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War on cancer.

Brain/Exercise

A study of brain cancer survival argues for the benefits of exercise. Admittedly, it can be difficult for such patients to exercise. But it can help prolong their lives. For instance, working out on an exercise bike for 30 minutes per day can prolong survival, even with aggressive forms of brain cancer such as glioblastoma multiforme (GBM). The research was published in the Journal of Clinical Oncology, a publication of the American Society of Clinical Oncology (ASCO) in July 2011. It looked at 243 patients with advanced recurrent malignant brain tumors (gliomas). Those who exercised briskly and regularly lived nearly 22 months compared with 13 months for those who were less active - nearly a doubling in survival. This level of activity is equivalent to walking briskly for 30 minutes five days per week (Libov 2011).

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"Numerous studies show exercise lowers fatigue and enhances physical function for cancer patients, but we wanted to look at whether exercise fundamentally is associated with the risk of cancer progressing or coming back," said Lee W. Jones, PhD, the study's senior author. Jones is also an exercise scientist and associate professor at Duke Cancer Institute in Durham, North Carolina. There were some shortcomings to the study. For instance, it is difficult to say whether the ability of exercise was itself associated with fewer symptoms and better overall health (and thus longer survival.) This issue may only be settled through a randomized trial. In the meantime, it would be a good bet for patients to contact a physical therapist who can help them strengthen their muscles and launch an exercise program, where appropriate. The American Physical Therapy Association (apta.org) is a good place to begin looking. Health insurance often pays for physical rehabilitation.

Leukemia/Vidaza

One of the most interesting new drugs for treating myelodysplasia syndrome (MDS) and leukemia is called azacitidine (Vidaza). In a phase 3 trial, patients with higher-risk MDS were randomly assigned to receive either Vidaza or conventional care (which could be best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomization).

Three hundred fifty-eight patients were randomized to receive Vidaza or one of these conventional care regimens. After a median follow-up of 21.1 months, median overall survival was 24.5 months for the Vidaza group versus 15.0 months for the conventional care group. At 2 years, 50.8% of patients in the Vidaza group were alive compared with just 26.2% in the conventional care group, a highly significant near doubling. Median time to acute myeloid leukemia transformation was 17.8 months in the Vidaza group compared with 11.5 months in the conventional care group (Fenaux 2009).

In a new analysis, Vidaza has been found to prolong survival and to be well tolerated in older patients with acute myelogenous leukemia (AML). The study in question focused on patients with a median age of 70 years. Half of these patients were treated with Vidaza and lived at least two years, compared with only 16% of patients who received conventional care (Al-Ali 2011).

Typically, the median survival of AML is less than one year, said Kathy Heptinstall, operating director of the Myelodysplastic Syndromes Foundation. At present, she said, a large portion of older AML patients are offered only supportive or palliative care. "We would hope that publication of these encouraging results will spread the word and help change the approach to treatment" (Gendel 2011).

The same study found that Vidaza also reduced the need for blood transfusions, which are often required in AML. For example, 41% of patients on Vidaza achieved what is called "transfusion independence," whereas this was true for only 18%. of those receiving conventional care. Vidaza also reduced the number of days spent in the hospital as well as serious infections.

Lung Cancer/Xalkori

In August 2011, the FDA approved Pfizer's new anticancer pill, Xalkori (crizotinib). The approval was unusual in several respects. Approval was for a very specific subpopulation of lung cancer patients. The drug was also approved simultaneously with an obligatory blood test for the abnormal anaplastic lymphoma kinase (ALK) gene. To get the drug, therefore, the patient first has to test positive on the new assay. The test itself has the unwieldy name of the "Vysis ALK Break Apart FISH Probe Kit" The abnormal ALK gene causes cancer to develop and grow. This is called a "companion diagnostic test" It is a trend that began with the marketing of a test for the Her2 gene to accompany the drug Herceptin (trastuzumab).

Earlier in 2011 the FDA approved the drug Zelboraf (vemurafinib), along with the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic that helps determine whether a patient's melanoma cells have the BRAF V600E mutation. (Jefferson 2011-A)

Only about 1% to 7% of non-small cell lung cancer patients carry this ALK gene abnormality. They are typically nonsmokers. The new drug works by blocking certain chemicals called kinases, including the protein that produces this abnormal ALK gene.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug," Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, wrote at the agency's website. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects" (Jefferson 2011-B).

