CAROTID ENDARTERECTOMY BETTER THAN STENTING IN SYMPTOMATIC PATIENTS

Better 30-Day Outcomes With Carotid Endarterectomy Than Stenting

February 6, 2009 (Watertown, Massachusetts) — Data from a national registry suggest that outcomes at 30 days are better with carotid endarterectomy (CEA) than with carotid artery stenting (CAS) [1]. Investigators report that the combined rate of death, stroke, and MI was significantly lower with the surgical approach vs the less invasive interventional technique.

"The debate about the interpretation of the results of this study as well as results of other CAS studies will continue until randomized trials such as International Carotid Stenting Study (ICSS) in Europe and [the Carotid Revascularization Endarterectomy vs Stenting Trial] CREST in North America are reported," note lead investigator Dr Anton Sidawy (Washington Veterans Affairs Medical Center, DC) and colleagues in the January 2009 issue of the Journal of Vascular Surgery.

The data, from the Society for Vascular Surgery (SVS), are the latest in a number of head-to-head comparisons between CEA and CAS that have often shown conflicting results. Two carotid-artery stenting studies--Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE) [2] and Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) [3]--were published in 2006, and both showed stenting to be inferior to endarterectomy.

Those findings contrasted with data from the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, a study that compared carotid stenting using distal embolic protection with carotid endarterectomy in patients at high surgical risk [4]. Based on the findings from SAPPHIRE, the Food and Drug Administration approved the use of carotid stenting in patients with high-grade symptomatic stenosis who are at high operative risk.

In this analysis, the researchers obtained data from the SVS vascular registry for carotid procedures. Rates of death, stroke, and MI were significantly higher among patients who underwent stenting compared with those had an endarterectomy. Both symptomatic and asymptomatic patients had significantly higher 30-day procedure rates of death, stroke, and MI compared with CEA patients. Similarly, in an analysis of only patients with atherosclerosis, the death, stroke, and MI combined end point was significantly lower among those who underwent CEA.

Outcomes at 30 Days by Treatment Arm in the 30-Day Follow-up Cohort

Outcome	CAS, n=1450 (%)	CEA, n=1368 (%)	p
Combined death, stroke, and MI	5.72	2.63	<0.001>
Death	2.07	0.73	0.004
Stroke	3.52	1.68	0.003
MI	1.17	0.58	0.110
Transient ischemic attack	1.59	0.80	0.060

Highlighting the inconsistencies in the field, the 5.72% event rate among CAS patients is consistent with outcomes observed in the BEACH and MAVERIC studies, higher than that observed in SAPPHIRE and other studies, and lower than that observed in the ARCHER and CAPTURE trials.

More data are expected sometime this year with the results of CREST, a study of 2511 asymptomatic and symptomatic patients who are not at high risk for surgery. The ICSS study is a head-to-head comparison of carotid stenting and endarterectomy in approximately 1700 asymptomatic patients with carotid stenosis.

The researchers note that the SVS registry could possibly supplement randomized trials "by providing real-world comparisons of CAS and CEA," especially in important patient subsets.

RADIOTHERAPY FOR DCIS

Combination Surgery and Radiotherapy Benefits All Women With DCIS

NEW YORK (Reuters Health) Feb 05 - A literature review "confirms the benefit of adding radiotherapy to breast-conserving surgery for the treatment of all women diagnosed with ductal carcinoma in situ (DCIS);" this strategy substantially reduces the risk of breast cancer recurrence.

The review, conducted by Dr. Annabel Goodwin at The University of Sydney in Camperdown, Australia, and colleagues, is published in the latest online issue of The Cochrane Library, a publication of The Cochrane Collaboration.

Dr. Goodwin's group searched the Cochrane Breast Cancer Group Specialized Register (January 2008); the Cochrane Central Register of Controlled Trials (2008); MEDLINE (February 2008); EMBASE (February 2008) and abstracts from major cancer conferences.

The investigators identified four well-designed, randomized controlled trials involving 3,925 women that compared the addition of radiotherapy to breast-conserving surgery.

"All the subgroups analyzed benefited from addition of radiotherapy," Dr. Goodwin and colleagues report.

There was a statistically significant benefit with the addition of radiotherapy on all ipsilateral breast events, with a hazard ratio of 0.49, and ipsilateral DCIS recurrence, with a hazard ratio of 0.64. Recurrence of invasive cancer did not reach statistical significance.

