Hand-Foot Syndrome Signals Xeloda Effectiveness | Fight Colorectal Cancer

This particular study isn't about H-F Syndrome from Sutent, but it's still interesting. - JHH

Hand-Foot Syndrome Signals Xeloda Effectiveness

Posted by Kate Murphy on August 13th, 2011

Developing tender swelling or rash on their hands and feet may actually be good news for patients being treated with Xeloda® (capecitabine).

During a recent clinical trial, colorectal cancer patients with hand-foot syndrome lived longer, and it took longer for their cancer to get worse.

Researchers comparing two Xeloda-based chemotherapies for people with advanced colorectal cancer, studied skin side effects from both Xeloda and Erbitux® (cetuximab). They found that about a third of patients experienced at least some hand-foot syndrome, and these patients lived almost 10 months longer than patients without skin changes.

WHAT WAS STUDIED?

As part of a Phase II clinical trial, the German AIO Colorectal Study Group randomized 185 patients in 35 cancer centers across Germany to receive either CAPOX-C (capecitabine, oxaliplatin, and cetuximab) or CAPIRI-C (capecitabine, irinotecan, and cetuximab). Their primary goal was to see if there was a difference in objective response rate — the percentage of complete and partial tumor shrinkage. They also looked at time to cancer progression, overall survival time, safety, and side effects.

In studying at side effects, they analyzed skin toxicity known to be associated with capecitabine: hand-foot syndrome and nail changes.

Hand-foot syndrome or palmar-plantar erythrodysesthesia (PPE) ranges from mild redness and swelling on the palms of the hands and soles of the feet to severe and painful cracking and sores that can interfere with walking or using hands and fingers. It appears to get worse with heat and friction. Patients are told to avoid hot water and aerobic exercise like running and jumping. Using hand tools can also create friction and make hand-foot syndrome worse.

WHAT WAS FOUND?

Comparing patients with no capecitabine-related skin toxicity (grade 0) with those with mild to severe symptoms (grades 1 to 3):

• 32.2 percent of all patients had some skin toxicity: 31 percent had hand-foot syndrome, 8 percent had nail changes. Only 2 patients had nail changes without hand-foot syndrome as well.
• Patients with skin toxicity had longer time before cancer got worse (progression-free survival):median 9.9 months vs. 5.6 months.
• Skin toxicity also meant longer median survival time (overall survival): 32.8 months vs. 22.4 months.
• Disease control (complete or partial tumor shrinkage or stable disease) was greater in those with skin changes: 97.9 percent vs 86.1 percent.
• Dose reductions were necessary more often in patients with skin toxicity: 45.1 percent required them compared to 29.3 percent without skin changes.

There were more skin problems in the CAPOX regimen (39.4%) than the CAPIRI plan (25.6%), although the research team attributes this to a higher dose of capecitabine used with CAPOX.

Hand-foot syndrome began to be diagnosed after a median of three treatment cycles and reached its maximum at five cycles.

The research team concluded:

In the setting of first-line chemotherapy with CAPIRI with cetuximab or CAPOX with cetuximab, capecitabine skin toxicity appears to be an early indicator of treatment efficacy. Capecitabine-induced skin toxicity is predictive for a longer progression-free survival and overall survival. The percentage of hand-foot syndrome is associated with higher dosing, so that patients not showing any HFS might be treated with higher doses.

SOURCE

Stintzing et al., British Journal of Cancer, Volume 105, Number 4, August 2011. doi:10.1038/bjc.2011.227

'Amazing' therapy wipes out leukemia in study

Wed, Aug 10, 2011

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This microscopy image provided by Dr. Carl June on Wednesday, Aug. 10, 2011 shows immune system T-cells, center, binding to beads which cause the cells to divide. The beads, depicted in yellow, are later removed, leaving pure T-cells which are then ready for infusion to the cancer patients. Scientists are reporting the first clear success with gene therapy to treat leukemia, using the patients' own blood cells to hunt down and wipe out their cancer. They've only done it in three patients so far, but the results were striking: two appear cancer-free up to a year after treatment, and the third had a partial response. Scientists are already preparing to try the approach in other kinds of cancer. (AP Photo/Dr. Carl June)

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Scientists are reporting the first clear success with a new approach for treating leukemia — turning the patients' own blood cells into assassins that hunt and destroy their cancer cells.

They've only done it in three patients so far, but the results were striking: Two appear cancer-free up to a year after treatment, and the third patient is improved but still has some cancer. Scientists are already preparing to try the samegene therapy technique for other kinds of cancer.

"It worked great. We were surprised it worked as well as it did," said Dr. Carl June, a gene therapy expert at the University of Pennsylvania. "We're just a year out now. We need to find out how long these remissions last."

