 2000 to January 2001, the multicenter study recruited 3190 current or former smokers, aged 55 to 74 years (

). Eligible participants had smoked ≥30 pack-years (packs/day x years smoking) and continued to smoke or had quit within the past 10 years. Ensuring nearly identical age, sex, and smoking characteristics between the two cohorts, investigators randomly assigned individuals to receive low-dose CT scanning (n = 1610) or chest radiography (n = 1580). Patients were screened at baseline. Those with a negative baseline screening were rescreened 1 year later. In patients who underwent CT scanning, noncalcified nodes >3 mm at baseline or >4 mm at year 1 were considered suspicious for cancer. Other abnormalities could lead to a positive finding, at the discretion of a board-certified radiologist. With chest radiography, several signs were considered suggestive of cancer: nodules with circular opacity of ≤3 cm in diameter; masses >3 cm; hilar or mediastinal lymph node enlargement (excepting calcified nodes); major atelectasis; infiltrates or consolidation; and pleural masses. The accuracy of positive results was evaluated in subsequent analyses. After a single screening, the probability of a false-positive result was 21% (95% confidence interval [CI], 19%-23%) for CT scanning and 9% (95% CI, 8%-11%) for conventional chest radiography. With 2 screenings, the cumulative probability of a false positive jumps to 33% (95% CI, 31%-35%) for CT scanning and 15% for chest radiography (95% CI, 13%- 16%). In light of the increased push for lung cancer screening by hospitals, advocacy groups, and even the US Congress through the Lung Cancer Mortality Reduction Act of 2009, which asserts without substantiation that “significant and rapid improvements in lung cancer mortality can be expected through greater use and access to lung cancer screening tests,” these data are alarming.

The authors said it would have been impractical and even harmful to biopsy every patient in whom screening detected abnormalities but was not definitive. Instead, they relied on a complete diagnostic work-up to evaluate a positive result. A false-positive screening was defined as one followed by a negative work-up or no lung cancer diagnosis within 12 months. Though false-positive rates were relatively high, the researchers predicted even greater numbers would have been observed had the screening not been limited to 2 rounds, with 12 months of follow-up after the second screening. They attributed any correlations between patient demographics and falsepositive risk to the modest sample size, small subgroups, and any multiplicity potential of the multivariable analysis. A false-negative test was defined as a negative screening result followed by a lung cancer diagnosis within 12 months.

A primary concern with false positives is the invasive procedures that often ensue, such as unnecessary surgeries or biopsies that can, on rare occasions, lead to a collapsed lung, bleeding, infection, nerve damage, pain, and discomfort. In the subgroup of patients that received false-positive results, 4% who had CT screening and 3% who had chest radiography underwent moderately invasive procedures, with 2% of patients in each cohort having major surgical procedures. Additionally, patients with positive screenings often undergo further imaging studies, increasing their radiation exposure and risk of radiation-induced carcinogenesis. In the trial, 61% (n = 308) of patients in the CT arm and 51% (n = 110) of those in the chest radiography arm who had a false-positive result received additional imaging tests. In some cases, higher doses of radiation were used in conducting follow-up imaging studies than in the initial screening examination.

Beyond potential physical harm, false positives leave patients feeling anxious as they wait for definitive results. For patients, the period of diagnostic uncertainty can last up to 2 years and cost them thousands of dollars for additional testing. The potential psychological damage is unknown, and the increased medical expenditures have not been quantified. Lung cancer researchers hope that the discovery of other diagnostic techniques, such as biomarker tests, will improve the accuracy and feasibility of screening.

The enormity of the risks associated with lung cancer screening challenges the guiding principal of medical ethics, 

, or “First, do no harm.” Physicians are left weighing the current options and awaiting NLST results. In the meantime, the authors say it is important for providers to discuss the benefits and harms of current technologies with patients who request lung cancer screening.

Croswell JM, Baker SG, Marcus PM, Clapp JD, Kramer BS. Cumulative incidence of false-positive test results in lung cancer screening: a randomized trial. 

Early-stage diagnosis gives patients their best chance against lung cancer. The rush to adopt lung cancer screening seems premature, however, because no randomized trials have definitively demonstrated that it improves survival outcomes. The National Lung Screening Trial (NLST), sponsored by the National Cancer Institute, aims to supply this data, with final results expected in ~1 year.

By Jason Broderick

Articles

Scientists Closer to Effectively Using Cord Blood to Treat Patients with Cancer

Aspirin May Reduce Breast Cancer Metastasis and Mortality Rates

Nab-Paclitaxel Outperforms Paclitaxel in NSCLC

Neratinib in Patients with Advanced HER2-Positive Breast Cancer

Lung Cancer: To Screen or Not to Screen?