NEPHRECTOMY FOR LOCALLY ADVANCED RENAL CANCER

Nephrectomy for Locally Advanced Renal Cancer Improves Survival

NEW YORK (Reuters Health) Dec 25 - Nephrectomy improves cancer-specific survival in patients with locally advanced renal cell carcinoma (RCC).

"Refer patients with locally advanced RCC to tertiary care centers where, if eligible, they can benefit from surgery," Dr. Pierre I. Karakiewicz, from the University of Montreal, told Reuters Health.

Dr. Karakiewicz and colleagues examined cancer-specific survival of 43,143 patients treated with nephrectomy for locally advanced, non-metastatic RCC and compared it with that of patients managed without surgery.

Cancer-specific mortality was 5.8-fold higher for nonsurgical therapy than for nephrectomy, the authors report in the December issue of BJU International.

In a second analysis, where a subset of patients treated without surgery were matched with up to four surgically treated patients, there was still a 5.1-fold higher rate of cancer-specific mortality in the nonsurgical group than in the nephrectomy group.

Overall, 5- and 10-year estimates of cancer-specific survival were 68.6% and 57.5%, respectively, for the nephrectomy group, compared with 14.5% and 10.6%, respectively, for the nonsurgical therapy group.

"Our findings showed that nonsurgical therapy is associated with a 44.1-57.5% worse survival than nephrectomy," the investigators conclude. "Based on these findings, nephrectomy should be considered as the treatment of choice for patients with locally advanced RCC."

ESOPHAGEAL CANCER AFTER ORAL BIPHOSPHONATES?

Esophageal Cancer in Patients Taking Oral Bisphosphonates

December 31, 2008 — Cases of esophageal cancer in patients who had been taking oral bisphosphonate drugs for osteoporosis have been reported by an official from the Food and Drug Administration (FDA) in the January 1 issue of the New England Journal of Medicine.

Twenty-three cases (of which 8 were fatal) have been reported in the United States, all of them in association with alendronate (Fosamax, Merck), which was cited as the suspect drug in 21 cases and as a concomitant drug in 2 cases. These reports were received by the FDA in the 12-year period between October 1995 (when alendronate was launched in the United States) and mid-May 2008. No reports were received about esophageal cancer and any of the other oral bisphosphonate products.

A further 31 cases (6 fatal) have reported in Europe and Japan, with alendronate as the suspected drug in 21 cases. Of the remainder, 6 cases were associated with risedronate (Actonel, Procter & Gamble/Sanofi-Aventis), ibandronate (Boniva, Roche/GlaxoSmithKline), etidronate (Didronel, Procter & Gamble), or a combination of these, and 4 cases cited bisphosphonates as concomitant drugs.

Writing in a letter to the journal, Diane Wysowski, PhD, from the FDA, gives few further details but points out that 4 of the patients had Barrett's esophagus, which is a precursor of esophageal adenocarcinoma. "Physicians should avoid prescribing oral bisphosphonates to patients with Barrett's esophagus," she writes.

Dr. Wysowski also points out that esophagitis has been associated with oral bisphosphonates, usually when the drugs are not taken according to directions. "Crystalline material similar to ground alendronate tablets has been found in patients with erosive esophagitis, and persistent mucosal abnormalities have been noted in some of these patients, suggesting a potential for carcinogenic effects," she writes.

Merck said in a statement that data from its clinical trials and postmarketing reports do not suggest any association between alendronate and esophageal cancer. The company pointed out that alendronate has been marketed for 13 years, during which time more than 150 million prescriptions have been written in the United States alone. Merck also noted that its clinical database includes more than 17,000 patients, of whom about 3000 osteoporosis patients took alendronate for 3 to 5 years and about 800 patients took alendronate for 8 to 10 years.

OVERCOME DRUG RESISTANCE

Drug Resistance in Myeloproliferative Disorders Can Be Overcome

NEW YORK (Reuters Health) Dec 24 - A newly identified apoptosis pathway is inhibited in cancerous myeloid cells, making them resistant to treatment. However, the researchers who identified this pathway have also discovered how to override its inhibition and restore the cells' susceptibility to chemotherapy.

They describe their findings in the December 25th issue of The New England Journal of Medicine.

The investigators, led by Dr. Denis R. Alexander at The Babraham Institute in Cambridge, UK, studied cells from patients with chronic myeloid leukemia (CML) or polycythemia vera. A press release from the Institute explains that in normal cells, DNA damage increases the activity of a proton pump in the cell membrane known as sodium-hydrogen exchanger isoform 1 (NHE-1). Activating NHE-1 raises cellular pH, which in turn triggers a deamidation process in which the prosurvival protein Bcl-xL is converted into a form that permits the damaged cells to die.

"In our study, we found that the signaling pathway leading from DNA damage to Bcl-xL deamidation and consequent apoptosis is inhibited" in myeloid cells in patients with CML or polycythemia vera, the authors report. "This is the first demonstration of a role for deamidation in human malignancy," according to the press release.

The researchers discovered further that in myeloproliferative cancer cells, the Bcl-xL deamidation pathway is being blocked by tyrosine kinases - BCR-ABL in CML and JAK-2 in polycythemia vera.

Furthermore, the researchers discovered that by "enforced alkalinization or overexpression of NHE-1" they could reverse inhibition of the Bcl-xL deamidation pathway and restore apoptosis.

In fact, in cells from a patient with CML who developed resistance to the BCR-ABL inhibitor imatinib, "the effects of imatinib resistance could be bypassed by NHE-1 overexpression, which caused increased intracellular pH and apoptosis, or by enforced alkalinization, which caused increased Bcl-xL deamidation and apoptosis."

"It is...notable that an increase in the expression of NHE-1 by a factor of 2 to 3 was sufficient to increase Bcl-xL deamidation and triple the level of apoptosis in imatinib-resistant CML cells," the researchers write. "Therefore, targeted stimulation of Bcl-xL deamidation provides a potential route for circumventing resistance to tyrosine kinase inhibitors and perhaps also for eradicating leukemic stem cells."

