PULMONARY FUNCTION LOWERED IN TESTICULAR CANCER SURVIVORS

NEW YORK (Reuters Health) May 22 - The results of a study published in the May 6 online issue of the Journal of Clinical Oncology suggest that decreased pulmonary function is a long-term adverse effect of cisplatin-based chemotherapy in survivors of testicular cancer.

"Today, germ cell testicular cancer has a favorable prognosis because of the introduction of cisplatin-based chemotherapy in the late 1970s, a multimodal treatment approach, disease monitoring by tumor markers, and more reliable radiologic staging," Dr. Hege S. Haugnes, of the University of Tromso, Norway, and colleagues write.

"Recently, a large international study reported a significantly increased mortality as a result of respiratory diseases among chemotherapy-treated testicular cancer survivors compared with the general population."

To investigate, Dr. Haugnes and associates examined pulmonary function of 1049 long-term testicular cancer survivors treated from 1980 to 1994. The subjects were assessed by spirometry and a questionnaire completed between 1998 and 2002. The median observation time was 11.2 years.

The participants were categorized by treatment group: surgery only (n = 202); radiotherapy only (n = 449); chemotherapy with a cumulative dose of cisplatin less than or equal to 850 mg (n = 306); chemotherapy with a cumulative dose of cisplatin greater than 850 mg (n = 62); or chemotherapy plus pulmonary surgery (n = 30).

Compared with the surgery only group, the higher dose cisplatin group and the cisplatin plus surgery group had significantly lower age-adjusted forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), percentage of predicted FVC value, and percentage of predicted FEV value.

These associations were not changed after adjustment for total testosterone, body mass index, smoking, and physical activity.

A total of 84 patients (8%) developed restrictive lung disease. The highest prevalence was seen in the higher dose cisplatin group and the cisplatin plus surgery group (17.7% and 16.7%, respectively).

"It is well known that bleomycin, also included in the standard chemotherapy regimen for testicular cancer, may cause pulmonary toxicity," Dr. Haugnes said in an interview with Reuters Health. "However, our findings indicate that the decreased pulmonary function observed in our long-term survivors probably is related to cumulative cisplatin doses rather than bleomycin doses."

"All doctors included in the treatment and follow-up of (testicular cancer patients) should be informed about potential long-term treatment-related toxicity," Dr. Haugnes said. "However, these findings need to be confirmed in a large prospective trial with measurements of the pulmonary function both before and after treatment, and should include both spirometry maneuvers and measurements of the lung transfer capacity for carbon oxide."

J Clin Oncol 2009;27.

STEREOTACIC BODY RADIOTHERAPY FOR STAGE I LUNG CANCER

NEW YORK (Reuters Health) May 21 - Stereotactic body radiotherapy (SBRT) appears to be highly effective for treating certain patients with non-small-cell lung cancer, providing a 3-year local tumor control rate of 90% or higher with minor toxicity, Scandinavian researchers report in a May 4th online edition of the Journal of Clinical Oncology.

"SBRT, developed at (our) hospital," lead investigator Dr. Pia Baumann told Reuters Health, has been shown to be "very efficient in eradicating the tumor with only limited side effects in patients with medically inoperable stage I non-small cell lung cancer."

Dr. Baumann of Karolinska University Hospital Solna, Stockholm, and colleagues conducted a phase II trial that included 40 patients with stage 1 tumors and 17 with stage 2 tumors who underwent SBRT every second day for a median of 5 days of treatment.

At 1 year, overall survival was 88% and cancer-specific survival was 93%. At 3 years, progression-free survival was 52%, overall survival was 60% and cancer-specific survival was 88%. There was no significant survival difference between patients with T1 and T2 tumors.

At a median follow-up of 35 months, 7 patients had died from lung cancer and 20 from concurrent disease. Estimated local control at 3 years was 92%. The estimated risk of failure due to local, regional or distant metastases was significantly greater in patients with T2 tumors than in those with T1 tumors (41% versus 18%).

The researchers suggest that based on these findings, SBRT "may even challenge surgery in operable instances."

