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Dealth Risk Found from Anemia Drugs

Anemia Drugs' Mortality Risk Supported in Cancer Patients

Increased death rates among cancer patients taking erythropoiesis-stimulating agents were supported in a large meta-analysis.

Among nearly 14,000 patients in 53 studies, those taking the anemia drugs were 17% (95% CI 6% to 30%) more likely to die during the study, and their overall survival chances were reduced by 6% (95% CI 0% to 12%), reported Julia Bohlius, M.D., M.Sc.P.H., of the University of Bern in Switzerland.

The findings, disclosed at the American Society of Hematology meeting, confirmed results reported earlier in individual studies.

The trials included Epogen, Procrit, NeoRecormon and Aranesp. The analysis was notable for relying on full data on each patient, contributed by the trial sponsors and individual investigators, not on outcome data as published.

And in fact, the on-study mortality results were higher than previously published. On-study mortality was defined as death from any cause occurring from randomization to four weeks after the active study's end. Overall survival was measured from randomization to the end of available follow-up.

When the patient pool was limited to about 10,000 patients treated with chemotherapy, the relationship between erythropoiesis-stimulating agents and mortality fell just short of statistical significance.

On-study mortality in the chemotherapy population was increased by 10% for those taking the anemia drugs (95% CI -2% to 24%), and the overall death rate was increased by 4% (95% CI -3% to 11%), the researchers found.

The results changed little when the researchers controlled for known risk factors.

Age, sex, hemoglobin, hematocrit at baseline, type and stage of tumor, and type of study were among the factors researchers took into account.

Patients getting no cancer treatment showed a 33% increase in on-study mortality if they were receiving erythropoiesis agents (95% CI 7% to 67%).

There were even higher increases in patients receiving other forms of cancer treatment (52% for chemoradiation, 52% for radiation alone, and 53% for "other" non-chemotherapies), but these did not reach statistical significance.

Moreover, a test for interaction among all the non-chemotherapy patient groups yielded a P value of 0.42.

Co-author Andreas Engert, M.D., of the University of Cologne in Germany, said the specific reasons for the increased deaths associated with erythropoiesis agents remained unclear, but on the basis of more recent studies, most of the excess deaths are probably from thromboembolic events.

The American Society of Hematology and the American Society of Clinical Oncology would convene a new guideline panel early in 2009 to consider revisions derived from these findings and other developments since the existing version was published.

Since the current guideline was produced, the FDA had required a boxed warning on epoetin and darbopoetin about increased mortality risks for cancer patients.

Source:

Bohlius J, et al., "Recombinant human erythropoiesis stimulating agents in cancer patients: individual patient data meta-analysis on behalf of the EPO IPD Meta-Analysis Collaborative Group" Blood 2008; abstract LBA-6.

Checking drugs out....

Thanks, JoanM and gdpawel, for the current follow up on this highly significant problem with these drugs that are so widely used.

http://her2support.org/vbulletin/showthread.php?t=27170

I have a normally low rbc - just below the lowest number in the normal range. Naturally on chemo it further plunged. During my second cycle of AC I got the last menstrual period I would have until 7 months after chemo ended. Needless to say, I went out with a bang. I heavily bled for 3 weeks (I had to change my pad every hour or there was a big problem. I had to protect the bed during the night and wear underwear for urine leakage for extra protection). After 3 weeks and a third AC, my rbc was horrible. However, I did my own research at the time and refused Procrit (my onc's drug choice). I wasn't bad enough for a transfusion and by the time the 4th AC rolled around I wasn't bleeding anymore (even though I spotted for 1 week after the heavy bleeding ended). I'm sure glad I found all the earlier studies on this. I also know the wbc boosters aren't much better but I took Leukine (instead of Neulasta) which at least also boost the monocytes, lymphocytes and most importantly, the dendrites so it at least gives you more than just neutrophils as Neulasta does.

The body likes to be in its own perfect balance and affecting one thing can affect so many other things. I suppose if one is seriously ill and in a potentially life threatening situation, one must consider all options but if one is on the edge (as I was), it might be best to use a wait and see as I did and proceed if absolutely necessary.

Death Risk Found from Anemia Drugs

Thank goodness I always refused those drugs. My doc "gets it" but the nurses keep pushing the stuff. I always refuse.

if you are looking for more info about Anemia you can find it there

Anemia may be adaptive to the body

Something else that may be unique about anemia. A study, published in the Canadian Medial Association Journal, suggested that patients with anemia may actually help heal the body rather than harm it, says the new study.

Dr. Ryan Zarychanski, the study's co-author and a scientist at the Ottawa Health Research Institute, felt that doctors have been taught for generations that anemia is bad and they want to help their patients by treating it. However, they failed to consider that anemia may be adaptive and may be exactly the response that the body needs at that time.

Tired blood (anemia) involves a shortage of healthy red blood cells to carry oxygen to the body tissues. In the past, blood transfusions were the only way to treat anemia, until a drug derived from erythropoietin (EPO), a hormone that stimulates bone-marrow cells to produce red-blood cells.

Dr. Zarychanski pointed to evidence that suggests anemia is an evolutionary response to illness occuring in humans. The body has adapted over thousands of years to be anemic at times of stress because it needs to conserve energy. It needs help to fight infection. And when you're anemic, bacteria doesn't grow so well in the blood (an evolutionary response to infection before antibiotics).

In general, healthy adults have red blood cell levels of 14 grams or more per 100 millilitres of blood, while patients are considered to need treatment if their levels are below 10 grams. Patients with mild to moderate anemia (those with levels between 10 and 14 grams) would be better off not being treated.

