Prostate treatment 95% effective, study shows

A study of early diagnosed prostate cancer patients suggests that 95 per cent of men treated using brachytherapy-- the planting of a radioactive particle in the prostate -- have had their cancer cured.

The results of the study of 1,006 consecutive patients treated through the BC Cancer Agency's prostate brachytherapy program from 1998 to 2003 will be published in this week's edition of the medical journal Urology.

The cancer agency said 95 per cent of men did not experience a biochemical recurrence--a rise in the blood level of PSA (prostate-specific antigen)--following brachytherapy,"which indicates a likely cure of prostate cancer."

"These are excellent results, demonstrating that brachytherapy should be considered the gold-standard treatment for men with localized prostate cancer,"Dr. Mira Keyes, head of the BC Cancer Agency's brachytherapy program, said Wednesday.
"We have only had one patient whose cancer reoccurred after five years."

Localized prostate cancer is early-stage cancer which has not spread outside of the prostate.

Men in the study group also experienced low rates of metastasis--spread of cancer--and death from cancer, she said.

To date, over 2,500 men have been treated by the agency using brachytherapy.

Other forms of treatment for prostate cancer are surgery to remove the cancer mass, or external beam radiation to destroy it.

Keyes said the agency has developed a fourth method called active surveillance, in which a man diagnosed in the early stages of prostate cancer will have his condition monitored and will be treated only if the cancer advances.

Keyes said the sexual potency rate is higher with brachytherapy than with surgery.

Phase II Trial Of Zolinza With Velcade

The Multiple Myeloma Research Consortium (MMRC) announced a Phase IIb study of Zolinza®, an oral histone deacetylase (HDAC) inhibitor, in combination with Velcade® for Injection, a proteasome inhibitor, in patients with relapsed and refractory multiple myeloma. The study is open for enrollment. This international, multicenter, open-label clinical trial is sponsored by Merck & Co. and is part of the VANTAGE (Vorinostat Clinical Trials in Hematologic and Solid Malignancies) program.

The trial will enroll 142 patients from more than 60 clinical centers including the following MMRC Member Institutions: City of Hope, Dana-Farber Cancer Institute, Emory University's Winship Cancer Institute, Hackensack University Medical Center, St. Vincent's Comprehensive Cancer Center of Saint Vincent Catholic Medical Centers of New York, and University Health Network (Princess Margaret Hospital). Patients must be refractory to Velcade taken alone or in combination with other anti-myeloma therapies and have been exposed to prior immunomodulatory therapies, such as Revlimid® (lenalidomide, Celgene Corporation) or Thalomid® (thalidomide, Celgene Corporation). The study will assess the objective response rate as well as progression-free survival, overall survival, time to disease progression and tolerability of the combination.

"Vorinostat is one of a promising class of drugs that may offer a new treatment option for patients with multiple myeloma, particularly when combined with bortezomib," said Kenneth Anderson, MD, a member of the MMRC Steering Committee and Chief of the Division of Hematologic Neoplasia and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

For more information about this and other clinical trials, please visit http://www.myelomatrials.org or call 866-603-MMCT (6628).

About Zolinza Zolinza is approved in the United States for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. In addition to the Phase II-b study, Merck has also initiated a Phase III, global, randomized, double-blind, placebo-controlled, multi-center trial (Vantage 088) investigating Zolinza in combination with Velcade in patients with relapsed multiple myeloma after 1-3 prior anti-myeloma regimen. The Phase III trial will enroll 742 patients at more than 200 centers. The study will compare progression-free survival in patients taking Velcade in combination with either Zolinza or placebo. The study is open for enrollment.

Clinical features associated with a response to bortezomib

Dawson MA, Opat SS, Taouk Y, Donovan M, Zammit M, Monaghan K, Horvath N, Roberts AW, Prince HM, Hertzberg M, McLean CA, Spencer A.

Clinical Haematology/Bone Marrow Transplant Department, The Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria, Australia 3181.

PURPOSE: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. EXPERIMENTAL DESIGN: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. RESULTS: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16(INK4A), cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. CONCLUSIONS: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.