OVERCOME DRUG RESISTANCE

Drug Resistance in Myeloproliferative Disorders Can Be Overcome

NEW YORK (Reuters Health) Dec 24 - A newly identified apoptosis pathway is inhibited in cancerous myeloid cells, making them resistant to treatment. However, the researchers who identified this pathway have also discovered how to override its inhibition and restore the cells' susceptibility to chemotherapy.

They describe their findings in the December 25th issue of The New England Journal of Medicine.

The investigators, led by Dr. Denis R. Alexander at The Babraham Institute in Cambridge, UK, studied cells from patients with chronic myeloid leukemia (CML) or polycythemia vera. A press release from the Institute explains that in normal cells, DNA damage increases the activity of a proton pump in the cell membrane known as sodium-hydrogen exchanger isoform 1 (NHE-1). Activating NHE-1 raises cellular pH, which in turn triggers a deamidation process in which the prosurvival protein Bcl-xL is converted into a form that permits the damaged cells to die.

"In our study, we found that the signaling pathway leading from DNA damage to Bcl-xL deamidation and consequent apoptosis is inhibited" in myeloid cells in patients with CML or polycythemia vera, the authors report. "This is the first demonstration of a role for deamidation in human malignancy," according to the press release.

The researchers discovered further that in myeloproliferative cancer cells, the Bcl-xL deamidation pathway is being blocked by tyrosine kinases - BCR-ABL in CML and JAK-2 in polycythemia vera.

Furthermore, the researchers discovered that by "enforced alkalinization or overexpression of NHE-1" they could reverse inhibition of the Bcl-xL deamidation pathway and restore apoptosis.

In fact, in cells from a patient with CML who developed resistance to the BCR-ABL inhibitor imatinib, "the effects of imatinib resistance could be bypassed by NHE-1 overexpression, which caused increased intracellular pH and apoptosis, or by enforced alkalinization, which caused increased Bcl-xL deamidation and apoptosis."

"It is...notable that an increase in the expression of NHE-1 by a factor of 2 to 3 was sufficient to increase Bcl-xL deamidation and triple the level of apoptosis in imatinib-resistant CML cells," the researchers write. "Therefore, targeted stimulation of Bcl-xL deamidation provides a potential route for circumventing resistance to tyrosine kinase inhibitors and perhaps also for eradicating leukemic stem cells."

MAJOR CANCER ADVANCES IN 2008

ASCO Highlights Major Cancer Advances of 2008

December 29, 2008 — Twelve major cancer advances and a further 19 notable advances made during 2008 have been highlighted in a report issued by the American Society of Clinical Oncology (ASCO). Compiled by a group of leading oncologists, the report selects studies that have significantly altered the way a cancer is understood or studies that had important impact on patient care.

"This report show that we are making important progress in preventing, detecting, and treating cancer," said Richard Schilsky, MD, president of ASCO. "Each of the studies highlighted in the report represents new hope for people with cancer and those who care for them."

To make their selection, the panel of experts reviewed scientific journals and presentations made at major scientific meetings between October 2007 and September 2008. Many of these studies have already been reported in some detail by Medscape Oncology, at the time when the research was presented or published.

The 12 major advances are listed as follows (not in rank order):

• Improvement in survival in advanced non–small-cell lung cancer with cetuximab (Erbitux, IMClone/Bristol-Myers Squibb), when added to chemotherapy in patients with tumors expressing epidermal growth factor receptor (EGFR). (FLEX study. Pirker R et al. ASCO 44th Annual Meeting, 2008.)
• Improvement in survival in early-stage resected pancreatic cancer with gemcitabine (Gemzar, Lilly). (CONKO-001 study. Neuhaus P et al. ASCO 44th Annual Meeting, 2008.)
• FDA approval of bevacizumab (Avastin, Genentech) for use in women with advanced breast cancer that does not express human epidermal growth factor receptor 2 (HER2) (the majority of breast cancers), based on 2 studies. (Miller K et al. N Eng J Med. 2007;357:2666-2676. Miles D et al. ASCO 44th Annual Meeting, 2008.)
• FDA approval of bendamustine (Treanda, Cephalon) for chronic lymphocytic leukemia (CLL). The drug had already been used in Europe for 30 years, but a new international trial showed bendamustine eliminated cancer completely in 30% of patients with CLL compared with only 2% treated with a standard treatment, chlorambucil. (Knauf WU et al. American Society of Hematology [ASH] 49th Annual Meeting and Exposition, 2007.)
• Reduction in the recurrence of early-stage breast cancer with additional years of hormonal therapy (either aromatase inhibitors or tamoxifen) after the standard 5 years of tamoxifen. (Several studies.)
• Reduction in the recurrence of early breast cancer with use of the osteoporosis bisphosphonate drug zoledronic acid (Zometa, Novartis). (Gnant M et al. ASCO 44th Annual Meeting, 2008.)
• Reduction in melanoma recurrence with pegylated interferon. (Eggermont AM et al. Lancet. 2008;372:117-126.)
• Prediction of response to cetuximab in colorectal cancer by KRAS mutations, with benefit from therapy seen only in patients who have normal (wild-type) KRAS and no benefit seen in those with KRAS mutations (CRYSTAL study. Van Cutsem E et al. ASCO 44th Annual Meeting, 2008.)
• Reduction of the risk of ovarian cancer from use of oral contraceptives, with estimates that these drugs may have prevented some 200,000 cases of ovarian cancer and 100,000 deaths to date worldwide. (Beral V et al. Lancet. 2008;371:303-314.)
• Increase in the incidence of human papilloma virus (HPV)–related head and neck oral cancers, perhaps due to an increase in oral sex, which in turn suggests a potential new use for the HPV vaccine. (Chaturvedi AK et al. J Clin Oncol. 2008;26:612-619.)
• Increase in number of cancer patients — expected to grow by 55% by the year 2020, significantly outpacing the availability of oncologists, leading to a shortage of some 2550 to 4080 oncologists in the United States by 2020. (Warren JL et al. J Clin Oncol. 2008;26:3242-3247.)
• Increase in risk of heart disease in childhood cancer survivors (about 5- to 10-fold increase compared with healthy siblings), emphasizing the need for life-long monitoring. (Childhood Cancer Survivor Study. Mulrooney D et al. ASCO 44th Annual Meeting, 2008.)