What Dr. Zarychanski argues is that we should exercise some caution when thinking the best treatment is to automatically transfuse or give drugs to correct anemia.

Source: Ottawa Health Research Institute

Blood components and possible "invisible" effects

An interesting article about platelets.... given that cancer therapies given via ports incorporate the use of blood thinners:

http://www.jci.org/articles/view/23823

Weizmann Institute of Science

Thanks AlaskaAngel! Seems to go along with what the Weizmann Institute of Science has found.

http://her2support.org/vbulletin/showthread.php?t=30924

I wonder if low potassium levels are possibly a coping mechanism due to cancer. Mom has to take supplements to avoid low levels that are said to be a risk to the heart. I don't remember her needing supplementation prior to her recurrence.

Death Risk Found From Anemia Drugs

Does your Mom take diuretics or other blood pressure medicines Rich? Blood pressure medicines that contain diuretics can lower potassium.
By the way, everyone, sometimes iron supplements can help anemia related to chemo. Iron pills can cause constipation, so I took liquid iron prescribed by a doctor the whole time I took chemo. I never had a procrit shot or a blood transfusion. I never needed any shots for low white blood counts either. I took prescription supplements for that too. I took common liquid iron that can be bought in a pharmacy when I ran out of the prescription liquid iron. No problems, thank goodness !!

No diuretics or BP meds. She does use Atrovent, Flovent and Albuterol inhalers for emphysema. ??

Death Risk Found from Anemia Drugs

I would ask the doctor and see if he or she knows what is causing lower potassium if your mom is not taking diuretics or blood pressure meds.
Try eating foods with potassium like bananas or dried fruit if you are worried about it. Alot of food has potassium. I think you can find a list online somewhere.

Anemia Drugs Increase Mortality in Cancer Patients

A recent review in the Lancet suggests that using erythropoiesis-stimulating agents like Aranesp, Epogen and Procrit may reduce fatigue and combat anemia in cancer patients, while promoting tumor growth, hasten their deaths from cancer and increase their risk of early death from strokes and other cardiovascular events. The study combined data from nearly 14,000 patients in 54 clinical trials.

Although the FDA had slapped a black box warning on the drugs, the study, which was funded by firms that made them, suggested that doctors explain to their patients that treatment of anemia with EPO agents may improve their quality of life by reducing anemia and fatigue, but their survival may be shortened. According to a MedPage Today analysis of the study, the drugs, which stimulate red blood cell production, increased mortality by 17 percent.

Federal laws bar drug companies from paying doctors to prescribe medicines that are given in pill form and purchased by patients from pharmacies. But companies can rebate part of the price that doctors pay for drugs, like the anemia medicines, which they dispense in their offices as part of treatment. The anemia drugs are injected or given intravenously in physicians' offices. Doctors receive the rebates after they buy the drugs from the companies. But they also receive reimbursement from Medicare or private insurers for the drugs, often at a markup over the doctors' purchase price. I am reminded it is still a "chemotherapy concession."

Last year, U.S. Oncology, which funds, develops and helps manage 443 cancer centers in 39 states, complained that patients were harmed by new Medicare coverage policy for anemic cancer patients. The Centers for Medicare & Medicaid Services (CMS) decision limited ESA (erythropoiesis-stimulating agents) treatment to a maximum of eight weeks after a chemotherapy session. It also required physicians to wait until hemoglobin levels dropped below 10 g/dl before starting therapy.

Because CMS did not receive any documented cases of negative outcomes from the oncology community, it stuck to its decision. The FDA backed CMS' National Coverage Decision (NCD), which limited use of the drugs because they have been shown to spur tumor growth. The FDA believed the approved labeling and CMS' NCD were generally consistent in their recommendations regarding the use of pharmaceutical EPO in patients with cancer undergoing chemotherapy.

However, major insurance companies had not embraced the CMS protocol. It was a "shot over the bow" by the oncology community of government stepping directly into patients lives and saying that they know what is a better course of treatment than doctors. During the ensuing year, we found out that drugs, given by injection, had been heavily advertised, and there was gathering evidence that they had been overused, in part because oncologists could make money by using more of the drug.

Resulting studies had suggested the drugs may make the cancer worse. Much of that evidence came from studies in which patients were treated more aggressively than the drugs' labels recommended. The FDA found mounting evidence of documented effects on survival, tumor progression and thrombotic events which required reassessment of the net benefit of this class of drugs.

Gee, could it be that increased numbers of red cells deliver more oxygen to the tumor cells and thereby their activity across the board, including with respect to invasion, proliferation and metastasis? On one hand we're developing drugs to halt and reverse angiogenesis while on the other hand we're helping the tumor to obtain more oxygen with existing vasculature.

Having said all of this, physicians, scientists and the public occasionally apply their own judgement and determine when the existing evidence is sufficient to support a personal decision to adopt - as opposed to impose upon others - certain drug treatments. No wonder the National Coalition for Cancer Survivorship emphasized the need for drastic changes in how physicians are reimbursed for care. Reward doctors for whole patient care - not just treatments.

http://www.medpagetoday.com/Hematolo...matology/14007

There is an article on Artemisin that mentions:
<link rel="File-List" href="file:///C:%5CDOCUME%7E1%5CRICH%7E1.RIC%5CLOCALS%7E1%5CTemp %5Cmsohtml1%5C01%5Cclip_filelist.xml"><style>  </style>http://seattlepi.nwsource.com/local/...cerherb14.html

<link rel="File-List" href="file:///C:%5CDOCUME%7E1%5CRICH%7E1.RIC%5CLOCALS%7E1%5CTemp %5Cmsohtml1%5C01%5Cclip_filelist.xml"><style>  </style>"The connection here is iron," explained Sasaki.
Artemisinin is good at killing malaria parasites because it reacts and becomes highly toxic in the presence of iron, he said. Malaria parasites cause illness in humans by consuming red blood cells, which contain iron in the hemoglobin protein that carries oxygen in the blood. Similarly, cancer cells use lots of iron as they proliferate in tumors.
.........

