High doses of vitamin C to improve cancer treatment passes human safety trial

Clinical trials found that it is safe to regularly infuse brain and lung cancer patients with 800-1000 times the daily recommended amount of vitamin C as a potential strategy to improve outcomes of standard cancer treatments. In a work presented March 30, 2017 in Cancer Cell, University of Iowa researchers also show pathways by which altered iron metabolism in cancer cells, and not normal cells, lead to increased sensitivity to cancer cell death caused by high dose vitamin C

This image shows differential susceptibility of normal cells (left) and cancer cells (right) to vtamin C.
Credit: Schoenfeld, et al.

This paper reveals a metabolic frailty in cancer cells that is based on their own production of oxidizing agents that allows us to utilize existing redox active compounds, like vitamin C, to sensitize cancer cells to radiation and chemotherapy,” says co-author Garry Buettner, who was one of the first to propose that cancer cells might have a vulnerability to redox active compounds over 40 years ago. Buettner, along with study senior authors Bryan Allen and Douglas Spitz, are faculty members at the University of Iowa’s Department of Radiation Oncology, Free Radical and Radiation Biology Program, in the Holden Comprehensive Cancer Center.

The 11 evaluable patients enrolled in the brain cancer safety trial received three infusions of vitamin C a week for 2 months followed by two infusions per week for 7 months while receiving standard care radiation and chemotherapy. The goal of each infusion was to raise the concentration of vitamin C in a patient’s blood to 20,000 μM, as compared to a blood level of about 70 μM found in most adults. The high dose is necessary because vitamin C has a half-life of about two hours in the circulation of humans. The treatment was generally well tolerated; with modest side effects including frequent trips to the bathroom and dry mouth. Rarely, some patients developed high blood pressure that subsided quickly following infusion.

Why is this approach safe? Vitamin C, even at high levels, isn’t toxic to normal cells. The research group at Iowa found, however, that tumor tissue’s abnormally high levels of redox active iron molecules (a by-product of abnormal mitochondrial metabolism) react with vitamin C to form hydrogen peroxide and free radicals derived from hydrogen peroxide. These free radicals are believed to cause DNA damage selectively in cancer cells (versus normal cells) leading to enhanced cancer cell death as well as sensitization to radiation and chemotherapy in cancer cells.

This is a significant example of how knowing details of potential mechanisms and the basic science of redox active compounds in cancer versus normal cells can be leveraged clinically in cancer therapy,” says co-senior author Douglas Spitz, who focused on the biochemical studies. “Here, we verified convincingly that increased redox active metal ions in cancer cells were responsible for this differential sensitivity of cancer versus normal cells to very high doses of vitamin C.”

The safety study sets the stage for phase II clinical trials looking at whether high dose vitamin C is effective at extending overall lifespan and quality of life for patients undergoing radiation and chemotherapy. The researchers are currently enrolling patients with stage 4 lung cancer and will soon begin enrolling people with glioblastoma multiforme (brain cancer) in these phase II trials. They are hopeful that brain cancer responses to radiation and chemotherapy can be enhanced in these phase II trials. This guarded optimism is based on the phase I trial data showing an increase in overall survival of 4-6 months in 11 glioblastoma multiforme patients (18-22 months) versus the 14-16 months survival typically seen with the standard treatment.

The majority of cancer patients we work with are excited to participate in clinical trials that could benefit future patient outcomes down the line,” says co-senior author Bryan Allen, who led the clinical side of the study. “Results look promising but we’re not going to know if this approach really improves therapy response until we complete these phase II trials.”

The cost per patient above standard insurance billing for the phase II vitamin C glioblastoma multiforme protocol is approximately $8000 spread over 9 months of test infusions. This cost can be less than a single dose of some immunotherapy and/or chemotherapy drugs.

Schoenfeld et al. O2 and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell, 2017; DOI: 10.1016/j.ccell.2017.02.018 [Abstract]

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Treatment significantly reduces chemotherapy-induced hearing loss in children

Investigators from Children’s Hospital Los Angeles and 37 other Children’s Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer,” said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles, who was lead author and chair of the study. “It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors.” Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.

Freyer et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncology, 2016; DOI: 10.1016/S1470-2045(16)30625-8 [Abstract]

Chemotherapy and exercise: The right dose of workout helps side effects

Researchers at the University of Rochester Wilmot Cancer Institute discovered something simple and inexpensive to reduce neuropathy in hands and feet due to chemotherapy – exercise.

The study, involving more than 300 cancer patients, is to be presented this weekend and honored as a “Best of ASCO” among 5,800 abstracts at the world’s largest gathering of oncologists, the American Society of Clinical Oncology (ASCO) annual meeting 2016. More than a dozen other Wilmot scientists also were invited to present data at the meeting.