"Several clinical trials in other countries are now underway to confirm these data," Dr. Baumann added. "SBRT is also useful for treating metastatic tumors in diverse organs."

J Clin Oncol 2009;27.

PROTEASOME LEVEL AS MARKER FOR MALIGNANT TRANSORMATION IN CIRRHOSIS

NEW YORK (Reuters Health) May 26 - Increasing levels of proteasome are an indicator that cirrhosis is transforming into hepatocellular carcinoma (HCC), French researchers report in the June issue of Gut.

Furthermore, they propose, proteasome inhibitors may be effective anticancer treatment in patients with cirrahosis and changing levels of the proteolytic entity.

Dr. L. Henry and colleagues at the University of Montpellier measured plasma proteasome and alpha-fetoprotein (AFP) levels in 83 patients with cirrhosis, 50 of whom had HCC and 33 who did not, and 40 controls.

"Plasma proteasome levels were significantly higher in patients with HCC than controls," with mean levels of 4841 ng/mL and 2534 ng/mL, respectively, Dr. Henry and colleagues report.

Patients with cirrhosis without HCC had a mean proteasome level of 2077 ng/mL.

Patients with HCC were categorized into three groups according to tumor mass, and even those with low tumor mass had elevated proteasome levels, with a mean level of 3970 ng/mL.

"With a cut-off of 2900 ng/mL, diagnostic specificity for HCC was 97% with a sensitivity of 72%, better than results obtained with AFP," the team reports.

"Diagnostic relevance of plasma proteasome measurement was also effective in low tumor mass patients," with a sensitivity of 76.2% compared with a sensitivity of 57.1% for AFP.

"Plasma proteasome is a novel and relevant marker of HCC, namely for early detection of HCC in patients with cirrhosis," the authors write. "Plasma proteasome levels were independent of the cause of cirrhosis and were weakly correlated with AFP levels."

They note that proteasome inhibitors are a new class of anticancer agents, and have been shown to be effective in conjunction with TNF-related apoptosis-inducing ligand (TRAIL) in models of HCC. "This therapeutic relevance reinforces the hypothesis that proteasome plays a crucial role in HCC onset and development," Dr. Henry and colleagues propose.

Gut 2009;58:833-838.

CAVEOLIN AS PROGNOSTIC MARKER FOR BREAST CANCER

NEW YORK (Reuters Health) May 22 - Researchers report in the June issue of The American Journal of Pathology that a loss of stromal caveolin-1 expression is "the single strongest predictor of breast cancer patient outcome."

"Among patients with estrogen receptor-positive breast cancer taking tamoxifen, a loss of stromal caveolin-1 predicted recurrence and poor clinical outcome," Dr. Michael Lisanti and colleagues at Thomas Jefferson University in Philadelphia, Pennsylvania, say.

"We show that caveolin-1 is a single independent predictor that is stronger than the existing breast cancer classification system that is the standard for diagnosis and treatment. This includes estrogen receptor, progesterone receptor and HER-2 status, and the nodal and tumor staging system," Dr. Lisanti, who is also editor-in-chief of The American Journal of Pathology, told Reuters Health.

"We think this could be used as a new classification system or in conjunction with the existing classification system. Given the right validation, it could even replace the existing classification system."

Dr. Lisanti and colleagues analyzed breast tissue samples from 154 women with breast cancer, using three tissue cores from each tumor sample, and analyzing each core for stromal caveolin-1.

"The absence of stromal caveolin-1 was strongly associated with other predictors of more aggressive disease, such as higher tumor stage and lymph node metastasis," the researchers report.

When grouped by prognostic factors such as hormone status, disease stage or lymph node status, a loss of stromal caveolin-1 remained the single strongest predictor of breast cancer patient outcome.

Among patients with estrogen receptor-positive breast cancer taking tamoxifen, a loss of stromal caveolin-1 still predicted recurrence and poor clinical outcome.

"Resistance to tamoxifen is thought to be an epithelial 'cancer cell' phenomenon, but we show here that it is clearly a 'stromal' phenomenon," Dr. Lisanti said.