<link rel="File-List" href="file:///C:%5CDOCUME%7E1%5CRICH%7E1.RIC%5CLOCALS%7E1%5CTemp %5Cmsohtml1%5C01%5Cclip_filelist.xml"><style>  </style>In the report published this month, the UW trio describe how they have created their own kind of artemisinin compound to enhance the herb's cancer-killing abilities. Basically, the scientists manipulated the herb's protein surface and boosted it with iron. When the cancer cells consume the compound, it releases toxic chemicals that kill the cells.
"The compound is like a little bomb-carrying monkey riding on the back of a Trojan horse," Lai said in a statement accompanying the report. Lai, who is perhaps best known publicly for his controversial studies linking cancer and cell phone use, is not afraid to mix humor with science, let alone metaphors.
Most chemotherapy drugs today have serious side effects, Sasaki said, because they generally kill one healthy cell for every 10 cancer cells. The UW's artemisinin compound used in cell cultures and in rats with breast cancer showed much better targeting and less collateral damage -- killing about 12,000 cancer cells for every healthy cell killed. Even regular artemisinin, without the UW alteration, only kills one good cell for every 100 cancer cells, he said.
"Normal cells don't use iron very often," Sasaki said. "When we deliver this artemisinin-iron package to cancer cells, we have much higher selectivity and much less toxic side effects."

And..
Anemia may be helpful
Anemia Of Chronic Disease: An Adaptive Response?

ScienceDaily (Aug. 12, 2008) — The anemia of chronic disease may be a beneficial, adaptive response to the underlying disease, rather than a negative effect of the illness, postulates an analysis article in CMAJ.
The authors argue that anemia may be beneficial to patients with inflammatory disease, and advocate restraint in treating mild to moderate forms of anemia.
"The general assumption is that anemia is a disorder and that patients would be better off without it," state the authors.
However, they suggest that anemia of chronic disease has the characteristics of an adaptive physiologic response, and their review of the literature shows that mortality appears to increase when treatment, given to raise hemoglobin levels, overrides mild to moderate anemia of chronic disease.
They call for better characterization of the cause of individual patients' anemia in future trials of anemia treatment, and careful monitoring of adverse outcomes, including mortality, if patients with anemia of chronic disease are included in such trials.
Journal reference:

Ryan Zarychanski, MD and Donald S. Houston, MD PhD. Anemia of chronic disease: A harmful disorder or an adaptive, beneficial response? Canadian Medical Association Journal, 2008; 179 (4): 333 DOI: 10.1503/cmaj.071131

Here is a previous Her2 forum thread on the issue:
http://her2support.org/vbulletin/sho...anemia+helpful

Anemia different in Her2 patients?

Cancer Res. 2009 Dec 15;69(24):9163-8.
Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation.

Li SH, Hawthorne VS, Neal CL, Sanghera S, Xu J, Yang J, Guo H, Steeg PS, Yu D.
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

PURCHASE TEXT

Abstract

ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers, including breast carcinomas. NGAL can inhibit erythroid cell production, leading to anemia. Anemia usually occurs in cancer patients and negatively affects quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we show that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor-kappaB (NF-kappaB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by a NF-kappaB inhibitor and ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-kappaB activation is involved in cancer-related anemia, and the ErbB2, NF-kappaB, and NGAL pathways may serve as potential therapeutic targets for cancer-related anemia.

PMID: 19951994 [PubMed - indexed for MEDLINE]PMCID: PMC2794902 [Available on 2010/12/15]

Using EPO in Cancer Is Harmful, Review Confirms

A new review of data confirms that erythropoietin - a drug to treat anemia in many cancer patients - might be harmful. The review found that patients with head and neck cancers who received erythropoietin in combination with radiation had poorer outcomes than those who received radiation treatment alone.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Severe anemia in cancer patients can lead to decreased oxygen supply to tumor cells. A lower level of oxygen in tumor cells is associated with more rapid tumor progression and a poorer response to therapy. Many use erythropoietin, or EPO, a hormone that controls red blood cell production, to correct anemia.

"It has therefore been thought logical that using erythropoietin to correct anemia before or during chemotherapy, radiotherapy or both would improve prognosis," the review authors write.

Dr. Philippe Lambin and colleagues at the MAASTRO (Maastricht Radiation Oncology) Clinic in the Netherlands conducted the review.

The investigators analyzed data from five published clinical trials that looked at whether combined radiation and EPO was better than standard radiation therapy alone in the treatment of head and neck cancers. Nearly 1,400 patients were included in the analysis. The researchers compared overall survival, the length of time during and after treatment in which the cancer did not progress, local tumor control and toxicity in the two different treatment groups.

Researchers found that patients who received EPO had significantly worse overall survival compared to patients who did not receive the drug. In addition, patients who took EPO had significantly shorter times before their cancers worsened.

Data included in the review suggest that decreased survival rates in cancer patients who took EPO were not due to some toxic effect of the drug itself, such as an increase in deaths due to blood clots. Instead, researchers have hypothesized that the drug might actually cause some types of tumors to grow.

Barbara Burtness, M.D., chief of the Head and Neck Medical Oncology division at the Fox Chase Cancer Center in Philadelphia, commented on the use of erythropoietin in head and neck cancer.