The report also highlighted a further 19 advances that the experts considered to be "notable," and these are listed as follows (again, not in rank order):

• Activity in relapsed/refractory Hodgkin's lymphoma with the investigational agent SGN-35 (Seattle Genetics) (an antibody targeting CD30 attached to the chemotherapeutic monomethyl auristatin E). (Younes A et al. ASCO 44th Annual Meeting, 2008.)
• Food and Drug Administration (FDA) approval of ixabepilone (Ixempra, Bristol-Myers Squibb) for advanced breast cancer in patients unresponsive to other types of chemotherapy. (Thomas ES et al J Clin Oncol. 2007;25:5210-5217.)
• Link between vitamin-D deficiency and worse breast cancer outcome. (Goodwin P et al. ASCO 44th Annual Meeting, 2008.)
• Increase in progression-free survival in glioblastoma with bevacizumab added to irinotecan (Camptosar, Pfizer). (Cloughesy TF et al. ASCO 44th Annual Meeting, 2008.)
• Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-fluorouracil-based chemotherapy in stage II and III colon cancer. (Sargent DJ et al. ASCO 44th Annual Meeting, 2008.)
• Activity in advanced hormone-refractory prostate cancer with abiraterone acetate (Cougar Technology) (an inhibitor of CYP17, an enzyme involved in testosterone production) (Attard G et al. ASCO 44th Annual Meeting, 2008) and also with the antisense oligonucleotide custirsen (OGX-011, OncoGenex), which increases sensitivity to chemotherapy, (Saad F et al. ASCO 44th Annual Meeting, 2008.)
• Activity in thyroid cancer with sorafenib (Nexavar, Bayer Healthcare) and the investigational agents axitinib (AG-013736, Pfizer) and motesanib (AMG 706, Amgen). (Gupta-Abramson V et al. Cohen EE et al. Pfister G et al. J Clin Oncol. 2008;26:4714-4719, 4708-4713, 4701-4704. Sherman SI et al. N Eng J Med. 2008;359:31-42.)
• Noninvasive method for genotyping tumor cells in blood for patients with non–small-cell lung cancer (Maheswaran S et al. N Engl J Med. 2008:359:366-377. )
• Identification of gene that increases risk of neuroblastoma. (Mosse YP et al ASCO 44th Annual Meeting, 2008.)
• Increased leukemia risk in childhood cancer survivors who were treated with platinum compounds and etoposide (Shankar SM et al. ASCO 44th Annual Meeting, 2008.)
• Prediction of leukemia outcome with the use of minimal residual disease (MRD) (Borowitz MJ et al. ASCO 44th Annual Meeting, 2008.)
• Activity in sarcoma with the investigational agent CP-751871 (Pfizer) (an anti-IGF-IR-antibody) (Olmos D et al. ASCO 44th Annual Meeting, 2008.)
• Activity of sorafenib in gastrointestinal stromal tumors (GIST) that had become resistant to imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer). (Wiebe L et al. ASCO 44th Annual Meeting, 2008.)
• Improvement of progression-free survival in melanoma with sorafenib plus dacarbazine. (McDermott DF et al. J Clin Oncol. 2008;26:2178-2185.)
• Value of dermoscopy for diagnosis of cutaneous melanoma in suspicious skin lesions. (Vestergaard ME et al. Br J Dermatol. 2008;159:669-676.)
• Explanation of the link that had been reported between finasteride and high-grade prostate cancer in the Prostate Cancer Prevention trial (PCPT) — new analyses found that the drug did not increase aggressive prostate cancer but decreased prostate volume and made such cancers easier to detect. (Cohen YC et al. Lucia MS et al. J Natl Cancer Inst. 2007;99:1366-1374, 1375-1383.)
• Cancer screening choices may change with health-insurance changes. (Wharam JF et al. Ann Intern Med. 2008;148:647-655.)
• Significant increase in cost of initial cancer treatment between 1991 and 2002 among elderly patients with breast, colon, prostate, and lung cancer. (Warren JL et al. J Natl Cancer Inst. 2008;100:888-897.)
• Benefit of acupuncture in easing pain and dry mouth after head and neck surgery. (Pfister D et al. ASCO 44th Annual Meeting, 2008.)

Call for Renewed Investment in Cancer Research

"This year's report illustrates that investment in cancer research pays off," says one of the report's executive editors, Eric Winer, MD, director of the Breast Oncology Center at the Dana-Farber Cancer Institute, in Boston, Massachusetts, and chair of ASCO's Cancer Communications Committee.

"But unless we reverse the effects of flat federal funding, the great potential we currently have to advance cancer treatment will go to waste," he commented in a statement.

The United States is in the midst of the longest sustained period of flat funding for cancer research in the country's history, ASCO points out. Budgets for both the National Institutes of Health and the National Institute of Cancer have remained unchanged for years and hence are not even keeping up with inflation. In the report, ASCO calls for renewed investment into cancer research.

"Scientifically, we have never been in a better position to advance cancer treatment. But 5 years of flat federal funding for cancer research puts future success at risk," commented Dr. Schilsky. "We're seeing signs of a slowdown already. Tighter budgets mean less funding for high-risk research that could have big payoffs, the most significant clinical cancer research is increasingly being conducted overseas, and talented young physicians are seeing less opportunity in the field of oncology and are opting instead for other specialties."

The other major recommendation that ASCO makes in its report is for increased patient participation in clinical trials. At present, only 5% of all cancer patients are involved in such studies, it points out.

"Clinical trials offer patients promising new therapies and high-quality care. But without greater participation, the pace of progress will slow," commented Julie Gralow, MD, associate professor of medicine/oncology at Washington University, in St. Louis, Missouri, another executive editor of the report.