In one recent study, the objective response rate (a combination of partial and complete responses) was 50%, with a median duration of response of 42 weeks. In another study, the overall response rate was 61% with a median duration of 48 weeks.

The most common side effects of Xalkori include not just nausea, diarrhea, vomiting, swelling (edema), and constipation, but also vision disorders. These include visual impairment, flashes of light, blurred vision, double vision, sensitivity to light, and visual field defects. Xalkori use has also been associated with inflammation of the lung tissue (pneumonitis), which can be life-threatening (Jefferson 2011).

Lymphoma/Adcetris

Last issue I mentioned that an FDA advisory panel had recommended that the agency approve a new drug for Hodgkin's lymphoma: brentuximab. In August 2011, the FDA gave conditional approval to the new drug, now trade named Adcetris, the first new agent targeted at Hodgkin's disease in 30 years. Adcetris is manufactured by Seattle Genetics Inc. Approval was for Hodgkin's patients who have already received a stem cell transplant, or have received two different chemotherapy treatments and are not eligible for a transplant. It was also approved for anaplastic large cell lymphoma (ALCL) patients who have already gone through one chemotherapy treatment. The drug has not yet been subjected to randomized trials. But in a single-arm trial involving 102 patients, 73% had either a complete response (CR) or partial response (PR) to the drug. The mean duration of the response was 6.7 months. In ALCL the results were somewhat better: 86% of patients responded, and the mean duration of response was 12.6 months (Foyil 2011).

Meanwhile, clinical tests of Adcetris continue. "We are focused on broadening out the use of Adcetris to bigger patient populations and bringing it to front line treatment," the company's Chief Executive Clay Siegall told Reuters. According to Medical News Today, each vial of Adcetris will cost $4500. Since patients typically need three vials per dose, and then seven to nine doses per course of treatment, the per patient cost will range from $94,500 to $121,500 (Nordqvist2011).

This is part of a notable upward trend in the cost of cancer drugs, in which it is no longer unusual to charge $100,000 or more for new cancer drugs.

Melanoma/Yervoy and Zelboraf

The year 2011 was noteworthy for the introduction of two new drugs to treat the dangerous form of skin malignancy, melanoma. In March, the FDA approved Yervoy (ipilumumab), which works by modifying the body's immune response to cancer cells.

Another new drug, vemurafenib (Zelboraf) has antimelanoma activity. It was tested in a clinical trial, where it improved overall survival compared with a standard drug: overall survival was 6.2 months with Zelboraf, compared with just 4.5 months for dacarbazine (DTIC). In August, the FDA approved Zelboraf for patients who had late-stage or unresected (i.e., inoperable) melanoma as well as the BRAF V600E genetic mutation.

Yervoy is quite toxic, with instances of immune-related adverse events and even the possibility of death. (In July 2011, I coauthored an article in Immunobiology on Yervoy's toxicity. See Bakacs reference, below.)

Zelboraf also has an unusual toxicity profile, including skin sensitivity to sunlight, joint pain, and rash. About a quarter of patients are reported to develop squamous cell skin cancer as a result of taking the drug. This is of course treatable with surgery.

The cost of these two drugs is considerable: six months of Zelboraf is expected to cost $56,400 for a six-month supply. This is about half of the $120,000 that Bristol-Myers Squibb intends to charge for Yervoy.

Melanoma/Exercise

While mainstream oncology focuses on new pharmaceutical treatments for melanoma, there is evidence that just maintaining the patient's underlying health can also have a major impact on survival.

A study at the University of Michigan showed that a younger patient who is in poor health is likely to have a worse outcome than an older patient who is in good shape. U-M scientists measured "core muscle density" as a surrogate for general frailty. Those patients who had decreased core muscle density were more likely to suffer metastases than stronger peers (Sabel 2011).

