Novartis has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) supporting European Union (EU) approval of everolimus for the treatment of patients with advanced renal cell carcinoma (RCC)3, the most common type of kidney cancer4.

The CHMP has recommended approval of everolimus based on data demonstrating that when compared with placebo, everolimus more than doubled median progression free survival in patients with advanced kidney cancer (4.9 vs. 1.9 months), whose disease progressed on or after treatment with VEGF-targeted therapy. Additionally, the data showed everolimus reduced the risk of disease progression or death by 67% (hazard ratio=0.33 with 95% confidence interval 0.25 to 0.43; P

References

1 Motzer RJ, Escudier B, Oudard S et al for the RECORD-1 study group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. The Lancet. August 2008; 372;9637:449-456

2 Novartis data on file AFT002

3 CHMP website emea.europa.eu/pdfs/human/press/pr/33058009en.pdf- Last accessed 1 June 2009

4 Novartis data on file AFT001

5 Escudier, B et al. 72O – Phase III Randomised Trial of Everolimus (RAD001) vs Placebo in Metastatic Renal Cell Carcinoma. Presented at the European Society for Medical Oncology (ESMO) 33rd Congress, Stockholm, Sweden on 16 September 2008.

6 FDA website fda/bbs/topics/NEWS/2009/NEW01980.html – Last accessed 28 May 2009

7 McLaughlin JK, Lipworth L, Tarone RE. Epidemiological aspects of renal cell carcinoma. Semin Oncol. 2006 Oct;33(5):527-33. [Abstract]

8 Eisen, et al. Sorafenib for Older Patients With Renal Cell Carcinoma: Subset Analysis From a Randomized Trial. Journal of the National Cancer Institute. 2008; 100(20):1454-1463.

About RCC

Renal cell cancer accounts for 2% of all new cancer cases worldwide with occurrence rates rising steadily around the world7 due in part to smoking and obesity8.

In the UK, RCC has increased by 22% over the last ten years. Each year, approximately 6,600 people in the UK are diagnosed with kidney cancer, which also causes around 3,600 deaths each year. There are several types of RCC, but the most common, called clear cell, accounts for 80% of diagnoses. In RCC, cancer cells develop in the lining of the kidney’s tubes and grow into a tumour4.

About Afinitor

Afinitor is approved in the US as the first oral, daily therapy (5 mg and 10 mg tablets) to treat patients with advanced RCC after failure of treatment with sunitinib or sorafenib6. Afinitor works by directly targeting mTOR, a protein in the cancer cell that controls tumour cell division and blood vessel growth. Preclinical and clinical data have established the important role of mTOR in the development and progression of several types of tumours.

Source
Novartis

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With each new publication of coronary artery disease (CAD) data from the Women’s Health Initiative (WHI) study, the inevitable reaction is “Why on earth did the WHI investigators claim in 2002 – 2004 that postmenopausal hormone therapy has deleterious effects on the risk for CAD, when, from the beginning, they were aware of the importance of the age factor in this clinical scenario?”. Women in the age group of 50 – 59 years who participated in the estrogen-alone arm of the WHI study were asked immediately after the early cessation of the trial to become part of an ancillary study the WHI-CACS which looked at the magnitude of coronary calcifications measured by ultra-fast coronary CT. Coronary calcium deposits develop as part of the atherosclerosis process and correlate well with findings of coronary angiography.

The results of WHI-CACS, now published in the New England Journal of Medicine [1] are very encouraging, since women who were randomized to the estrogen arm of the WHI had significantly smaller calcification scores than their counterparts in the placebo arm. The effect was recorded for all degrees of severity, with estrogen users having a 20 30% reduction in the likelihood of being categorized as having a mild to moderate increase in calcification scores (less than 100), and a more than 50% reduction in the likelihood of being categorized as advanced cases with calcification scores above 100. This study re-affirms what was actually known for many years, based on animal data and observational studies in women. Estrogen has a wide range of well-documented beneficial metabolic and vascular effects: it reduces the pace of accumulation of atherosclerosis, and decreases the risk of coronary events, provided that treatment is started early in the menopause. In addition, the CT in the WHI-CACS was performed at a mean age of 64.8 years, 7.4 years after randomization to the WHI trial, which suggests a new “safety margin” for age and duration of estrogen therapy, as women can be reassured that estrogen therapy is cardioprotective at least until age 65.