He led the study, published Wednesday by two journals, New England Journal of Medicine and Science Translational Medicine.

It involved three men with very advanced cases of chronic lymphocytic leukemia, or CLL. The only hope for a cure now is bone marrow or stem cell transplants, which don't always work and carry a high risk of death.

Scientists have been working for years to find ways to boost the immune system's ability to fight cancer. Earlier attempts at genetically modifying bloodstream soldiers called T-cells have had limited success; the modified cells didn't reproduce well and quickly disappeared.

June and his colleagues made changes to the technique, using a novel carrier to deliver the new genes into the T-cells and a signaling mechanism telling the cells to kill and multiply.

That resulted in armies of "serial killer" cells that targeted cancer cells, destroyed them, and went on to kill new cancer as it emerged. It was known that T-cells attackviruses that way, but this is the first time it's been done against cancer, June said.

For the experiment, blood was taken from each patient and T-cells removed. After they were altered in a lab, millions of the cells were returned to the patient in three infusions.

The researchers described the experience of one 64-year-old patient in detail. There was no change for two weeks, but then he became ill with chills, nausea and fever. He and the other two patients were hit with a condition that occurs when a large number of cancer cells die at the same time — a sign that the gene therapy is working.

"It was like the worse flu of their life," June said. "But after that, it's over. They're well."

The main complication seems to be that this technique also destroys some other infection-fighting blood cells; so far the patients have been getting monthly treatments for that.

Penn researchers want to test the gene therapy technique in leukemia-related cancers, as well as pancreatic and ovarian cancer, he said. Other institutions are looking at prostate and brain cancer.

Dr. Walter J. Urba of the Providence Cancer Center in Portland, Ore., called the findings "pretty remarkable" but added a note of caution because of the size of the study.

"It's still just three patients. Three's better than one, but it's not 100," said Urba, one of the authors of an editorial on the research that appears in the New England Journal.

What happens long-term is key, he said: "What's it like a year from now, two years from now, for these patients."

But Dr. Kanti Rai, a blood cancer expert at New York's Long Island Jewish Medical Center, could hardly contain his enthusiasm, saying he usually is more reserved in his comments on such reports.

"It's an amazing, amazing kind of achievement," said Rai, who had no role in the research.

One of the patients, who did not want to be identified, wrote about his illness, and released a statement through the university. The man, himself a scientist, called himself "very lucky," although he wrote that he didn't feel that way when he was first diagnosed 15 years ago at age 50.

He was successfully treated over the years with chemotherapy until standard drugs no longer worked.

Now, almost a year since he entered the study, "I'm healthy and still in remission. I know this may not be a permanent condition, but I decided to declare victory and assume that I had won."

___

Online:

New England Journal: http://www.nejm.org

Science journal: http://stm.sciencemag.org

Meta-analysis defines risk of congestive heart failure with sunitinib - Reuters Health • The Doctor's Channel Daily Newscast Videos - The Doctor's Channel

Well, this is worrying.

NEW YORK (Reuters Health) - Pooled data suggest that cancer patients who are treated with sunitinib (Sutent; Pfizer) have about a 2-fold increased relative risk of developing high-grade congestive heart failure (CHF) and about a 3-fold increased risk of developing high-grade CHF. The absolute risks are about 4% and less than 2%.

With the clinical use of sunitinib “expected to expand greatly, I think this is something to be concerned about in several situations,” Dr. Toni K. Choueiri, from Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, noted in an interview with Reuters Health.

“I think it is reasonable to evaluate the cardiac function of patients before sunitinib,” he explained, “especially older patients and those with a history of heart problems. It doesn't mean I won't give sunitinib to these patients; it means I will monitor them and counsel them about signs of CHF because a lot of times it can present as vague symptoms, or I might use an alternative drug.”

Sunitinib and the Heart

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant GI stromal tumor (GIST). It is currently being investigated in more than 30 tumor types in more than 300 clinical trials, Dr. Choueiri and colleagues note in a paper in the Journal of Clinical Oncology, published online August 1.

CHF associated with sunitinib use has been reported sporadically in several cancer trials but the true risk associated with its use remains undefined. Dr. Choueiri and colleagues conducted a meta-analytic review of 16 clinical trials of sunitinib involving 6935 patients with RCC and non-RCC tumors. There were 4 phase III trials and 11 phase II trials. One study was an expanded access protocol.

In sunitinib-treated patients, the overall incidence of any CHF and high-grade CHF was 4.1% and 1.5%, respectively, the investigators report.

The relative risk of any CHF and high-grade CHF with sunitinib compared with placebo was statistically significant, at 1.81 and 3.30, respectively. There was no evidence of publication bias for incidence or relative risk of CHF events, the investigators note.