PMID: 19147779 [PubMed - in process]

Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010

Brenner H, Gondos A, Pulte D.

German Cancer Research Center, Heidelberg, Germany.

New therapeutic options have led to substantial increases in survival expectations of younger patients with multiple myeloma in recent years. In the past, the impact of these innovations on long-term survival has been disclosed only with substantial delay. We aimed to derive up-to-date estimates of long-term survival expectations of concurrently diagnosed multiple myeloma patients. Using data from the 1973-2005 database of the Surveillance, Epidemiology, and End Results (SEER) Program, we employed a novel model-based projection method to project 5-and 10-year relative survival expectations of multiple myeloma patients in the United States diagnosed in 2006-2010. Preliminary empirical evaluation of the method using historical data indicated good performance. Projected 5-year relative survival for patients diagnosed in 2006-2010 below 45 years of age is 68.0%, which exceeds the most up-to-date estimates obtained from traditional cohort and period analysis by 15.5 and 7.0 percent units respectively. Ten-year relative survival projection for patients in this age group is 55.3%, exceeding the most up-to-date estimates from traditional cohort and period analysis by 19.7 and 7.4 percent units respectively. By contrast, survival projections remain much lower and hardly exceed estimates from traditional survival analysis for older patients. Patients diagnosed with multiple myeloma in 2006-2010, especially those diagnosed at younger ages, are expected to have much higher long-term survival perspectives than suggested by previously available survival statistics.
PMID: 19144659 [PubMed - as supplied by publisher]

Videos from ASH 2008 on the Web

http://myeloma.org/main.jsp?source=link&source_link_id=3768&type=index&tab_id=1&menu_id=0&id=175

The IMF is pleased to provide you with a broad sampling of myeloma presentations and posters from the 2008 annual meeting of the American Society of Hematology in San Francisco, California. They report significant progress in myeloma research. IMF Scientific Advisor, Dr. Morie Gertz said, "This is the most exciting ASH meeting that I've been to, and I've been a member for over 25 years."

Nifuroxazide inhibits survival of multiple myeloma cells

Erik A. Nelson1, Sarah R. Walker1, Alicia Kepich1, Laurie B. Gashin1, Teru Hideshima1, Hiroshi Ikeda1, Dharminder Chauhan1, Kenneth C. Anderson1,2, and David A. Frank1,2

1 Department of Medical Oncology, Dana-Farber Cancer Institute, and 2 Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA

Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126.
Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.

New Agents for Multiple Myeloma treatment presented at ASH 2008

At the 2008 meeting of the American Society of Hematology in San Francisco in December, there were several oral presentations of new and promising agents for the treatment of patients with multiple myeloma.

Zolinza™ (vorinostat) and Velcade®
Zolinza is a histone deacetylase inhibitior that is being tested in a variety of lymphoid malignances. On October 6, 2006, the U.S. Food and Drug Administration approved Zolinza for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease following two systemic therapies. At ASH 2008, U.S. researchers reported that the combination of Zolinza™ (vorinostat) and Velcade® (bortezomib) is active for the treatment of relapsed/refractory myeloma.[1] There were 34 patients with relapsed/refractory myeloma in this study. The partial response rate was 26%, with an additional 21% having a minimal response and 53% having stable disease. Dexamethasone was added to Zolinza and Velcade in 21 additional patients. Two achieved a very good partial response, seven had a partial response, and 10 had stable disease. These authors concluded that the combination of Zolinza and Velcade was active even in patients previously treated with Velcade.

