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Wednesday, November 25, 2015
BY MEERI KIM, PHD
Secondary lymphedema may develop after days, months, or even years after treatment for breast cancer has ended. For patients with chronic lymphedema, the residual swelling can serve as a constant reminder of their disease and be accompanied by pain, weakness, or infection. Breast cancer survivors with lymphedema report a lower physical and mental quality of life, with some experiencing depression and anxiety as a result.
However, a pilot study published in Annals of Surgical Oncology (2015;22:3296-3301) indicates that a new microsurgical technique may help prevent the development of secondary lymphedema in breast cancer patients. Node-positive women at NewYork-Presbyterian/Columbia University Medical Center were treated with lymphatic-venous anastomosis at the time of axillary lymph node dissection.
The procedure was successfully completed in 26 patients who had no related complications. While two subjects had yet to reach three-month follow-up and were excluded from analysis, lymphedema developed in only three out of the remaining 24 patients (12.5%) during a mean follow-up time of six months. According to a seven-year retrospective review of 170 patients at the same institution, the documented clinical lymphedema rate for those who underwent axillary node dissection was 30.6 percent.
The technique has been named the lymphatic microsurgical preventative healing approach—LYMPHA--and is used in conjunction with axillary reverse mapping.
Done at Time of Lymph Node Removal
“LYMPHA uses equipment and expertise that is available at the vast majority of hospitals, so it's a very practical procedure that is done at the time of lymph node removal,” the first author, Sheldon Feldman, MD, Chief of the Division of Breast Surgery at NewYork-Presbyterian/Columbia University Medical Center, said in an interview.
“It's very safe, and what we're demonstrating in our pilot study is that the rate of lymphedema is much lower in patients who have this procedure.”
A surgical technique involving microsurgical lymphovascular anastomosis to prevent lymphedema was conceived as early as 1988, and despite early evidence of efficacy, it failed to become widespread. In 2009, two physicians from the University of Genoa--surgeon Corradino Campisi and medical oncologist Francesco Boccardo--revived the technique among women undergoing axillary dissection for breast cancer, naming it LYMPHA. In a 2014 study published in the journal Microsurgery (2014;34:421-424), they saw a secondary lymphedema rate of only about four percent in 74 patients who underwent LYMPHA after more than four years of follow-up.
Feldman recalls first meeting Campisi and Boccardo in 2012, and later he received on-site training from them in Genoa to learn the technical aspects of the procedure. To prevent a build-up of fluid, he explained, LYMPHA creates a bypass to restore lymphatic flow by connecting lymph vessels to a branch of the axillary vein, a pathway normally severed by node removal. The procedure takes approximately 45 minutes, according to the current study, in addition to the standard time taken by axillary dissection.
“The motivation was that we're very focused on the quality of life of our patients, and lymphedema is a big issue for those who have had breast cancer,” Feldman said. “These are patients who may have been cured years ago of breast cancer, but the lymphedema is a chronic reminder that they had this disease.”
LYMPHA was offered as an option to breast cancer patients with documented axillary node metastasis undergoing planned axillary node dissection or modified radical mastectomy. The procedure was performed during each subjects' planned axillary dissection. A half-hour before surgery, blue dye was injected as a tracer in the upper arm to map the lymphatics. Using axillary reverse mapping, afferent blue lymphatics were identified and later reconnected with a branch of the axillary vein with valve intact.
“It's important that this vein has a competent valve, which basically prevents the blood from backing up--we don't want any blood to be leaking from the vein,” Feldman emphasized. “Then using microsurgical techniques, we basically dunk these lymphatics into the axillary vein.”
Three out of 24 patients developed lymphedema (12.5%) with onset occurring between six and 10 months after surgery. Notably, all of these women had a high body mass index, and two had received external-beam radiotherapy. Women at the highest risk for developing lymphedema are those with a BMI greater than 30 kg/m2 advanced age, who have a complete lymph node dissection, and who received radiation in addition to lymph node dissection, he said.
Nine patients who originally consented for LYMPHA were unable to undergo the procedure at the time of surgery due to inadequate lymphatic mapping, lack of a suitable vein for anastomosis, or extensive axillary disease. Out of the four subjects who had at least three months of follow-up, two developed clinically apparent lymphedema.