"We need to reduce unnecessary barriers so that doctors can enroll patients and patients have the information and the coverage they need to participate," she said.

The report outlines several steps that would encourage participation, including nationwide public and private insurance coverage of clinical trials and full reimbursement to oncology practices for the costs incurred in participating in such studies.

J Clin Oncol. Published online December 22, 2008. Abstract

PEGINTRON AND MELANOMA

Pegylated Interferon Alfa-2B Has Impact on Advanced Melanoma

July 11, 2008 — Pegylated interferon alfa-2b (Pegintron, Schering-Plough) offers an attractive alternative to high-dose interferon for many melanoma patients, according to an editorial published in the July 12 issue of the Lancet. It accompanies the publication of the results of a large phase 3 study showing that the product had a significant and sustained effect on recurrence-free survival.

Pegylated interferon alfa-2b is not indicated for melanoma; it is currently marketed for use in chronic hepatitis C, either alone or in combination with ribavirin. In pegylated interferon alfa-2b, interferon is attached to the inert polyethylene glycol molecule, which leads to slower elimination from the body. This means that it can be dosed once a week instead of 3 times a week, which is required for standard interferon.

The trial, known as EORTC 18991, was conducted under the auspices of the European Organization for Research and Treatment of Cancer, but Schering-Plough provided financial support and the product. Preliminary results were reported by lead investigator Alexander Eggermont, MD, PhD, from Erasmus University Medical Center, in Rotterdam, the Netherlands, at the American Society of Clinical Oncology 44th Annual Meeting in June.

"Advanced-stage melanoma remains difficult to treat," Dr. Eggermont said in a statement. "These results demonstrate the benefit of an increased relapse-free survival despite no difference in overall survival."

Largest Trial of Adjuvant Therapy to Date

The study involved 1256 patients with postsurgery stage 3 melanoma, and is said to be the largest trial to date of an adjuvant melanoma therapy. Half the patients were randomized to receive pegylated interferon, at a dose of 6 μg/kg body weight for 8 weeks (induction), which was then reduced to 3 μg/kg for an intended duration of 5 years (maintenance). The other half of the patients were followed with observation alone.

Dr. Eggermont and colleagues report that at a median follow-up of 3.8 years (range, 3.2–4.2 years), the median length of treatment was 1 year (range, 3.8–33.4 months). During that time, pegylated interferon reduced the risk for recurrence by 18%, the researchers report. There were 328 recurrences in the pegylated-interferon group and 368 recurrences in the observation group (hazard ratio [HR], 0.82; 95% confidence interval, 0.71–0.96, P = .01).

Response to therapy appeared to be most pronounced in a subgroup of patients with microscopic nodal disease (N1). In this subgroup, which accounted for 43% of the total trial population, there were 108 events in the pegylated-interferon group and 137 events in the observation group (HR, 0.71; P = .01 on multivariate analysis).

However, there was no significant difference in overall survival between the 2 groups, Dr. Eggermont and colleagues report. Distant metastasis-free survival was numerically better in the pegylated-interferon group than in the observation group, but this difference was not statistically significant.

Treatment with pegylated interferon was discontinued because of toxicity in 191 patients (31%). The most common grade 3 or 4 adverse effects were fatigue (97 patients; 16%), hepatotoxicity (66 patients; 11%), and depression (39 patients; 6%).

Follow-Up Too Short for Final Conclusions

The median follow-up of 3.8 years "is too short for final conclusions," comment the editorialists, Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center and the University of South Florida College of Medicine, in Tampa, and Lawrence Flaherty, M, from the Karmanos Cancer Institute and Wayne State University School of Medicine, in Detroit, Michigan.

"The effect on recurrence-free survival could disappear after therapy ends, but further follow-up might show a significant survival advantage for the N1 population; that would represent the real advance we've been waiting for," they comment.

Recurrence-free survival, the end point used in this study, is appropriate in advanced melanoma, the editorialists comment, because many patients are willing to accept significant toxicity in exchange for a modest improvement in recurrence-free survival, even in the absence of an overall survival benefit. However, they question whether the toxicity of pegylated interferon, which is lower than that of the high-dose interferon currently used in the United States, will be sufficient to persuade skeptical clinicians who demand an overall survival benefit.

Approached for a comment, Jeffrey Weber, MD, from the H. Lee Moffitt Cancer Center, said: "In my view, this was a successful trial, with benefit for relapse-free survival. It should not to be discounted."

"This is apparently a better-tolerated product than standard high-dose interferon, and this trial has received a lot of attention in Europe," Dr. Weber told Medscape Oncology. "I am not sure if physicians will be able to use this product in the United States, but that wouldn't be unreasonable."

Dr. Weber and the editorialists stated, however, that pegylated interferon should be studied in combination with other products in further clinical trials.

NITROFURANTOIN IS BACK

UTI Pathogens Show Less Resistance to Nitrofurantoin

NEW YORK (Reuters Health) Dec 30 - In the wake of growing bacterial resistance to fluoroquinolones and increasing use of these agents for urinary tract infections (UTIs), a paper in the December issue of BJU International argues that "an old friend" nitrofurantoin should become the first-line therapy of choice.

Dr. James Kashanian and colleagues at the Maimonides Medical Center in Brooklyn, New York, reviewed antimicrobial susceptibility patterns of urinary isolates obtained between 2003 and 2007.

Overall, they say, 10,417 cultures from that period grew Escherichia coli, and 95.18% of E. coli isolates were susceptible to nitrofurantoin, with an average resistance rate of 2.3%.

In contrast, susceptibility rates for the E. coli isolates to ciprofloxacin and levofloxacin were 75.6% and 75.9%, respectively, and resistance rates were 24.2% to ciprofloxacin, 24% to levofloxacin, and 29% to trimethoprim/sulfamethoxazole.

"The broad range of bactericidal action of nitrofurantoin explains the relative lack of accumulated resistance to the drug over the past 50 years," the researchers write.