"The primary use of erythropoietin in cancer patients is to raise hemoglobin when patients become anemic, either because of the cancer or because of a side effect of the cancer treatments," she said. "It's been a part of practice for a long time."

Burtness said that there has been a specific reason for studying EPO in head and neck cancers. "When radiation treatments are given for bulky cancers in the head and neck area, it's thought that cancer cells that don't have a high oxygen content are less susceptible to being killed by radiation. The hypothesis has been that if you could correct a patient's anemia, there would be more red blood cells traveling to the area of cancer. This would lead to correction of the low oxygen content in the tumors - and the patient would be more likely to respond to the radiation treatment," she said.

"But what we've been hearing for some time is that erythropoietin is actually making cancer outcomes worse," she said.

She said the United States has tightened guidelines EPO use in response to data from recent studies. "Giving erythropoietin can have a negative impact on survival. We certainly are not using it here [at Fox Chase Cancer Center]. Among our patients who've received radiation elsewhere, its use does not appear to be common."

Manufacturers promoted EPO to improve anemia, and to help anemic patients to feel better overall. However, the U.S. Food and Drug Administration has issued several public health advisories underscoring the possible risks of using EPO in cancer, including faster tumor growth and early death. The FDA warnings also say that EPO does not improve symptoms associated with anemia, such as fatigue. Nor does EPO improve a patient's quality of life or sense of well-being, the advisories say.

The authors of the review conclude that patients with head and neck cancer should not receive EPO as an addition to radiation therapy.

Source: Health Behavior News Service and GoozNews on Health

Drug therapy for the management of cancer related fatigue

http://www.cfah.org/hbns/archives/vi...rtingDocID=527

Re: Dealth Risk Found from Anemia Drugs

1: Med Hypotheses. 2009 Aug 17. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif <script language="JavaScript1.2"></script>Links
<dd class="abstract">
Aspirin-associated iron loss as an anticancer mechanism.

Mascitelli L, Pezzetta F, Sullivan JL.
Medical Service, Comando Brigata Alpina "Julia", Udine, Italy.
A consensus view has emerged favoring an anticancer effect of long-term aspirin use. Aspirin-induced loss of stored iron from chronic gastrointestinal bleeding is proposed as a mechanism underlying this beneficial effect. In iron depletion, less iron may be available for carcinogenesis through free-radical mediated mechanisms and for promotion of tumor growth. Low-dose aspirin increases gastrointestinal losses of transfused radiolabeled autologous red cells. Observational studies report lower serum ferritin values with regular aspirin use. A protective effect of induced iron reduction against cancer mortality has been confirmed in a recent trial (FeAST) with subjects randomized to iron reduction or observation. Serum ferritin reductions in the FeAST trial were within conventionally normal reference ranges and were quantitatively similar to ferritin reductions in observational studies in regular aspirin users. Delayed anticancer effects of aspirin are compatible with the proposed mechanism, as continual microbleeding has a gradual cumulative effect on stored iron.
PMID: 19692186 [PubMed - as supplied by publisher</dd><dt>
</dt><dt>
</dt>

Re: Dealth Risk Found from Anemia Drugs

Clin Transl Oncol. 2009 Nov;11(11):727-36.
Spanish Society of Medical Oncology consensus on the use of erythropoietic stimulating agents in anaemic cancer patients.

Alberola Candel V, Carrato Mena A, DÃ*az-Rubio GarcÃ*a E, GascÃ³n Vilaplana P, GonzÃ¡lez BarÃ³n M, MartÃ*n JimÃ©nez M, Alba Conejo E, Cassinello Espinosa J, Colomer R, Cruz HernÃ¡ndez JJ, Barnadas I Molins A, Camps Herrero C, Casas FernÃ¡ndez de Tejerina AM, Carulla Torrent J, Constenla Figueiras M, GavilÃ¡ Gregori J, Isla Casado MD, Massuti Sureda B, Provencio Pulla M, RodrÃ*guez SÃ¡nchez CA, Sanz Ortiz J.
Servicio de OncologÃ*a MÃ©dica, Hospital Arnau de Vilanova, Valencia, Spain.
Treatment of anaemia is a very important aspect in the management of cancer patients. In order to carry out a consensus process about the use of erythropoietic stimulating agents (ESAs) in cancer patients, the Spanish Society of Medical Oncology (SEOM) elaborated a working group which coordinated a panel of medical oncology specialists. This working group has reviewed the main issues about the use of ESAs. In addition a consensus meeting was held in Madrid on 25 April 2007. The following conclusions were made: Since ESA treatment increases the haemoglobin (Hb) level and decreases the red blood cell (RBC) transfusion requirements, ESAs should be used within the approved indications in patients undergoing chemotherapy treatment, beginning at a Hb level below 11 g/dl and maintaining it around 12 g/dl, with iron supplements if necessary. Neither increasing the ESA dose in nonresponders nor the use of ESAs in the treatment of chronic cancer-related anaemia is recommended.

PMID: 19917536 [PubMed - in process

FDA Unveils Risk Management Plan for ESAs

Nearly two years after a Food and Drug Administration advisory committee called for restrictions on the use of red blood cell-stimulating drugs in cancer patients (erythropoiesis-stimulating agents or ESAs), the agency unveiled a stringent risk management plan that should further lower use of the drugs, which are already in freefall in cancer patients. The plan, which affects Amgen's Aranesp and Epogen and Johnson & Johnson's Procrit (manufactured by Amgen and identical to Epogen), requires the companies:
Register oncologists who prescribe the drugs;

Educate them about their risks, which include tumor progression and earlier death; and

Fully inform patients about the risks with an updated medication information guide, both at the time they are initially treated and every time treatment is given; and

Obtain signatures from patients that they've been apprised of the risks.