“We have some controls from our study on which the LYMPHA procedure was not done, and those patients had a 50 percent incidence of lymphedema,” Feldman continued. “For historical controls from our own institution, the incidence of lymphedema was about 30 percent.”
Next Step: Wider Scale, Longer Follow-up, and Randomized Study
Asked for her perspective for this article, Deanna Attai, MD, Assistant Clinical Professor of Surgery at the David Geffen School of Medicine at UCLA and President of the American Society of Breast Surgeons, said: “Given that it's a pilot study, I think it was very well-done. It's the first step--it shows that the surgery can be done with a low complication rate, and the next step is to offer this on a wider scale and ideally in a randomized fashion.”
As a caveat, Attai added that longer-term follow-up should be investigated before assuming that LYMPHA will be effective. Because lymphedema can develop even years after treatment for breast cancer ends, future trials should extend follow-up for many more months than seen in the current study.
Feldman said he agrees and will continue to keep an eye on his LYMPHA patients, as well as plan for a much larger clinical trial for the future.
“The follow-up from Genoa is four years now--ours is much shorter, but we will continue to accrue patients at both sites and do longer follow-up. Our goal is really to do a multicenter trial both in the U.S. and Europe, and in an ideal world, it would be a randomized trial where two patients get LYMPHA and one doesn't.”
Although this pilot study does show proof-of-principle, Attai said she remains curious about how training knowledge will be disseminated, and about whether the procedure will be available only at select institutions that have a wealth of available resources. Attai pointed out that while most physicians today are trying to improve postoperative awareness of secondary lymphedema and early referral to physical therapy, such methods do not actually serve as primary prevention. For that reason, she said, a technique like LYMPHA--if able to be widely available--could be a huge patient benefit in lowering the risk of lymphedema.
“It's a very specific technology, and it's not something that's going to be available in all centers. So I think it will be challenging to roll out the benefit to large numbers of patients over time, and that's the only thing that would keep me from saying 'Let's go, let's do this.'” she said. “It's the sort of thing that will probably be available at certain centers, where they have microvascular techniques, ICU support, trained physicians, and equipment to do these procedures.”
Wednesday, November 25, 2015
BY MEERI KIM, PHD
Patients with Cowden syndrome, a hereditary condition characterized by multiple benign, tumor-like growths called hamartomas, have a heightened risk of developing certain cancers due to their disorder. Cancer in these individuals often arises at a younger age--typically in their 30s or 40s--with breast, thyroid, and uterus being the most common primary sites.
A number of genetic mutations have been identified as being associated with Cowden syndrome, most notably those within the tumor-suppressor gene PTEN. However, recent research showed that only about 25 percent of individuals who met the diagnostic criteria for Cowden syndrome had germline pathogenic PTEN mutations.
Now, a new study, published in the November issue of American Journal of Human Genetics (2015;97:661-676) has shed light on yet another cancer-predisposing gene in Cowden syndrome, SEC23B, which appears to account for a proportion of patients without mutations in PTEN or other known genes.
SEC23B was also found to be associated with apparently sporadic cancers--particularly papillary thyroid cancer--and was linked to a younger age of diagnosis. The findings, the authors noted, have implications for predictive testing, cancer risk assessment, genetic counseling, and clinical management of Cowden syndrome.
“As the years have gone on--it has now been 17 years since the discovery of PTEN--we have found more and more Cowden syndrome patients who had no mutation in the PTEN gene,” said the lead author of the study, Charis Eng, MD, PhD, FACP, ACS Clinical Research Professor, the Sondra J. & Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine, Chairwoman of the Genomic Medicine Institute, and Director of the Center for Personalized Genetic Healthcare at the Cleveland Clinic.
“It turns out that about 75 percent of Cowden patients do not have the PTEN mutation, and although we have found other genes associated with Cowden syndrome, many of them were in the PTEN signaling pathway--so for us to see SEC23B was more of a surprise.”
Eng and her colleagues discovered the first susceptibility gene for Cowden syndrome, the phosphatase and tensin homolog (PTEN) gene, in the late 1990s. In a study of 368 individuals with deleterious germline PTEN mutations, they found elevated lifetime risks for carcinomas of the breast (85.2%), thyroid (35.2%), endometrium (28.2%), colorectum (9.0%), kidney (33.6%), and melanoma (6%) (Nature Genetics 1997;16:64-67).