The investigators conclude, on the basis of their own data and similar reports by others, "that nitrofurantoin might be extremely effective in treating uncomplicated urinary tract infections. The lower cure rates and the increasing resistance associated with ciprofloxacin and levofloxacin should no longer make quinolones the first choice for treatment."

CELLSEARCH MISSES TUMOR SUBTYPE

Prognostic Test for Breast Cancer Misses Tumor Subtype

December 31, 2008 – The only Food and Drug Administration–approved test for detecting circulating breast cancer cells apparently does not pick up normal-like breast cancer, 1 of the subtypes of breast cancer, according to a report in the January 7 issue of the Journal of the National Cancer Institute.

The CellSearch circulating tumor cell test (Veridex, San Diego, California) is used to detect circulating cancer cells in patients with metastatic disease (prostate, colorectal, and breast) before and during treatment and allows clinicians to monitor treatment effectiveness, said Anieta Sieuwerts, PhD, from the Erasmus Medical Center, in Rotterdam, the Netherlands, in an interview with Medscape Oncology.

Thus, in patients whose breast cancer includes the normal-like subtype, the test will not indicate whether or not treatment is working effectively against this type of breast cancer. The normal-like subtype is not as common as the basal subtype or as well-known as the HER2-positive subtype. However, it generally has "aggressive features," said Dr. Sieuwerts.

Dr. Sieuwerts believes this discovery is important but was not alarmist about the test's deficiency. "The test has proven its usefulness in breast, colon, and prostate cancer, and the test may not be useful for only a minority of metastatic breast cancer patients," she said.

Normal-Like Subtype Bypassed by Technique

There are 5 subtypes of breast cancer that have been identified by their gene-expression patterns. The subtypes — basal, HER2-positive, luminal A and B, and normal-like — vary in their natural history and response to therapy. In the new study, the Dutch researchers investigated whether the 5 subtypes were identified by CellSearch, which uses antibodies against the cell surface–expressed epithelial cell-adhesion molecule (EpCAM) to isolate circulating tumor cells.

Specifically, they wanted to see whether the assay could isolate cells of breast cancer cell lines whose subtype is known and that had been added to human blood from a healthy volunteer. The investigators tested cells from a total of 34 cell lines that represented a mix of the 5 breast cancer subtypes (15 luminal, 9 normal-like, 5 basal-like, and 5 HER2-positive). The assay did not detect the 9 normal-like breast cancer cells but did detect the other subtypes.

The reason that the test misses the normal-like subtype is that "these [normal-like] cells lack the expression of EpCAM, the target used to catch the circulating tumor cells from the blood — the assumption was that all subtypes would be captured by the anti-EpCAM antibody," said Dr. Sieuwerts. EpCAM is integral to the CellSearch test.

Dr. Sieuwerts and her colleagues are working to identify and validate markers that would capture the normal-like subtype.

Next Steps

"New tests that include antibodies that specifically recognize normal-like breast tumor cells are needed," said Dr. Sieuwerts. The first step in that process is to find a marker that captures normal-like breast cancer.

"Once such a marker has been identified and thoroughly validated in a clinical setting, the introduction of this marker in the CellSearch test would be relatively easy," she added.

Dr. Sieuwerts acknowledged that clinicians may not be highly familiar with the normal-like breast cancer subtype. "This subtype lacks the more distinct characteristics that are associated with the other subtypes, eg, estrogen-receptor expression for the luminal subtypes, HER2 expression for the ERBB2 subtype, and expression of specific cytokeratins for the basal tumors, which in addition lack the expression of estrogen and progesterone receptors, and HER2 [triple-negative breast cancer]," she observed.

However, in their report, the Dutch researchers indicate that the normal-like cells can, for example, be identified by their ubiquitous expression of the markers TWIST1 and caveolin-1.

"Thus, the normal-like breast cancer cell subtype is an important target for the development of individualized therapy and should not be overlooked when assessing circulating tumor cells," write the report authors.

OXALIPLATIN AND OTOTOXICITY

Why the Difference in Ototoxicity Between Cisplatin and Oxaliplatin?

December 30, 2008 — Ototoxicity is a well-recognized adverse effect of cisplatin, resulting in hearing loss and tinnitus. It is often dose-limiting and can hamper optimal cisplatin-based chemotherapy. The related third-generation platinum compound, oxaliplatin (Eloxatin, Sanofi-Aventis) appears to be free of this adverse effect, and new studies have shed light as to why there is such a difference between the 2 drugs.

"Pharmacokinetic differences between cisplatin and oxaliplatin may be sufficient to explain their different ototoxic profiles," say researchers from the Karolinska Institute, in Sweden. In the January 7 issue of the Journal of the National Cancer Institute, they report studies showing differences in the way the 2 drugs are transported from the blood to the extracellular compartments of the cochlea in the inner ear.

The inner ear is protected by a blood-labyrinth barrier, in a manner analogous to the way that the central nervous system is protected by the blood-brain barrier, the researchers explain. This barrier consists mainly of endothelial cells sealed by tight junctions, and in the inner ear, it is most likely the major barrier for pharmacological substances in reaching the sensory epithelium of the hearing and balance organs.

The researchers, headed by Victoria Hellberg, MD, conducted a series of experiments in guinea pigs, which involved — among other procedures — obtaining samples from the scala tympani perilymph from the cochlea, a task that "is highly demanding methodologically," they comment. Using these samples, they showed that drug concentrations and also the total concentration of platinum in the perilymph section of the blood-labyrinth barrier were lower after oxaliplatin than after cisplatin administration, even though both drugs were administered at equimolar doses. "Limited cochlear uptake of oxaliplatin is a major explanation for the lower ototoxicity of oxaliplatin than cisplatin," the researchers conclude.

One limitation of their study, they say, is that it was conducted in guinea pigs. "It should not be taken for granted that human subjects have the same cochlear pharmacokinetics," they write. However, they point out that "for technical and ethical reasons, it is impossible to repeat our experiments in human subjects. We do believe, though, that the major aspects of our conclusions are valid for humans."