Progression-free survival was affected by the loss of stromal caveolin-1. An absence of stromal caveolin-1 was associated with a progression-free survival rate that was 3.6-fold lower than observed in patients with breast tissue that expressed caveolin-1.

Patients with lymph node involvement had even lower survival rates. The approximate 5-year survival rate for patients positive for stromal caveolin-1 was 80% compared with only 7% for patients negative for stromal caveolin-1.

"That is an approximate 11.5-fold reduction in 5-year progression-free survival," the researchers report.

"We believe that patients who lack caveolin-1 would benefit from angiogenesis inhibitors," Dr. Lisanti told Reuters Health. "The cancer fibroblasts, which lack caveolin-1, tend to become endothelial cells, therefore driving angiogenesis."

"Essentially, (caveolin-1) is a marker of angiogenic potential. It is sort of a 'crystal ball' that predicts angiogenesis, which leads to early tumor recurrence, metastasis and poor clinical outcome," Dr. Lisanti said.

Testing for stromal caveolin-1 expression "would be no more expensive than testing for current markers and doesn't require any fancy DNA tests," Dr. Lisanti said. "Currently, antibody staining is routine for these patients, so they would only have to add this antibody staining to their existing list of markers. But this marker, so far, outperforms other existing markers."

Before this can be used in clinical practice, "there need to be prospective clinical trials," Dr. Lisanti added. So far, caveolin-1 has been "validated in three independent cohorts, in two different countries." One of these studies is published in this same issue of The American Journal of Pathology.

Am J Pathol 2009;174.

XELODA COULD ERASE FINGERPRINTS

May 27, 2009 — A 62-year-old Singapore man was temporarily denied entry into the U.S. because a cancer drug he was taking had made his fingerprints disappear, according to a letter published in the Annals of Oncology.

Eng-Huat Tan, MD, a senior consultant in the medical oncology department at Singapore's National Cancer Center, says his patient, identified as "Mr. S," had been taking the drug Xeloda since July 2005 to prevent recurrence of advanced cancer that had responded well to chemotherapy.

The cancer patient was detained by U.S. Customs officials for four hours in December 2008 because they could not detect fingerprints. The Customs officials later determined that the man was not a security threat.

Tan says people being treated with Xeloda, described as an oral chemotherapy drug, should carry a letter from their doctor that they are taking the medication if they want to travel to countries that require fingerprints for identification.

According to the letter in Annals of Oncology, other cancer patients taking the drug have reported similar side effects.

Foreign visitors have been asked to provide fingerprints at U.S. entry points for a number of years. The images are matched with millions of visa holders to detect whether the visitor has a visa under a different name; visitors' fingerprints are also compared to fingerprints of criminals, Tan says in the letter.

"Mr. S" did not know his fingerprints had disappeared, according to Tan.

Xeloda is indicated for the treatment of breast and colorectal cancers. One of its side effects is be a condition known as hand-foot syndrome. Symptoms include swelling, redness, tingling, numbness, and pain of the hands and/or feet; the skin can peel, bleed, and develop ulcers or blisters.

"This can give rise to eradication of fingerprints with time," Tan says.

According to the letter, "Mr. S" developed a mild case of hand-foot syndrome and was kept on the drug because it was not affecting his daily life.

"In December 2008, after more than three years of [Xeloda], he went to the United States to visit his relatives," Tan writes. It was on that visit that he was detained by customs officials.

Tan says it's "uncertain'' how long people would have to take the drug for their fingerprints to disappear. It's possible, he adds, that a growing number of people treated with the drug could experience the same problem and all should "prepare adequately" before traveling to avoid the "inconvenience" experienced by his patient.

Tan says "Mr. S" traveled again to the U.S., this time equipped with a doctor's letter, and had fewer problems getting through.

RESEARCH DREAM TEAMS

May 29, 2009 — Funds for cancer research raised by the huge celebrity-studded telecast organized by the Stand Up to Cancer campaign have now been allocated to 5 research "dream teams." The total allocated is $73.6 million.

