TARGETS FOR BREAST CANCER BONE METASTASIS

Src

• Src activity regulates many pro-metastatic abilities of breast cancer cells and is also required for the generation of functional, bone-resorbing osteoclasts, making it an ideal candidate for therapeutic intervention for breast cancer bone metastasis.
• A Src-related gene expression signature has been identified in a subset of primary breast tumors and is highly predictive of the development of bone metastases. Several Src inhibitors are being tested in clinical trials, with many more in preclinical development.

TGF-β

• The TGF-β pathway is believed to exert opposing roles during cancer progression, acting as a growth inhibitor in normal epithelium and as a promoter of cancer invasiveness and metastasis as the disease progresses. Ample data exists to support both of these roles, and the diverse, often opposing effects, of TGF-β signaling on both cancer cells and cells within the tumor microenvironment make this a challenging pathway to target therapeutically. However, the large body of data pointing to the ability of this pathway to augment breast cancer metastasis will justify the continued development and testing of TGF-β inhibitors for use as anticancer agents.

Receptor activator of NF-κB ligand

• Receptor activator of NF-κB ligand (RANKL) is a critical mediator of osteoclast formation and is commonly deregulated during the process of breast cancer bone metastasis. Denosumab, a RANKL-neutralizing antibody, has demonstrated superior efficacy as an antiresorptive agent when compared with bisphosphonates. This agent is currently being investigated as an antibone metastatic therapy in PhaseIII clinical trials for patients with breast cancer or multiple myeloma.

Cathepsin K

• Cathepsin K is a proteolytic enzyme produced by osteoclasts, and contributes to the Collagen I degradation that occurs during bone resorption.
• Cathepsin K may facilitate breast cancer cell invasion.
• Odanacatib is a highly specific Cathepsin K inhibitor that is currently being investigated for its utility in treating numerous disorders that are characterized by excessive bone resorption.

CXCR4

• CXCR4 is a G-protein-coupled receptor commonly expressed in breast cancer cells that can facilitate the development of bone metastasis. It is also expressed by hematopoietic precursor cells and promotes their retention in the bone marrow.
• While CXCR4 inhibition may diminish the pro-metastatic abilities of breast cancer cells and promote the mobilization of hematopoietic precursor cells, it may also result in increased osteoclast activity. Thus, the effects of pharmacological CXCR4 inhibitors, such as plerixafor and CTCE-9908, should be investigated with respect to these undesirable effects on the promotion of bone resorption if they are to be used as antibone metastasis therapies.

Glycoprotein nonmetastatic B

• Glycoprotein nonmetastatic B (GPNMB) is a novel target expressed on the surface of breast cancer cells, which can promote bone metastasis in vivo. Its role in bone physiology is beginning to be elucidated and appears to be required for osteoblast and osteoclast function. CDX-011 is a GPNMB-targeted antibody drug conjugate that is yielding promising results in PhaseII trials for the treatment of metastatic breast cancer.

EGF-family ligands

• Recent data suggests that EGF initiated signaling can have profound effects on bone resident cells, including their ability to impair osteoblast differentiation and promote osteoclast formation. The net effect is to promote conditions that favor breast cancer induced osteolysis during the formation of breast cancer bone metastasis. A re-evaluation of therapeutic agents designed to impair EGFR signaling, which have displayed modest effects in treating primary breast cancer, may be warranted in the context of breast cancer metastasis to bone.

MELOXICAM FOR EXTRAABDOMINAL DESMOID TUMORS

January 5, 2010 — Meloxicam (Mobic), a cyclooxygenase (COX)-2 inhibitor drug used for arthritis, has shown promise as a treatment for extraabdominal desmoid tumors, according to the results of a small pilot study.

The study results, which were published online December 21 in the Journal of Clinical Oncology, showed that of 20 patients treated with meloxicam who were available for evaluation, 19 (95%) had a final status of stable disease or better.

Extraabdominal desmoid tumors are generally sporadic in nature and can occur in virtually any body site, note the authors. However, they are primarily found in the extremities, chest, abdominal wall, and neck. They can be locally aggressive and invasive to surrounding anatomic structures, leading to pain, functional impairment, and deformity.

Management usually involves a multidisciplinary approach that includes surgery and radiation, but these have potential associated morbidities. This has led to investigations of both cytotoxic and noncytotoxic chemotherapy, but because the tumors are rarely fatal, finding a pharmacologic treatment with fewer complications is desirable, according to the authors.

"We recommend meloxicam for patients with extraabdominal desmoid tumors, instead of surgery first," said lead author Yoshihiro Nishida, MD, PhD, from the Department of Orthopedic Surgery at Nagoya University Graduate School of Medicine in Japan.

"However, our study included only a small number of patients, so if tumors do not respond to meloxicam treatment, we would then use surgery or other modalities such as radiotherapy or chemotherapy," he told Medscape Oncology.

Meloxicam Induced Responses, Well Tolerated

The authors hypothesized, on the basis of previous studies, that COX-2 might be a potential therapeutic target. Experimental in vitro and in vivo research demonstrated decreased cell proliferation in desmoid cell cultures and small tumors when COX-2 was blockaded with pharmacologic agents.

In this study, between 1991 and 2003, Dr. Nishida and colleagues identified 30 patients who were surgically treated for extraabdominal desmoid tumors at their institutions (excluding those with intraabdominal, familial adenomatous polyposis-associated, and unresectable tumors). Because of the high rate of relapse after surgery (53%), 22 patients have been prospectively treated with meloxicam since 2003.

None of the 22 patients had a known history of gastrointestinal disorders, such as gastritis or gastric ulcer, and no one in the cohort was receiving hormonal medications. Baseline imaging of desmoid tumors by magnetic resonance imaging (MRI) was obtained prior to beginning treatment with oral meloxicam 10 mg/day.

Patients were followed with physical examinations and MRI and/or computed tomography every 3 to 6 months, and meloxicam was administered for a median of 20 months (range, 3 to 66 months). Of this group of 22, 2 patients discontinued treatment because of adverse events and were not included in the final evaluation.

Among the 20 patients evaluated, the researchers observed 1 complete response, 7 partial responses, 11 patients with stable disease, and 1 patient who had progressive disease. Although the 2 patients who discontinued treatment were not included in the evaluation, they had stable disease at the time they stopped the therapy. Patient sex, tumor size, tumor site, follow-up interval, and period of medication were not significant prognostic factors of responsiveness. However, age appeared to play a role; good responders were significantly older than poor responders (P = .0091).

Meloxicam was well tolerated and none of the patients in the final analysis experienced any adverse effects. Of the 2 patients who discontinued treatment, 1 did so because of mild gastritis, and the other was elderly with had a history of cerebral infarction and suffered from intermittent pneumonia and diarrhea.

Surgery remains the mainstay for resectable sporadic desmoid tumors, especially extraabdominal ones, the authors write, and there is growing evidence that chemotherapy might be effective in managing life-threatening intraabdominal desmoid tumors. "However, the significant morbidity of aggressive chemotherapy should be avoided in patients with extraabdominal desmoids tumors," they say.

The authors point out that this was a prospective and consecutive-case–control study with a small number of patients. Even though 95% of the patients achieved stable disease or better, they note that they still cannot conclude that these results were "solely attributable to the meloxicam itself."

However, they add that it was crucial to prove that meloxicam had potential for treating extraabdominal desmoid tumors before undergoing a large placebo-controlled trial.

Further investigations are needed, but on the basis of these results, the authors recommend "meloxicam as the initial treatment for patients with extraabdominal desmoid tumors."

Unfortunately, these results cannot be extrapolated to children. "In the pediatric population, a pilot study is necessary," said Dr. Nishida. "Currently, we do not recommend meloxicam treatment for pediatric patients with extraabdominal desmoids tumors."