There was no significant long-term toxicity from radiotherapy and no reports of short-term toxicity or adverse effects on the quality of life.

In a comment from the Health Behavior News Service, Dr. Monica Morrow of Memorial Sloan-Kettering Cancer Center in New York, New York, said that the review confirms what is currently recommend by most physicians for their patients with DCIS who undergo breast-conserving treatment.

"The best way to minimize the chance of recurrence is with radiation," Dr. Morrow said.

Most physicians will recommend breast-conserving surgery for DCIS. However, "studies show that the bigger the patient's role in decision-making, the greater the likelihood the patient will end up with mastectomy," she said.

"This is because most patients don't distinguish between DCIS and invasive breast cancer, because a lot of the stuff they find on the Internet is written about invasive cancer."

Dr. Morrow pointed out that there is little difference in survival rates between mastectomy and breast-conserving surgery for women with DCIS.

"What I tend to emphasize to my patients with DCIS is that no matter which treatment they choose, their risk over the next 15 years of dying of something else is greater than their risk of dying of breast cancer."

J Clin Oncol. 2009 Feb 2. [Epub ahead of print]

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Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer: AVAiL.

Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C.

Krankenhaus Grosshansdorf, Grosshansdorf; Asklepios Fachkliniken München-Gauting, Muenchen-Gauting; St. Vincentius-Kliniken, Karlsruhe; Heidelberg University Medical Center, Mannheim, Germany; Third Faculty of Medicine, Charles University, Postgraduate Medical School, Prague, Czech Republic; Wielkopolskie Centrum Chorob Pluc i Gruzlicy, Poznan, Poland; Cancer Research Center, Moscow, Russia; McGill University Health Centre-Royal Victoria Hospital, Montreal, Quebec; Princess Margaret Hospital, Toronto, Ontario, Canada; and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

PURPOSE: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m(2) and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). RESULTS: PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade >/= 3 pulmonary hemorrhage rates were

FERTILITY DRUGS AND OVARIAN CANCER

Fertility Drugs Do Not Increase Risk for Ovarian Cancer

February 5, 2009 — Fertility drugs do not increase the risk for ovarian cancer, concludes the largest study of the subject to date.

There was no convincing association with ovarian cancer for any the 4 different types of drugs used to treat infertile women — gonadotrophins, clomiophene citrate, human chorionic gonadotrophin, and gonadotrophin-releasing hormone.

Instead, the data suggest that factors related to the diagnosis of infertility (for example, genetic or biological factors) — and not the use of fertility drugs — increase the overall risk for ovarian cancer, say the researchers.

However, they also point out that there is a major limitation to this study — many of the participants have not yet reached the age at which the incidence of ovarian cancer peaks (early 60s).

The study, headed by Allen Jensen, PhD, assistant professor of cancer epidemiology at the Danish Cancer Society's Institute of Cancer Epidemiology, in Copenhagen, Denmark, is reported online February 5 in BMJ.

"These data are reassuring and provide further evidence that fertility drugs do not increase a woman's risk of ovarian cancer to any great extent, although small increases in risk cannot be ruled out," said Penelope Webb, from the Queensland Institute of Medical Research, in Brisbane, Australia, in an accompanying editorial.

"Given the increasing numbers of women seeking fertility treatment, this is important information for clinicians and patients," she adds.

Main Limitation is Age of Participants

"The data are reassuring," agrees senior author Susanne Kruger Kjaer, MD, professor of cancer epidemiology at the Danish Cancer Society and the Juliane Marie Center at Copenhagen University Hospital.

A link between fertility drugs and increased risk for ovarian cancer was suggested by several studies in the early 1990s, and this has caused a lot of worry for patients undergoing infertility treatment, she commented an interview with Medscape Oncology. However, many of the studies over the past 8 to 10 years have been very small, and "none were really able to reject or confirm the hypothesis and the worries," she continued.

"Our study was big enough," she added.

Dr. Webb concurs, and writes: "This study is important because it included 156 women with ovarian cancer, more than 3 times as many as any previous cohort."

However, Dr. Kjaer noted 2 caveats. One is that the study was restricted to epithelial ovarian cancer; 6 cases of ovarian cancer of unknown histology and 11 cases of ovarian cancer that was nonepithelialere excluded because these cancers may have different behaviors, she explained.