HYPERINSULINEMIA AND BREAST CANCER

Hyperinsulinemia May Be Risk Factor for Postmenopausal Breast Cancer

December 30, 2008 — There is a "strong positive association" between fasting insulin levels and the risk for breast cancer among postmenopausal women, according to a new analysis of 1651 women who were both hormone-replacement-therapy users and nonusers in the Women’s Health Initiative Observational Study.

The new study appears in the January 7 issue of the Journal of the National Cancer Institute.

Women with the highest insulin levels had a nearly 1.5-fold higher risk of developing breast cancer than women with the lowest insulin levels, when the women were divided into insulin-level quartiles, according to lead author Marc Gunther, PhD, assistant professor of epidemiology and population health at the Albert Einstein College of Medicine, in the Bronx, New York.

Among a subset of women who did not use hormone-replacement therapy, those individuals with the highest insulin levels had a nearly 2.5-fold increased risk of developing breast cancer compared with those with the lowest levels, Dr. Gunther told Medscape Oncology.

"Everyone has insulin. We see an incremental increase in breast cancer risk as insulin levels go up," said coauthor Howard Strickler, MD, who also participated in an interview with Medscape Oncology and is a professor in the same department at Albert Einstein.

Interventions aimed at lowering fasting insulin levels may reduce the risk for breast cancer in postmenopausal women, note the authors.

Dr. Stringer believes that research in this area is poised to take off. "Clinicians can look forward to fast progress in identifying methods for mitigating the insulin pathways related to breast cancer," he said.

The new study also supports laboratory findings in which insulin has been shown to stimulate cell proliferation in breast cancer cell lines, suggested Dr. Strickler. "There is now a confluence of data between lab scientists showing biologic plausibility and molecular epidemiologists showing the existence of associations in human beings," he commented.

First Study to Control for Estrogen Levels

Previous epidemiological studies into the association between circulating insulin levels and the risk for breast cancer have had inconsistent findings. Two studies that included women who were using hormone-replacement therapy reported no association. A third study, which was conducted among nonusers of hormone-replacement therapy, found a positive association between hyperinsulinemia and postmenopausal breast cancer, but only among women who were overweight or obese.

Notably, the new study is the first to prospectively examine the role of insulin in breast cancer while controlling for estrogen levels. "It is widely hypothesized that the association between obesity and postmenopausal breast cancer partly reflects the higher-than-average circulating estrogen levels present in obese women," write the authors.

In this study, Drs. Gunter, Strickler, and colleagues examined the association between incident breast cancer and the baseline serologic factors, including fasting insulin, insulinlike growth factor-I (IGF-I), and endogenous estradiol levels, as well as body-mass index (BMI). They compared these factors in 835 women enrolled in the Women's Health Initiative Observational Study who developed breast cancer and a randomly selected sample of 816 women in the study who did not develop breast cancer.

Fasting levels of insulin and endogenous estradiol were associated with a statistically significantly increased risk for incident breast cancer (hazard ratio [HR] for the highest vs lowest quartile of insulin, 1.46; 95% CI, 1.00 – 2.13; P = .02; HR for highest vs lowest quartile of endogenous estradiol, 1.59; 95% CI, 1.00 – 2.55; P = .04). The hazard ratios were adjusted for a wide range of breast cancer risk factors, including age, onset of menopause, smoking, physical activity, and use of contraceptives and nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, BMI was not associated with an increased risk for breast cancer in this model.

The new study also separately looked at a subset of women who did not use hormone-replacement therapy. This was important because the therapy "makes the analysis of insulin complicated due to the way it impacts the hormonal milieu," said Dr. Strickler.

Among these women, fasting insulin level was associated with an even greater statistically significantly increased risk for incident breast cancer among nonusers of hormone-replacement therapy (HR for highest vs lowest quartile of insulin, 2.48; 95% CI, 1.38 – 4.47; P < .001).

In addition, among nonusers of hormone-replacement therapy, high BMI was associated with an increased risk for breast cancer in multivariable models that adjusted for breast cancer risk factors (HR for BMI ≥ 30 kg/m² vs 18.5 to <>2, 2.12; 95% CI, 1.26 – 3.58; P = .003). When estradiol levels were incorporated into these models, there was only a "modest" 10% reduction in the BMI–breast cancer association (HR for BMI ≥ 30 kg/ m² vs 18.5 to <>2, 1.91; 95% CI, 1.11 – 3.27; P = .02). However, adjustment for insulin levels attenuated this association by 30% (HR for BMI ≥ 30 kg/m² vs 18.5 to <>2, 1.50; 95% CI, 0.80 – 2.83; P = .40).

"Insulin explains much of the relationship here [between the risk for breast cancer and BMI]," commented Dr. Gunter.

There was no association between fasting insulin level and incident breast cancer among women who used estrogen and progestin (HR for highest vs, lowest quartile of insulin, 1.15; 95% CI, 0.34 – 3.84; P = .40) and a possible inverse association among those who used estrogen alone (HR for highest vs lowest quartile of insulin, 0.33; 95% CI, 0.12 – 0.92; P = .31).

"Our data indicate that hyperinsulinemia and high endogenous estradiol levels are independent risk factors for breast cancer and largely explain the relationship between obesity and the risk for breast cancer in postmenopausal women," the authors conclude.

The insulin pathway is "obviously important" in part because the related problem of obesity is so common, noted Dr. Strickler. "The doubling of risk related to a common exposure [high levels of insulin often due to obesity] means that this pathway can explain a substantial portion of breast cancer in postmenopausal women," he said.

IMMUNIZATION SCHEDULE

Childhood and Adolescent Immunization Schedules Revised

December 31, 2008 — The 2009 recommended childhood and adolescent immunization schedules have been approved by the American Academy of Pediatrics, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, and the American Academy of Family Physicians. The updated recommendations are published in the January issue of Pediatrics.