Whether CHF observed in sunitinib-treated patients is a dose-dependent or reversible effect remains to be determined. There is some evidence in the literature that a decline in left ventricular ejection fracture with sunitinib may indeed be reversible, the investigators note.

Class Effect

Sunitinib is a small-molecule tyrosine kinase inhibitor that blocks the intracellular domain of the vascular endothelial growth factor (VEGF) receptor. The VEGF pathway is critical in maintaining functional cardiac myocardium, the investigators point out in their report.

They say their findings support “emerging data” suggesting that members of this class of drugs may carry increased risk cardiac toxicity. For instance, a recent meta-analysis of the anti-VEGF antibody bevacizumab found a greater than 3-fold increased risk of CHF in patients with breast cancer.

Sunitinib has also been shown to increase the risk of hypertension, in line with other VEGF inhibitors, such as sorafenib and bevacizumab. As hypertension is a well known risk factor for CHF, it's possible that sunitinib use increased CHF through this mechanism, the investigators note.

Summing up, Dr. Choueiri and colleagues say clinicians need to be aware of the risk of CHF with sunitinib treatment to provide early intervention and balance therapeutic benefit with this potentially life-threatening adverse effect.

Reference:
Incidence and Risk of Congestive Heart Failure in Patients With Renal and Nonrenal Cell Carcinoma Treated With Sunitinib
J Clin Oncol 2011;29. Published online August 1, 2011.

AstraZeneca finally lands name for new cancer drug | The News Journal | delawareonline.com

AstraZeneca finally lands name for new cancer drug | The News Journal | delawareonline.com

Thyroid cancer stem cells : Abstract : Nature Reviews Endocrinology

Thyroid cancer stem cells : Abstract : Nature Reviews Endocrinology

Researcher finds thyroid cancer gene inhibits spread of malignant cells

A mutant gene long thought to accelerate tumor growth in thyroid cancer patients actually inhibits the spread of malignant cells, showing promise for novel cancertherapies, a Mayo Clinic study has found. The findings will be presented by Mayo Clinic researcher Honey Reddi, Ph.D., at the Endocrine Society meeting in Boston.

Dr. Reddi's discovery could have widespread implications in cancer research andendocrinology. It could help oncologists sharpen the diagnosis of specific types of thyroid cancers, while leading pharmaceutical researchers toward therapeutics derived from a protein once thought to feed tumor growth.

"It's not an oncogene like everyone thought it was," Dr. Reddi says, referring to a genewith the potential to cause cancer. "We all knew what happened in the cell culture, but we said, 'That's not good enough,' so we asked, 'What would it do in mice?'"

Thyroid cancer is the sixth most common cancer in the world, and 15 to 20 percent of all thyroid cancer cases are follicular, a type that is more aggressive. Dr. Reddi's findings could aid this diagnosis and treatment for thousands of patients.

Distinguishing benign from malignant follicular thyroid cancer poses a unique challenge to oncologists. An accurate diagnosis of malignant follicular cancer cannot be made until after cancerous material is removed. That has led to countless unnecessary surgeries in patients with benign thyroid tumors. Patients who now present with non-papillary cancerous growths on thyroid cells must undergo surgery to remove the tumor — even if the cancer is benign.

Dr. Reddi's research found that the PAX8/PPARγ fusion protein, developed from a mutated fusion gene found in many follicular thyroid carcinomas, functions as a tumor suppressor by upregulating (encourages natural production of) microRNA-122 and PTEN, both naturally occurring anti-tumor agents.

PAX8/PPARγ results from the translocation of genetic material between humanchromosomes 2 and 3. Previous in vitro studies of the PAX8/PPARγ protein found rapid acceleration of cell growth, which led researchers to the false interpretation that PAX8/PPARγ functioned as an oncogene, a type of mutated gene that encourages tumor propagation, Dr. Reddi says.
Mayo Clinic's in vivo animal studies show that PAX8/PPARγ upregulates the well-known anti-cancer protein PTEN, as well as microRNA-122, and likely facilitates other cancer-fighting molecules.
PAX8/PPARγ does not boost tumor progression when exposed to cancerous cells, Dr. Reddi says. Rather, its facilitation of other native anti-cancer molecules appears to outweigh the tumor propagation. Tumors grew about four times slower in mice exposed to the PAX8/PPARγ gene than those who were deprived of the protein's cancer-fighting qualities.
Among the team's goals in future research is the identification of other microRNA-like markers, which could identify a benign disease and obviate the need for immediate and unnecessary surgery.
Based on her discussions with clinicians at Mayo Clinic, Dr. Reddi says, "There are many complications from thyroid surgery, and having early detection markers could save thousands of unnecessary surgeries every year. We're just getting started and look towards a rapid translation from bench to bedside."
Source: Mayo Clinic