The updated medication guide will contain information for chronic and end-stage renal disease patients, who also get ESAs for anemia. But renal physicians will not be facing the same registration and education requirements.

The company was given a year to come into full compliance. Officials at a press briefing yesterday were uncertain what would happen to oncologists or the companies if they prescribe or use the drugs without giving the proper warnings.

The program is called, appropriately enough, APPRISE. And while it's tough, it's not unprecedented. The FDA adopted a similar registration program for some opioids.

When pressed by a reporter on why it took so long to come up with the program, Richard Pazdur, head of the oncology office at the Center for Drug Evaluation and Research at FDA, said "this took many many months of discussion. It's a delicate balance. We don't want to interfere in a draconian fashion with the practice of medicine."

Pazdur distinguished between patients undergoing therapy where there is a chance of cure, and those receiving palliative care for incurable cancers. In the latter case, patients may opt for the greater energy that comes from alleviating cancer- and chemo-related anemia, even if it results in a shorter end game.

"The risks-benefit balance is a delicate one," Pazdur said. The goal of the program wasn't to restrict use of the drugs, but "to help patients make the best choice given their individual situation."

The failure to simultaneously force the companies to reeducate the renal physician community was disappointing. There's mounting evidence that high doses of ESAs in renal disease patients is associated with increased risk of heart attacks, strokes and earlier mortality. Many of these patients are poor and unaware of the quality of care they receive at dialysis centers. They, just as much as cancer patients, need to be informed about the risks posed by overuse of ESAs.

Source: Gooznews on Health

Re: Dealth Risk Found from Anemia Drugs

Neoplasia. 2007 Dec;9(12):1122-9.
Effects of recombinant erythropoietin on breast cancer-initiating cells.

Phillips TM, Kim K, Vlashi E, McBride WH, Pajonk F.
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, 10833 LeConte Ave, Los Angeles, CA 90095-1714, USA.
BACKGROUND: Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway. METHODS: In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays. RESULTS: EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects. CONCLUSIONS: Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

PMID: 18084619 [PubMed - indexed for MEDLINE]

Clin Cancer Res. 2009 Sep 1;15(17):5552-9. Epub 2009 Aug 25.
Erythropoietin receptor expression and correlation to tamoxifen response and prognosis in breast cancer.

Larsson AM, JirstrÃ¶m K, Fredlund E, Nilsson S, RydÃ©n L, Landberg G, PÃ¥hlman S.
Center for Molecular Pathology, Department of Laboratory Medicine, University Hospital MAS, MalmÃ¶, Sweden.
PURPOSE: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen. EXPERIMENTAL DESIGN: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS). RESULTS: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression. CONCLUSION: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior.

PMID: 19706814 [PubMed - indexed for MEDLINE]

Annu Rev Med. 2009;60:181-92.
Erythropoietin in cancer patients.

Glaspy JA.
Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California, Los Angeles, California 90095, USA. jglaspy@mednet.ucla.edu
Therapy with erythropoiesis-stimulating agents (ESAs) is associated with well-documented benefits to anemic cancer patients undergoing chemotherapy, most importantly a reduction in the likelihood of needing red cell transfusions. One challenge in supportive cancer care is a relative resistance to ESAs, requiring high doses with a significant rate of nonresponse. Recent advances in our understanding of iron metabolism in patients with chronic illness and the results of clinical trials indicate that parenteral iron improves ESA response in this setting. Another issue is the safety of ESA treatment in cancer patients. There is an increased risk of venous thrombosis that must be considered in clinical decision making. There are also recent data raising concerns that ESAs may enhance tumor progression or decrease patient survival. Although the preponderance of the data suggests that ESAs do not alter survival when used to treat chemotherapy-induced anemia, large well-controlled trials addressing this issue are needed.

PMID: 18980468 [PubMed - indexed for MEDLINE]

Am J Health Syst Pharm. 2009 Jul 1;66(13):1180-5.
Use of erythropoietin-stimulating agents in breast cancer patients: a risk review.

Crouch Z, DeSantis ER.
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
PURPOSE: The treatment of cancer-induced anemia with erythropoietin-stimulating agents (ESAs) is reviewed. SUMMARY: Before the introduction of ESAs, the only treatment option for cancer-related anemia was red blood cell (RBC) transfusion. The use of ESAs in multiple disease states has been well established and is now considered first-line treatment for many forms of anemia. Chang et al. evaluated the effect of epoetin alfa (40,000 units administered subcutaneously every week) and standard-of-care therapy on quality of life (QOL), transfusion requirements, and hemoglobin levels in 354 patients with breast cancer who had a baseline hemoglobin concentration of <15 g/dL. The authors concluded that early initiation of treatment with epoetin alfa in patients with breast cancer is effective in maintaining hemoglobin levels, reducing transfusions, and improving QOL. Leyland-Jones et al. conducted a study evaluating the effects of early intervention with epoetin alfa (40,000 units administered subcutaneously every week) on survival and QOL of mainly nonanemic patients with metastatic breast cancer. In contrast to Chang et al., this study was discontinued because of lower overall survival rates within the epoetin alfa group. In 2008, the Food and Drug Administration issued a black-box warning for both epoetin alfa and darbepoetin alfa. The warning acknowledges that ESAs have shortened overall survival and time to disease progression in patients with advanced breast cancer who are given these agents to achieve a target hemoglobin concentration of > or =12 g/dL. CONCLUSION: When used in patients with cancer-induced anemia, ESAs should only be given at the lowest dose possible to prevent RBC transfusions. During treatment, hemoglobin levels should be monitored closely and ESA doses need to be adjusted accordingly.