One of the main arguments that were raised at the time of publication of the preliminary data of the WHI 5 years ago, in attempt to explain the disconcordance between the results of previous large-scale, long-term, observational studies and the WHI cardiac data, was that randomized, placebo-controlled trials are always better and suffer less bias. With randomized trials being Level I evidence and observational trials considered Level II evidence, devaluation of good observational data became state-of-the-art. The recent post-hoc analyses from WHI show that, by the end of the day, the observational studies did give valuable information, which was comparable to that obtained by the randomized trials.

Even for the issue of coronary calcifications and hormone therapy, a literature search shows that “lower grade” encouraging clinical data were there for at least 10 years. Clearly, a real long-term, randomized, double-blind, placebo-controlled study on hormone therapy cannot be performed. The IMS therefore suggests that available long-term data from the Nurses’ Health Study and other major observational studies should be considered while making decisions on hormone therapy in clinical practice. Since most, if not all, women do not start hormone therapy at an old age, safety concerns on its possible adverse cardiac effects are actually invalid for the vast majority of hormone users. In fact, treatment seems to be associated with reduction of risk for coronary artery disease if initiated early.

Reference

1. Manson JE, et al. N Engl J Med 2007;356:2591

THE INTERNATIONAL MENOPAUSE SOCIETY

The aims of the Society (IMS) are to promote knowledge, study and research on all aspects of aging in men and women; to organize, prepare, hold and participate in international meetings and congresses on menopause and climacteric; and to encourage the interchange of research plans and experience between individual members. The Society is a non-profit association, within the meaning of the Swiss Civil Code. It was created in 1978 during the first World Congress on the Menopause. In addition to organizing congresses, symposia, and workshops, the IMS owns its own journal: Climacteric. See website: imsociety.

International Menopause Society
PO Box 687, Wray
Lancaster LA2 8WY
United Kingdom
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Diabetes Sunday: Faith Access to Community Economic Development on Feb. 17 sponsored the 11th annual Diabetes Sunday at Mt. Calvary Missionary Baptist Church in Flint, Mich. The event featured no-cost blood sugar, cholesterol, blood pressure and glaucoma tests, and a panel of health experts to answer questions from attendees (Blondin, Flint Journal, 2/17).

Integris Health: About 15 Oklahoma City churches are participating in Integris Health’s weight-loss challenge for predominantly black congregations. Zora Brown, director of cultural affairs for Integris, said she created the challenge to encourage church members to tackle obesity as a way to target health disparities in the black community. Each team will be weighed at the first of the month, and the congregation with the largest percentage of weight loss wins the contest (Hinton, Oklahoman, 2/17).

Susan G. Komen for the Cure: The group’s Puget Sound Affiliate has announced more than $1.8 million in grants to 19 western Washington state breast cancer programs, including three that focus on minority women. International Community Health Services, Samoan National Nurses Association and Franciscan Health System each received grants to support their work among Asian, Pacific Islander and other minority women (Northwest Asian Weekly, 2/16).

Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation© 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved. Continue reading →

Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM) reported that researchers will present data at the SNM 2009 Annual Meeting showing that its brain cancer agent Cotara(R) specifically localizes to brain tumors at high concentrations with minimal radiation exposure to other organs. Cotara is a targeted monoclonal antibody linked to a radioisotope being developed as a potential new treatment for glioblastoma multiforme (GBM), a deadly form of brain cancer. The results reported from an ongoing dosimetry study at U.S. brain cancer centers show that in patients dosed in the first two cohorts of the study, the concentration of Cotara in brain tumors was on average more than 300-fold higher than in other normal organs. In addition, these patients have all either met or exceeded the expected median survival time of six months for recurrent GBM patients. Cotara is currently being tested in this Phase I dose response and dosimetry trial and in a Phase II clinical trial in recurrent GBM patients.

Cotara specifically targets cells at the center of brain tumors, so its radioactive payload is able to kill cancer cells while leaving healthy tissue largely unaffected. In this study, lead author Sui Shen, Ph.D., associate professor of radiation oncology at the University of Alabama at Birmingham, and his colleagues assessed the concentration of Cotara in GBM patients’ tumors and in their healthy brain tissue, as well as in their thyroid, stomach, heart and bone marrow. He found that Cotara was concentrated in the brain tumor with minimal exposure to the contralateral healthy brain. The thyroid, which can have active uptake of radioiodine, showed only minimal uptake of Cotara. Similarly, uptake of Cotara was very low in the stomach, heart and bone marrow, important potential sites for radiation toxicity. On average, the tumor received more than 300 times the dose of radiation compared to these normal organs.