The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online December 21, 2009. Abstract

CT IMAGING AND CANCER RISK

The use of computed tomographic (CT) scans has increased dramatically over the last few decades. Regardless of the recognized benefits from the radiologic definitions achieved with this technology, there is growing concern about radiation exposure associated with CT imaging, particularly with the lifetime attributable risk for radiation-related secondary cancer development. Conservative estimates are that more than 60 million CT examinations are done yearly in the United States, representing an estimated 70% of all medical x-ray exposure. Since the development of the first commercial CT scanners in 1972, CT has become the major source of medical radiation.

The potentially harmful consequences of ionizing radiation are divided into deterministic and stochastic effects.^[1] Deterministic effects of ionizing radiation result from cell and tissue death. Such changes occur only at doses above a certain threshold and are proportional to the dose given. Radiation doses from medical diagnostic procedures are usually far below this threshold, but adverse effects, such as skin burns, have been reported after interventional procedures that use fluoroscopy. The term stochastic radiation effect refers to irradiated cells that are modified rather than killed. Modified cells may develop into cancer after a latency period of years. In principle, stochastic effects have no threshold. Exposed individuals do not incur ill effects with certainty, but they have a higher statistical chance for toxicity, including cancer. The doses delivered in diagnostic procedures are large enough to cause stochastic radiation effects, and the probability increases with the magnitude of the dose.

Although exact risk estimates related to low doses of radiation exposure are difficult to ascertain, the ionizing radiation exposure from a single abdominal or chest CT scan may be associated with elevated risk for DNA damage and cancer formation.^[2] The seventh National Academy of Science report on Biological Effects of Ionizing Radiation estimated that a single dose of 10 mSv produces a lifetime risk of developing a solid cancer or leukemia of 1 in 1000.^[3]

Two recently published studies^[4,5] further addressed the issue of CT-related radiation exposure. A multicenter study sponsored by the US National Institutes of Health and the National Cancer Institute in Bethesda, Maryland, estimated the number of cancers that would arise from all CT studies performed in the United States during the year 2007.^[4] Risk models with organ-specific radiation exposures were used to estimate age-specific cancer risks for each type of CT scan. Overall, approximately 29,000 future cancers could be related to CT scans performed in 2007 alone. The largest contributions to incident cancers were from abdominal and pelvic scans (14,000 cancers), followed by chest CT (41,000 cancers), head CT (4000 cancers), and CT angiography (2700 cancers). One third of the projected cancers were the result of CT exposure from ages 35 to 54 years, and 15% were related to exposure in patients younger than 18 years of age.

A second retrospective cross-sectional study evaluated the radiation doses received by 1119 consecutive adult patients who had diagnostic CT.^[5] The study authors were surprised to find that radiation doses for common CT exams were higher and far more variable than previous estimates. Within each type of CT study, effective doses varied significantly both within and across institutions, with a mean 13-fold variation between the highest and lowest dose for each study type. The overall median dose of radiation for a routine abdomen/pelvis CT scan with contrast ranged from 12 mSv to 20 mSv, and for multiphase abdomen and pelvis CT scans, the dose ranged from 24 mSv to 45 mSv. These documented figures are considerably higher than those previously cited for abdominal CT radiation exposure (5-10 mSv). The investigators then estimated the number of patients who had each type of CT scan and the development of radiation-induced cancers. The risk for CT-related cancer varied by sex, age, and study type. There was a higher cancer risk in women and in patients with exposure at earlier ages. CT angiography was associated with the highest relative risk (1 cancer for every 150 examinations in 20-year-old women). The relative risks for CT of the abdomen are shown in the Table.

Table. Relative Risks for Cancer After Abdominal CT

CT Study	20 Years		40 Years		60 Years
	Female	Male	Female	Male	Female	Male
Abdomen/pelvis (with contrast)	1/470	1/620	1/870	1/942	1/1320	1/1250
Multiphase abdomen/pelvis	1/250	1/330	1/460	1/498	1/700	1/660

CT = computed tomography

Viewpoint

Advances in radiologic imaging have fundamentally changed the approach to diagnostic evaluation of patients with many disorders. With continuing growth in radiography, medical providers should be aware of the potential for radiation risk associated with CT scanning.

The popularity of CT imaging is high for many reasons, ranging from its speed and ease of use, to the relentless development of new imaging techniques, and finally to a growing body of evidence showing its images to be reliable for diagnosis. Unfortunately, drivers of increasing scan volumes also include financial rewards -- particularly for in-office procedures and the practice of defensive medicine -- resulting in unnecessary scans to minimize the threat of a lawsuit resulting from a missed diagnosis.

As these 2 studies made clear, radiation doses are higher than previously thought. They also demonstrated that radiation dose reduction is not yet a universal phenomenon and raised further doubt about whether the risk-benefit ratios and alternatives to CT scanning are seriously considered for every patient and CT scan.

In a recent article,^[6] we suggested that patients and physicians need to discuss the choice for radiologic imaging and the relative risks associated with this choice. This is particularly important for discussions of screening in asymptomatic patients. Furthermore, both physicians and patients need to be cognizant of previous radiation exposure as well as the age when the previous exposures occurred. Because radiation-related risks may be cumulative over time, this information should become a key element of the patient's medical history. Most healthcare providers do not think of potential "downstream" radiation-related consequences of diagnostic and screening radiologic imaging that may occur decades later. Therefore, it is time for a paradigm shift in the way in which we approach the use of CT imaging as we balance the risk-benefit profile for our patients!

GFR ESTIMATION

Question

Is a value of 150 or 160 mL/min really accurate when using the Cockcroft and Gault equation to calculate creatinine clearance (CrCl)?

Response from Michael J. Postelnick, BSPharm
Senior Infectious Diseases Pharmacist, Clinical Coordinator, Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois

An accurate estimate of a patient's glomerular filtration rate (GFR) is a critical element in the safe and effective dosing of renally eliminated medications. Serum creatinine, which is an endogenous marker of glomerular filtration, is commonly used to help estimate the GFR. The GFR estimate is derived using either the Cockcroft-Gault^[1] or modification of diet in renal disease (MDRD) equation.^[2] The MDRD equation estimates the GFR directly, whereas the Cockcroft-Gault equation estimates creatinine clearance (CrCl). CrCl is the parameter most often used in clinical trials to determine dose adjustments for renally eliminated medications.

Many problems are associated with using estimation equations^[3]:

1. The use of the filtration marker creatinine, which is generated by the breakdown of creatine in muscle, limits both estimation equations.
2. Patient-to-patient variation in muscle mass and diet have a significant effect on creatinine generation and subsequent clearance estimates produced by these equations.
3. CrCl slightly overestimates the GFR due to the fact that creatinine is not only filtered by the glomerulus but also secreted by the proximal tubule.
4. In patients with acutely increasing serum creatinine, the CrCl and GFR are overestimated, whereas in patients with declining serum creatinine, the CrCl and GFR are underestimated.
5. CrCl and GFR equations are less accurate at higher levels of the estimated CrCl and GFR.

Given the aforementioned list, there are reasons that clinicians should be circumspect of extremely elevated estimates:

1. The highest CrCl value for participants in the Cockcroft and Gault study was 130 mL/min^[1]; the highest value in the MDRD study was 90 mL/min/1.73 m².^[2] The accuracy of values higher than those from which the estimating equation was derived and tested is likely to be suboptimal.
2. Patients with altered muscle mass caused by poor nutrition, paralysis, amputation, or deconditioning due to chronic illness will have decreased creatinine production. This will result in lower serum creatinine values than would be expected for a similar patient without altered muscle mass. Estimating the CrCl or GFR using these values will result in an overestimate that can be quite significant.

Due to all the potential factors that affect calculated CrCl or GFR estimates, it is important for the clinician to use judgment when using these values to adjust drug dosages. Rather than blindly following recommendations derived from calculated estimates, careful assessment of the clinical status of the patient and the desired therapeutic outcomes as well as the risks associated with subtherapeutic or supratherapeutic doses of the pharmacologic agent must always be considered. When possible, drug level monitoring will give more accurate guidance to ensure appropriate dosing.

