Risk for leukemia after treatment for early-stage breast cancer higher than reported

The risk of developing leukemia after radiation therapy or chemotherapy for early stage breast cancer remains very small, but it is twice as high as previously reported, according to results of a new study led by researchers at the Johns Hopkins Kimmel Cancer Center.

The study team reviewed data on 20,063 breast cancer patients treated at eight U.S. cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network. In that group, 50 patients had developed some form of leukemia within 10 years after radiation therapy, chemotherapy or a combination of the two. That translates to roughly a cumulative risk of 0.5 percent.

Data from earlier randomized clinical trials, which typically include just a few hundred patients, found that about 0.25 percent of breast cancer patients develop leukemia as a late effect of chemotherapy, says Judith Karp, M.D., professor emerita of oncology at the Johns Hopkins University School of Medicine, who retired in 2013 as director of the Kimmel Cancer Center’s Leukemia Program. Results  were published online in the Journal of Clinical Oncology.

The frequency of bone marrow cancers such as leukemia is small, there’s no question about it,” Karp says. “However, the cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down five years after treatment.”

Most medical oncologists have come to think that the risk is early and short-lived,” says Karp. “So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Antonio Wolff, M.D., a professor of oncology at the Johns Hopkins University School of Medicine, says the study could help early-stage breast cancer patients and their physicians think more carefully about the use of chemotherapy for “just-in-case” reasons, especially when patients have a low risk of cancer recurrence.

Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” says Wolff. “It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

In recent years, oncologists have learned that postsurgical chemotherapy for breast cancer mostly benefits a small and select group of patients. The National Comprehensive Cancer Network clinical guidelines no longer recommend it for all patients with stage 1 breast cancers, the term for invasive breast cancers no larger than 2 centimeters that have not spread to nearby lymph nodes.

Wolff says that each patient’s treatment plan for early-stage cancer could differ depending on a variety of factors, including the size of the tumors; whether the cancer has spread to the lymph nodes; and whether the tumor tests positive for certain breast cancer-related hormone and growth receptors, such as estrogen receptors (ER) and human epidermal growth factor receptor 2 (HER2).

The study team, led by Johns Hopkins researchers, also included a hypothetical case to put the risks of early-stage breast cancer and chemotherapy treatment in perspective. She was a 60-year-old woman in average health, diagnosed with stage 1 breast cancer that was rapidly growing and ER-positive, and who is calculated to have a 12.3 percent risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8 percent with four cycles of chemotherapy, but she would also increase her risk of leukemia over that same time by 0.5 percent.

The good news is that the majority of patients with stage 1 breast cancer will survive their breast cancer diagnosis,” he adds, “and of all the solid tumors, breast cancer is among the most curable of them.”

Wolff says it isn’t yet clear whether the increased risk of leukemia after post surgical chemotherapy applies to patients with other kinds of solid tumors, especially since the drug regimens used in breast cancer differ from those used for other cancers.

Boileau et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: The SN FNAC study. J Clin Oncol. 2014; Epub ahead of print. doi:10.1200/JCO.2014.55.7827 [Abstract]

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Dysfunctional mitochondria may underlie resistance to radiation therapy

New role discovered for gene
The resistance of some cancers to the cell-killing effects of radiation therapy may be due to abnormalities in the mitochondria – the cellular structures responsible for generating energy, according to an international team of researchers. Their findings are published in the Nov. 25 issue of Developmental Cell.

Maxim Frolov, associate professor of biochemistry and molecular genetics at the University of Illinois at Chicago, and colleagues investigated the effects of a mutation in a gene called E2F, which controls other genes responsible for initiating programmed cell death, a normal function in most cells. Cells undergo programmed cell death — or apoptosis — when they are no longer needed, as a normal part of aging, or in response to environmental factors like radiation that damage cellular DNA.

When Frolov and colleagues exposed fruit flies carrying a mutant E2F gene to radiation, genes that initiate apoptosis were activated, but the flies did not die.