This study, which appeared in the August 2011 issue of the Annals of Surgical Oncology, examined 101 patients being treated for stage 111 melanoma at the U-M comprehensive cancer center. The researchers examined, via CT scans, the size and density of each patient's psoas muscle, which runs along both sides of the spine. Patients who were suffering from sarcopenia (i.e., loss of muscle density) had higher rates of cancer recurrence, regardless of such factors such as the initial size of their tumor or their age. In fact, every 10 units of decreased muscle density translated into a 28% increase in recurrence. Frailer patients also had more complications from surgery. It was previously thought that increased age alone led to a worse outcome in melanoma. But it now seems that one's vitality, not one's age, is critical. In order for these new pharmaceutical treatments to work well, it may therefore be necessary to also address the underlying strength of the patient through diet and exercise (Fawcett 2011).

Pancreas/Folfirinox vs. Gemzar

While chemotherapy is not particularly effective in advanced pancreatic cancer, researchers continue to try to eke out some extra months of survival for such patients by using toxic drugs. But what is the most effective treatment for pancreatic cancer? Some people think the best thing is to use a single drug (such as gemcitabine or Gemzar). Others favor more complicated regimens such as Folfox or Folfiri.

A 2011 study in the New England Journal of Medicine (NEJM) championed a complicated regimen called Folfirinox. This is composed of four drugs: oxaliplatin, irinotecan, fluorouracil, and leucovorin. In this study, Folfirinox was compared with gemcitabine alone as first-line therapy in patients with metastatic pancreatic cancer (Vaccaro201l).

The authors randomly assigned 342 patients with relatively good performance scores to receive either Folfirinox or Gemzar for 7 of 8 weeks and then weekly for 3 of 4 weeks. The primary end point was overall survival.

Overall survival was 11.1 months in the Folfirinox compared with 6.8 months in the Gemzar group. The median progression-free survival was 6.4 months in the Folfirinox group and 3.3 months in the gemcitabine group. The objective response rate was 31.6% in the Folfirinox group vs. just 9.4% in the Gemzar group.

However, no surprise, the combination treatment was more toxic. Folfirinox now becomes an option for treating patients with metastatic pancreatic cancer who also have good performance status. It is said to be the first real advance in the treatment of advanced pancreatic cancer since the introduction of Gemzar more than a dozen years ago.

References

Al-Ali HK, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phaseI/II study. Leuk Lymphoma. 2011 Aug 24.

Bakacs T, Mehrishi JN, Moss RW. Ipilimumab (Yervoy) and the TGN1412 catastrophe. Immunobiology. 2011 Jul 7.

Fawcett N. Patients' underlying health linked to worse outcomes for melanoma, U-M study finds. UofMHealth.org. August 30, 2011. Available at: http://www.uofmhealth.org/news/cancer-melanoma-0830.

Fenaux P, Mufti Gj, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10:223.

Foyil KV, Kennedy DA, Grove LE, Bartlett NL, Cashen AF. Extended retreatment with brentuximab vedotin (sgn-35) maintains complete remission in patient with recurrent systemic anaplastic large-cell lymphoma. Leuk Lymphoma. 2011 Aug 25.

Gendel S. The MDS Foundation says newly published study finds vidaza prolongs survival in acute myeloid leukemia. Business Wire, Feb. 2, 2010. Available at: http://tinyurl.com/3z7w58a.

Jefferson E. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. FDA News release, August 1 7, 2011 (Designated as Jefferson 2011-A). Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm.

--. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. FDA News release, August 26, 2011 (Designated as Jefferson 2011-B). Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Libov C. Exercise may help brain cancer patients live longer. CureToday.com, Aug. 28, 2011. Available at: http://tinyurl.com/3se6rra.

Nordqvist, Christine. Adcetris may cost $4,500 per vial, or over $100,000 for a course of lymphoma treatment. MedicalNewsToday.com, Aug. 22, 2011. Available at: http://www.medicalnewstoday.com/articles/233141.php.

Sabel MS, Lee J, Cai S, et al. Sarcopenia as a prognostic factor among patients with stage III melanoma. Ann Surg OncoL 2011. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21822551.

Vaccaro V, Sperduti I, Milella M. FOLFIRINOX versus Gemcitabine for metastatic pancreatic cancer. N Engl I Med. 2011;365:768-769.

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.

by Ralph Moss, PhD www.cancerdecisions.com
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Title Annotation:the benefits of exercise on cancer patients; Vidaza trial for leukemia; approval of Xalkori, an antineoplastic agent for lung cancer,
Author:Moss, Ralph
Publication:Townsend Letter
Geographic Code:1USA
Date:Dec 1, 2011
Words:2436
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