The main limitation of the study, however, is the age of the participants. These were young women, Dr. Kjaer explained — they were first evaluated for infertility at a median age of 30 years. Despite a long follow-up, the median age of these women at the end of the follow-up period was 47 years. This is some way below the usual age at which women are diagnosed with ovarian cancer, which reaches a peak incidence in women in their early 60s. So there is a possibility that there could still be a spate of ovarian cancers diagnosed as these women age, which could alter the conclusions.

"This is my only 'but' in the results, so to speak," Dr. Kjaer told Medscape Oncology.

"This is a question that nobody can answer yet," she added. Hence, she continued, " we should say that the data so far are really reassuring . . . at this moment, with this observation period, and with this age of the cohort, we cannot see any association with an increase in the risk of ovarian cancer."

The researchers intend to revisit the data at regular points in the future to check on the progress of the study cohort with "passive surveillance," she said. The Danish system of personal identification numbers and nationwide health and cancer registries will allow them to track any new diagnosis of ovarian cancer, she added.

Cannot Exclude Small Possibility

The Danish study investigated the records of 54,362 women with infertility problems, and compared 156 women who developed invasive epithelial ovarian cancer with 1241 controls.

However, although this study was much larger than previous investigations, it still could not exclude the possibility of a small increase in the risk for ovarian cancer in users of fertility drugs, Dr. Webb writes in the editorial. The rate ratio for use of any fertility drug was 1.03, but the upper bound of the 95% confidence interval was 1.47, she points out.

"Larger numbers of women will need to be studied to answer this question, and these will come with further follow-up of the cohort as they enter the age range where ovarian cancer is most common," Dr. Webb comments. "Some women who take fertility drugs will inevitably develop ovarian cancer by chance alone, but current evidence suggests that women who use these drugs do not have an increased risk."

SACROCOCCYGEAL TERATOMA

Pediatr Surg Int. 2009 Jan 28. [Epub ahead of print]

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Long-term outcomes of surgery for malignant sacrococcygeal teratoma: 20-year experience of a regional UK centre.

Khalil BA, Aziz A, Kapur P, Humphrey G, Morabito A, Bruce J.

Department of Paediatric Surgery, Royal Manchester Children's Hospital, Pendlebury, Hospital Road, Manchester, M27 4HA, UK, Kba_bas@hotmail.co.uk.

BACKGROUND: The timing of surgery for malignant sacrococcygeal teratoma is controversial. The long-term outcomes and complications of surgery for this rare tumour are presented. METHODS: All cases of malignant sacrococcygeal teratoma in the 20-year period 1987-2006 were identified and the case notes retrieved. The age at diagnosis, investigations, presentation, type of surgery, early complications, recurrence rates, long-term complications and outcomes were recorded. RESULTS: Twelve patients (three males, nine females) were identified. Mean age at presentation was 20.8 months (range: 12-39 months). All had the Carboplatin-Etoposide-Bleomycin chemotherapeutic protocol. The average time of follow-up was 10.6 years (range: 1-17 years). Ten patients had excision of their tumours following chemotherapy, whilst two patients had excision prior to chemotherapy. Two patients had recurrence of their tumours. There was one death (8%), which was due to disseminated metastasis. The other 11 children were all well at the last follow-up. CONCLUSION: Surgery for malignant sacrococcygeal teratoma is safe and has a low complication rate. The long-term outcomes are favourable with minimal side effects.

AN INTERESTING REGIMEN

Cancer Chemother Pharmacol. 2009 Jan 31. [Epub ahead of print]

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Phase II study of an all-oral combination of vinorelbine with capecitabine in patients with metastatic breast cancer.

Nolè F, Crivellari D, Mattioli R, Pinotti G, Foa P, Verri E, Fougeray R, Brandely M, Goldhirsch A.

Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy, franco.nole@ieo.it.