Each of the teams will receive funding for 3 years for translational research projects, with the aim of moving the project from bench to bedside at "what will be an extraordinarily quick pace," said head of the committee that chose the teams.

Philip Sharp, PhD, institute professor at the Massachusetts Institute of Technology in Cambridge and a Nobel Laureate, headed a committee assembled by the campaign's scientific partner, the American Association of Cancer Research. The committee reviewed 237 applications before deciding on the 5 chosen teams.

"The Dream Teams bring together leading laboratory scientists and physicians, collaborating in ways that are unprecedented with a laser-like focus on research that has enormous potential to help patients and saves lives," Dr. Sharp said in a statement. Each team will comprise 300 researchers and at least 2 individuals from patient-advocacy groups to ensure that patients' perspectives are integrated into the research on an ongoing basis.

"The Stand Up to Cancer model could very well change the face of cancer," Dr. Sharp remarked.

The majority of the funds were raised during an hour-long television campaign, aired simultaneously on the 3 largest networks in the United States last September, as reported by Medscape Oncology at the time. The announcement of the research dream teams was broadcast on morning shows on each of the 3 networks earlier this week.

Executive producer of the telecast, cancer survivor Laura Ziskin, commented: "Every single minute of every single day, we lose someone to cancer in this country. We urgently need more and better treatments, and we need everyone to support the scientists who are working so hard to develop more effective treatments. That, in a nutshell, is what Stand Up to Cancer is trying to facilitate."

The 5 dream teams have diverse targets, as detailed below.

Epigenetic therapy at the forefront of cancer management — This team will focus on epigenomes, material outside of DNA that can turn genes on and off. Inappropriate epigenetic activity contributes significantly to cancer causation and growth but, unlike DNA mutations, these epigenetic changes can be reversed. The hope is that epigenetic therapy will return defective genes to normal functioning. The initial focus will be on breast, colon, and lung cancer, and leukemia. This team is headed by Stephen Baylin, MD, from the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland; and Peter Jones, PhD, DSc, from the University of Southern California in Los Angeles.

Targeting the PI3K pathways in women's cancers — PI3K mutations occur in breast, ovarian, and endometrial cancers, and drugs that inhibit this pathway are already in clinical trials. However, only some patients respond. This team aims to find ways of predicting who will respond. It is headed by Lewis Cantley, PhD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts; Charles Sawyers, MD, from Memorial Sloan-Kettering Cancer Center in New York City; and Gordon Mills, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

Targeting breast cancer molecular subtypes and their "resistance" phenotypes — This project will focus on the most significant issues related to the 3 major subtypes of breast cancer — estrogen-receptor (ER) positive, HER2 positive, and triple negative (ER negative, progesterone-receptor negative, and HER negative) — to develop innovative less-toxic therapies, with the potential to improve treatment outcomes for women with this disease. The team will be headed by Joe Gray, PhD, from Lawrence Berkeley National Laboratory in California; and Dennis Slamon, MD, PhD, from the University of California Los Angeles.

Circulating tumor cells chip technology — The measurement of circulating tumor cells that are released from a primary tumor has already shown potential clinical value, but so far this approach has been limited by technology. This team plans to build a chip based on microscopic fluid dynamics that will be 100 times more sensitive than existing systems and has the potential to revolutionize the way in which cancers are detected and treated, say the researchers. The team is headed by Daniel Haber, MD, PhD, from Massachusetts General Hospital Cancer Center in Boston; and Memhet Toner, PhD, from Harvard Medical School in Boston.

Cutting off the fuel supply: a new approach to the treatment of pancreatic cancer — Most cancers require a supply of glucose for their survival, but pancreatic cancer is unique in that it is addicted to glutamine, an amino acid used to build muscle mass. This can lead to extreme weight loss, which is often seen in patients with pancreatic cancer. This team aims to develop drugs designed to deprive pancreatic cancer of essential nutrients and to test them in combination with chemotherapy, with the aim of improving survival; currently, less than 90% of patients survive beyond 1 year. This team is headed by Craig Thompson, MD, from Abramson Cancer Center, University of Pennsylvania in Philadelphia; and Daniel Von Hoff, MD, from the Translational Genomics Research Institute in Phoenix, Arizona.