[ CLOSE WINDOW ]

References

1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. Abstract
2. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470. Abstract
3. National Kidney Foundation. Frequently asked questions about GFR estimates. Available at: http://www.kidney.org/professionals/kls/pdf/faq_gfr.pdf Accessed December 17, 2009.

ANTICOAGULANTS FOR PROSTATE CANCER?

November 5, 2009 (Chicago, Illinois) — Anticoagulants are indicated for the treatment of cardiovascular disease but might have a role to play in prostate cancer.

Anticoagulants, including aspirin, warfarin, and clopidogrel, were associated with improved biochemical control of localized prostate cancer in men treated with radiation therapy, according to a new retrospective study of 662 men.

The potential benefit is most pronounced in patients with high-risk localized disease, according to the study's lead author, who presented a poster here at the American Society for Radiation Oncology 51st Annual Meeting.

The current study looked only at men with prostate cancer treated with radiation, not with surgery, explained Kevin S. Choe, MD, PhD, from the University of Chicago Pritzker School of Medicine in Illinois.

The benefit seen in men who undergo radiotherapy while taking anticoagulants likely stems from an "interaction" between the radiation and the drugs, reported Dr. Choe.

At 4 years, biochemical control, or the absence of biochemical relapse as measured by prostate-specific antigen testing, was statistically significantly better in the group of prostate cancer radiotherapy patients receiving anticoagulants than in the group not receiving the blood-thinning therapy (91% vs 78%; P = .0002).

"We need more data before recommending that men undergoing radiotherapy consider taking anticoagulants," said Dr. Choe. However, the young investigator, who is a resident in radiation oncology at the University of Chicago, also put a positive spin on the results. "Those men with localized prostate cancer who already are on anticoagulants for cardiovascular disease may receive additional benefit when they undergo radiotherapy."

An expert in cancer and anticoagulants approached by Medscape Oncology for comment believes that the use of these agents holds considerable promise in oncology. "There is much that can be done that is low cost and effective," said Leo R. Zacharski, MD, from the White River Junction VA Medical Center in Vermont and the Dartmouth School of Medicine in Hanover, New Hampshire.

There is a "very large" literature on the subject, said Dr. Zacharski, citing the "dramatic effects" of anticoagulants on small-cell lung cancer as an example. "It is too bad that few people pay attention to the literature on this," opined Dr. Zacharski.

Dr. Zacharski also had a theory about the current findings. "In my opinion, the most likely explanation for the findings is that people who take anticoagulants tend to have slightly increased blood loss, which reduces the amount of iron in their bodies," he said.

In a randomized trial of iron reduction in men with peripheral arterial disease, Dr. Zacharski and colleagues found a statistically significant reduction in new cancer diagnosis and cancer-specific mortality (J Natl Cancer Inst. 2008;14:996-1002). The effect was seen for prostate cancer as well as other cancers, he said.

he current study was an outgrowth of another study in prostate cancer patients, in which Dr. Choe and colleagues investigated rectal bleeding. Prostate cancer patients treated with radiotherapy while taking anticoagulants had a significantly higher risk for this bleeding than patients not taking anticoagulants, he said.

Given this complication, if anticoagulants were ever to be recommended for use in these men, "it would need to be planned out very carefully," said Dr. Choe.

Subgroup Analysis: Benefit Only Significant in High-Risk Men

The new study looked at men with localized prostate cancer, Dr. Choe noted. This is appropriate, suggested Dr. Zacharski, who said that "established prostate cancer does not respond to anticoagulants."

The study cohort consisted of 662 patients with prostate cancer who were treated with radiotherapy at the University of Chicago from 1988 to 2005. Of these men, 243 were receiving warfarin, clopidogrel, and/or aspirin. Most of the men were receiving aspirin alone (n = 161) or warfarin alone (n = 42).

The men were treated with seed implants and/or external-beam radiation. The type of radiation received did not influence biochemical control outcomes, said Dr. Choe. About half the men also received short-term androgen-deprivation therapy.

Among the 243 patients, risk was low in 38%, intermediate in 38%, and high in 25%, according to National Comprehensive Cancer Network criteria.

In a subgroup analysis, the improvement in biochemical control was apparent among low- and intermediate-risk men taking anticoagulants, compared with the respective risk groups of men not taking the drugs.

However, biochemical control was only statistically significant in the high-risk men (n = 165). In that subgroup, the men taking anticoagulants (n = 52) had a 4-year rate of freedom from biochemical recurrence (i.e., biochemical control) of 82.4%, compared with 57.6% of those not taking anticoagulants (n = 113; P = .0007).

"The benefit of biochemical control appears to be most pronounced in men with localized high-risk disease," said Dr. Choe.

Anticoagulants had another benefit in the study: the drugs were associated with a reduced rate of metastasis.

The distant metastasis rate at 4 years was lower in the group taking anticoagulants than in the group not taking anticoagulants (1% vs 5%; P = .0248). "Anticoagulants may inhibit a tumor's ability to spread," said Dr. Choe, adding that "mounting preclinical evidence" supports this hypothesis.

Dr. Choe and Dr. Zacharski have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Abstract 2269. Presented November 2, 2009

TELOMERASE INHIBITORS IN ACTION

Experimental Drug May Help in Brain, Prostate Cancers
Study finds that imetelstat targets mechanism that allows cancer cells to divide

MONDAY, Jan. 4 (HealthDay News) -- An experimental drug called imetelstat shows promise in treating glioblastoma brain cancer and prostate cancer, according to the results of preclinical studies in which the drug was tested on human prostate cancer cells and in rodents with glioblastoma.

Researchers from the University of Texas Southwestern Medical Center found that the drug had an effect on most tumor cells, as well as cancer stem cells believed to cause most of a cancer's growth. Tests in mice with glioblastoma also showed that the drug was able to cross from the bloodstream into the brain. Most drugs cannot cross the blood-brain barrier.

The glioblastoma study is published in the January issue of Clinical Cancer Research, and the prostate cancer study was published online in the International Journal of Cancer.

Imetelstat (also called GRN163L) is being tested in clinical trials as a treatment for breast cancer, lung cancer and lymphocytic leukemia. The drug targets a mechanism that allows cancer cells to continue dividing.

"Because it attacks a mechanism that's active in most cancers, it might prove to be widely useful, especially when combined with other therapies," Dr. Jerry Shay, a professor of cell biology at the university and senior co-author of both studies, said in a university news release.

PPIs FOR BARRETT'S ESOPHAGUS

NEW YORK (Reuters Health) Jan 01 - Proton pump inhibitors (PPIs) can reduce the risk of high-grade dysplasia and neoplasia in patients with Barrett's esophagus, according to a new retrospective study.

On the other hand, patients who took non-steroidal anti-inflammatory drugs (NSAIDs) had only a non-statistically significant reduction in risk, and statins did not show any effect, Dr. Dang M. Nguyen of the Michael E. DeBakey Veterans Affairs Medical Center in Houston and his colleagues found.

Barrett's esophagus patients are at 30- to 125-fold greater risk of esophageal adenocarcinoma than the general population, Dr. Nguyen and his team note in the December issue of Clinical Gastroenterology and Hepatology.

Researchers have suggested that suppressing acid to limit esophageal inflammation could prevent neoplasia, because of the link between chronic inflammation and cancer. That means that PPIs and NSAIDs could be protective. And other studies have found that statins inhibit proliferation and induce apoptosis in esophageal carcinoma cells.

However, there are few data on the effectiveness of various medications. To investigate, the researchers looked at 344 patients diagnosed with Barrett's esophagus between 1982 and 2004. Mean follow-up was 7.6 years, and totaled 2,620 patient-years. During that time, 33 of the study participants developed high-grade dysplasia or esophageal adenocarcinoma.

After being diagnosed with Barrett's esophagus, 67.2% of patients had been prescribed PPIs (mean duration of use, 5.1 years); 51% were prescribed an NSAID or aspirin (3.6 years); and 25.3% were prescribed statins (2.8 years).

After adjusting for gender, age at Barrett's esophagus diagnosis, and Barrett's esophagus length, patients who had filled their PPI prescriptions were at 61% lower risk of high-grade dysplasia or esophageal adenocarcinoma.