“Something else was preventing the flies from dying, even though the genes needed to undergo cell death were turned on,” Frolov said.

A closer look within the cells of the flies revealed that their mitochondria were misshapen and produced less energy than normal mitochondria. Flies with the most severely deranged mitochondria were the most resistant to radiation-induced cell death.

The observation in fruit flies suggested a previously unknown role for the E2F transcription factor — the protein encoded by E2F that regulates expression of other genes — in mitochondrial function.

“It seems their mitochondria were also affected by the E2F mutation and were not functioning at full strength,” said Frolov. “You need properly functioning mitochondria to carry out programmed cell death.”

Turning to human cells, the researchers found the same effects: those that lacked the E2F gene were resistant to the effects of radiation. Frolov said the similarity in the findings shows that basic cellular functions do not change much across the vast evolutionary distance between fruit flies and humans.

“This result highlights a remarkable degree of conservation between fruit flies and humans and illustrates the advantages of using model organisms in cancer research,” said Frolov, whose laboratory is part of the UIC Cancer Center.

Frolov and his colleagues think that dysfunctional mitochondria might underlie the differences in how patients respond to radiation therapy. Previous studies have suggested that the inability of some patients’ mitochondria to support apoptosis might account for differences in their response to chemotherapy for acute myelogenous leukemia.

“If we could develop a small-molecule drug that could enhance mitochondrial function in these patients, we may be able to improve the effectiveness of radiation therapy,” Frolov said.

Ambrus et al., (2013). Loss of dE2F compromises mitochondrial function. Develop. Cell27, 438-451 [Abstract]

Overuse of radiation therapy when urologists profit from self-referral

IMRT use is 2.5 times greater when self-referral’s financial incentives are involved

A comprehensive review of Medicare claims for more than 45,000 patients from 2005 through 2010 found that nearly all of the 146 percent increase in intensity-modulated radiation therapy (IMRT) for prostate cancer among urologists with an ownership interest in the treatment was due to self-referral, according to new research, “Urologists’ Use of Intensity-Modulated Radiation Therapy for Prostate Cancer,” released today in The New England Journal of Medicine (NEJM) for its October 24, 2013 issue. This study corroborates the increased IMRT treatment rates among self-referrers reported in the Government Accountability Office’s (GAO) August 2013 report, “Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny.”

Authored by Jean M. Mitchell, PhD, economist and professor at the McCourt School of Public Policy at Georgetown University, the NEJM manuscript provides an intricate analysis of treatment patterns by urologists before and after they acquired ownership of IMRT services, compared to the treatment patterns of non-self-referring urologists and urologists who practice at National Comprehensive Cancer Network® (NCCN®)-designated cancer centers (also non-self-referrers).

ASTRO Chairman Colleen A.F. Lawton, MD, FASTRO, voiced the Society’s grave concerns regarding this study’s results, “Dr. Mitchell’s study provides clear, indisputable evidence that many men are receiving unnecessary radiation therapy for their prostate cancer due to self-referral. While I am a prostate cancer specialist impassioned to eradicating the disease, I am equally dedicated to utilizing these powerful technologies prudently and in the best interest of each individual patient. We must end physician self-referral for radiation therapy and protect patients from this type of abuse.”

The two cohorts for the NEJM study data, obtained through Medicare claims from January 1, 2005 through December 31, 2010, include Medicare patients in 26 geographically dispersed states who were 1) treated at 35 self-referring urology groups in private practice matched to a control group of 35 non-self-referring urology groups in private practice, for a total of 38,765 patients; and 2) treated by 11 self-referring urology groups in private practice within close proximity to and matched directly to non-self-referring urologists at 11 NCCN® centers, for a total of 6,713 patients. Patient records were followed for a period of six months from the initial prostate cancer diagnosis to track treatment choices. Sixty percent of the self-referring urologists established their IMRT services during the period from January 1, 2008 through January 15, 2010.