PURPOSE: Combination of intravenous (i.v.) vinorelbine and capecitabine was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience and to prolong infusion-free survival, we investigated in first-line treatment a regimen combining oral vinorelbine and capecitabine in a phase II study. PATIENTS AND METHODS: Fifty-two patients (median age, 60 years) with MBC received the combination consisting of oral vinorelbine 60 mg/m(2) on days 1, 8 and 15 plus capecitabine 1,000 mg/m(2) bid given from day 1 to day 14 in an open-label, multicentre phase II study [the recommended doses were established in a phase I study (Nolé et al. in Ann Oncol 17:332-339, 2006)]. Cycles were repeated every 3 weeks. RESULTS: Seventy-nine percent of the patients had received prior adjuvant chemotherapy and 81% presented with visceral involvement. The median number of administered cycles per patient was 7 (range 1-18). Twenty-three responses were documented and validated by an independent panel review, yielding response rates of 44.2% (95% CI, 30.5-58.7) in the 52 enrolled patients and 54.8% (95% CI, 38.7-70.2) in the 42 evaluable patients. Median progression-free survival and median overall survival were 8.4 and 25.8 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, only one patient having experienced febrile neutropenia. Other frequently reported adverse events included, fatigue, nausea, vomiting, diarrhoea and constipation, stomatitis and hand-foot syndrome, which were rarely severe. CONCLUSIONS: This regimen combining oral vinorelbine with capecitabine is effective and manageable in the first-line treatment of MBC. Oral vinorelbine on days 1, 8 and 15 with capecitabine from days 1 to 14 every 3 weeks represents a convenient option which offers an all-oral treatment to the patients and prolongs their infusion-free survival.

BREAST CANCER AND HORMONE THERAPY

Breast Cancer Risk Declines Quickly After Stopping Hormone Therapy: WHI Data in NEJM

February 4, 2009 — The well-documented increased risk for breast cancer associated with combined estrogen-plus-progestin therapy in postmenopausal women declines markedly after stopping therapy, according to Women's Health Initiative (WHI) data published in the February 5 issue of the New England Journal of Medicine.

The same data were presented in December 2008 at San Antonio Breast Cancer Symposium, and reported at the time by Medscape Oncology.

The women on estrogen-plus-progestin therapy, also known as hormonal-replacement therapy, had a median of 5.6 years of treatment and had a 26% increased risk for breast cancer, compared with placebo controls.

However, according to the new data, the risk returns to baseline in about 2 years.

"We can't define a safe interval for hormone-replacement therapy," study lead author Roman Chlebowski, MD, PhD, from the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, in California, said at a press conference in San Antonio.

DO NOT COMBINE BEVACIZUMAB AND CETUXIMAB IN COLORECTAL CANCER

Combining Targeted Therapies for Metastatic Colon Cancer Is Not Beneficial

February 4, 2009 — More is not better when it comes to targeted therapies for metastatic colorectal cancer.

This was the finding from 2 new studies in which an anti-epidermal growth-factor receptor (EGFR) was added to a chemotherapy–bevacizumab combination, which is the standard first-line treatment for metastatic colorectal cancer.

Bevacizumab acts on vascular endothelial growth factor (VEGF) and thus, like an EGFR, is a monoclonal antibody or targeted therapy.

Both new studies showed that the addition of an EGFR (either cetuximab or panitumumab) to the standard first-line treatment reduced progression-free survival — and produced other negative results.

In effect, targeted therapies do not seem to act like chemotherapies, which provide greater benefit when given in combination with one another, notes Robert J. Mayer, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, in an editorial that accompanied the Dutch study published in the February 5 issue of the New England Journal of Medicine.

"Combing multiple forms of targeted therapies may not be analogous to combining different types of cytotoxic chemotherapy," notes Dr. Mayer.

"Since combining cytotoxic drugs that act through different mechanisms improved outcomes in patients with metastatic colorectal cancer, it seemed logical that further progress would result from combining bevacizumab with either cetuximab or panitumumab and administering these monoclonal antibodies together with chemotherapy," explains Dr. Mayer.

The negative results of this Dutch study and another new study, the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial, which was published online December 29 in the Journal of Clinical Oncology, were unexpected because preclinical and early clinical studies had shown promise.

Nevertheless, targeted therapies have value in this setting, writes Charles D. Blanke, MD, from the University of British Columbia, in Vancouver, in an editorial accompanying the PACCE trial. "Antibodies to either VEGF or the EGFR, utilized as the sole targeted agent, clearly have a place in the therapy of advanced metastatic colorectal cancer."

However, Dr. Blanke also concludes that "the concept of using double-antibody therapy in metastatic colorectal cancer is falling out of favor."

Addition of Cetuximab Also Reduces Median Overall Survival

Both of the new studies were phase 3 multicenter randomized trials conducted in patients with previously untreated metastatic colorectal cancer.

The Dutch study, led by Jolien Tol, MD, from the Radboud University Nijmegen Medical Center, was conducted in the Netherlands. It involved 732 patients treated with capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in cycles administered every 3 weeks.