“These findings confirming Cotara’s potential to target its radioactive payload to brain tumors while minimizing radiation exposure to healthy organs, including the thyroid, are very encouraging,” said Dr. Shen. “With a mean dose ratio showing 300-fold greater delivery of radiation to the tumor as compared to other organs, Cotara represents a potentially valuable new therapy for GBM patients.”

The main objectives of the open label dosing and dosimetry study are to confirm the maximum tolerated dose of Cotara, to determine radiation dosimetry and to assess overall patient survival, progression free survival and the proportion of patients alive at six months following Cotara administration. In this study and in the ongoing Phase II trial, Cotara is delivered using convection-enhanced delivery (CED), a method developed by the U.S. National Institutes of Health that targets the specific tumor site in the brain. The final planned patient in the dosimetry study is currently being enrolled.

“These positive data analyzed by a leading dosimetry expert validate a key principle underlying the Cotara program, confirming its ability to specifically concentrate in and deliver a high radiation dose to brain tumors,” said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. “In this trial and in our other Cotara clinical trials, Cotara has been well tolerated, and we continue to see longer- term survivors among the treated patients. We are very pleased to have the opportunity to share this promising data from our current U.S.

Cotara clinical trial with experts at this prestigious conference, and we look forward to reporting further data from this study and from our Phase II trial in patients with recurrent GBM.”

More than 65 patients with recurrent GBM have received Cotara in the current and previous clinical studies. Localization and accumulation of the drug to the tumor have been excellent and longer-term survivors (greater than one year from the time of Cotara treatment) have been observed in all of the trials, with some GBM patients from early clinical studies now alive more than 8.5 years after treatment with Cotara. Expected survival for patients with GBM is approximately six months from the time of disease recurrence.

The Cotara data will be presented today at the 2009 Society for Nuclear Medicine (SNM) Annual Meeting in Toronto, Canada, in a session scheduled from 12:30 PM to 2:00 PM EDT in Room 701B.

Abstract No: 150240; Publication No: 445: S. Shen(1), R. Lustig(2), K. Judy(2), W. Shapiro(3), K. Spicer(4), S. Patel(4), J. Fiveash(1), J. Lai(5), J. Shan(5), “Dosimetry of phase I interstitial 131I-chTNT-1/B MAb (Cotara) for the treatment of recurrent glioma.”

(1)U Alabama, Birmingham, AL; (2)U Penn, Philadelphia, PA; (3)BNI St. Joseph’s MedCtr, Phoenix, AR; (4)Med U S Carolina, Charleston, SC; (5)Peregrine Pharma Inc, Tustin, CA

About Cotara(R)

Cotara is an experimental treatment for brain cancer that links a radioactive isotope to a targeted monoclonal antibody designed to bind to the DNA histone complex that is exposed by dead and dying cells found at the center of solid tumors. Cotara’s targeting mechanism enables it to bind to the dying tumor cells, delivering its radioactive payload to the adjacent living tumor cells and essentially destroying the tumor from the inside out, with minimal radiation exposure to healthy tissue. In a previous clinical study, a subset of patients with recurrent glioblastoma treated with Cotara achieved a median survival of 38 weeks, a 58% increase over the historical median survival time of 24 weeks for patients treated with standard of care therapy. In this study, 25% of 28 recurrent patients survived for more than a year post-treatment and 10% of patients survived for more than three years. These data are considered a promising development in this deadly disease. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration. A Phase I dosimetry trial in GBM patients in the U.S. is in the final stages of patient enrollment and a Phase II safety and efficacy trial in GBM patients in India is ongoing.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing three separate clinical programs in cancer and hepatitis C virus infection with its lead product candidates bavituximab and Cotara(R). Peregrine also has in-house manufacturing capabilities through its wholly owned subsidiary Avid Bioservices, Inc., which provides development and biomanufacturing services for both Peregrine and outside customers.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals’ intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that dose-limiting toxicities may be experienced in future stages of the trial that will use higher doses of Cotara or the risk that results from larger trials may not be consistent with the results of earlier stage trials. It is important to note that the company’s actual results could differ materially from those in any such forward-looking statements. Factors that could cause actual results to differ materially include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company’s SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2008 and the quarterly report on Form 10-Q for the quarter ended January 31, 2009. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

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Attempts to treat critical limb ischemia in peripheral arterial disease (PAD) patients with below-the-knee angioplasty are still thwarted by restenosis (the re-narrowing of the artery at the site of angioplasty or stenting), the need for repeat treatments and the continued progression of atherosclerotic disease, leading to tissue death (gangrene) and amputation. Interventional radiologists have been studying a potential solution – the use of drug-eluting stents – and have found that these types of stents lessened the rate of repeat procedures to open these small arteries, according to results presented at the Society of Interventional Radiology’s 34th Annual Scientific Meeting.