A difference-in-differences analysis was used to isolate the impact of self-referral on changes of IMRT utilization over time, according to self-referral status. This approach controls for initial differences in practice patterns during the pre-ownership period as well as secular trends that affect the use of IMRT and are unrelated to ownership status. The analysis found that:

  • IMRT utilization among self-referring groups increased from 13.1 percent to 32.3 percent once they became self-referrers, an increase of 19.2 percentage points (146 percent). In contrast, IMRT utilization by non-self-referring urologists who were peers practicing in the same community-based setting was virtually unchanged—with a modest increase of 1.3 percentage points. Therefore, the difference-in-differences analysis reveals that self-referral accounts for 93 percent of the growth in IMRT.
  • IMRT utilization among the subset of 11 self-referring urology practices near NCCN® centers increased from 9 percent to 42 percent, an increase of 33 percentage points (367 percent), from the pre-ownership to the ownership period, compared to an insignificant increase of 0.4 percentage points at the NCCN® centers.
  • In addition to increased IMRT utilization, the data demonstrate decreases in utilization of other effective, less expensive treatment options by self-referring urologists. For example, brachytherapy decreased by 14.9 percentage points to just 2.7 percent of patients receiving this treatment in self-referring urology practices. These results are in stark contrast to non-self-referring urologists, for whom the study reports “virtually no change in practice patterns.”

The NEJM report concludes that “men treated by self-referring urologists, as compared with men treated by non-self-referring urologists, are much more likely to undergo IMRT, a treatment with a high reimbursement rate, rather than less expensive options, despite evidence that all treatments yield similar outcomes.”

At a press conference unveiling the study tomorrow, one of the nation’s leading urologists, James L. Mohler, MD, of Roswell Park Cancer Institute in Buffalo, will release a joint statement on the overtreatment of prostate cancer and physician self-referral from the expert members of the NCCN® Prostate Cancer Guidelines Panel, which he chairs.

“We are concerned unanimously by the prostate cancer treatment patterns identified in today’s article,” says Dr. Mohler. “We are disappointed to learn that urologists who self-refer for IMRT services use this expensive technology more than urologists who don’t self-refer and more than NCCN® Member Institutions.” He added, “Prostate cancer treatment recommendations should be based on the best available clinical evidence and not influenced by business or personal interests of the care provider.”

“This study confirms that permitting physicians to self-refer, particularly urologists to self-refer for IMRT, leads to unnecessary treatment and added health care costs to Medicare and beneficiaries,” continued Dr. Lawton. “Prostate cancer is a complicated disease that needs input from multiple specialists, not just one, to determine the best treatment for the individual patient. There are many different treatments available, and in many cases, no treatment at all is the right thing to do, particularly among the elderly. For many men with early stage prostate cancer, active surveillance, or watchful waiting, is the best option. Unfortunately, the continuous stream of data indicates that patient choice is being restricted—patients are being steered to the treatment that provides the most profit for the urologist. As a result, patients are subjected to unnecessary treatment and side effects, and millions of dollars are wasted.”

The federal “Ethics in Patient Referrals Act,” also known as the self-referral law, prohibits physicians from referring a patient to a medical facility in which he or she has a financial interest in order to ensure that medical decisions are made in the best interest of the patient without consideration of any financial gain that could be realized by the treating physician. However, the law includes an exception that allows physicians to self-refer for so-called “ancillary services,” including radiation therapy. Over the years, abuse of the in-office ancillary services (IOAS) exception has weakened the self-referral law and diminished its policy objectives, making it simple for physicians to avoid the law’s prohibitions by structuring arrangements that meet the technical requirements of the law, thereby circumventing the intent of the law. Numerous studies have shown that physician self-referral leads to increased utilization of services that may not be medically necessary, poses a potential risk of harm to patients and costs the health care system millions of dollars each year.