Because earlier studies used more stringent diagnostic criteria, the proportion of patients with Cowden syndrome that harbored mutations in PTEN once hovered at around 85 percent, Eng noted. But as clinicians began to recognize more subtle features of the disorder, including individuals with characteristics now referred to as Cowden-like, researchers today cite a much lower percentage of patients with classic PTEN mutations.
“Cowden syndrome is a hereditary cancer syndrome associated with the inheritance of deleterious mutations in the PTEN gene,” said another researcher asked for her perspective, Mary B. Daly, MD, PhD, FACP, Chair of Clinical Genetics, the Timothy R. Talbot Jr. Chair for Cancer Research, and Primary Member of the Cancer Prevention and Control Program at Fox Chase Cancer Center--Temple Health.
“Because a large proportion of individuals who meet the clinical criteria for Cowden’s syndrome do not actually have mutations in the PTEN gene, there has been a search for additional genes that may cause the same clinical picture.”
For the current study, Eng and her colleagues (first author is Lamis Yehia, PhD) used a combination of whole exome sequencing and family studies--specifically, they started with a single multi-generation, Cowden syndrome-affected family. The family had a history of thyroid cancer in four generations, and three candidate genetic variants were identified from the available DNA of members who met Cowden syndrome diagnostic criteria.
Out of those candidates, the deleterious SEC23B variant was focused on exclusively because of its higher index of pathogenicity, as well as the gene's expression in thyroid, breast, and endometrial normal/cancer tissues.
The researchers then tested an additional 96 Cowden or Cowden-like individuals for the same gene and found deleterious SEC23B variants in three subjects (3.1%), all of whom had papillary thyroid cancer.
The gene was also associated with apparently sporadic cancers, as observed in data analyzed from papillary thyroid (n = 494), breast invasive (n = 222), and uterine corpus endometrioid (n = 156) carcinomas in The Cancer Genome Atlas (TCGA). The highest frequency (4%) was seen in thyroid cancer, and those individuals who tested positive for SEC23B variants tended to have a younger age of diagnosis.
Also asked for his opinion, Ezra Cohen, MD, Professor in the Division of Hematology/Oncology and Associate Director for Translational Science at the University of California, San Diego Moores Cancer Center, said: “For a long time we have realized that there is a hereditary component to thyroid cancer that predisposes individuals and families to this disease. However, there have been few genes identified. This study adds another gene that likely predisposes individuals to thyroid cancer in both familial and sporadic cases.”
Change in Function, Not Loss in Function
Lastly, Eng and her colleagues studied the function of the SEC23B variant and found that the deleterious mutation causes a change in function rather than a loss of function.
SEC23B encodes for a protein that is an essential component of vesicles coated with coat protein complex II (COPII) that serve as transportation for secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex within cells. Functional experiments confirmed that the SEC23B genetic variant found in Cowden and Cowden-like individuals is consistent with carcinogenic activity and favors tumorigenesis even, or especially, under stressful micro-environmental conditions.
“We went on to do functional studies to show that this SEC23B mutation adapted the cells to ER stress,” Eng said. “ER stress can induce apoptosis in cells, but for those with the mutation, the cells seemed to like the ER stress and even became addicted to it.”
Her laboratory will continue to observe patients with Cowden and Cowden-like syndrome and follow them carefully to see how different genetic variants will manifest themselves. For instance, she predicts that those with SEC23B mutations may be more highly predisposed to thyroid cancer, which isn't always the case with other Cowden syndrome susceptibility genes that have been found.
Daly commented: “There are a lot of patients whose family history suggests a hereditary cancer syndrome, but for whom we can’t find any of the known mutations. Studies like this will gradually uncover more, mostly rare genes that we can begin to test families for. This will increase their chance of finding something that can guide their risk management and their treatment.”
Also, in normal clinical practice, Eng notes that SEC23B testing will be offered to patients who have Cowden-like features and especially those with thyroid cancer who have tested negative for PTEN and other susceptibility genes.