PMID: 19535656 [PubMed - indexed for MEDLINE]

Br J Cancer. 2009 Dec 15;101(12):1961-71. Epub 2009 Sep 29.
Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events.

Aapro M, Osterwalder B, Scherhag A, Burger HU.
Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, 1, route du Muids, Genolier CH-1272, Switzerland. maapro@genolier.net
Comment in:

Br J Cancer. 2009 Dec 15;101(12):1947-8.

BACKGROUND: Epoetin-beta is used to treat patients with cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life (QoL). METHODS: This meta-analysis of all 12 randomised, controlled studies of epoetin-beta evaluated the impact of therapy at different Hb-initiation levels and to different target Hb levels on overall survival, tumour progression and thromboembolic events (TEE). An analysis of risk factors pre-disposing patients to TEEs under epoetin-beta therapy was also performed. A total of 2297 patients are included in the analysis. RESULTS: Analyses based on various Hb-initiation levels indicate no detrimental impact on survival (HR 0.99; 95% CI 0.70, 1.40) and a favourable impact on disease progression (HR 0.73; 95% CI 0.57, 0.94) when epoetin-beta was used within its licensed indication (Hb initiation < or = 10 g dl(-1)) or the EORTC recommended level of 11 g dl(-1). An increased risk of TEEs is seen for all Hb-initiation level strata and a detrimental impact on survival is seen when initiating epoetin-beta therapy at Hb levels >11 g dl(-1). We observe no association between high target Hb levels (> or = 13 g dl(-1)) and an increased risk of mortality, disease progression or TEEs with epoetin-beta compared with control. CONCLUSION: The results of this analysis indicate that epoetin-beta therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl(-1). Furthermore, there is no evidence to suggest that high Hb values achieved during epoetin-beta therapy are associated with an increased mortality, disease progression or TEE rate.

PMID: 19997109 [PubMed - indexed for MEDLINE]

Acta Haematol. 2011;125(1-2):55-67. Epub 2010 Dec 8.
Twist and shout: one decade of meta-analyses of erythropoiesis-stimulating agents in cancer patients.

Bohlius J, Tonia T, Schwarzer G.
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

FREE TEXT
Abstract

Anemia associated with cancer and cancer therapy is a common and important issue in the treatment of patients with malignant disease. Conventionally, blood transfusions are used to treat severe cancer-related anemia. Short- and long-acting preparations of recombinant human erythropoiesis-stimulating agents (ESAs) offer an alternative treatment option. Multiple studies and subsequent meta-analyses have demonstrated that ESA treatment increases hemoglobin levels and reduces the likelihood of transfusion for a proportion of treated patients. However, studies that attempted to evaluate whether ESAs improve tumor response and survival have generated conflicting evidence. Results of smaller trials reporting improved survival outcomes were contradicted by large randomized controlled trials that reported more deaths in patients receiving ESAs. In addition, there is strong evidence that cancer patients receiving ESAs have an increased risk of thromboembolic and cardiovascular events. We herein review the main meta-analyses published in the field, their strengths and weaknesses, their contribution to patient management and future perspectives for systematic reviews.
Copyright Â© 2010 S. Karger AG, Basel.
PMID: 21150188 [PubMed - in process]Free Article

Quote:

The findings of several meta-analyses on ESAs in cancer patients demonstrate that ESAs reduce the risk for RBCT and increase the risk for TVEs and mortality. There is an ongoing debate whether or not ESAs increase mortality in cancer patients receiving chemotherapy as well. However, the currently available data are insufficient to exclude an increased risk for death in cancer patients undergoing chemotherapy and receiving ESAs. In clinical practice, the increased risks of death and TVEs should be balanced against the benefits of treatment with ESAs, taking into account each patient’s clinical circumstances and preferences.

Amgen's troubles keep compounding; Aranesp studies reveal greater risks

Posted 5:00 PM 11/11/09

See full article from DailyFinance: http://srph.it/cE2OUB

Quote:

Aranesp (darbepoetin alfa) is an injectable drug that stimulates the production of red blood cells in the body. Often, patients who undergo dialysis or chemotherapy develop severe anemia that leaves them weak. Aranesp helps them recover from the tough treatments faster and reduces the need for transfusions. Amgen's drug Epogen and Johnson & Johnson's (JNJ) Procrit belong to the same family of drugs, called erythropoiesis-stimulating agents (ESAs).
Concerns over these drugs have been mounting in recent years after a series of studies found that high doses can lead to increased risks of heart attack, stroke, heart failure and tumor growth in some patients. As a result, in 2007, the Food and Drug Administration issued a black-box warning -- the strongest warning possible about potential side affects -- for Aranesp, Epogen and Procrit. Aranesp sales have declined in recent years as a result.
Less than two weeks ago, a new study published in The New England Journal of Medicine raised fresh safety concerns about the widely used anemia medicine. The study found that Aranesp nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis.

Re: Dealth Risk Found from Anemia Drugs

Patients May Die When Doctors Moonlight as Big Pharma's "Key Opinion Leaders"

As the crimson sun slipped into the gray Pacific Ocean, a multibillion-dollar drug deal took shape. A group of board-certified doctors greeted each other in a private room at a luxury hotel in California. The oncologists were big buyers of an anti-anemia drug called Procrit, sold by Ortho Biotech, a Johnson & Johnson (J&J) division. That Friday evening, the company toasted its top clients and their wives with bottles of Beaujolais, porterhouse steaks and free weekend accommodations.