Patients who had filled at least one NSAID or aspirin prescription were 44% less likely to develop dysplasia or neoplasia, but that risk reduction was not statistically significant. There was no association between statins and dysplasia or neoplasia risk.

"This cohort study suggests that PPI therapy may reduce the incidence of high-grade dysplasia or esophageal carcinoma in patients with Barrett's esophagus," Dr. Nguyen and his team write. "NSAIDs/aspirin may also have a role as chemopreventive agents in Barrett's esophagus."

Evidence from this and other studies supports the use of acid-suppressing drugs to treat symptoms in Barrett's esophagus patients, but does not warrant "high-dose PPI therapy beyond that needed for symptom relief and mucosal healing," Dr. Douglas A. Corley of Kaiser Permanente in San Francisco writes in an accompanying editorial.

While aspirin use is supported for patients who have other indications for antiplatelet therapy, he adds, there is insufficient evidence to support its use in Barrett's esophagus patients who are not at increased risk of cardiovascular disease.

Clin Gastroenterol Hepatol 2009;7:1266-1268,1299-1304.

DIAMANTIDOU SPEAKING

Eur J Surg Oncol. 2009 Dec 28. [Epub ahead of print]

A phase II study of cetuximab, capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer.

Velenik V, Ocvirk J, Oblak I, Anderluh F.

Department of Radiotherapy, Institute of Oncology, Ljubljana, Slovenia.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) reduces local tumor recurrence in locally advanced rectal cancer (LARC). This phase II study assessed neoadjuvant cetuximab with capecitabine-based CRT in LARC. METHODS: Patients with stage II/III LARC received capecitabine 1250 mg/m(2) twice daily for 2 weeks followed by intravenous cetuximab 400 mg/m(2) at week 3, then weekly intravenous 250 mg/m(2) cetuximab plus CRT including capecitabine 825 mg/m(2) twice daily (including weekends during radiotherapy) with radiotherapy of 45 Gy (25 x 1.8 Gy), 5 days a week for 5 weeks. Total mesorectal excision was scheduled 4-6 weeks following completion of CRT. The primary endpoint was pathological complete response (pCR). RESULTS: Thirty-seven patients were eligible for safety and efficacy. TMN staging at baseline was: T4N2, 11%; T3N2, 40%; T2N2, 3%; T3N1, 35%; T2N1, 3% and T3N0 8%. The most common adverse events included, grade 1/2 acneiform skin rash (86%), and grade 3 radiodermatitis, (16%), diarrhea (11%) and hypersensitivity (5%). pCR was achieved in 3 patients (8%). Overall-, T- and N-downstaging rates were 73%, 57% and 81% respectively. Total sphincter preservation rate was 76%, and 53% in 17 patients whose tumors were located within 5 cm from the anal verge. Non-fatal perioperative complications occurred in 13 patients (35%) with delayed wound healing occurring in 6 patients (16%). One death was recorded due to sepsis following colonic necrosis. CONCLUSION: Neoadjuvant cetuximab with capecitabine-based CRT is tolerable in patients with resectable LARC. Whilst the pCR rate was similar to recent reports, a high pathological downstaging rate was achieved. Copyright © 2009 Elsevier Ltd. All rights reserved.

MANAGMENT OF BARRETT'S ESOPHAGUS

December 31, 2009 — Strategies and recommendations for diagnosing and managing Barrett's esophagus are presented in a review published in the December 24 issue of the New England Journal of Medicine.

"Barrett's esophagus is a premalignant lesion detected in the majority of patients with esophageal and gastroesophageal adenocarcinoma — cancers that are associated with a low rate of survival (5-year survival rate, 15 to 20%)," writes Prateek Sharma, MD, from the Veterans Affairs Medical Center and University of Kansas School of Medicine in Kansas City. "The risk of esophageal adenocarcinoma is 30 to 40 times as high among patients with Barrett's esophagus as among patients without this condition. The progression of Barrett's esophagus may involve the development of low-grade dysplasia and high-grade dysplasia before the eventual development of cancer."

In the United States, the incidence of esophageal adenocarcinoma has been increasing. Although the prevalence of Barrett's esophagus in the general US population is unknown, Barrett's esophagus is diagnosed at endoscopy in approximately 10% to 15% of patients referred for this test. In 1 report of endoscopic screening in patients without chronic reflux symptoms, the prevalence of Barrett's esophagus was 5.6%.

Based on extrapolation from a population-based study in Sweden, 1.5 to 2.0 million adults in the United States may have Barrett's esophagus. Risk factors for Barrett's esophagus include older age, male sex, white race, reflux symptoms, and obesity, whereas drinking red wine, infection with Helicobacter pylori, and black race may be protective.

Some gastroenterology societies recommend endoscopic screening for Barrett's esophagus in patients with symptoms of chronic reflux, but such screening is controversial because the absolute risk for esophageal adenocarcinoma is low in these patients; Barrett's esophagus may develop without chronic reflux symptoms; and there is no evidence that endoscopic screening lowers mortality rate from esophageal adenocarcinoma.

Barrett's esophagus is diagnosed by endoscopy and graded with use of the Prague circumference and maximum (C and M) criteria, which is a standardized, validated system based on the circumferential and maximal extent of the columnar-lined esophagus. Mucosal biopsy specimens from the columnar segment are used to identify metaplastic or neoplastic epithelium. Sites for biopsy should include any visible mucosal abnormalities as well as a systematic 4-quadrant biopsy protocol, with specimens obtained every 2 cm along the extent of the Barrett's esophagus.

Clinicians should counsel patients with Barrett's esophagus that they are at increased risk for the development of esophageal adenocarcinoma but that this risk is low. Based on recent evidence, this risk is approximately 0.5% per year, or from 0.6% to 1.6% per year in patients with low-grade dysplasia. Most patients with low-grade dysplasia identified endoscopically no longer have evidence of dysplasia on the next endoscopic examination. In patients with high-grade dysplasia, however, the risk for the development of esophageal adenocarcinoma is high (approximately 6.6 cases per 100 patient-years).

Most patients with Barrett's esophagus should undergo endoscopic surveillance with detailed inspection and systematic biopsies. When making clinical decisions, however, the clinician should consider patient age, comorbid conditions, and life expectancy, recognizing the lack of proof that such surveillance lowers mortality rates because of esophageal adenocarcinoma.

Frequency of surveillance can probably be reduced to once every 3 years in patients with nondysplastic Barrett's esophagus who have at least 2 endoscopic examinations with no evidence of disease progression. Annual surveillance is typically recommended for patients with low-grade dysplasia in whom an advanced lesion has been ruled out.

Enhanced optical imaging techniques may improve the efficiency and accuracy of endoscopic surveillance, although head-to-head comparisons with standard endoscopy are generally lacking. Enhanced techniques that may be promising include narrow-band imaging (electronic chromoendoscopy) and confocal laser endomicroscopy.

To manage reflux symptoms and heal erosive esophagitis in patients with Barrett's esophagus, use of proton-pump inhibitors for acid suppression and/or surgery to correct reflux may be helpful. However, evidence to date has not proved that these treatments are associated with a lower risk for neoplastic progression.

"Indications for antireflux surgery in patients with Barrett's esophagus are the same as those in patients with chronic reflux (e.g., a lack of response to or an inability to tolerate proton-pump inhibitors); the presence of Barrett's esophagus should not be viewed as an indication for antireflux surgery," Dr. Sharma writes. "The primary goal of both treatment with proton-pump inhibitors and surgery is symptom control; 24-hour pH monitoring to document normalization of exposure to esophageal acid is not routinely recommended."

Endoscopic treatment or surgical resection should be considered in patients with high-grade dysplasia. Because of high risk for progression and high prevalence of coexisting adenocarcinoma, esophagectomy is generally recommended.