Not Necessarily Causative
In Cohen's opinion, the methodology and scope of the study are “excellent.” He said he had no real criticisms of the paper, but felt that the main limitation would be that, while the variants in SEC23B were associated with Cowden syndrome and thyroid cancer, the relationship cannot yet be viewed as causative.
More data would be needed to confirm the link: He suggests, for example, delving into the genomics of families with a history of thyroid cancer to see if SEC23B variants occur frequently.
Monday, November 23, 2015
BY CHRISTINE KILGORE
Discussing prognosis with patients who have advanced cancer is associated with more realistic patient perceptions of life expectancy and more advanced care planning, and it doesn’t appear to harm the patient-physician relationship or patients’ emotional well-being. That was the conclusion of a recent analysis of the multi-site, prospective Coping with Cancer study, published in the November 10 issue of the Journal of Clinical Oncology (2015;33:3809-3816).
The findings reinforce the importance of conversations about life expectancy, according to the study’s authors and other experts asked to comment for this article.
The analysis also suggests, however, that quality prognostic conversations are not occurring frequently enough: While 71 percent of the 590 patients in the study wanted to be told their life expectancy, only 17.6 percent recalled such a conversation with their physician.
“When we care for patients, we try to protect them from a lot of this news because it’s devastating. I don’t think our findings should be taken to mean that each and every patient should be told how long they have to live, but these data show that we grossly underestimate how many of our patients want this information, and how powerful these conversations can be,” said the study’s lead author, Andrea C. Enzinger, MD, Attending Physician with the Adult Palliative Care Program at Dana-Farber/Brigham and Women’s Cancer Center and Instructor in Medicine at Harvard Medical School.
In this sense, the findings also highlight an increasingly appreciated dichotomy between the desire of many patients to understand their prognosis and physicians’ level of comfort and skills for having effective conversations, the researchers said.
The National Cancer Institute’s Coping with Cancer study--various aspects of which have been analyzed in other published studies--enrolled patients at the outpatient clinics of eight cancer centers from 2002 to 2008. Patients had metastatic cancer and disease progression after one or more courses of palliative chemotherapy. They underwent a 45-minute interview at baseline and then were followed until they died. The researchers used the National Death Index to record deaths that occurred after the study site closures.
This most recent analysis looked at responses to the questions “Have the doctors talked with you about how much time you have left to live?” and “If your doctor knew how long you had left to live, would you want him or her to tell you?” Patients were also asked to estimate their own life expectancy, and they were asked whether they trusted and respected their physician.
Various tools were used to measure mood, anxiety, and mental illness, and patients were asked if they had completed advance care planning and if they preferred end-of-life care that is focused on life extension or palliative care.
Numerous studies have shown that patients with advanced cancer overestimate their life expectancy and are overly optimistic about the benefit of chemotherapy. The findings from this study were no different: Approximately half of the patients were willing to estimate their life expectancy, and most of those patients who shared estimates were indeed overly optimistic. Yet there was a significant difference in expectation between the patients who recalled receiving a diagnostic disclosure and those who did not.
“Patients who recalled a prognostic conversation estimated they had about a year to live, on average. Patients who didn’t recall a conversation estimated four years, on average, which is extremely unrealistic… These were patients with very advanced cancers—on average, they lived only five months,” Enzinger said.
“So when patients had conversations with their doctors, they were still optimistic, but it was much more realistic,” she said. “I found this effect really powerful.”
Patients who had a more realistic understanding of their life expectancy were significantly more likely to complete a DNR order, living will, or health care proxy, and significantly more likely to prefer palliative care over life-prolonging care. Moreover, they were no more likely to have a worried or anxious mood or to meet the criteria for major depression or generalized anxiety disorder than patients who did not recall a prognostic disclosure. And there were no differences in the proportion of patients reporting a strong relationship with their physician.
The study’s senior author, Holly G. Prigerson, PhD, principal investigator of the larger Coping with Cancer study and the Irving Sherwood Wright Professor in Geriatrics and Director of the Center for Research on End of Life Care at Weill Cornell Medical College, said that physicians should feel reassured about the results: “The data show that prognostic disclosures won’t harm the physician-patient relationship, and that in most cases they’ll actually be helpful. … There are few downsides,” she said.