STATIN THERAPY AFTER FIRST STROKE

May 27, 2009 (Ioannina, Greece) — Statin therapy after a first stroke reduces the 10-year risk of recurrent stroke, a new study has shown [1]. Statin use also reduced the risk of mortality, even after adjustment for potential confounders, such as blood-pressure control, report investigators.

"Given the global burden of cerebrovascular disease, which affects almost all population groups, the potential benefits of statins cannot be overlooked," write Dr Haralampos Milionis (University of Ioannina School of Medicine, Greece) and colleagues in the May 26, 2009 issue of Neurology.

The new study, a retrospective observational analysis involving linked hospitalization and death records, included first-ever acute ischemic stroke patients from the Athenian Stroke Registry. The analysis includes a period, from January 1997 onward, during which poststroke statin therapy was not common practice.

The researchers note that since this time, there is now "compelling evidence from intervention trials in patients with coronary artery disease that statin treatment reduces stroke incidence." They point out, however, that risk factors for recurrent stroke "do not parallel those for first stroke," and data regarding the secondary prevention of stroke are lacking.

During follow-up of the 794 patients hospitalized for a first-time ischemic stroke, the recurrence rate was 14.1%. Of those stroke patients treated with a statin postdischarge, the recurrence rate was 7.6%, while the recurrence rate was 16.3% for those not treated with a statin. The median time to follow-up was 44 months for patients treated with statins and 40 months for those not receiving the lipid-lowering medication.

Regression analysis showed that only statin therapy prescribed after discharge from the index stroke event was an independent predictor of recurrent stroke. Statin therapy remained a strong predictor of long-term recurrence even after adjustment for the efficacy of control of blood pressure and lipid levels achieved 12 months after the index stroke.

Statin Therapy Postdischarge on Stroke Recurrence and Mortality Risk

Statin therapy postdischarge	Hazard ratio (95% CI)
1-y stroke recurrence	0.61 (0.35–0.92)
Mortality	0.22 (0.12–0.40)

As estimated by the Kaplan-Meier method, patients on statins also had a significantly lower 10-year mortality risk after the first cerebrovascular event. Cox regression analysis showed that age, history of coronary and peripheral artery disease, atrial fibrillation, and heart failure were associated with an increased risk of death, while statin therapy was associated with a lower risk of all-cause mortality.

Milionis and colleagues note that the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study investigated cardiovascular end points, including recurrent stroke, in stroke patients, and that treatment with high-dose atorvastatin reduced the five-year risk of recurrence 16%. These results, despite benefits in men and women and the elderly and younger subgroups, are not generalizable, as SPARCL included only patients without cardiovascular disease and treated patients with the maximum statin dose. Their study, instead, suggests a drug class effect to prevent recurrence and improve mortality, suggest the investigators.

They add that hyperlipidemia was not a risk factor for stroke recurrence and mortality in the analysis, and this could be attributed to statins' cholesterol-independent effects, including various antithrombotic, antioxidative, anti-inflammatory, vasodilatory, and plaque-stabilizing mechanisms. Future studies, however, will need to fully explore the mechanism of benefit with statins in stroke.

HER2 STATUS IN DCIS PREDICT DEVELOPMENT OF INVASIVE BREAST CANCER

May 28, 2009 — Cases of ductal carcinoma in situ (DCIS) that overexpress the protein HER2/neu are much more likely to develop into invasive breast cancer than DCIS without the overexpression, according to a new study.

Analyzing biopsies of 106 women diagnosed with DCIS, researchers from the University of Pennsylvania found that 37% of the women had DCIS that overexpressed HER2 and that the likelihood a woman with DCIS had early invasive disease was 6.4-fold higher when a tumor overexpressed HER2.

The study appears in the May issue of Cancer Epidemiology, Biomarkers & Prevention.