Neoplastic lesions associated with Barrett's esophagus should be removed by mucosal ablative techniques, which may include photodynamic eradication therapy, radiofrequency ablation, cryoablation, or argon plasma coagulation. Eradication therapy is associated with a complication rate of 10% to 15%, with adverse effects including chest pain, odynophagia, strictures, perforation, and bleeding.

"Among patients with esophageal adenocarcinoma, endoscopic eradication therapy should be considered only for those with mucosal disease, in whom the rate of lymph-node metastasis is extremely low (≤3%); once the cancer invades the submucosa, the risk of lymph-node metastasis at diagnosis increases to 20 to 25%," Dr. Sharma writes. "Endoscopic eradication therapy is not currently recommended in patients with nondysplastic Barrett's esophagus. Because of the overall low risk of esophageal adenocarcinoma among patients with Barrett's esophagus, if the procedure is confirmed to be preventive, the estimated number of patients who would need to be treated to prevent one case of esophageal adenocarcinoma would be 250 or more."

The American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, the British Society of Gastroenterology, the French Society of Digestive Endoscopy, and the Society for Surgery of the Alimentary Tract have published guidelines for the management of Barrett's esophagus, which are generally consistent with the clinical recommendations offered in this review article.

"Given the low overall risk of neoplastic progression of Barrett's esophagus, there is an interest in biomarkers that might identify persons at particular risk for the development of cancer," Dr. Sharma concludes. "Among biomarkers reported to be predictive of neoplastic progression are abnormalities in the tumor-suppressor genes CDKN2A (which encodes the cyclin-dependent kinase inhibitor p16INK4a) and TP53 (which encodes tumor protein p53), and the presence of tetraploidy or aneuploidy in epithelial cells. However, data are needed from large prospective studies to confirm the predictive value of these and other markers, and they are not currently used in routine clinical management."

Dr. Sharma has received consulting fees from AstraZeneca, Santarus, and Takeda and grant support from Given Imaging, Barrx Medical, Olympus, Cogentus, Mauna Kea Technologies, and Takeda.

N Engl J Med. 2009;361:2548-2556.

SWITCH OF AI ON MUSCULOSKELETAL SYMPTOMS

Breast Cancer Res Treat. 2009 Dec 25. [Epub ahead of print] Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (articular tolerance of letrozole) study. Briot K, Tubiana-Hulin M, Bastit L, Kloos I, Roux C. Rheumatology Department, Cochin Hospital, Rheumatology Department, Paris Descartes University, 27 rue Faubourg Saint Jacques, 75014, Paris, France. The objective of the present study was to evaluate the effect of the switch of aromatase inhibitors (AIs) on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer. This was a 6-month, prospective, non-randomized, multicenter study. Patients who had discontinued anastrozole due to musculoskeletal symptoms were eligible to participate in this study, and received letrozole, which was initiated 1 month after anastrozole discontinuation. Musculoskeletal symptoms were systematically assessed for severity, location of the symptoms, presence of swelling and of morning stiffness by the oncologist patients when patients stopped taking their anastrozole, 1 month after the discontinuation of anastrozole, and 1, 3, and 6 months after initiating the letrozole therapy. The primary endpoint was the percentage of patients who discontinued letrozole due to the severe musculoskeletal symptoms. After switching from anastrozole therapy, and at the end of the 6-month letrozole treatment, 128 (71.5%) out of 179 patients (61.3 +/- 8.4 years) continued with letrozole. Fifty-one patients (28.5%) discontinued treatment due to severe joint pain. At the end of the 6-month, 116 patients (73.9%) had arthralgia, 33 (21.0%) myalgia, 25 (15.9%) arthritis, 22 (14.0%) tendinitis, and 20 (12.7%) polyalgic syndrome. Bivariate analysis of the factors associated with letrozole discontinuation showed that the duration of a prior anastrozole treatment was a significant predictor (P = 0.04). This study shows that in patients intolerant to one AI, switching to another agent allows a higher proportion of patients to continue the therapy and maximize hormonal adjuvant therapy and disease outcome benefits.

PMID: 20035381 [PubMed - as supplied by publisher]

CINACALCET EFFECTIVE FOR PRIMARY HYPERPARATHYROIDISM

NEW YORK (Reuters Health) Dec 31 - In patients with primary hyperparathyroidism, treatment with the calcimimetic agent cinacalcet for up to 5.5 years maintains normocalcemia and reduces parathyroid hormone levels, according to a report in the December Journal of Clinical Endocrinology & Metabolism.

Parathyroidectomy usually cures the disease, but what of patients who are not candidates for surgery or who don't wish to undergo it? "Medical therapies capable of reducing serum calcium and parathyroid hormone concentrations and increasing bone mass in primary hyperparathyroidism patients are needed," the authors maintain.

Dr. Munro Peacock from Indiana University School of Medicine, Indianapolis, and colleagues assessed the long-term tolerability, safety, and efficacy of cinacalcet in 45 patients with mild to moderate primary hyperparathyroidism who completed a 1-year placebo-controlled trial and then continued for another 4.5 years in an open-label extension phase.

During the original study, serum calcium levels normalized in patients who received cinacalcet. When patients who had been in the placebo group took cinacalcet in the extension phase, their serum calcium levels normalized as well. Mean serum calcium levels remained in the normal range in all subjects throughout the remainder of the extension.

Parathyroid hormone levels followed a similar pattern in both groups, the authors report, although they never reached normal levels.

Mean levels of serum phosphate and total alkaline phosphatase increased within the normal range throughout the study with administration of cinacalcet.

Mean areal bone mineral density remained in the normal range for the duration of the study, the researchers note, and there were no significant changes in T-scores or Z-scores.

More than 98% of patients experienced at least one mild to moderate adverse event, with similar rates in both groups of the original study. Thirteen patients had treatment-related adverse events, none of which was serious, life-threatening, or fatal; most (9/13) lasted less than one month.

"Cinacalcet is useful in the management of primary hyperparathyroidism in patients in whom parathyroidectomy is contraindicated or who have failed surgical correction of their primary hyperparathyroidism," the investigators conclude.

J Clin Endocrinol Metab 2009;94:4860-4867.

TROPONIN T AND MORTALITY AFTER PULMONARY EMBOLISM

NEW YORK (Reuters Health) Dec 24 - Elevated troponin T levels in patients with pulmonary embolism are associated with higher in-hospital and 1-year mortality, according to a report in the European Respiratory Journal for December.

A recent meta-analysis suggested an association between mortality and plasma levels of troponins in patients with acute pulmonary embolism, the researchers explain, but the predictive value of elevated troponins for adverse outcomes has remained unclear.

Dr. Karin M. Janata from the Medical University of Vienna, Austria, and colleagues investigated the relationship between troponin T (TNT) and survival in 737 patients diagnosed with pulmonary embolism.

During 1 year of follow-up, 44 (29%) of the TNT-positive patients died, compared with 42 (10%) of the TNT-negative patients.

The in-hospital death rate was 21% among TNT-positive patients, the authors report, but only 6% among TNT-negative patients.

For patients who survived the initial hospitalization, 1-year mortality was 10% in TNT-positive patients versus 5% in TNT-negative patients.

TNT independently predicted mortality after adjusting for cancer, immobility, and age, the investigators say, and after exclusion of initially hemodynamically unstable patients.

"Elevated TNT levels meant a four-times higher risk of in-hospital death and a three-times higher risk of 1-year mortality, even after adjustment for the other most important risk factors of death in this population," the authors report.

Although researchers should perform more trials to determine whether TNT-positive patients could benefit from thrombolysis, the authors conclude, TNT has the advantage of being an objective measure for a condition marked by "soft" subjective parameters.

Eur Respir J 2009;34:1357-1363.

CANCER MORTALITY TRENDS IN EUROPE

December 31, 2009 — New figures for cancer mortality rates in Europe for 2000 to 2004 show "persistent favourable trends over the last years," according to a report published online in the November 30 Advance Access issue of the Annals of Oncology.

Overall cancer mortality rates in the European Union decreased by 9% in men and 8% in women from 1990 to 1994 and from 2000 to 2004.