After a median follow-up of 23 months, the addition of cetuximab to the combination of capecitabine, oxaliplatin, and bevacizumab significantly decreased median progression-free survival time, from 10.7 months to 9.4 months (P = .01). Furthermore, the addition of cetuximab was also associated with reduced median overall survival (19.4 months), compared with capecitabine, oxaliplatin, and bevacizumab treatment (20.3 months).

The investigators assessed tumor tissue for KRAS gene status in 71% of patients; mutations were found in 40% of the specimens. Anti-EGFR treatments, such as cetuximab, have been shown to be effective only in colorectal cancer patients with wild-type KRAS tumors.

However, in this study, the addition of cetuximab did not improve progression-free survival in patients whose tumors contained wild-type KRAS, and was harmful for those with tumors bearing a mutant KRAS gene. Nonetheless, it can be said that KRAS genotype affected the response to cetuximab, the researchers comment.

The rate of adverse events was similar in the 2 treatment groups, except that there were significantly more cetuximab-related cutaneous adverse effects (P < .001).

The Dutch study authors speculate that the negative results might be due to a "negative interaction between cetuximab and bevacizumab."

However, as Dr. Mayer notes in his editorial, there is "no obvious explanation" for the results, which were unexpected.

The PACCE Study

The PACCE study, led by J. Randolph Hecht, MD, from the David Geffen School of Medicine at the University of California at Los Angeles, was conducted in the United States and published online December 29 in the Journal of Clinical Oncology. It involved 823 patients treated with the FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen who also received either bevacizumab alone (the control group) or bevacizumab plus panitumumab (the panitumumab group).

In addition, a cohort of 230 patients treated with the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen received either bevacizumab alone (the control group) or bevacizumab plus panitumumab (the panitumumab group).

Panitumumab was discontinued after a planned interim analysis of 812 patients in the FOLFOX cohort showed worse efficacy in the panitumumab group than in the control group.

In the final analysis of the FOLFOX cohort, median progression-free survival was worse in the panitumumab group (10.0 months vs 11.4 months) than in the control group (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52). Median survival was also worse, at 19.4 months in the panitumumab group and 24.5 months in the control group.

In addition, grade 3/4 adverse events in the FOLFOX cohort were more frequent in the panitumumab group than in the control group, including skin toxicity (36% vs 1%), diarrhea (24% vs 13%), infections (19% vs 10%), and pulmonary embolism (6% vs 4%).

Increased toxicity without evidence of improved efficacy was also observed in the panitumumab group of the FOLFIRI cohort, write the study authors.

KRAS analyses showed adverse outcomes for the panitumumab group in both wild-type and mutant groups, they add.

Only Patients With Wild-Type KRAS

One other major clinical trial in metastatic colorectal cancer patients is ongoing, and consists of a treatment group with both antibody classes or targeted therapy types, writes Dr. Blanke.

C80405 is the North American Intergroup trial that combines FOLFOX- or FOLFIRI-based chemotherapy (investigator's choice) with bevacizumab, cetuximab, or both antibodies in untreated advanced metastatic colorectal cancer.

In 2008, the investigators decided to continue the study with its existing groups, but to modify it to include only patients with wild-type KRAS. "This indicated that at least some experts feel the jury is still out on the double-antibody question in that population," writes Dr. Blanke. However, he also notes that the PACCE trial has already demonstrated "less than ideal outcomes" in patients with wild-type KRAS given double-antibody therapy.

PROSTATE CANCER IS NOT THE MAIN CAUSE OF DEATH

Other Health Issues May Be Neglected in Men With Prostate Cancer

NEW YORK (Reuters Health) Jan 27 - The majority of men with early-stage low/moderate-grade prostate cancer die from causes other than prostate cancer, researchers report in the January issue of the Journal of the American Geriatric Society. Therefore, they say, prevention and management of comorbid health conditions is important.

"Once a diagnosis of cancer has been made, it can become the sole focus of medical care," Dr. James S. Goodwin and colleagues write. "This is understandable, because cancer is typically life threatening and often requires dramatic therapy, but earlier cancer diagnoses, due to screening, and improvements in treatment have been associated with lower cancer mortality," they note.

"Thus, patients are living longer after a diagnosis of cancer, to the point where existing comorbidities may substantially affect their overall survival," they point out.