The event could have been just another "grin and grip" affair, but there was a catch: J&J wanted to pump the sales of its biotech drug to beat its rival Amgen and its anti-anemia drugs. "The idea," as J&J drug rep Dean McClellan later explained, "was to get the docs to increase their Procrit dosage to 40,000 units."

There was just one problem. Regulators had approved a weekly drug dose of 30,000 units, and J&J was prohibited by the Food, Drug, and Cosmetic Act (FDAC) from marketing its drugs in unapproved ways. But the doctors could prescribe in any "off-label" manner they wanted. So, McClellan, a star rep and medical consigliere, led a "discussion" about high-dose experiments. Taking his cue, one physician explained how he routinely injected patients with 40,000 units of Procrit. Another oncologist pumped his people with 10,000 units for ten consecutive days - triple the approved amount. "That seems a little extreme," said McClellan, frowning.

"Oh no," the doctor said. "I haven't seen any side effects so far."

A few months later, Procrit sales hit the $1 billion mark, beating Amgen by a hair. The resort trip had certainly helped. But it was just one part of an expansive, long-running off-label marketing campaign, according to sales documents. Slowly but surely, oncologists around the country began administering so many high Procrit doses that, in time, the off-label therapy became the "community standard."

There were problems since insurers don't always reimburse doctors for off-label use. In fact, when Medicare refused to pay the Arizona Cancer Center, a huge client, for its high-dose Procrit injections, an Ortho manager ghost wrote a letter on behalf of its chief oncologist Daniel Von Hoff. After a few more company calls - ipso presto! - the center began receiving more than $1 million in Medicare payments for the illegal therapy. As McClellan claimed in a whistleblowing suit, the cancer market grew so saturated with high doses, that six years later the Food and Drug Administration finally approved them.

The decision might have been defensible had the 40,000-unit regime had been proven to be safe and effective. But independent research later revealed that cancer patients died sooner than expected, and company trials found an alarming number of dialysis patients suffered strokes and heart attacks. Meta-studies showed that 17 percent of patients died from the drug, and stories told of blood counts so high, patients actually spit up blood and choked on their own tumors. Turns out there was little scientific evidence that Procrit, and its cousins Epogen and Aranesp, actually helped people at any dosage.

Last summer, regulators announced that the drugs should be avoided entirely by most patients. "It turns out many people are better off taking placebos," said Dennis Cotter, president of Medical Technology and Practice Patterns, a nonprofit research institute.

What this illustrates is that drug companies can create entire cultures of over-prescribers for untested, even fatal indications, and that doctors can be easily corrupted. In light of a flurry of recent federal settlements for off-label marketing crimes, it also underlines how you, dear taxpayer, foot the bill for reckless marketing.

In the case of Procrit, the J&J unit formed advisory committees made up of academic physicians and clinical oncologists. These key opinion leaders (KOLs) were paid honoraria of at least $1,000 for every speech they delivered touting off-label use. McClellan selected some pliant clients to be the featured speakers. "Some guys wanted to give three or four speeches a weekend so they can get three or four thousand dollars," he said. A few actually did. Many talks were delivered at company "conferences" organized for other doctors, who earned hourly credits toward their annual continuing medical education (CME) units, required by state licensing boards. As if that wasn't enough, Ortho also paid physicians for their rooms, meals and transportation.

Ortho eventually assembled boards of KOLs who specialized in every type of cancer. According to sales documents, the goal was "to build thought leader endorsement [sic] to establish Procrit as standard of care," not just for approved indications such as AIDs and chemotherapy, but for cancer-related fatigue, depression, and other off-label indications.

These friendly prescribers were not Dr. Feelgood types working the tenderloin. They were distinguished professors from respected institutions such as John Hopkins University, Harvard Medical School, University of Chicago, Memorial Sloan-Kettering Cancer Center, Emory University Hospital, Cornell University, Long Island Jewish Medical Center, University of Texas MD Anderson Cancer Center, and others. Dr. Nicholas J. Vogelzang of the University of Chicago was a paid spokesman for the Fatigue Coalition, a group bankrolled by Ortho. Dr. John Glaspy of UCLA penned a seminal article in the Journal of Clinical Oncology that drew rosy conclusions about high-dose Ortho-sponsored studies.

Dozens of other doctors agreed to "influence their colleagues to use Procrit" for unapproved indications such as cancer-related fatigue. One was Dr. von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. "When I saw how many shares he owned in biotech and drug firms, my jaw dropped," McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's "fatigue" advisory board and was quoted often in The New York Times extolling the drug, according to public records.

Groopman also penned a bestseller called "How Doctors Think." In it, he talks about the importance of talking with patients about their diagnosis and treatments. But Groopman doesn't explain what role Big Pharma checks and trips play in his own decision making. This is noteworthy since he goes on about the influence of high-pressure drug reps and the need for physicians to weigh scientific assessments against "going with your gut."

Clearly, even esteemed doctors were swayed by Procrit's marketers. In reviewing the basic science research behind these costly anti-anemia drugs, Dr. Charles Bennett of Northwestern University found that physicians and investigators who collected money from the two drug makers were "less likely to criticize the safety, effectiveness, or cost-effectiveness of drugs" and "more likely to endorse novel and less proven treatments" like off-label. No matter what prescribers say, they seem to have indeed been bought by golf trips, grants and banquets.

The overprescribing of anti-anemia drugs roared alongside an astonishing rise in American health care expenses. For several years, Procrit and the others topped Medicare's reimbursement list. By 2007, the drugs' domestic sales approached $11 billion a year. So far, US taxpayers have shelled out more than $60 billion over the past 20 years, reimbursing doctors, KOLs and hospitals for a drug that never worked as advertised.