Carfilzomib and Dexamethasone
Carfilzomib is a novel, irreversible, epoxomicin-related proteasome inhibitor. Carfilzomib currently has orphan drug status for the treatment of multiple myeloma. Preclinical studies have shown that carfilzomib can overcome the resistance of myeloma cells to conventional agents and acts synergistically with dexamethasone.[2] At ASH 2008 researchers involved in a U.S. multi-center trial (PX-171-004) reported that carfilzomib and dexamethasone was a promising new agent for the treatment of myeloma.[3] There were 31 patients with relapsed myeloma in this study. Eighty-seven percent had received a prior stem cell transplant. For 13 patients who had not received Velcade, the overall response rate was 54%, including one complete response, two very good partial responses, and four partial responses; four patients had stable disease. Sixteen patients had received prior treatment with Velcade, and 19% achieved a partial response. One patient had a minimal response, and nine had stable disease.
A second study (PX-171-003) evaluated carfilzomib in 39 patients, all of whom had received prior treatment with Velcade; in addition, 89% had received a prior stem cell transplant.[4] The clinical benefit rate was 26%, including five patients with a partial response.
Carfilzomib will undoubtedly be evaluated in patients with less advanced disease and probably compared with Velcade for up-front treatment of myeloma.

Pomalidomide (CC4047)
Pomalidomide is an oral analog of thalidomide with significant immunomodulatory effects. It stops the growth of blood vessels, stimulates the immune system, and may directly kill cancer cells. Pomalidomide is also an inhibitor of angiogenesis. A Phase I study showed a complete remission rate of 17% in patients with relapsed or refractory myeloma with daily pomalidomide.[5] Fifty-four percent of patients in this study had a 50% or greater decrease in paraprotein. The main side effects were deep vein thrombosis, which occurred early and late. A Phase II study used an alternate day regimen of pomalidomide in an attempt to decrease thrombotic side effects.[6] The alternate day schedule appeared to eliminate thrombotic complications. There were 20 patients in this study, and the complete response rate was 10%; a greater than 50% reduction in paraprotein was achieved in half the patients. At ASH 2008 daily pomalidomide and low-dose dexamethasone were evaluated in 37 patients with relapsed or refractory myeloma.[7] All patients receive aspirin for prophylaxis against thrombotic complications. Seventy-six percent of patients had received a prior stem cell transplant, and 62% had received Thalomid® (thalidomide) or Revlimid® (lenalidomide). The overall response rate was 62%, and 24% had a very good partial response. The response was 29% in patients who had received prior Revlimid. Pomalidomide promises to be a rival of Revlimid and Thalomid in the treatment of patients with myeloma.

CNTO 328
CNTO 328 is a chimeric monoclonal antibody that specifically binds to and neutralizes human IL-6 with high affinity. A Phase I study has been performed in patients with lymphoma and myeloma. Preclinical studies suggest synergy of CNTO with Velcade.[8] At ASH 2008 researchers involved in a U.S. multi-center trial reported that the combination of Velcade and CNTO 328 was active in patients with relapsed or refractory myeloma.[9] This study included 21 patients, of whom 11 had received a prior stem cell transplant and eight had received prior Velcade or Thalomid. Fifty-seven percent achieved a partial or complete remission, and the median time to disease progression was 280 days. These authors will be performing a trial of Velcade plus CNTO 328 versus Velcade and placebo.

Velcade® and Perifosine
Researchers from several U.S. institutions have reported a 40% overall response rate to the combination of perifosine and Velcade® (bortizomib) in patients with multiple myeloma who had been previously treated with Velcade.[10] Perifosine belongs to a new class of anti-tumor drugs that targets cell membranes, inhibits Akt activation, and induces apoptosis.
The current study involved the treatment of 76 patients with relapsed/refractory multiple myeloma treated with perifosine and Velcade with or without dexamethasone. All patients had received prior therapy with Velcade and 35 were deemed refractory to Velcade. Fifty-seven patients in this study were evaluable for response. The overall response rate was 40%, with 30% having stable disease. The median time to tumor progression for all patients was 19 weeks, while the median time to tumor progression for responders had not been achieved. The overall response rate for patients deemed refractory to Velcade was 37%, and the median time to tumor progression was 23 weeks. The combination of Velcade and perifosine was described as well tolerated. These data suggest that pirifosine may be a new useful agent for the treatment of patients with myeloma.
Comments: It appears that new and novel agents for the treatment of multiple myeloma are continuing to be developed at a relatively rapid rate; many of these may have a major impact on future therapy.