"Not all DCIS is the same," said study senior author Brian Czerniecki, MD, PhD, codirector of the Rena Rowan Breast Center at the University of Pennsylvania in Philadelphia, in a press statement.

He explained that the patients in the study were not followed over time, but instead were analyzed at a single point in time after a diagnosis of DCIS.

"We merely asked, in a group of patients with clinical presentation of DCIS, how often and what predicts whether you see early invasive cancer develop," Dr. Czerniecki told Medscape Oncology.

Dr. Czerniecki illustrated 1 potential affect of the findings: "From a practical standpoint, if you know that a patient has a greater chance of invasive cancer when you're doing a lumpectomy or mastectomy, then you might want to do a sentinel node biopsy, because there is a greater chance the cancer has spread to the lymph nodes," he said.

However, the study needs to be validated by additional investigation, write Dr. Czerniecki and his coauthors.

Nevertheless, the authors suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression. "If HER2 is associated with invasion or plays a role in the development of invasive disease, then maybe targeting it early can keep people from moving from DCIS to invasive cancer," said Dr. Czerniecki.

Study Details

In this study of women who were diagnosed with DCIS between 2003 and 2007 at the University of Pennsylvania, the mean patient age was 53.4 years. Their biopsy specimens were diagnosed either by core needle biopsy or by needle localization biopsy, and were subjected to immunohistochemical staining for HER2, estrogen-receptor (ER), and progesterone-receptor (PR) expression.

Lesions were characterized as luminal A (ER positive or PR positive, HER2 negative), luminal B (ER positive or PR positive, HER2 positive), HER2 positive (ER negative and PR negative, HER2 positive), or basal-like (ER egative, PR negative, and HER2 negative).

Luminal A was the most common tumor phenotype and accounted for the most lesions (59%), and basal-like accounted for the fewest (3%).

The HER2-positive phenotypes — HER2 positive and luminal B — accounted for 21% and 17% of lesions, respectively.

Invasive disease was seen in HER2-positive DCIS in 8 of 23 cases (35%) and in luminal B DCIS in 7 of 17 cases (41%).

The DCIS specimens were also characterized by nuclear grade (high, intermediate, or low), assessed for the presence of comedo necrosis, and measured for tumor size.

Univariate analysis revealed significant associations between invasion and high nuclear grade, HER2 overexpression, and tumor size of more than 3 cm. However, of these associations, only tumors with HER2 overexpression remained significant upon multivariate analysis. DCIS lesions that overexpressed HER2 were more than 6 times as likely to be associated with invasive disease than were DCIS lesions in which HER2 overexpression was not present (odds ratio, 6.4; P = .01), write the authors.

The study is not the first to identify factors that predict the presence of invasive disease in patients diagnosed with DCIS, but few studies have looked at HER2 status. Nevertheless, among those that did, the findings echoed the current study's, suggest the authors. "The clustering of invasive foci in patients with HER2-overexpressing tumors suggests a disease pattern hinted at in other studies; specifically, HER2 expression may reflect an important pathway through which DCIS lesions may progress toward invasion," they write.

HER2 Expression May Be Fleeting

The authors note that there is a low frequency of HER2 expression in advanced disease and a higher frequency in early disease.

Given the results of their study, the authors speculate about the possible reason for these differing frequencies. "HER2 expression may be characteristic of tumors at a discreet stage of pathogenesis and may represent a transient phenomenon. Specifically, HER2 may be upregulated as in situ tumors progress to invasive disease and downregulated again in more advanced tumors," they write.

The researchers have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. 2009;18:1386-1389. Abstract

ALP AS PROGNOSTIC FACTOR IN METASTATIC COLORECTAL CANCER

Ann Oncol. 2009 May 22. [Epub ahead of print]

Related Articles, LinkOut

FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study.

Chibaudel B, Tournigand C, Artru P, André T, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, Mineur L, Carola E, Rivera F, Perez-Staub N, Louvet C, de Gramont A.

Department of Medical Oncology, Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, Paris.

BACKGROUND: Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. PATIENTS AND METHODS: Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level