To-date, the GAO has issued three reports in a four-part series on physician self-referral, the most recent one, from August 2013, also details abuse in radiation therapy treatment for prostate cancer. The report found a 356 percent increase in IMRT utilization by self-referrers, compared to a 5 percent decrease by non-self-referrers, and that the number of treatments rose by 509 percent compared to a 3.8 percent decrease at non-self-referring multi-specialty groups. In July 2013, the GAO report, “Action Needed to Address Higher Use of Anatomic Pathology Services by Providers Who Self-Refer,” found that self-referring providers likely referred nearly one million more unnecessary anatomic pathology services than non-self-referring providers, costing Medicare approximately $69 million. “Higher Use of Advanced Imaging Services by Providers Who Self-Refer Costing Medicare Millions,” the first GAO report in November 2012 on self-referral in advanced diagnostic imaging, found that “providers who self-referred likely made 400,000 more referrals for advanced imaging services than they would have if they were not self-referring”—at a cost of more than $100 million in 2010. The final report, expected by the end of this year, will detail self-referral for physical therapy services.

“Unfortunately, when you look at the numbers in this report, you start to wonder where health care stops and where profiteering begins,” said Senate Finance Committee Chairman Max Baucus (D-Mont.), in a statement about the GAO’s August 2013 report on radiation therapy self-referral. “Enough is enough. Congress needs to close this loophole and fix the problem.”

“ASTRO urges Congress to promptly pass the ‘Promoting Integrity in Medicare Act of 2013′ (PIMA), introduced August 1, 2013, by Rep. Jackie Speier (D-Calif.) and Rep. Jim McDermott (D-Wash.). PIMA will close the self-referral loophole for radiation therapy, advanced imaging, anatomic pathology and physical therapy services, resulting in better care for patients and billions of Medicare dollars saved that could offset the costs of repealing the Medicare physician payment formula (sustainable growth rate—SGR).

“PIMA closes the self-referral loophole in a conscientious and strategic manner that abolishes abuse while allowing truly integrated multi-specialty groups and high-performing health systems to continue to provide high-quality and efficient care,” concluded Dr. Lawton. “This blatant abuse of our patient’s trust and our country’s limited financial resources endangers our ability to work with health policy leaders in developing a new quality- and value-based payment system for Medicare. Closing the self-referral loophole will protect patients, restore trust, reduce costs and strengthen Medicare.”

Reps. Speier’s and McDermott’s PIMA legislation would enact the recommendations of influential bipartisan groups who have examined self-referral abuse. In September 2012, a New England Journal of Medicine article, authored by leading health policy experts including former CMS administrator Donald Berwick, MD, MPP, called for closing the self-referral loophole for radiation therapy and other so-called “ancillary services.” The Center for American Progress agreed with narrowing the IOAS exception, as well as several notable bipartisan groups, including the Bipartisan Policy Center, under the leadership of former Senate Majority Leaders Tom Daschle (D-S.D.) and Bill Frist (R-Tenn.), and the Moment of Truth Project, headed by Erskine Bowles and former Senator Alan Simpson (R-Wyo.). President Obama’s proposed FY 2014 Budget also recommended closing the self-referral loophole and estimated savings of more than $6 billion during the standard 10-year budget window for Medicare.

A November 2012 Bloomberg News investigative report scrutinized questionable IMRT treatment for prostate cancer by a self-referring urology clinic in California and concluded that physician self-referral resulted in mistreated patients and higher health care costs. The Wall Street Journal, The Washington Post and The Baltimore Sun have published similarly critical reports since 2009 to call attention to the mounting evidence that limited specialty [urology] groups who own radiation therapy equipment have utilization rates that rise rapidly and are well above the national norms for radiation treatment of prostate cancer.

JM  Mitchell (2013). Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N. Engl. J. Med., 369:1629-1637 [Abstract]

Microencapsulation produces uniform drug release vehicle

Consistently uniform, easily manufactured microcapsules containing a brain cancer drug may simplify treatment and provide more tightly controlled therapy, according to Penn State researchers.