“This is encouraging news for PAD patients with critical limb ischemia. The smaller blood vessels below the knee are more difficult to treat due to their size (3 millimeters) and are more prone to reclog than larger vessels. The use of drug-eluting stents in the tiny infrapopliteal arteries of the leg may significantly impact their care,” said Dimitris Karnabatidis, M.D., assistant professor of interventional radiology at Patras University Hospital in Rion, Greece. “Drug-eluting (or drug-coated) stents have emerged as a potential solution to the limitations of endovascular treatment of PAD patients with critical limb ischemia,” he added. An interventional radiologist performs a balloon angioplasty to open a clogged blood vessel and then places a drug-eluting stent in that artery. The stent acts as scaffolding to hold the narrowed artery open. Drug-eluting stents slowly release a drug for several weeks to block cell proliferation or regrowth, thus inhibiting restenosis.

Researchers from a single center studied 103 patients in a double-arm prospective registry who had critical limb ischemia and who underwent infrapopliteal revascularization with angioplasty and placement of either a drug-eluting stent (with sirolimus, an immunosuppressant drug) or a bare-metal stent (without a drug coating). The patients had regular follow-ups up to three years, and researchers studied how they did by stent type. In the first group, 41 patients (75.6 percent diabetics) were treated with bare-metal stents, and in the second group 62 patients (87.1 percent diabetics) were treated with drug-eluting stents.

At three years, those patients with drug-eluting stents had “significantly higher patency” (length of time the blood vessels stayed open and moved blood flow efficiently); reduced restenosis of the vessels; and consequently less clinical recurrence requiring repeat angioplasty, said Karnabatidis. “In the drug-eluting stent group, an estimated 60 percent of the treated arteries remained open at three years. This is significantly longer than the bare-metal stent group, where the arteries remained open only approximately 10 percent at 3 years,” said Karnabatidis. “This corresponds to a more than 5 times increased risk of vessel reclogging when bare metal stents were used,” he added. “Because of the reduced vessel restenosis, repeat angioplasties were necessary in only 15 percent of the patients in the drug-eluting stent group versus almost 35 percent in the bare-metal stent group up to 3 years – this being the equivalent to an almost 2.5-fold risk of repeat procedures in the case of bare metal stents,” noted Karnabatidis. “These statistical results are based on three-year adjusted survival analysis after application of a Cox model for multivariable analysis,” he explained.

If a person has critical limb ischemia, it means he or she is at great risk for tissue death due to lack of blood flow, which carries oxygen and nutrients to the cells. The severely restricted blood flow results in severe pain in the feet or toes, even while resting, and sores and wounds that will not heal. Tissue death (gangrene) and amputation are imminent at this advanced stage of PAD, which is caused by atherosclerosis, the hardening and narrowing of the arteries over time due to the buildup of fatty deposits called plaque.

“Multicenter randomized trials are necessary to support these promising results and build on the level of clinical evidence supporting the integral value of infrapopliteal drug-eluting stents in critical limb ischemia treatment,” he added. In the United States, drug-eluting stents are FDA-approved for the coronary arteries but not for infrapopliteal arteries. In Europe, drug-eluting stents have CE Mark approval for below-the-knee use.

Notes:

More information about PAD and interventional radiology can be found online at SIRweb.

Abstract 223: “Infrapopliteal Sirolimus-Eluting Versus Bare Metal Stents for Critical Limb Ischemia: Long-Term Angiographic and Clinical Outcome in More Than 100 Patients,” K. Katsanos, Guy’s and St. Thomas’ Hospitals, London, United Kingdom; A. Diamantopoulos, S. Spiliopoulos, A. Karatzas, D. Karnabatidis, D. Siablis, Patras University Hospital, Rion, Greece; and G. Kagadis, School of Medicine – medical physics, Patras, Greece, SIR 34th Annual Scientific Meeting March 7-12, 2009. This abstract can be found at SIRweb.