Dr. Goodwin, of the University of Texas Medical Branch, Galveston, and colleagues used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database to assess outcomes in 208,601 men between the ages of 65 and 84 years diagnosed with prostate cancer from 1988 through 2002. Overall, 59.1% of the entire cohort had early-stage prostate cancer with low- to moderate-grade tumors.

Mortality in these subjects was similar to that of men without prostate cancer. Among the men with early-stage, low- or moderate-grade tumors, mortality from prostate cancer was 2.1% versus 6.4% from heart disease and 3.8% from other cancers.

"The substantial effect of comorbid conditions on survival and the high rate of mortality related to non-prostate cancer have important implications," Dr. Goodwin's team writes.

"First, as others have suggested, decisions about management of localized prostate cancer should incorporate not only life expectancy based on age, but also the important contributions of specific comorbid conditions," they note. "Second, the choice to use androgen deprivation therapy, now a common treatment even for early-stage prostate cancer, should be made carefully in the presence of significant comorbidity."

Overall, the team concludes, older men with early-stage prostate cancer "would be well served by an ongoing focus on screening and prevention of cardiovascular disease and other cancers."

DO NOT USE HORMONES IN BREAST CANCER PATIENTS

Lancet Oncol. 2009 Feb;10(2):135-46. Epub 2009 Jan 23.

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Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial.

Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M, Mulder R, van Os S, Beckmann MW; LIBERATE Study Group.

Department of Obstetrics and Gynaecology, VU University Medical Centre, Amsterdam, Netherlands. kenemans@vumc.nl

BACKGROUND: Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints. METHODS: Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T(1-3)N(0-2)M(0)) with vasomotor symptoms were randomly assigned to either tibolone 2.5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1.278. This study is registered with ClinicalTrials.gov, number NCT00408863. FINDINGS: Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52.7 years (SD 7.3) and mean time since surgery was 2.1 years (SD 1.3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6.5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6.4 (SD 5.1). After a median follow-up of 3.1 years (range 0.01-4.99), 237 of 1556 (15.2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10.7%) on placebo (HR 1.40 [95% CI 1.14-1.70]; p=0.001). Results in the per-protocol population were similar (209 of 1254 [16.7%] women in the tibolone group had a recurrence vs 138 of 1213 [11.4%] women in the placebo group; HR 1.44 [95% CI 1.16-1.79]; p=0.0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo. INTERPRETATION: Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss. FUNDING: Schering-Plough (formerly NV Organon, Oss, Netherlands).

GERM CELL TUMORS AND BONE METASTASES

Hinyokika Kiyo. 2008 Dec;54(12):803-7.

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[Three case reports of metastatic germ cell tumors in the lumbar vertebra during first-line chemotherapy]

[Article in Japanese]

Dobashi M, Son S, Ikeda M, Fujita T, Matsumoto K, Satoh T, Iwamura M, Baba S.

The Department of Urology, Kitasato University School of Medicine.

We report three patients with germ cell tumors whose diagnosis was confirmed in the progress of the first-line chemotherapy regimen as metastatic cancer in the lumbar vertebra. Two of the 3 cases were mixed-type nonseminoma, and the other case was an extragonadal tumor. After the first-line chemotherapy regimen, the patients underwent salvage chemotherapy using Paclitaxel either with or without irradiation. We confirmed the efficacy that the bone metastasis had completely been resolved and the lymph node metastasis was significantly reduced after the completion of all treatments.

RISK OF SECOND MALIGNANCIES IN RETINOBLASTOMA SURVIVORS

Risk of Second Malignancies in Survivors of Retinoblastoma: More Than 40 Years of Follow-up

Abstract

Background: Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce.
Methods: Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided.
Results: After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease.
Conclusion: Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.

MICROMETASTATIC SENTINEL NODE DISESASE HAS NO PROGNOSTIC ROLE

Sentinel Node Tumor Burden According to the Rotterdam Criteria Is the Most Important Prognostic Factor for Survival in Melanoma Patients: A Multicenter Study in 388 Patients With Positive Sentinel Nodes

van Akkooi AC, Nowecki ZI, Voit C, et al
Ann Surg. 2008;248:949-955

Summary

This study evaluated survival in patients with sentinel node-positive melanoma using information from a multicenter study. Three European centers combined data from 388 patients with sentinel node-positive melanoma to study survival in relation to the burden of melanoma within the sentinel node. Breslow thickness was a strong predictor of survival, but the most important survival factor was the extent of metastatic disease within the sentinel node. Overall survival in patients with micrometastatic disease (<> 0.1 mm, the mortality rate was 4-5 times greater than in patients with micrometastases.