These decreases are comparable in magnitude to those observed in the last decade in the United States (–0.8% per year in men, –0.4% per year in women) and are similar to those seen in Japan, say the study authors.

Led by Carlo La Vecchia, MD, head of epidemiology at the Mario Negri Institute for Pharmacological Research in Milan, Italy, the team of authors comments that the favorable trend of decreasing cancer mortality rates was seen in all European countries, with the sole exception of Romania.

However, there remains an approximately 2-fold difference in cancer mortality rate (as well as incidence) across European countries. For men, the highest mortality rates were seen in Hungary, the Czech Republic, and Poland, whereas the lowest rates were in Sweden, Finland, and Switzerland. For women, the highest mortality rates were seen in Denmark, Hungary, and Scotland, and the lowest were seen in Spain, Greece, and Portugal.

These differences between the sexes reflect, in part, the different spread of cigarette smoking among men and women across various European countries, the study authors comment. Smoking had declined substantially among men during the last few decades but has increased among women in several countries, they note.

Cancers Linked to Tobacco and Alcohol

These trends in smoking have influenced the patterns seen for several cancers, most noticeably lung cancer. In the European Union as a whole, the lung cancer mortality rate has been declining in men (decreasing by 17% from the late 1980s to the early 2000s), but has increased in women (by 27% during the same period).

A similar, though less pronounced, pattern was seen for oral cancer. Overall, the mortality rate from oral cancer declined by approximately 10% from 1990 to 1994 and from 2000 to 2004, but increased mortality rates were seen in women.

However, mortality rates from oral cancer have also been influenced by changing patterns of alcohol consumption. Together, tobacco and alcohol are associated with more than 80% of cases of cancer of the oral cavity and pharynx, the study authors point out.

Countries such as France and Italy, which had the highest rates of drinking up to the 1980s, have seen a substantial reduction in alcohol consumption in the last few decades. They have also seen a reduction in mortality rates from oral cancer since the mid to late 1980s.

In contrast, alcohol consumption has been increasing in most countries from northern Europe, and the trends for oral cancer here are less favorable, the study authors comment. In particular, the highest rates of mortality from oral cancer were seen in Hungary and Slovakia, and this trend may point to a specific role of fruit-based alcoholic drinks that are popular in these areas, they suggest.

These trends in alcohol consumption have also influenced patterns in mortality from liver cancer. France and Italy had some of the highest mortality rates from primary liver cancer, but these have been decreasing in recent years, mainly because of the reduction in alcohol consumption in these countries since the early 1980s, the authors note. In contrast, mortality rates for liver cancer have been increasing in several central and northern European countries, reflecting the recent increase in drinking there, they add.

Esophageal cancer is also strongly associated with tobacco and alcohol use, and the patterns for this cancer are similar to those for oral cancer, at least in part. As for oral cancer, in the last decade, mortality rates for esophageal cancer were substantially decreased in France, Italy, and Spain, following the decline in alcohol consumption in these countries and a decline in smoking among men. In contrast, the esophageal cancer mortality rate has increased in most northern, central, and eastern European countries.

However, part of the increase in northern Europe is because of an increase in esophageal adenocarcinoma, which is related to obesity, as well as to gastroesophageal reflux disease and tobacco (but not alcohol) use. "Therefore, at least part of the rise in esophageal cancer mortality in northern Europe can be attributed to increased prevalence of obesity," the authors comment.

Factors Influencing Mortality Rates

For several individual cancers, the authors highlight factors that have contributed to the decline seen in mortality rates.

Mortality rates for gastric cancer declined by approximately 30% in both sexes from 1990 to 1994 and from 2000 to 2004. This is attributed to improved diet, diet variety, and food conservation, as well as a decline in the prevalence of Helicobacter pylori infection in more recent generations.

Mortality rates for breast cancer declined by 13% from 1990 to 1994 and from 2000 to 2004, and the variation in rates across Europe was relatively limited. Breast cancer mortality rates have been declining substantially in the last 2 decades in western Europe, the authors note. Improved treatment through antiestrogens and chemotherapy has played a major role, but a favorable impact from screening mammography is also likely in recent years, they comment.

Mortality rates for prostate cancer showed a modest 4% decline from 1900 to 1994 and from 2000 to 2004. Both in western Europe and in the United States, peak mortality rates for prostate cancer were observed in the 1990s, with a levelling off thereafter, the authors comment. This trend likely reflects a favorable impact of advances in treatment, such as androgen deprivation therapy, wider adoption of radical prostatectomy in the elderly population, and radiotherapy for patients with locally advanced disease, they suggest. Less likely to have had an impact is the introduction of prostate-specific antigen testing, they add.

Testicular cancer mortality rates have declined steadily, with a decrease of 26% seen between 1990 and 1994 and 2000 and 2004. This follows a favorable trend observed since the 1970s, which was, however, delayed vs that observed in the United States, the authors comment. Adoption of standard therapeutic protocols has played a role, they suggest.

Testicular cancer is one of the most curable neoplasms if adequate treatment is adopted, they point out. However, such treatment involves platinum-derived chemotherapy and other expensive drugs, and the inadequate availability of these therapies accounts for the smaller decline seen in eastern European vs western European countries, and also in Latin America vs the United States.

"Widespread adoption of efficacious therapy is therefore a priority to avoid unnecessary deaths from testicular cancer worldwide," Dr. La Vecchia and colleagues comment.

The study authors have disclosed no relevant financial relationships.

Ann Oncol. Published online November 30, 2009. Abstract.

COLONOSCOPY REDUCES LEFT SIDE CANCER RISK

December 30, 2009 — Another study of colonoscopy screening in the community setting has shown that it does reduce the risk for colorectal cancer, but this reduction is seen only for left-sided, not right-sided, colorectal cancer.

The latest findings come from Germany, from a study of 3287 participants, and are published online December 30 in the Journal of the National Cancer Institute.

Advanced colorectal cancer was detected by colonoscopy in 36 (6.1%) of 586 participants who had undergone a previous colonoscopy in the preceding 10 years vs 308 (11.4%) of 2701 participants with no previous colonoscopy.

This is a "substantial risk reduction," comment the study authors, headed by Hermann Brenner, MD, MPH, from the German Cancer Research Center in Heidelberg, Germany.

However, the risk reduction was seen only in left-sided advanced neoplasms and not right-sided ones, the researchers point out. A previous colonoscopy was associated with a 67% reduced risk for advanced neoplasia in the left side of the colon and the rectum, but no risk reduction was seen in the right side of the colon.

"However, because most neoplasms in the colon and rectum are located on the left side, substantial overall risk reduction for colorectal cancers and advanced adenomas was observed," they add.

"Remarkably Consistent" With Previous Studies

These results are "remarkably consistent with a number of recently published studies, all of which demonstrate the overall effectiveness of colonoscopy for reduction of colorectal cancer incidence and mortality but with a marked variance in effectiveness for proximal and distal cancers," comment editorialists Nancy Baxter, MD, PhD, from St. Michael's Hospital, Toronto, Ontario, Canada, and Linda Rabeneck, MD, MPH, from the Odette Cancer Center, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

They add that the study is an important contribution to the observational evidence that "must inform our understanding of the effectiveness of colonoscopy."

The editorialists also point out that observational evidence is all that is available at present to address the question of how effective colonoscopy is at reducing the burden of colorectal cancer in the population. A definitive answer can come only from a randomized trial, and although one is underway (the Northern European Initiative on Colorectal Cancer), outcome data are not expected until 2026.

In the meantime, as the observational evidence continues to mount, the answer to this question becomes less certain, they suggest.

Is Right-Sided Colon Cancer Different?

One of the limitations of this study was the small number of advanced neoplasms found at any location, the researchers comment. "Nevertheless, consistent patterns of risk reduction in all parts of the left colon and rectum were observed, with absence of risk reduction in all parts of the right colon," they add. These site-specific findings are also "remarkably consistent" with several previous studies, they note.

"Possibly, the lack of effect in the right colon could be overcome to some extent by enhanced training of endoscopists, by enhanced measures of quality assurance, and by development of technology that enhances inspection of the right colon," they suggest.