About the Society of Interventional Radiology

Interventional radiologists are physicians who specialize in minimally invasive, targeted treatments. They offer the most in-depth knowledge of the least invasive treatments available coupled with diagnostic and clinical experience across all specialties. They use X-ray, MRI and other imaging to advance a catheter in the body, usually in an artery, to treat at the source of the disease internally. As the inventors of angioplasty and the catheter-delivered stent, which were first used in the legs to treat peripheral arterial disease, interventional radiologists pioneered minimally invasive modern medicine. Interventional oncology is a growing specialty area of interventional radiology.

Today many conditions that once required surgery can be treated less invasively by interventional radiologists. Interventional radiology treatments offer less risk, less pain and less recovery time compared to open surgery. Visit SIRweb.

An estimated 5,300 people are attending the Society of Interventional Radiology’s 34th Annual Scientific Meeting in San Diego.

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BioVex Inc, a company developing new generation biologics for the treatment and prevention of cancer and infectious disease, announced that updated survival data from its Phase II study in metastatic melanoma will be presented at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place from May 29, 2009 – June 2, 2009 in Orlando, FL.

Senior clinical investigator, Neil N. Senzer, M.D., will present the data in an abstract (number 9035) entitled “Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpes virus in unresectable metastatic melanoma,” at ASCO on Monday, June 1, 2009 from 8:00am – 12:00pm EDT during the melanoma poster session located in Level 2, West Hall C.

The Phase II trial enrolled 50 patients with Stage IIIc (10 patients) and Stage IV melanoma (40 patients) who were treated with OncoVEX GM-CSF as a stand-alone therapy. The trial was designed to measure overall objective response, which is defined as a complete response (CR), where disease is completely eliminated, or partial response (PR), where there is a >30% reduction in disease burden. The vast majority of patients who entered the study had progressive disease after having failed conventional and experimental prior therapies. 13 objective systemic responses (26% objective response rate) were achieved including nine CRs, eight of which remain alive and free of disease. 12 responses have so far continued for more than 6 months (range 6-29+ months). Responses were observed in patients with all stages of disease, including the complete resolution of un-injected visceral deposits.

The abstract for the presentation reports that, at the time of submission, overall median survival (by Kaplan-Meier estimation) exceeded 16 months for all patients as well as for those patients with only Stage IV disease. Estimated one year survival was 61% for all patients, 58% for all Stage IV patients and 48% for Stage IV M1c patients. The 1-year survival of the patients who achieved PR, CR or surgical CR (n=15) was 93% compared to 48% for those with stable or progressive disease.

Commenting on these results, Dr. Neil N. Senzer of The Mary Crowley Cancer Research Center in Dallas, TX, the lead author for the presentation, said:

“Compared to any historical benchmarks for patients with Stage IIIc and Stage IV melanoma, this survival data, especially when coupled with a low toxicity profile, is provocative. Additionally, of the responses previously reported the vast majority have been maintained for up to more than three years from enrollment. I look forward to the results of the subsequent Phase III study which has recently initiated.”

OPTiM Phase III Trial

The trial is a multi-national, open label, randomized Phase 3 study to assess the efficacy and safety of treatment with OncoVEX GM-CSF as compared to sub cutaneously administered GM-CSF in patients with unresectable stage III (b-c) and Stage IV (M1a-c) disease. The primary endpoint is the rate of durable (maintained for six months) objective response. Patients will have received at least one prior therapy for active disease which includes any type of therapy including investigational drugs. A total of 360 patients will be enrolled (240 to the OncoVEX GM-CSF arm and 120 to the control arm). The study design was agreed with the FDA under the Special Protocol Assessment (“SPA”) process. The SPA process provides for a designation from the FDA that the trial’s design, clinical endpoints and statistical analysis can be used for regulatory approval.

About Metastatic Melanoma

According to the American Cancer Society, more than 8,000 people died in the U.S. of melanoma in 2007. Prevalence of stage III and stage IV disease is 120,000 and median survival for Stage IV disease is six months.

Treatment of melanoma depends on the stage of the disease with surgical resection being effective in less severe non metastatic forms of the disease. However, survival rates for later Stage III and IV patients are poor, reflecting the lack of any efficacious drugs for metastatic disease. Current systemic therapies are not generally effective in terms of generating durable responses or in impacting survival. As a result, many patients presenting with metastatic disease are directly enrolled into a clinical trial. The vast majority of experimental therapies have failed to show more than a single digit durable response rate.

About BioVex

BioVex is a privately held biotechnology company based in Woburn, MA where it also has an operational launch grade manufacturing facility. The Company is developing a new class of potent biologics for the treatment of cancer and prevention of infectious disease.