References:
[1] Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.
[2] Kuhn DJ, Chen O, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2008;110:3281-3290.
[3] Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzommib (CFZ) in patients with relapsed myeloma (MM). Blood. 2008;112:320, abstract number 865.
[4] Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-labele, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). Blood. 2008;112:319, abstract number 864.
[5] Schey SA, Field SP, Bartlett JB, et al. Phase I study of an immunomodulator thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. Journal of Clinical Oncology. 2008;22:3269-3276.
[6] Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. British Journal of Haematology. 2008;141:41-51.
[7] Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood. 2008;112:320, abstract number 866.
[8] Voorhees PM, Chen O, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clinical Cancer Research. 2007;13:6469-6478.
[9] Rossi J-F, Manges RF, Sutherland HJ, et al. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood. 2008;112:320, abstract number 867.
[10] Richardson P, Wolf J, Jakubowiak et al. Phase I/II results of a multicenter trial of perisosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood. 2008;112:321, abstract number 870.

1.2 Million Dollars Awarded to Institute for Myeloma and Bone Cancer Research

FJC, a foundation of philanthropic donor-advised funds and the Myeloma Research Foundation are the latest major donors to the "Cure Myeloma Project", an ongoing research initiative at the Institute for Myeloma and Bone Cancer Research, (IMBCR), in Los Angeles, CA.

IMBCR's "Cure Myeloma Project" is the nation's foremost effort to find a cure for multiple myeloma, a blood cancer that resides in bone marrow. Led by premier scientists in the world of myeloma research, James R. Berenson, M.D., Haiming Chen, M.D., Ph.D. and Zhi-Wei Li, Ph.D., this multi-phase research project's overall goal is to specifically target myeloma cells while leaving surrounding healthy cells untouched.

Over the past five years, researchers and scientists at IMBCR have been responsible for creating many of the novel therapeutics currently used to extend the quality of life and lifespan of myeloma patients throughout the world.
About Multiple Myeloma and Blood Cancers: The American Cancer Society predicts that over 80,000 people are currently living with myeloma in the US and over 20,000 new cases are diagnosed each year. Approximately 10,000 people die each year from multiple myeloma. The Leukemia & Lymphoma Society estimates that 894,543 people in the US are presently battling blood cancers that include leukemia, lymphoma and myeloma. Blood cancers are the second most fatal form of cancer, second only to lung cancer.

About IMBCR: Headquartered in Los Angeles, California, IMBCR is the only independent non-profit cancer research institute working to find improved treatment, and ultimately a cure for multiple myeloma and other forms of blood cancer. IMBCR research findings have been presented at numerous scientific meetings throughout the world and its research has been published in most major oncology journals. www.imbcr.org

Acidic diet eats away at your health, author says (Edmonton Journal, 19 Jan 2009, Page D2)

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Acidic diet eats away at your health, author says
MICHELLE MAGNAN
Edmonton Journal
19 Jan 2009

How acidic are you today? Pee on a piece of pH test paper, which tells you whether your body is acidic or alkaline based on the pH scale of 14, and you’ll find out. If your diet consists of typical foods — foods that are high in starch, fat and sugar...read more...

Tech Tags: Edmonton Journal newspaper BODY & HEALTH

Cylene Initiates Phase I Trial of CX-4945

Cylene Pharmaceuticals announced that it has initiated a Phase I clinical trial of its oral CK2 protein kinase
inhibitor, CX-4945, in patients with advanced solid tumors, Castleman's disease, or multiple myeloma. The primary endpoints of the oral dose escalating trial are determination of safety, tolerance and PK properties of CX-4945 and to select the appropriate dose for Phase II trials. In addition, multiple mechanism-related pharmacodynamic biomarkers that were validated in preclinical studies will also be evaluated in the trial to assess the ability of CX-4945 to hit its target in patients.

CX-4945 is a first-in-class, orally administered small molecule anticancer agent that delivers highly selective and potent inhibition of CK2, a constitutively active protein kinase that is overexpressed in a wide range of cancers. CK2 drives the excessive proliferation phenotype of cancer cells through its potentiating role in key cell survival pathways and angiogenesis. CX-4945 demonstrates potent tumor regression activity in murine xenograft models, as well as favorable PK/ADMET and safety properties in preclinical studies.