The problem is, physicians are sometimes hesitant to discuss life expectancy. Researchers have described a variety of reasons over the years, from concern about damaging patients’ well-being and concern about the accuracy of their estimates, to uncertainty about whether patients want specific prognostic information and uncertainty about how to have such conversations.
Added to this unease is a layer of differing perception and perspective of physicians and their patients. “Patients and physicians often come away from conversations with very different perspectives,” said Christopher Daugherty, MD, Professor of Medicine at the University of Chicago Medicine, who has studied doctor-patient communication. ”The oncologist will come out and say ‘I had a prognostic discussion because I always do.’ And the patient will come out of that conversation and, most of the time, will say ‘we didn’t talk about prognosis.’”
Longitudinal Studies Needed
Does this mean that oncologists’ messages are too vague or too nuanced? Or are patients misinterpreting or missing what doctors say, or not getting the information they need? Or are various factors at plan? Right now, it’s hard to say exactly, said Areej El-Jawahri, MD, an oncologist specializing in hematologic malignancies at Massachusetts General Hospital.
“What’s missing in the field are longitudinal studies that look specifically at the conversation or conversations taking place between patients and physicians,” El-Jawahri said. “What we’re seeing in this study is recall of a conversation. But we don’t know the content of the conversation and how the information was conveyed.”
The study also did not capture prognostic conversations that might have occurred after the baseline assessment. This is important to note because “helping people understand their prognosis is a process… it may actually involve multiple conversations over time,” she said. “Most patients want to know [their life expectancy], but they want information “on their own terms and in their own timeframe.”
Also asked for his perspective, Anthony L. Back, MD, Professor in the Department of Medicine, Division of Oncology, at the University of Washington School of Medicine, suggested asking patients how they would like to talk about the future and whether they want statistics on life expectancy at that point in time: “Patients often think of [prognosis] as, what can I expect in the future? What kind of plans should I make?
“It’s not always prognosis in the sense of median survival,” said Back, who also has researched patient-physician communication. “It’s up to us as oncologists to figure out what patients are really asking for, and what they need at that point in time.
“Some patients will say “I don’t’ want to know the numbers.’ But virtually everyone wants to know about their future in some way, and the challenge for me is to help them talk about it… so they can do even a little planning,” he said.
Prigerson said she has questions about the delivery and characteristics of prognostic conversations, and plans to publish more insight soon. With an NCI Outstanding Investigator Award, she is leading a series of studies examining how various types of communication influence patients' understanding about end-of-life choices.
Sunday, November 22, 2015
BY HEATHER LINDSEY
The combination of rituximab and lenalidomide shows evidence of effectively managing mantle cell lymphoma (MCL), generally considered incurable, while avoiding the side effects associated with more intensive treatments, according to a study in The New England Journal of Medicine (2015;373:1835-1844).
While studies of lenalidomide and rituximab in refractory MCL have demonstrated clinical responses, “the efficacy of the combination in the first-line setting, when provided as induction and maintenance treatment, was beyond our expectations,” said the lead author, Jia Ruan, MD, PhD, Associate Professor of Clinical Medicine at Weill Cornell Medicine.
“Because of the ease of administering this outpatient, fairly low-intensity treatment, it may be a useful option for MCL patients, particularly for those who would otherwise not tolerate or would like to avoid a more intensive approach,” said Ruan, who receives clinical research funding from Celgene, the maker of lenalidomide (Revlimid) and the sponsor of the study.
“Lenalidomide and rituximab are approved for MCL in the relapsed/refractory, setting, so we knew this combination was active,” commented Paul Barr, MD, Associate Professor of Medicine and Director of the Clinical Trials Office for the Wilmot Cancer Institute of the University of Rochester Medical Center. “What warrants publication in The New England Journal of Medicine was how efficacious this combination looks given as first-line therapy. It does look incredibly active.”
Still, said Andre Goy, MD, MS, Chairman and Director of the John Theurer Cancer Center and Chief of the Division of Lymphoma at Hackensack University Medical Center, who was also asked for his perspective, although the data presented on the combination of lenalidomide and rituximab as frontline therapy appears very promising, the number of patients was relatively small and the follow-up is still short.