The Company’s lead cancer technology platform, OncoVEX GM-CSF is a first-in-class oncolytic, or cancer destroying virus technology. OncoVEX GM-CSF works by; replicating and spreading within solid tumors (whilst leaving healthy tissue unharmed), causing the death of cancer cells; and through stimulating the immune system to destroy un-injected metastatic deposits. Both modes of action have been clearly validated in the clinic, where multiple patients with metastatic disease progressing at enrollment have been declared disease free. BioVex believes OncoVEX GM-CSF has the potential to become a leading standard of care in the treatment of many solid tumors based on the strength of clinical data generated to date, coupled with a benign side effect profile. Previous clinical trials have enrolled patients with breast cancer, head and neck cancer, and pancreatic cancer in addition to melanoma, and clinical activity has been observed in each of these cancer types. The Company plans to submit a second Phase 3 protocol in head and neck cancer to the FDA under the SPA procedure in the middle of the year.

The Company’s second program is a vaccine for genital herpes, ImmunoVEX HSV2, which provides complete protection in animal models of the disease. The vaccine has been authorized to commence clinical testing in the UK.

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A dose-intensive regimen of the chemotherapy drugs cisplatin and doxorubicin offered no clinical benefit over standard doses of the chemotherapy drugs in patients with a bone cancer called osteosarcoma, according to results from a randomized trial in the January 17 issue of the Journal of the National Cancer Institute. Although the dose-intensive regimen killed tumor cells better than the standard regimen after surgery, survival rates were similar in both groups.

Some studies in cancers such as non-Hodgkin lymphoma and breast cancer have suggested that increasing the intensity of a chemotherapy regimen–that is, decreasing the number of days between chemotherapy treatments–may improve survival. Because chemotherapy drugs can be very toxic, doctors often have to add additional medications to such dose-intense regimens so the patient can tolerate them. For example, some chemotherapy drugs cause a patient’s white blood cell count to drop, so doctors also give patients a drug called granulocyte colony-stimulating factor (G-CSF) to increase their production of white blood cells.

In the new study, Ian J. Lewis, M.D., of St. James University Hospital in Leeds, England, with colleagues at the Medical Research Council Clinical Trials Unit in London and the European Osteosarcoma Intergroup, tested whether a dose-intensive regimen consisting of standard drugs used to treat osteosarcoma would improve survival when given before surgery to remove the tumor. A total of 497 patients age 40 or younger with high-grade osteosarcoma that had not spread elsewhere in the body were randomly assigned to receive six cisplatin??”doxorubicin treatments at 3-week intervals (standard regimen) or to receive the treatments at 2-week intervals (dose-intense regimen). The patients receiving the dose-intense regimen also received injections of G-CSF to help them better tolerate the chemotherapy.

The researchers observed favorable tumor responses–measured by tumor cell death–in 36 percent of patients receiving the standard treatment and in 50 percent of those receiving the dose-intense regimen. However, after an average of about 5 years, overall survival and progression-free survival were similar in both groups; for example, overall survival was 55 percent in the conventional-treatment group and 58 percent in the dose-intense group. Those who received the dose-intense regimen had a lower risk of leukopenia (low white cell count) and neutropenia (low neutrophil count) but a higher risk of thrombocytopenia (platelet deficiency) and mucositis (inflamed mucus membranes).

“[The dose-intense regimen] resulted in more tumors having good histologic response to preoperative chemotherapy, but this did not translate into a demonstratable patient benefit in overall survival or progression-free survival over [the conventional regimen],” the authors write. “This emphasis placed on histologic response as the key treatment-related predictive factor is thereby challenged.”

Indeed, writes editorialist Stephen L. George, Ph.D., of Duke University Medical Center, “promising early results measured by response rates often do not translate into long-term benefits such as longer progression-free survival or overall survival.” Part of the reason for this, he writes, is that large increases in response rates are needed to translate into measurable differences in survival. George reviews the conditions under which response rate is a useful endpoint, and notes that this osteosarcoma clinical trial doesn’t meet those circumstances. “It is clear that response rate as an endpoint is most useful in early phase clinical trials, in which interest focuses more on assessing activity than proving clinical benefit, and as an important but secondary outcome in more definitive trials,” he writes.