"CK2 overexpression drives key cell survival pathways and proliferation of cancer cells, but it has been notoriously difficult to inhibit because it has an unusual active site. CX-4945 represents the first potent and selective inhibitor of CK2 with a favorable safety profile and the ability to promote tumor regressions as a single agent in preclinical studies. We are delighted to have advanced CX-4945 into the clinic ahead of schedule, and we are thoughtfully planning our Phase II program in particular CK2 driven cancers."

The primary objectives of the study will be to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of CX-4945, and to define the phase II dose. The secondary objectives are to characterize the pharmacokinetics, as well as observe for signs of anti-tumor activity via pharmacodynamic as well as radiographic assessments.

About CX-4945: an oral CK2 protein kinase inhibitor, CX-4945 is a first-in-class small molecule that has been optimized to selectively inhibit CK2 activity. The CK2 protein kinase plays a multifunctional role in cell cycle regulation, signal transduction, transcriptional control, angiogenesis, apoptosis and inflammation. Because CK2 contributes to the cancer phenotype via multiple cellular events, CX-4945 has been designed with the objective of creating a multifunctional inhibitor by targeting a single protein and affecting potentially many cancers. CX-4945 demonstrates broad spectrum anti-proliferative activity against diverse cancer cell lines, and the data attribute the anti-tumor activity of CX-4945 to intracellular inhibition of the CK2 enzyme.

Source: Cylene Pharmaceuticals

Trial of 'accurate' radiotherapy

Clinical trials are being carried out in the UK using radiotherapy that is highly targeted so can be given at much greater doses to destroy cancerous cells in the bone marrow without harming healthy cells.

Pauline Pain, 58, became the first patient in the world to receive the radiotherapy. Mrs Pain, who has multiple myeloma, was able to return home after her radiotherapy to await her bone marrow transplant. A conventional total body irradiation would have meant a long stay in hospital.

She said: "The only side-effects were a little temporary tiredness and mild sickness; other than that I felt very, very well. It was incredible to be walking around knowing that something inside me was fighting the cancer, but I couldn't feel it at all.
"The beauty of it was that I had the big dose of radiotherapy in the morning and I was at home by 5pm the same evening."

The two-year trial at Southampton General Hospital will involve 80 patients, half of whom will receive the new radiotherapy with chemotherapy and the other half will have chemotherapy alone.

The early results are "very encouraging", doctors said.

The radiotherapy is used to kill the cancer cells in the system before a transplant of healthy stem cells to replace the lost ones. The same dose of traditional radiotherapy would cause severe or even fatal damage to the body, proving toxic to the liver and kidneys. But because the new system delivers a radioisotope that attaches only to the surface of cancer cells, the healthy tissue is not affected.

Dr Kim Orchard, a senior lecturer at the University of Southampton's School of Medicine who is leading the trial, said: "Radiotherapy is used to clear the bone marrow of myeloma cells before a stem-cell transplant. Current treatment uses high doses of radiation, which are delivered by X-rays, but the sensitivity of healthy organs limits the dose that can be tolerated.

"Previous attempts to use antibodies to deliver the radioactivity have been frustrated by their accumulation in the liver, lungs and kidneys, which can cause grave complications. The key to this new treatment is that the antibody accumulates only in the bone marrow.

"We hope that the trial will show a clear benefit in better and longer remissions from myeloma. If we are successful, this approach offers great promise for the treatment of a range of other blood cancers."

Dr David Grant, Scientific Consultant at Leukaemia Research, which is funding the study, said: "This trial is very exciting. One of the main reasons why stem cell transplants have been less successful in the long-term treatment of myeloma is that patients are not cleared of all the cancer cells before the transplant.

"This new radiotherapy is not only more effective and potentially cheaper than existing treatments, it is far less toxic for the patient. It also enables patients to go home immediately after the procedure, reducing time spent in hospital."