"There are 3 schedules: 1 for children 0 through 6 years of age, 1 for people 7 through 18 years of age, and a catch-up immunization schedule for children and adolescents who start late or fall behind," write Joseph A. Bocchini, Jr, MD, chairperson of the Committee on Infectious Diseases, 2008 to 2009, and colleagues. "These schedules reflect current recommendations for use of vaccines licensed by the US Food and Drug Administration."

Changes from last year's schedule include the following:

• Children 6 months through 18 years of age should have annual influenza vaccine administration. All eligible close contacts of children 0 through 59 months of age should also receive influenza vaccine, as should contacts of children 5 through 18 years of age who have an underlying medical condition predisposing them to complications of influenza.
• The US Food and Drug Administration has licensed a second oral rotavirus vaccine and has harmonized the dosing schedules for the 2 licensed rotavirus vaccines. The first dose of either vaccine should be administered at 6 weeks through 14 weeks 6 days of age, and the final dose by 8 months 0 days of age. Immunization should not be started for infants 15 weeks 0 days of age or older.
• To give additional information and to clarify recommendations given in the schedules, most of the footnotes for the individual vaccines have been revised.

The Vaccine Adverse Event Reporting System should be notified of clinically significant adverse events following immunization (online at http://www.vaers.hhs.gov or by telephone at 800-822-7967).

Statements from the Advisory Committee on Immunization Practices containing detailed recommendations for individual vaccines and for vaccinating children with high-risk conditions are posted online at http://www.cdc.gov/vaccines/pubs/ACIP-list.htm or at Red Book Online (http://www.aapredbook.org).

New vaccine releases, vaccine supplies, interim recommendations related to vaccine shortages, and recommendations regarding specific vaccines are described online at http://www.aapredbook.org/news/vaccstatus.shtml and http://www.cdc.gov/vaccines/pubs/ACIP-list.htm.

ANTI-CA125 DOES NOT WORK IN OVARIAN CANCER

Oregovomab Not Effective for Maintenance Therapy in Ovarian Cancer

NEW YORK (Reuters Health) Dec 29 - Following chemotherapy for advanced ovarian cancer, maintenance mono-immunotherapy with the CA-125-specific murine monoclonal antibody oregovomab does not improve outcomes, according to a report published online ahead of print by the Journal of Clinical Oncology.

Lead investigator Dr. Jonathan Berek told Reuters Health, "This randomized prospective double-blind placebo-controlled study showed that oregovomab used as a maintenance therapy for patients with ovarian cancer in remission after front-line platinum and taxane chemotherapy did not further extend progression-free survival."

Dr. Berek of Stanford University School of Medicine, California and colleagues randomly assigned 371 patients with stage III to IV ovarian cancer to oregovomab or placebo after they had undergone chemotherapy.

Although the agent was well tolerated, there were no significant between-group differences in outcome. Overall, the median time to relapse following chemotherapy was 10.3 months with oregovomab and 12.9 months with placebo.

"However," concluded Dr. Berek, "in this and other studies, the monoclonal antibody produced immune responses in patients receiving oregovomab, suggesting that this agent or similar agents might be useful when combined with front-line chemotherapy."

CEA AND METASTATECTOMY

Low CEA After Resection of Colorectal Liver Metastases Predicts Better Survival Odds

NEW YORK (Reuters Health) Dec 30 - Patients with the lowest carcinoembryonic antigen (CEA) levels after liver resection for colorectal metastases have the highest survival rates, according to a report in the December issue of the Archives of Surgery.

CEA blood level is the most commonly used tumor marker to monitor patients after resection of primary colorectal cancer and colorectal liver metastases, the authors explain, but few studies have investigated its prognostic value among patients undergoing resection of colorectal liver metastases.

Dr. Daniel Jaeck from Hopitaux Universitaires de Strasbourg-Universite Louis Pasteur, Strasbourg, France, and colleagues evaluated the value of CEA measurements obtained a week before and 6 weeks after surgery to predict cure after resection of colorectal liver metastases in 213 patients.

Five-year overall and disease-free survival rates were highest (50.2% and 21.9%, respectively) among patients with normal preoperative and postoperative CEA levels, the authors report. They were lower (38.5% and 18.3%, respectively) for patients with elevated preoperative and normal postoperative CEA levels, and lowest (0.0% and 0.0%, respectively) for patients with elevated preoperative and postoperative CEA levels.

"Normalization of CEA levels 6 weeks after colorectal liver metastases resection may indicate improved long-term outcomes in these patients," the investigators say.

"CEA levels as early as 6 weeks after surgery may be helpful in assigning patients to adjuvant chemotherapy after resection of colorectal liver metastases," the authors conclude

Phase III Study of Immediate Compared With Delayed Docetaxel After Front-Line Therapy With Gemcitabine Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer

JCO Early Release, published online ahead of print Dec 15 2008
Journal of Clinical Oncology, 10.1200/JCO.2008.17.1405
Panos M. Fidias,* Shaker R. Dakhil, Alan P. Lyss, David M. Loesch, David M. Waterhouse, Jane L. Bromund, Ruqin Chen, Maria Hristova-Kazmierski, Joseph Treat, Coleman K. Obasaju, Martin Marciniak, John Gill, and Joan H. Schiller 

From the Massachusetts General Hospital, Boston, MA; Penrose Cancer Center of Kansas, Wichita, KS; Missouri Baptist Cancer Center, St Louis, MO; Central Indiana Cancer Centers; Eli Lilly & Co, Indianapolis, IN; Oncology Hematology Care, Inc, Cincinnati, OH; and University of Texas Southwestern Medical Center, Dallas, TX.

* To whom correspondence should be addressed. E-mail: pfidias2@partners.org


Purpose: Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non–small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression.

Patients and Methods: The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m2) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m2 on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL).

Results: Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups.

Conclusion: We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.