Contact:

* Article: Medical Research Council Press Office

* Editorial: Chris Difrancesco, News Office, Duke University Medical Center

Citation:

* Article: Lewis IJ, Nooij M, Whelan J, Sydes MR, Grimer R, Hogendorn PCW, et al. Improvement in Histologic Response, But Not Survival, in Osteosarcoma Patients Treated With Intensified Chemotherapy: A Randomized Phase III Trial of the European Osteosarcoma Intergroup (MRC BO06, EORTC 80931, ISRCTN86294690 ). J Natl Cancer Inst 2006; 99:112-129.

* Editorial: George SL. Response rate as an endpoint in clinical trials. J Natl Cancer Inst 2006; 99:98-99.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jnci.oxfordjournals/.

Contact: Andrea Widener

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A prior study of congenital heart surgery mortality rates used hospital statistics that were misleading. An article in the British Medical Journal (BMJ) this week wonders whether this data is valid, and if so, whether it should be made public.

Professor Westaby and team found that in the prior study, published in the BMJ in 2004, the information gathering system was such that the number of infant deaths had been underestimated. Oxford had been singled out at having a mortality rate for open heart surgery on infants which was significantly higher than the national average. However, this new paper, which used differently sourced data (the Central Cardiac Audit Database) indicates they were well within the mean for all centres.

The researchers studied the report from the “Dr. Foster” unit at Imperial College that was published after the highly publicized inquiry into the Bristol congenital heart surgery deaths. The inquiry had a profound effect on surgical practice in the UK. That inquiry used HES (Hospital Episode Statistics) to compare cardiac surgical units’ mortality rates nationally. The 2004 study by Dr. Aylin described these mortality statistics.

In this current study, the researchers compared the mortality rates from the administrative HES database to an alternative system – the clinically based Central Cardiac Audit Database (CCAD) for infants under 12 months who underwent cardiac operations. The period covered was from April 1st 2000 to March 31st 2002.

The HES data, say the authors, did not have reliable patient numbers or thirty-day mortality data. In fact, they found that HES recorded 20% fewer cases than CCAD, on average. HES only collected 27% and 78% of thirty-day deaths, with a median shortfall of 40%.

The authors explain that in Centre A, which had the highest number of operations, 38% of all patients were missed by HES, while only 27% of total deaths were logged. They calculate that mortality statistics were underestimated by 4% when HES data was used.

Public confidence is undermined if the statistics are inaccurate, say the authors. Mortality statistics should be beyond reproach, they stress.

“Given the problems with data quality, the imprecision of risk stratification models, and the confrontational agenda in the media, we question the value of placing mortality statistics in the public domain,” the writers conclude.

“Comparison of hospital episode statistics and central cardiac audit database in public reporting of congenital heart surgery mortality”
BMJ Online First
bmj

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Los Angeles study underscores benefits of physical activity during off hours

LOS ANGELES – Several researchers have suggested that employees whose jobs require a lot of physical activity face a greater risk for heart disease, but investigators from the Keck School of Medicine of the University of Southern California and colleagues may have found the reason behind it: job stress.

In an article in the July issue of the American Journal of Medicine, the research team discussed the latest findings from the Los Angeles Atherosclerosis Study, in which investigators followed the physical activity of 500 middle-aged employees while monitoring progression of their atherosclerosis.

Atherosclerosis, the gradual build-up of fatty material along the inner lining of artery walls, can eventually result in life-threatening heart attacks and stroke. The disease causes one of every two deaths in the United States.

They found that while arteries thickened more slowly in those who exercised more during their leisure time, arteries actually thickened faster among those who were very physically active during the workday.

But when the researchers measured psychological stress related to work (asking how much sleep participants lost over worries about work, for example) they found an interesting connection.

‘We found that atherosclerosis progressed significantly faster in people with greater stress, and people who were under more stress also were the ones who exercised more in their jobs,’ says James Dwyer, Ph.D., professor of preventive medicine at the Keck School and the study’s principal investigator.

When investigators grouped participants according to the amount of stress at their workplace, they no longer saw an adverse relationship between physical activity in the workplace and atherosclerosis progression.

‘This suggests that the apparent harmful effect of physical activity at work on atherosclerosis-and heart disease risk-may be due to the tendency of high-activity jobs to be more stressful in modern workplaces,’ Dwyer says.

‘It appears from our findings that the psychological stresses associated with physically active jobs overcomes any biological benefit of the activity itself. It’s also possible that physical activity in the context of a body activated by psychological stress does not have the same benefits as exercise conducted in the reduced stress usually associated with leisure time.’

The study found that leisure-time exercise benefits were considerable.