McClellan's whistleblowing case may be in limbo. But many prestigious doctors will soon wind up in the confessional. Thanks to the Physician Payments Sunshine Act, doctors who accept speaking fees, meals, travel, stock options, or any other compensation from drug or medical device companies will soon see their names - and their gifts - revealed publicly on the web. The rule is part of the Patient Protection and Affordable Care Act, aka "Obamacare." Data collection was supposed to begin this January, but the first report won't appear until March 31, 2013. When that day dawns, patients will gain some insight into their treatments. Was that off-label prescription supported by scientific evidence; or did my doctor "go with his gut?" If so, how often was that gut filled by the maker of my medication?

From Kathleen Sharp's book, "Blood Feud: The Man Who Blew the Whistle on One of the Deadliest Prescription Drugs Ever."

"Dozens of other doctors agreed to 'influence their colleagues to use Procrit' for unapproved indications such as cancer-related fatigue. One was Dr. Von Hoff, the director at the Arizona Cancer Center. He collected advisory fees and perks from not just Ortho, but from about 30 other pharmaceutical firms, earning directors' fees for sitting on several companies' boards. 'When I saw how many shares he owned in biotech and drug firms, my jaw dropped,' McClellan later said. Many others, like Dr. Jerome Groopman of Harvard Medical School, performed J&J-funded clinical trials. He was paid to sit on Procrit's 'fatigue' advisory board and was quoted often in The New York Times extolling the drug, according to public records."

In 2010, Dan Von Hoff got the Karnofsky award from the American Society of Clinical Oncology (ASCO), which is sort of a lifetime achievement award for clinical research. This is a nuclear explosion for clinical oncology. I'm wondering who was involved in the Harvard side of it? Interestingly, it is the highest levels of academia who are most tainted. One in particular, Dan Von Hoff. These ivory tower docs were the culprits. Unfortunately, this will probably play out as one more cudgel to beat the more reasonable and gentle practitioners, who either largely avoided such abuse or were led down the path by the scholars, who will themselves skip out unfazed.

Re: Dealth Risk Found from Anemia Drugs

The first article on platelets was very interesting. Glad this discussion was brought back up. If I read the article correctly, platelets could possibly play a role in metastais. When I started Navelbine in November my platelets started to rise, as my platelets went up, so did my tumor markers. My platelets were the highest they have been in over four years. I stopped Navelbine three weeks ago, and my platelets have come back down into the 200 range. I wonder if the increase of platelets were aiding my bone metatasis?

Amelia

Re: Dealth Risk Found from Anemia Drugs

Amelia

Granulocyte colony-stimulating factor is one of the about 15 proteins known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth.

A growth factor is about twenty small proteins that attach to specific receptors on the surface of stem cells in bone marrow and promote differentiation and maturation of these cells into morphotic constituents of blood. And blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction.

Colony-stimulating factor is a substance that stimulates the production of blood cells. Colony-stimulating factors include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and promegapoietin.

Examples:

White Blood count boosters = Neupogen (Filgrastim ), Neulasta (Pegfilgrastim), Leukine (Sargramostim)

Red Blood cell boosters: Procrit, Epogen (epoetin alpha, Erythropoietin), Aranesp (Darbepoetin)

The agents include epoetin alfa (Epogen, Procrit), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp). Neulasta has to do with wbc (white blood cells) and pricrit has to do with rbc (red blood cells).

Blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). Problems with blood composition or circulation can lead to downstream tissue (which is made up of cells) dysfunction.

The big difference is that white blood cells help fight infection, red blood cells transport oxygen throughout the body.

Erythropoiesis is basically a process where hemoglobin is synthesized, and eventually passes into the bloodstream.

Erythroprotein (EPO) is a natural substance made by the kidney.

Pharma EPO is a hormone that stimulates bone-marrow cells to produce red-blood cells.

Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels. Pharma EPO is helping them along (growth factor).

Drugs that would stimulate white blood cells would not involve erythropoiesis (above). They would be involved with leukopoiesis, the process of making leukocytes, stimulated by various colony-stimulating factors (CSFs), and hormones produced by mature white blood cells.

Growth factors cause endothelial cell (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide "structural support" for the new blood vessels.

Greg

Re: Dealth Risk Found from Anemia Drugs

<dt>2/16/12 update: </dt>Raised platelets reduce survival in ovarian cancer LINK

The crux of the research was nicely summed in the MD Anderson press release:

“Highly elevated platelet levels fuel tumor growth and reduce the survival of ovarian cancer patients.”

Re: Dealth Risk Found from Anemia Drugs

The same MD Anderson researcher (Sood) said that patients whose tumors produced high levels of interleukin-8 (IL-8) protein had a worse outcome than those with less IL-8. Blocking expression of IL-8 in mouse models of ovarian cancer slowed tumor growth by reducing blood vessel growth.

IL-8 expression is elevated in many human tumors. Previous work indicated that the protein stimulates tumor growth, blood vessel development, and metastasis in animal models. Suppressing its activity with antibody therapy slowed tumor growth in those models.

In his previous study, Anil Sood, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston and colleagues tested 102 human ovarian cancer tumor samples for IL-8 expression. Of those, 43 (42 percent) had high levels of the protein and 69 (58 percent) had low or no IL-8 expression. The researchers found that the women whose tumors had higher levels of IL-8 were more likely to have advanced disease and poorer survival.

When the team used small-interfering RNAs to block IL-8 gene expression in animal models of ovarian cancer, they saw that tumor growth was substantially reduced. The slowed growth appeared to be due to less blood vessel development.

"Our findings suggest that IL-8 may be a potential therapeutic target in ovarian cancer," the authors write.

IL-8 and/or IL-6?