For the Phase II study of 38 patients, researchers at four medical centers—Weill Cornell Medicine/NewYork Presbyterian, Moffitt Cancer Center, the University of Pennsylvania Abramson Cancer Center, and the University of Chicago Medical Center—conducted the study between July 2011 and April 2014. Patients had a median age of 65, and at baseline, 34 percent had low-risk disease, 34 percent had intermediate-risk, and 32 percent had high-risk disease.
For the induction phase, physicians gave oral lenalidomide at 20 mg daily, for 21 days of a 28-day cycle, for 12 cycles. If patients had no dose-limiting adverse events, the dose was raised to 25 mg after the first cycle. For the induction phase, participants also received four weekly infusions of rituximab, given at a dose of 375 mg per square meter of body surface, and received subsequent infusions every two months.
After 12 months, participants transitioned to a maintenance phase, the duration of which was for as long as they wanted to continue treatment while receiving benefit, up to a maximum of five years. Lenalidomide was reduced to 15 mg daily during the maintenance phase and the rituximab infusions remained the same.
Of the 36 patients who could be evaluated after a median follow-up time of 30 months, the overall response was 92 percent, while the complete response was 64 percent. At 30 months, median progression-free survival had not been reached.
The two-year progression-free survival rate was 85 percent, and two-year overall survival was 97 percent. Progression-free survival, which is an endpoint often evaluated in Phase II studies, appears better with rituximab-lenalidomide than with R-CHOP or with bendamustine plus rituximab, Barr noted. “However, it’s not completely fair to compare against other studies.”
Side Effects Manageable
The investigators reported that half of patients experienced grade 3 or 4 neutropenia,13 percent had thrombocytopenia, and 11 percent experienced inflammatory syndrome. Anemia occurred in 11 percent of patients, serum sickness was reported in eight percent, and fatigue was also reported in eight percent of patients; there were also seven secondary cancers in the patients in the study.
Overall, the side effects experienced by patients were expected and manageable, Ruan said. For example, cytopenias were managed with lenalidomide dose adjustments.
Goy said that even though this was an early follow-up, there were a significant number of secondary cancers, including skin cancer, pancreatic cancer, and Merkel-cell carcinoma in a small population of patients who had not been previously treated: “This obviously needs more follow-up and observation and larger group of patients,” he said.
While the side effects of rituximab are well known and very manageable, adding lenalidomide may result in additional adverse events, and the long-term effects in younger patients are not yet known, commented Leo I. Gordon, MD, the Abby and John Friend Professor of Cancer Research at Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine.
Ruan said that in addition to manageable side effects, how well patients were responding to treatment and whether their symptoms were subsiding were measured on study and showed that patients appeared to either maintain their quality of life or improve through the induction and maintenance phases.
Role Yet to Be Determined
Gordon said that while the study is well done, it remains to be determined where the drugs fit in in terms of aggressive chemo-immunotherapy, ibrutinib, and stem cell transplant. The study demonstrates that the drug combination may be an option for patients who are older and may not tolerate high-dose chemotherapy, although long-term follow-up is still needed.
And although treatment of MCL is still debated, there is clear evidence that high-dose chemotherapy, with or without autologous stem cell transplantation, leads to a very high and early complete response rate and molecular complete response, which translates into long-term clinical benefit and a survival advantage, Goy said.
In addition, the median age of people diagnosed with MCL is in the mid to late 60s, sometimes making intensive strategies difficult to use. Bendamustine plus rituximab has become the treatment backbone for patients who cannot receive these intensive regimens, but the complete response and progression-free survival rates are much shorter that intensive strategies.
“I don’t think that with these [NEJM] data we are ready to abandon chemotherapy,” Goy continued. This is especially true in younger patients who can tolerate high-dose therapy. However, having non-chemotherapy options for elderly patients is appealing, and using lenalidomide and rituximab could be one such approach, he said.
Several studies incorporating lenalidomide and rituximab are ongoing, Barr noted. For example, a national clinical trial being led by the Eastern Cooperative Oncology Group (E1411) uses the bendamustine rituximab backbone to treat previously untreated MCL patients and incorporates randomizations to study the effect of adding bortezomib to the induction phase and lenalidomide to the maintenance phase--“This is another strategy of incorporating these novel agents into the first-line setting,” he said.