Viewpoint

This study had sufficient power to state conclusively that patients with small deposits of melanoma cells in sentinel nodes (<>

A NEW ONCOLYTIC VIRUS FOR PROSTATE CANCER

Engineered Measles Virus a Novel Oncolytic Prostate Cancer Therapy

NEW YORK (Reuters Health) Feb 02 - Recombinant attenuated live measles virus strains derived from the Edmonston (MV-Edm) vaccine strain can effectively infect, replicate in, and kill prostate cancer cells, according to a study appearing in the current issue of The Prostate.

Oncolytic strains of measles virus represent a novel class of therapeutic agents against cancer, Dr. Evanthia Galanis of the Mayo Clinic, Rochester, Minnesota, and colleagues point out. These viruses demonstrate no cross-resistance with existing treatment approaches, and can therefore be combined with conventional treatment methods.

After demonstrating the susceptibility of prostate cancer cell lines to MV-Edm, the researchers then found that intratumoral administration of a MV-Edm vector engineered to express carcinoembryonic antigen (MV-CEA) resulted in a statistically significant delay in tumor growth (p = 0.004) and prolonged survival (p = 0.001) in a subcutaneous xenograft model of advanced (androgen-resistant) prostate cancer.

The median survival of MV-CEA-treated mice in the study nearly doubled compared to control mice, and complete tumor regression was observed in one-fifth of MV-CEA-treated animals, they report.

In a written statement, Dr. Galanis said: "Based on our preclinical results as well as the safety of measles derivatives in clinical trials against other tumor types, these viral strains could represent excellent candidates for clinical testing against advanced prostate cancer, including androgen-resistant tumors."

IRINOTECAN NOT USEFUL IN ADJUVANT CHEMOTHERAPY

Ann Oncol. 2009 Jan 29. [Epub ahead of print]

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A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).

Ychou M, Raoul JL, Douillard JY, Gourgou-Bourgade S, Bugat R, Mineur L, Viret F, Becouarn Y, Bouché O, Gamelin E, Ducreux M, Conroy T, Seitz JF, Bedenne L, Kramar A.

CRLC Val d'Aurelle, Montpellier.

BACKGROUND: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. PATIENTS AND METHODS: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). RESULTS: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P <>0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < class="yshortcuts" id="lw_1234023582_21">hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. CONCLUSION: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

CARBOPLATIN AND ETOPOSIDE FOR PROSTATE CANCER

Ann Oncol. 2009 Jan 29. [Epub ahead of print]

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Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features.

Loriot Y, Massard C, Gross-Goupil M, Di Palma M, Escudier B, Bossi A, Fizazi K.

Department of Medicine, Institut Gustave Roussy, Villejuif, France.

BACKGROUND: There is currently no standard treatment for patients with castration-resistant prostate cancer (CRPC) whose disease progresses after docetaxel-based chemotherapy. The purpose of this study was to prospectively assess the anticancer activity and tolerance of the carboplatin-etoposide combination in this setting while evaluating neuroendocrine (NE) features. PATIENTS AND METHODS: Patients with CRPC and metastases who experienced failure after first-line docetaxel-based chemotherapy were treated with carboplatin (area under the curve 5, day 1) and etoposide (80 mg/m(2)/day from days 1 to 3), repeated every 3 weeks. The association between serum chromogranin A (CgA), neuron-specific enolase (NSE), prostate-specific antigen-doubling time (PSADT), and treatment efficacy was studied. RESULTS: Forty patients with CRPC who had received docetaxel with (n = 20) or without (n = 20) estramustine received the carboplatin-etoposide combination as second-line chemotherapy. A prostate-specific antigen (PSA) response defined as a PSA decline >/=50% was achieved in nine patients (23%). Median progression-free survival (PFS) was 2.1 months (range 0.6-9.6) and median overall survival was 19 months (range 2.1-27.7). Pain response was achieved in 15 (53%) of 28 assessable patients. Toxicity, including mainly grades 3-4 anaemia (25%) and febrile neutropenia in only 2% of patients, was manageable. Baseline CgA, NSE, or PSADT were not significant predictors for response or PFS. The PSA response rates were 18% and 31% in patients with normal and elevated serum CgA, respectively. It was 25% and 20%, respectively, in patients with normal and elevated serum NSE. CONCLUSIONS: Combining carboplatin and etoposide as second-line chemotherapy in patients with CRPC is active and well tolerated in spite of a limited PFS. Activity was observed in CRPC with and without NE features.