“Broad spectrum” cancer suppressor gene discovered

Portuguese researchers have discovered a "broad spectrum" cancer suppressor gene - called LRP1B – which acts by removing proteins crucial for cancer development from the tumour environment. The fact that LRP1B does not act on the tumour itself (in this study thyroid tumours) but, instead, on molecules which are known to be important to many different cancers is what makes it so interesting. Because this means that LRP1B, and also therapies capable of inducing it (or mimicking its effect), could, in theory, be used to treat a variety of cancers. The study by Hugo Prazeres and Paula Soares from IPATIMUP and University of Porto along with colleagues Fernando Rodrigues and Teresa Martins from Portuguese Institute of Oncology, Coimbra was just published in the journal Oncogene(1).

LRP1B is a protein/receptor on the cell membrane with the function to carry molecules from outside to the inside of the cell. But a 2010 study looking for mutated genes in 3312 patients with 26 different cancers showed that LRP1B was one of the 10 most frequently found deleted genes triggering the interest of researchers by suggesting that the receptor could play a role in cancer.

To investigate this possibility Prazeres, Soares and colleagues looked into the thyroid gland where LRP1B is normally found in high quantities. Thyroid cancer was also one of those with LRP1B deletions in the 2010 study and, even more interesting, a still unidentified susceptibility gene is known to be localised in same chromosomal area of LRP1B. And in fact, all the thyroid cancer samples analysed by Prazeres and colleagues - whether from patients with familial (inherited) or sporadic (non-inherited) thyroid cancers – turned out to have abnormally low levels of LRP1B. This suggested that the loss of LRP1B was linked to the appearance of cancer. Two other experiments supported this idea. First a comparison of normal and cancerous thyroid tissues showed that the less LRP1B a thyroid cancer had, the more aggressive it seemed to be. And when the researchers re-inserted LRP1B into the cancerous cells they saw how the new LRP1B positive cells lost much of their capacity to divide and invade new tissues (so in effect their capacity to form metastasis, the deadly marker of cancer).

Once the link LRP1B /cancer prevention was established the next step was to understand how this occurred.

Since LRP1B function is to transport molecules from the outside to the inside of the cells the researchers hypothesised that LRP1B could be removing one or more molecules important for tumour development from around the cancer cells. To test that Prazeres and Soares compared the composition of the environment around cells with or without LRP1B and discovered much lower quantities of a protein called matrix metalloproteinase (MMP) on those with LRP1B. MMP breaks down other proteins and, in cancers, is known to destroy the (protein) matrix, which gives cells structural support in the tissues. By destroying the matrix MMP allows the tumours space and “freedom” to expand and invade other tissues and MMP disappearance can explain LRP1B effects stopping tumour development. Interestingly LRP1B is also known to affect uPA another protein involved with MMP in the destruction of the cellular matrix.

Prazeres and Soares also looked into the mechanism behind LRP1B loss and found a surprising combination of mechanisms. In fact, either the LRP1B gene (or parts of it) have been deleted, or the gene was methylated (a chemical group called methyl binds to LRP1B blocking access to molecules that activate it) or the gene was being suppressed by a micro RNA. MicroRNAs are small RNAs that instead of being used as "information carriers" act by activating or suppressing other genes (normally RNA carries information from the DNA to be used as blueprint to make proteins). In the case of the thyroid cancers analysed by Prazeres and colleagues a microRNA that suppresses LRP1B was found in aberrantly high quantities. This data is particularly important if one day scientists attempt to develop treatments capable of restoring LRP1B and its cancer “watchdog” functions

In conclusion, Prazeres and Soares’ study reveals a new tumour suppressor gene - LRP1B - that acts by changing the tumour microenvironment, or, more specifically, by removing a receptor crucial for tumour development called MMP. And because most tumours depend on MMP to grow and invade other tissues this means that a large number of cancers can potentially be controlled by LRP1B. It also suggests that treatments capable of increase this receptor (or reproduce its effect) could be used against several types of cancer including lung, esophagus, breast, hepatocellular, renal, neural and colorectal cancer (to name just a few of those already linked to LRP1B loss).

So, where next? “Future works - says Paula Soares the group leader - is already on course to identify if other extracellular molecules are affected by changes in LRP1B and what exactly is happening inside the cell too. Also if this protein is in fact confirmed to be deleted in multiple cancers - like others and also our group have suggested - then strategies based on decoy proteins –proteins with the same function of LRP1B – could be developed to restored normal conditions."

(1) Oncogene (2011) 30, 1302–1317; doi:10.1038/onc.2010.512;

Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells

http://www.nature.com/onc/journal/v30/n11/abs/onc2010512a.html

camorim is based in Oxford, England, United Kingdom, and is Anchor for Allvoices