“Brain tumors are one of the world’s deadliest diseases,” said Mohammad Reza Abidian, assistant professor of bioengineering, chemical engineering and materials science and engineering. “Typically doctors resect the tumors, do radiation therapy and then chemotherapy.”

The majority of chemotherapy is done intravenously, but, because the drugs are very toxic and are not targeted, they have a lot of side effects. Another problem with intravenous drugs is that they go everywhere in the bloodstream and do not easily cross the blood brain barrier so little gets to the target tumors. To counteract this, high doses are necessary.

Perfect microspheres were produced using 4 percent by weight of the polymer.
Click here for more information.

Current treatment already includes leaving wafers infused with the anti-tumor agent BCNU in the brain after surgery, but when the drugs in these wafers run out, repeating invasive placement is not generally recommended.“We are trying to develop a new method of drug delivery,” said Abidian. “Not intravenous delivery, but localized directly into the tumor site.”

“BCNU has a half life in the body of 15 minutes,” said Abidian. “The drug needs protection because of the short half life. Encapsulation inside biodegradable polymers can solve that problem.”

Encapsulation of BCNU in microspheres has been tried before, but the resulting product did not have uniform size and drug distribution or high drug-encapsulation efficiency. With uniform spheres, manufacturers can design the microcapsules to precisely control the time of drug release by altering polymer composition. The tiny spheres are also injectable through the skull, obviating the need for more surgery.

Microfibers were produced using 10 percent by weight solutions of the polymer.
Click here for more information.

Abidian, working with Pouria Fattahi, graduate student in bioengineering and chemical engineering, and Ali Borhan, professor of chemical engineering, looked at using an electrojetting technique to encapsulate BCNU in poly(lactic-co-glycolic) acid, an FDA-approved biodegradable polymer. In electrojetting, a solution containing the polymer, drug and a solvent are rapidly ejected through a tiny nozzle with the system under a voltage as high as 20 kilovolts but with only microamperage. The solvent in the liquid quickly evaporates leaving behind anything from a perfect sphere to a fiber.

“Electrojetting is a low cost, versatile approach,” said Abidian. “We can produce drug-loaded micro/nano-spheres and fibers with same size, high drug-loading capacity and high drug-encapsulation efficiency.”

The researchers tested solutions of polymer from 1 percent by weight to 10 percent by weight and found that at 1 to 2 percent they obtained flattened microspheres, at 3 to 4 percent they had microspheres, at 4 to 6 percent they had microspheres and microfibers, at 7 to 8 percent they had beaded microfibers and above 8 percent they obtained only fibers. They report their results in the current issue of Advanced Materials.


This is a scanning electron micrograph of BCNU-loaded microspheres (black and white background) with 3D rendered images of brain cancers cells (yellow) and released BCNU (purple).
Click here for more information.

The researchers also investigated the sphericality of the spheres.“Depending on the desired applications, all the shapes are useful except for the beaded fibers,” said Abidian. “While fibers are not good for drug delivery, they are good for tissue engineering applications.”

“We looked at how spherical they were and found they were perfect,” said Abidian. They have a height versus width ratio of 1.05 and they have size uniformity. A perfect sphere would have a ratio of 1.

The researchers also looked into how BCNU releases from the microcapsules. Using mathematics, the researchers established a drug diffusion coefficient for the encapsulation system. This helps in designing how much drug to include in each microcapsule and how long the microcapsules will deliver the required dosage.

The researchers note that BCNU is not the only drug that can be encapsulated in polymer beads for drug delivery. Other drugs can be used but would have their own diffusion coefficients and half lifes.

Fattahi et al., (2013). Microencapsulation: Microencapsulation of chemotherapeutics into monodisperse and tunable biodegradable polymers via electrified liquid jets: Control of size, shape, and drug release.Adv. Mater., 25: 4529 [Abstract]