About
JCO Editorial
Roster Adver

Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma

A North Central Cancer Treatment Group study, N047A
Domingo G. Perez, MD 1, Vera J. Suman, PhD 2, Tom R. Fitch, MD 3, Thomas Amatruda III, MD 1, Roscoe F. Morton, MD 4, Shamim Z. Jilani, MD 5, Costas L. Constantinou, MD 6, James R. Egner, MD 7, Lisa A. Kottschade, RN, MSN, CNP 2, Svetomir N. Markovic, MD, PhD 2 *§
1Metro-Minnesota Community Clinical Oncology Program, St Louis Park, Minnesota
2Mayo Clinic and Mayo Foundation, Rochester, Minnesota
3Mayo Clinic and Mayo Foundation, Scottsdale, Arizona
4Iowa Oncology Research Association CCOP, Des Moines, Iowa
5Hematology and Oncology of Dayton, Inc. Dayton, Ohio
6Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa
7Carle Cancer Center CCOP, Urbana, Illinois
email: Svetomir N. Markovic (markovic.svetomir@mayo.edu)


*Correspondence to Svetomir N. Markovic, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905
Additional participating institutions included: Wichita Community Clinical Oncology Program, Wichita, Kansas; Sioux Community Cancer Consortium, Sioux Falls, South Dakota; Missouri Valley Cancer Consortium, Omaha, Nebraska; Mayo Clinic Jacksonville, Jacksonville, Florida.
Roscoe F. Morton owns shares of stock in Genentech.
§Fax: (507) 284-5045

Funded by:
 Public Health Service; Grant Number: CA-25224, CA-35267, CA-60276, CA-35101, CA-35090, CA-52352, CA-35195, CA-35269, CA-35431, CA-35103, CA-63849
Keywords
metastatic melanoma • angiogenesis • chemotherapy • phase 2 trials

Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastatic progression of melanoma. Exposure of melanoma cells to chemotherapy induces VEGF overproduction, which in turn may allow melanoma cells to evade cell death and become chemotherapy resistant. Therefore, in patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets VEGF might be able to control tumor growth and progression more effectively than chemotherapy alone. METHODS: A 2-stage phase 2 clinical trial was conducted in patients with unresectable stage IV (metastatic) melanoma to assess antitumor activity and the toxicity profile of the combination of carboplatin (area under the curve 6 iv on Day 1 of a 28-day cycle), paclitaxel (80 mg/m2 iv on Days 1, 8, and 15), and bevacizumab (10 mg/kg iv on Days 1 and 15). Treatment was continued until progression or intolerable toxicity. RESULTS: Fifty-three patients (62.3% male) were enrolled. Nine (17%) patients achieved partial remission, and another 30 (57%) achieved stable disease for at least 8 weeks. Median progression-free survival and median overall survival were 6 months and 12 months, respectively. One patient died after 8 treatment cycles from intracranial hemorrhage into undiagnosed brain metastases. The most common severe (grade 3) toxicities were neutropenia (53%), thrombocytopenia (11%), hypertension (9%), and anemia (8%). CONCLUSIONS: This combination of carboplatin, paclitaxel, and bevacizumab appears to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma. Further study of this combination is warranted. Cancer 2009. © 2008 American Cancer Society.

Received: 3 April 2008; Revised: 29 July 2008; Accepted: 4 August 2008

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Risedronate for the Prevention of Bone Loss in Premenopausal Women Undergoing Chemotherapy for Primary Breast Cancer

JCO Early Release, published online ahead of print Dec 15 2008

Journal of Clinical Oncology, 10.1200/JCO.2008.19.1783

Stephanie L. Hines,* Betty Anne Mincey, Jeff A. Sloan, Sachdev P. Thomas, Elaine Chottiner, Charles L. Loprinzi, Mark D. Carlson, Pamela J. Atherton, Muhammad Salim, and Edith A. Perez 

From the Mayo Clinic Jacksonville, Jacksonville, FL; Mayo Clinic Rochester, Rochester, MN; Illinois Oncology Research Association, Peoria, IL; Michigan Cancer Research Consortium, Ann Arbor, MI; Missouri Valley Cancer Consortium, Omaha, NE; and Saskatchewan Cancer Foundation, Regina, Saskatchewan, Canada.

* To whom correspondence should be addressed. E-mail: hines.stephanie@mayo.edu


Purpose: Risedronate prevents bone loss in postmenopausal women. The purpose of this study was to determine whether risedronate prevents bone loss in premenopausal women undergoing chemotherapy for breast cancer.

Patients and Methods: Premenopausal women undergoing chemotherapy for breast cancer were treated with oral calcium 600 mg and vitamin D 400 U daily and randomly assigned to receive oral risedronate 35 mg weekly or placebo, with all these therapies beginning within a month of the start of chemotherapy. Most chemotherapy regimens included anthracyclines, taxanes, or cyclophosphamide. Bone mineral density (BMD) was measured at baseline and 1 year. The primary end point was the change in lumbar spine (LS) BMD from baseline to 1 year.

Results: A total of 216 women enrolled; 170 women provided BMD data at 1 year. There was no difference in the mean change or percent change in LS BMD between groups, with a loss of 4.3% in the risedronate arm and 5.4% for placebo at 1 year (P = .18). Loss of BMD at the femoral neck and total hip were also similar between treatment groups. Risedronate was well tolerated, with no significant differences in adverse events compared with placebo, except that arthralgias and chest pain were worse in those receiving the placebos.

Conclusion: Risedronate did not prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer.

J Hist Neurosci. 1997 Apr;6(1):86-9.

A neolithic case of Down syndrome.
Diamandopoulos AA, Rakatsanis KG, Diamantopoulos N.

Athens University, Department, St. Andrew's Regional Hospital, Patras, Greece.

The aim of the study is to draw attention to the existence of a Neolithic figurine from Greece with characteristics compatible with Down syndrome. We have reviewed the relevant medical and archaeological literature, and we have compared photographs of the figurine with photographs of a patient with typical Down syndrome (DS). From the above data we conclude that the 7000 years old artefact may well be the most ancient representation of the disease in Western civilisation.

PMID: 11619201 [PubMed - indexed for MEDLINE]