Researchers asked study participants how often they exercised vigorously (jogging, biking or performing other aerobic activities long enough to speed up heart beat and work up a sweat).

They found that atherosclerosis progression slowed dramatically as the level of physical activity during leisure increased. This effect on atherosclerosis was stronger than that for most other risk factors, such as smoking and LDL cholesterol levels.

The team also found that moderate exercisers, such as regular walkers, had slower atherosclerosis progression than those who were couch potatoes. And those who exercised vigorously three or more times a week benefited the most. Relative to vigorous exercises, arteries thickened at twice the rate in moderate exercisers and at three times greater rate in the couch potatoes.

‘These results are important because they demonstrate the very substantial and almost immediate-within one or two years-cardiovascular benefit of greater physical activity,’ Dwyer says. ‘These benefits are seen in moderately active persons relative to sedentary persons, and they are seen for regular aerobic activity relative to moderate activity.’

Researchers measured atherosclerosis progression by using ultrasound to measure the thickness of the main arteries in the neck, called carotids. They took measurements at 18 months and three years after the study began.

Study subjects were selected from healthy employees of a utility company ages 40 to 60 years during 1995 to 1996.

The study, which was supported by the National Institutes of Health, differs from other recent studies on workplace and leisure-time exercise because it measured progression of atherosclerosis during its development and monitored exercise at the same time; other recent studies relied on memories of activity in the past, after heart attacks had occurred.

This study also looked at stress as a possible link between workplace exercise and atherosclerosis.

Notes Dwyer: ‘The results of our epidemiologic study show that randomized trials of the effects of physical activity on the development of cardiovascular disease are now feasible. We now have the technology to unambiguously answer many of the difficult questions about the form of physical activity that will maximize cardiovascular health in studies of one or two years duration.’

Cheryl K. Nordstrom, Kathleen M. Dwyer, C. Noel Bairey Merz, Anne Shircore and James H. Dwyer, ‘Leisure Time Physical Activity and Early Atherosclerosis: The Los Angeles Atherosclerosis Study,’ American Journal of Medicine. Vol. 115, No. 1, pp. 19-25.

Contact: Jon Weiner
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323-442-2830
University of Southern California Continue reading →

In concept, the human immune system has the power to destroy cancer cells with great specificity. Therefore, cancer vaccines, like vaccines against influenza or other diseases, offer the hope of enticing the immune system to recognize proteins found on the surface of cancerous cells. The reality, however, is that the immune system rarely takes the bait that these vaccines offer, and that other approaches to stimulating anti-cancer immunity are needed.

Researchers at Fox Chase Cancer Center, in collaboration with colleagues at Memorial Sloan-Kettering Cancer Center, have shown that an engineered antibody called DTA-1 led to rejection of 50 to 60 percent of tumors in a mouse model of melanoma. The antibody allows the immune system to overcome its natural reluctance to attack tumor cells, the researchers say.

“Despite the promise of cancer vaccines, it has become clear that a vaccine alone won’t necessarily generate an effective immune response, in large part due to suppressive elements within the tumor,” says the project’s lead researcher Adam D. Cohen, M.D., an oncologist at Fox Chase. “Here we show that we can use DTA-1 to impair regulatory T cells, in effect waking the immune system to the presence of a cancer.”

Cohen presented his findings at the 100th Annual Meeting of the American Association for Cancer Research, in Denver, Colorado.

DTA-1 is an antibody designed to stimulate the glucocorticoid-induced tumor necrosis factor receptor (GITR), a protein found on the surface of many T cells, including the regulatory T cells that suppress immune function and the effector T cells that help carry out an immune response. DTA-1 was developed by Shimon Sakaguchi, M.D., Ph.D., at the Institute for Frontier Medical Sciences in Kyoto, Japan. According to Cohen, their studies show that DTA-1 helps the immune system overcome its natural reluctance to attack tumor cells that it would otherwise have thought of as part of the body.

“Of course, we wouldn’t want to completely shut down the immune system’s ability to differentiate its own cells, which can lead to autoimmune disease,” Cohen says. “Our findings suggest, however, that DTA-1 can temporarily and focally skew the ratio between regulatory and effector T cells in our favor.”

According to Cohen, their findings provide further support for the continued development of GITR-targeting antibodies, either alone or in combination with cancer vaccines, as an immunotherapeutic strategy for treating cancer.

Funding for this research comes from grants from the National Cancer Institute, the Charles A. Dana Foundation, the American Society of Clinical Oncology, and philanthropic funds from Swim Across America.

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