Ruan and her colleagues hope this Phase II study generates enough interest in lenalidomide combined with rituximab to support larger clinical trials with longer follow-up, including the E1411 trial. She said they would like to see studies that compare this combination with treatment options such as chemotherapy, stem cell transplant, and other biologics.
Ibrutinib is another an important second-line therapy in MCL that may also prove to be an excellent first-line treatment, Gordon said, adding that combinations of lenalidomide, rituximab, and ibrutinib could also be tested.
Ruan said the team hopes the pilot study leads to further research, with an increased interest in novel approaches among patients and physicians both in the academic and community settings.
We really need to think about clinical trials for all of our patients, especially those with MCL,” Barr said. “Performing studies like this is the only way we advance knowledge about disease and treatment. This manuscript is a good example of multiple centers working together to answer important questions.”
Tuesday, November 17, 2015
Tyrosine kinase inhibitors (TKIs) have changed the treatment paradigm for patients with chronic myelogenous leukemia (CML), and new research suggests one of the agents could potentially do the same for patients with Parkinson’s disease. Researchers found that nilotinib (marketed as Tasigna by Novartis)—approved by the U.S. Food and Drug Administration for the treatment of patients with CML (OT 7/10/10 issue)—improved cognition, motor skills, and non-motor function for patients with Parkinson’s disease and Lewy body dementia. Complete data from the Phase I clinical trial were presented at the Annual Meeting of the Society for Neuroscience in October (Program #/Poster#: 12.01).
"When used in higher doses for CML, nilotinib forces cancer cells into autophagy—a biological process that leads to the death of tumor cells,” study coauthor Charbel Moussa, MD, PhD, Director of Georgetown’s Laboratory of Dementia and Parkinsonism, explained in a news release. “The dose used in CML treatment is significantly higher than what we used in our Parkinson's study.
"It appears that in smaller doses once a day, nilotinib turns on autophagy for about four to eight hours—long enough to clean out the cells without causing cell death. Then proteins that build up again will be cleared when the drug is given again the next day."
The observed efficacy in cognition, motor skills, and non-motor function improvement (such as constipation) for many patients was the most dramatic result, the researchers reported, according to the news release. One individual confined to a wheelchair was able to walk again; three others who could not talk were able to hold conversations.
The study included 11 patients with advanced Parkinson’s disease, Parkinson’s disease with dementia, or Lewy body dementia, who received 150 to 300 mg nilotinib daily for six months. All patients benefited from the drug, and 10 had clinically meaningful improvements. Patients also showed positive changes in relevant cerebrospinal fluid biomarkers of Parkinson's, including alpha-synuclein (α-synuclein), amyloid beta-40/42 (Abeta-40/42), and dopamime, with statistically significant changes in total Tau and p-Tau. Prior studies show that α-synuclein and Abeta 40/42 in cerebrospinal fluid are decreased as Parkinson's worsens, while Tau and p-Tau are increased in cerebrospinal fluid with the onset of dementia.
"The changes in Tau, p-Tau, α-synuclein and Abeta-40 and 42 in spinal fluid suggest the clearance of toxic proteins in the brain," another study coauthor Fernando Pagan, MD, a Georgetown University Medical Center Associate Professor of Neurology and Director of the Movement Disorders Program at MedStar Georgetown University Hospital, said, also in a news release.
"To my knowledge, this study represents the first time a therapy appears to reverse—to a greater or lesser degree depending on stage of disease—cognitive and motor decline in patients with these neurodegenerative disorders," Pagan added. "But it is critical to conduct larger and more comprehensive studies before determining the drug's true impact."
No serious side effects were reported and the drug was well tolerated by the patients on the trial.
Why Try a Cancer Drug
Moussa’s preclinical research led him to think about using cancer drugs to treat neurological disorders. He was looking for an FDA-approved drug that could penetrate the blood-brain barrier and turn on the “garbage disposal machinery” inside neurons to clear toxic intracellular proteins and prevent their accumulation within, or secretion outside of, brain cells, he noted. Moussa is an inventor on a Georgetown University patent application for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative disease.
At the end of this study patients were given the option to continue taking nilotinib (provided by Novartis) as part of an expanded access study. Moussa and other Georgetown researchers are now planning larger clinical trials with nilotinib for patients with Parkinson's and other similar diseases including Alzheimer's disease, likely to begin in 2016.
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