NSAIDs HARMFUL FOR HEART FAILURE PATIENTS

More Evidence That NSAIDs Are Harmful to Heart-Failure Patients

January 30, 2009 (Hellerup, Denmark) — Further evidence that even commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) are harmful to heart-failure patients has come from a new study [1].

The study, published in the January 26, 2009 issue of the Archives of Internal Medicine, shows dose-related increases in risk of death and rehospitalization for heart failure or MI with all COX-2 inhibitors or other NSAIDs.

Lead author Dr Gunnar Gislason (Gentofte University Hospital, Hellerup, Denmark), commented to heartwire: "Although our study is observational, and you can never exclude all confounding factors, we have very consistent results estimated using two different statistical methods. And these results are similar to many other previous studies. In addition, we see a strong dose-related response. I think the data are very convincing."

And it is not just the COX-2 inhibitors that are the problem, as diclofenac showed a similar risk. "This is very disturbing, as this drug is so widely used and is available off prescription in many countries," Gislason noted.

He described the effect as "quite considerable." For example, for rofecoxib (Vioxx, Merck), the number of patients needed to treat for one year to cause one death was just nine, and the corresponding number for celecoxib (Celebrex, Pfizer) was 14 and diclofenac 11. "These numbers are very low," Gislason said, noting that for antihypertensive drugs, the number needed to treat for one year to save one life is in the range of 50 to 100. "Everyone agrees that it is worth treating hypertension. So the harmful effect of some NSAIDs is much greater than the beneficial effect of antihypertensive treatment."

Even Naproxen Risky at High Dose

"Our results suggest that all NSAIDs have harmful effects in heart-failure patients, even naproxen at high doses. Naproxen is probably the best of the bunch, but it still increases fluid retention, which is bad news for heart-failure patients," Gislason added.

But he points out that these drugs are still being used in this population. "I don't think doctors are aware of this problem. We need to raise awareness. I think the main culprits are primary-care doctors, as these drugs are so widely prescribed in general practice," he commented. "The fact that some of these drugs are available over the counter makes the situation much worse, as anyone can buy them without advice from a doctor. All NSAIDs should be prescription-only drugs. Making them available in petrol stations and supermarkets gives the impression that they are not harmful. Many heart-disease patients will not be aware that they shouldn't take them."

In the current study, Gislason and colleagues used Danish national records of hospitalizations and pharmacy drug dispensing to identify 107 092 patients surviving their first hospitalization due to heart failure between 1995 and 2004 and their subsequent use of NSAIDs.

They found that 36 354 patients (33.9%) claimed at least one prescription of an NSAID after discharge; 60 974 patients (56.9%) died, and 8970 (8.4%) and 39 984 (37.5%) were rehospitalized with MI or heart failure.

After adjustment for age, sex, calendar year, comorbidity, medical treatment, and severity of disease, the authors found a clear dose-related increase in risk with the drugs.

The authors conclude that patients with heart failure should, if possible, avoid using NSAIDs, and if they do need to use one, they should take an agent that is more COX-1 selective, in as low a dosage and for as short a period as possible. "I know NSAIDs are useful drugs, and they will always be used to some extent, but we need to be careful about which drug is selected and which dosage used. More thought should go into trying to combine them with other agents so that a lower dose could be used," Gislason added.

SEQUENTIAL THERAPY FOR ORGAN PRESERVATION

Ann Oncol. 2009 Jan 29. [Epub ahead of print]

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Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival, surgery, and organ preservation.

Posner MR, Norris CM, Wirth LJ, Shin DM, Cullen KJ, Winquist EW, Blajman CR, Mickiewicz EA, Frenette GP, Plinar LF, Cohen RB, Steinbrenner LM, Freue JM, Gorbunova VA, Tjulandin SA, Raez LE, Adkins DR, Tishler RB, Roessner MR, Haddad RI; for the TAX 324 Study Group.

Division of Adult Oncology.

BACKGROUND: Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. PATIENTS AND METHODS: These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. RESULTS: Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31-not reached] versus 24 months (95% CI: 13-42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41-0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12-59) versus 11 months (95% CI: 8-14) for PF (HR: 0.66; 95% CI: 0.45-0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37-0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). CONCLUSIONS: In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.