"Nevertheless, the possibility that cancer in the right colon simply does not lend itself equally well to early detection on biological grounds has to be considered," they continue. "If this possibility could be demonstrated in other investigations, then the relative merits of sigmoidoscopy and colonoscopy in the early detection and prevention of colorectal cancer would need to be re-evaluated."

In their editorial, Drs. Baxter and Rabeneck add that there is "compelling evidence that colonoscopy is a less effective tool in the proximal colon than [the] distal colon," but they also add that the "underlying reasons for the differential performance are unclear."

"There may be biological differences that limit the potential effectiveness of colonoscopy in the proximal colon," the editorialists continue. "Right-sided colonic adenomas tend to be flatter than left-sided lesions and are, therefore, harder to identify and remove."

The potential limitations of colonoscopy for preventing colorectal cancer in the proximal part of the colon — as identified in this and other studies — raises very important questions, the editorialists note. Is there an incremental benefit of colonoscopy vs flexible sigmoidoscopy for colorectal cancer screening? Also, if there is an incremental benefit, is it large enough to justify the additional risks and cost of colonoscopy for screening in the population, they ask.

The study was supported in part by a grant from the Central Research Institute of Ambulatory Health Care in Germany. The study authors and editorialists have disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online December 30, 2009.

BIOMARKERS FOR OVARIAN CANCER DETECTION NOT SUFFICIENTLY ACCURATE

December 30, 2009 — Ovarian cancer is often a lethal disease, and one reason for this dismal prognosis is that it is usually not diagnosed until it has reached an advanced stage. Early detection could help reduce the associated mortality rate, but currently there are no specific and sensitive screening methods. Potential ovarian cancer biomarkers include cancer antigen CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 proteins. Researchers now report that serum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before a clinical diagnosis is made.

However, these biomarkers only become substantially elevated in the last year before diagnosis, according to findings published in the January 6, 2010, issue of the Journal of the National Cancer Institute.

However, although these markers are not accurate enough to prompt early intervention in existing screening protocols, the study authors explain, modest but statistically significant increases in risk associated with CA125, HE4, and mesothelin were identified. This finding is consistent with many of the established epidemiologic risk factors for ovarian cancer.

"I still think biomarkers may play a role in a cost-effective screening program, although none of these seem accurate enough either alone or together to justify their use in average-risk women," lead author Garnet Anderson, PhD, told Medscape Oncology.

"I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted," said Dr. Anderson, who is with the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

One problem, cites Dr. Anderson, may lie in the approach used in identifying candidate biomarkers. "Most of the discovery work done so far has been conducted in women with advanced-stage disease and compared them to healthy women," she explained. "If discovery work were done in samples like the ones we used here, representing specimens collected months to years prior to the advanced stage diagnosis, we might have a better chance of finding earlier signals of aggressive disease."

Another opportunity for improving screening and early diagnosis lies in imaging, she adds. "Currently the most common and only affordable imaging option that could be considered for routine screening is transvaginal ultrasound, but it performs poorly in terms of accurately determining those women [who] have ovarian cancer from those who do not," said Dr. Anderson. "A substantial improvement in this area would be very exciting."

Detectable Levels Reached Shortly Before Diagnosis

In this study, Dr. Anderson and colleagues analyzed prediagnostic serum samples and patient data from the Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial that evaluated the effects of beta-carotene and retinol on the incidence of lung cancer among individuals at high risk for the disease.

The serum samples were obtained 0 to 18 years before a diagnosis of ovarian cancer was made in 34 patients (15 with advanced-stage serous carcinoma) and during a comparable interval before the reference date from 70 matched control subjects. Immunoassays were conducted to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in the samples.

Results showed that concentrations of CA125, HE4, and mesothelin became slightly elevated in patients with ovarian cancer vs the control subjects approximately 3 years before their diagnosis. However, these biomarkers only reached detectable elevations within the final year before diagnosis. Thus, the discriminatory power of the markers was limited, the study authors note, because accuracy only increased shortly before diagnosis.

Not the Last Word

In an accompanying editorial, Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, Bethesda, Maryland, notes that it has been "surprisingly difficult" to create a successful screening program for asymptomatic women with ovarian cancer.

However, the authors of this study have taken a "valuable step toward the successful design of such a screening program by demonstrating one reason why screening regimens that are based on markers, or panels of markers, can fail," writes Dr. Hartge.

She points out that these results are "not the last word in serum markers or in combinations of markers." Instead, serum markers are likely to form a key element in any screening regimen, with the lead time and other parameters being taken into account.

However, for right now, there are no proven biomarkers, panel of biomarkers, or overall screening program that works well, explained Dr. Hartge. "The current report, with its sobering implications, brings us closer to understanding the crucial elements in designing any effective early detection program for ovarian cancer."

The National Cancer Institute funded the study. Dr. Anderson has disclosed no relevant financial relationships. Coauthor Lieling Wu is currently employed by Baxter Healthcare, Inc, and holds stock in this company but is not involved in projects related to ovarian cancer.

J Natl Cancer Inst. 2010;102:1-3, 26-38.

FIGITUMUMAB FOR EWING SARCOMA

December 29, 2009 — An experimental agent has demonstrated antitumor activity in Ewing's sarcoma, according to results of a preliminary study published in the December 24 online issue of the Lancet Oncology.

Figitumumab, developed by Pfizer, was shown to be safe for both adult and pediatric patients with sarcoma and also showed single-agent antitumor activity in different subtypes of the disease.

Of 28 patients who were assessed for a response to figitumumab, 2 patients with Ewing's sarcoma experienced objective responses — 1 complete response and 1 partial response. In addition, 8 other patients had disease stabilization (6 with Ewing's sarcoma, 1 with synovial sarcoma, and 1 with fibrosarcoma) that lasted 4 months or longer.

Possible Benefit From Insulin-Like Growth-Factor-1 Receptor Inhibitors

Figitumumab is a fully human immunoglobulin G2 monoclonal antibody that targets the insulin-like growth-factor-1 receptor (IGF-1R). The IGF-1R signaling pathway is involved in sarcomagenesis and regulates cellular growth, proliferation, survival, and transformation, and plays a critical role in the growth of tumor cells, the study authors note. IGF-1R has also specifically been implicated in the growth, metastasis, and angiogenesis in Ewing's sarcoma, with early reports showing antitumor activity of IGF-1R-targeting drugs in these conditions.

However, although there is reason for optimism regarding use of IGF-1R inhibitors in patients with Ewing's sarcoma, it is also crucial to identify the subset of patients who are most likely to respond to this therapy, notes an accompanying editorial.

"Despite the strong preclinical evidence that suggests a universal benefit with inhibiting IGF-1R, the progressive disease seen in some patients indicates that not all tumors are addicted to IGF-1R signaling or develop rapid resistance," write Jeffrey A. Toretsky, MD, from Georgetown University, Washington, DC, and Richard Gorlick, MD, from the Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.

Because many drug makers are currently developing IGF-1R inhibitors, there could be "ample opportunity to optimize clinical benefit from IGF-1R blockade, although the development of these antibodies may be complicated," they explain. "Five-drug chemotherapy is routine in the treatment of Ewing's sarcoma; therefore, improvement in outcome for these patients will likely require demonstration of the feasibility of combining the antibody with standard chemotherapy."

Well Tolerated and Responses Seen

The phase 1 study was conducted by Johann S. de Bono, MBBS, PhD, of the Institute for Cancer Research, Sutton, United Kingdom, and the Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, and colleagues. Between January 2006 and August 2008, a total of 29 patients with refractory, advanced sarcomas were separated into 2 groups within the same trial: the first cohort (n = 15) included patients 18 years or older with multiple subtypes of sarcoma, and the second group (n = 14) consisted of patients 9 years or older with refractory Ewing's sarcoma.

All patients received intravenous figitumumab 20 mg/kg and continued with their treatment until disease progression or unacceptable toxicity. The primary endpoint of the study was to assess the safety and tolerability of figitumumab, and secondary endpoints included pharmacokinetic profiling and preliminary antitumor activity.

For all patients in this study, the rate of nonprogression at 3 months was 34% (95% confidence interval [CI], 10% - 58%) and at 6 months was 28% (95% CI, 5% - 51%). The authors observed objective antitumor activity in patients with Ewing's sarcoma. One patient had a complete response that has lasted 21.5 months to date, whereas a second patient had a partial response that has lasted 11.4 months. Both are still continuing to receive treatment, the authors note. In addition, disease stabilization has lasted more than 9 months in 4 patients (range, 9.8 - 16.1 months), and 2 of these patients also are continuing to receive this treatment.

Apart from the 2 patients who had a response, 5 other patients with Ewing's sarcoma experienced shrinkage of the target tumor lesions, and the authors observed small reductions in tumor size among some patients with chondrosarcoma, fibrosarcoma, and synovial sarcoma.

Figitumumab was well tolerated in this population, and adverse events were primarily mild to moderate in severity and were reversible. Grade 3 events included deep venous thrombosis (n = 1), vomiting (n = 1), and back pain (n = 1). Grade 3/4 laboratory abnormalities were seen in 2 patients, and grade 1 hyperglycemia occurred in 4 patients. A delayed onset of puberty was noted in 1 prepubertal male patient who is still receiving treatment.

The researchers conclude that figitumumab is well tolerated and has antitumor activity in Ewing's sarcoma, thus warranting further investigation. "Phase 2 studies of figitumumab and other anti-IGF-R agents in Ewing's sarcoma and other sarcoma subtypes are now completing accrual and rational combinations with other treatments are also being pursued," they write.

Pfizer Global Research and Development funded the study. Several of the study authors have received research funding from, have served in a consultant or advisory role, are employees, own stock, or received honoraria for Pfizer Oncology, as detailed in the original article.

Lancet Oncol. Published online December 24, 2009.

PSA VELOCITY AND PROSTATE CANCER RISK

NEW YORK (Reuters Health) Dec 21 - Prostate-specific antigen velocity (PSAV), increasingly recognized as a marker of potentially lethal prostate cancer, can also predict the likelihood that a given patient's cancer is insignificant, researchers say.

"A controversy of current prostate specific antigen based prostate cancer screening is the over detection of potentially insignificant prostate cancer," Dr. William J. Catalona, of Northwestern Feinberg School of Medicine, Chicago, and colleagues write. "A promising marker is prostate specific antigen velocity (rapidly increasing PSA)."

The 2010 National Comprehensive Cancer Network Guidelines recommend a PSAV threshold of about 0.35 to 0.4 ng/mL per year for prostate cancer screening protocols. Dr. Catalona and his co-authors sought to determine "whether this PSAV threshold is associated with...histologically insignificant prostate cancer at radical prostatectomy."

As they report in the January issue of the Journal of Urology, their study focused on 1073 men who underwent radical prostatectomy between 1992 and 2008. Insignificant prostate cancer was defined (on the basis of the Ohori criteria) as confined to the prostate, with a tumor volume 0.5 cc or less and no Gleason pattern 4 or 5.

The patients' mean age was 62 years. Their median PSA at diagnosis was 4.3 ng/mL, and most had a clinical stage T1c disease with a Gleason score of 6.

Preoperative PSAV greater than 0.4 ng/mL per year was significantly associated with positive surgical margins (19% versus 12%, p = 0.003) seminal vesicle invasion (4% versus 1%, p = 0.007), a Gleason score of 7 or greater (p = 0.008), and greater tumor volume.

Sixty-nine men (6%) had pathologically insignificant cancer. Insignificant disease was significantly more likely in men with preoperative PSAV less than 0.4 ng/mL per year (10%, vs. 5% for PSAV greater than 0.4 ng/mL per year; p = 0.003).

"These results suggest that PSAV may be useful in conjunction with other variables to help enhance the specificity of prostate cancer screening to detect clinically significant prostate cancer," the authors conclude.

J Urol 2010;183:112-117.

NEW STANDARD IN EARLY STAGE HODGKIN LYMPHOMA

December 21, 2009 (New Orleans, Louisiana) — A new standard of care for the treatment of early-stage Hodgkin's lymphoma has now been established. The final results from a large German study presented here at the American Society of Hematology 51st Annual Meeting show that the best results were seen with a combination of chemotherapy and radiation.

Two cycles of chemotherapy with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) followed by 20 Gy involved-field radiotherapy (IFR) is the new standard of care for patients with Hodgkin's lymphoma in early favorable stages, concluded lead researcher Andreas Engert, MD, from the University of Cologne, Germany.

In the discussion period following his presentation, several experts congratulated him and agreed that this should be the new standard of care. In an interview with Medscape Oncology, Richard Van Etten MD, PhD, director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts, explained that there was a long-standing question about the treatment of these patients with favorable early-stage disease, and this trial has finally offered an answer as to what is the best option.

Ongoing Debate About Best Approach

In the ongoing debate about the best approach to the treatment of patients with early favorable Hodgkin's lymphoma, one of the main questions has been whether to use chemotherapy alone or chemotherapy in combination with radiation, but there have also been questions about the optimum radiation dose and about the optimal number of chemotherapy cycles, Dr. Engert explained.

The German Hodgkin Study Group addressed these questions in a large trial, conducted in 1370 patients, which had 4 treatment groups. Each group had a different combination of chemotherapy with ABVD (2 or 4 cycles) and IFR (20 Gy or 30 Gy).

The 4 treatment groups were: 4 cycles of ABVD plus 30 Gy IFR; 4 cycles of ABVD plus 20 Gy IFR; 2 cycles of ABVD plus 30 Gy IFR; and 2 cycles of ABVD plus 20 Gy IFR.

All of the groups showed a similar efficacy, but there were significant differences in toxicity, Dr. Engert told the meeting.

Complete remission was achieved in 97% of patients who were treated with either 4 or 2 cycles of ABVD and who received 20 Gy IFR, and in 99% of patients who received 30 Gy.

With a median follow-up of 79 to 91 months, there was no significant difference between 4 and 2 cycles of chemotherapy in terms of overall survival at 5 years (97.1% with 4 cycles of ABVD and 96.6% with 2 cycles), in freedom from treatment failure (93% vs 91.1%), or in progression-free survival (3.5% vs 91.2%).

There were also no significant differences between the 2 doses of radiotherapy in terms of overall survival at 5 years (97.6% with 30 Gy and 97.5% with 20 Gy), in freedom from treatment failure (93.4% vs 92.9%), or progression-free survival (93.7% vs 93.2%).

"Importantly, there were also no significant differences in overall survival, freedom from treatment failure, or progression-free survival when all 4 arms were compared," Dr. Engert explained.

However, there were significant differences in toxicity, Dr. Engert reported. Four cycles of ABVD were significantly more toxic than 2 cycles. Overall adverse events were reported in 52% of patients receiving 4 cycles and in 33% receiving 2 cycles; leukopenia was seen in 24% and 15%, respectively, and alopecia was seen in 28% and 15%, respectively.

A similar pattern was seen with radiotherapy, with more toxicity at the higher dose. Overall adverse events were reported in 8.2% of patients treated with 30 Gy and in 2.9% treated with 20 Gy, dysphagia was seen in 3% and 2%, respectively, and mucositis was seen in 3.4% and 0.7%, respectively.

Dr. Engert concluded that because all of the treatment groups showed a similar efficacy, the new standard of care should be the least toxic treatment of 2 cycles of ABVD and 20 Gy IFR.

Dr. Engert also said that his group is continuing with this research and is looking at whether the radiotherapy portion of the treatment is necessary. A new trial will compare 2 cycles of ABVD with and without the addition of 20 Gy IFR. In addition, an ongoing study is looking at the various components of the chemotherapy regimen to see if any drug can be dropped, he said. This trial is comparing ABVD with ABV, AVD, and AV, he added.

The researchers have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 716. Presented December 7, 2009.