Investigators in the exercise study directly compared the neuropathic symptoms in non-exercisers to the pain among patients who took part in a specialized six-week walking routine with gentle, resistance-band training at home.

The exercisers reported significantly fewer symptoms of neuropathy – which includes shooting or burning pain, tingling, numbness, and sensitivity to cold – and the effects of exercise seemed to be most beneficial for older patients, said lead author Ian Kleckner, Ph.D., a biophysicist and research assistant professor in Wilmot’s Cancer Control and Survivorship program. Kleckner also won an ASCO Merit Award in the pain and symptom management category, and was invited to give a talk about his work.

Not all chemotherapy drugs cause neuropathy, but 60 percent of people with breast cancer and other solid tumors who receive taxanes, vinca alkaloids, and platinum-based chemotherapies will likely suffer this type of side effect, Kleckner said. Neuropathy is more commonly associated with diabetes or nerve damage. No FDA-approved drugs are available to prevent or treat chemotherapy-induced neuropathy, he added.

Wilmot’s specialized exercise program, called EXCAP (Exercise for Cancer Patients), was developed several years ago at the UR by Karen Mustian, Ph.D., M.P.H., an associate professor in the Cancer Control program. In recent years she has copyrighted and evaluated EXCAP in several clinical trials. Last year at ASCO, Mustian presented data from a randomized, controlled study of 619 patients showing that EXCAP reduced chronic inflammation and cognitive impairment among people receiving chemotherapy. Kleckner’s study involved a subset of patients from Mustian’s trial, which is the largest phase 3 confirmatory exercise study ever conducted among cancer patients during chemotherapy. Their work is funded by the National Cancer Institute and Mustian’s PEAK lab.

Exercise – as a cancer prevention tool and potential treatment – is a hot topic among the nation’s oncologists and their patients.

Kleckner, a longtime drug-free body builder and former college rugby player, said he’s committed to understanding more deeply the benefits of exercise for cancer patients. “Exercise is like a sledgehammer because it affects so many biological and psychosocial pathways at the same time – brain circuitry, inflammation, our social interactions – whereas drugs usually have a specific target,” he said. “Our next study is being designed to find out how exercise works, how the body reacts to exercise during cancer treatment, and how exercise affects the brain.”

Mustian is also giving two talks at ASCO, about the use of exercise in geriatric cancer patients and how innovation can help exercise investigators reach their goals.

Our program at the University of Rochester, which now includes more than  half a dozen researchers, is becoming a real powerhouse in exercise oncology,” Mustian said. “Twelve years ago when we started this work a lot of people said it was not safe for most cancer patients to exercise. Now we know it can be safe when done correctly, and that it has measurable benefits. But more exercise isn’t always better for patients who are going through chemo – so it’s important to continue our work and find a way to personalize exercise in a way that will help each individual.”

Eye movement affected in former childhood cancer patients

Nowadays, the lives of the majority of all children with cancer can be spared. However, the cure for the disease comes with a price: some of the survivors will suffer long-term injury from the treatment. A study from Lund University in Sweden now shows that commonly used chemo toxins impair the eyesight in childhood cancer survivors in a way that indicates an impact on the central nervous system.

It was not the former patients’ visual acuity that had been damaged; rather their eye motor skills – the eyes’ ability to follow moving objects.”We observed that most of these patients were not able to move their eyes smoothly and steadily, but jerkily and fitfully. Eye movement like that makes it harder to focus on moving objects in traffic, for instance. It can also cause headaches and dizziness“, says reader Per-Anders Fransson at Otorhinolaryngology in Lund.

The study included 23 childhood cancer survivors, at the current age of 20 to 30, and compared them to 25 healthy people of the same age. Only a few in the first group experienced no visual disorders, headaches and dizziness. The degree of the problem appeared to be related to the degree of which the eye motor skills had been affected, which suggests damage to the central nervous system from the chemotherapy.

It has been previously known that cisplatin, methotrexate, and ifosfamide – the types of chemo which the subjects of the study had been treated with – can penetrate the so-called blood-brain barrier, and thereby damage the nervous system. What has not been known, however, is whether the eye motor skills could be affected, and the consequences of that.An average of 15 years had passed since the patients underwent cancer treatment. The study could not determine whether any of them had experienced side-effects which by now had worn off, but it’s clear that the majority of them are still suffering the effects of their treatment. Age, at the time of treatment, appears to play an important role: those who were youngest at the time of treatment were the most affected.

A child’s brain has not completely developed, which makes it more susceptible to the influence of foreign substances“, says Thomas Wiebe, consultant in paediatric oncology.

He argues that for the time being, despite the risks, we must continue to use the medicines in question – after all, curing the cancer and saving lives is most important. However, the Lund University study reinforces the importance of coming up with new and better treatments. In the future, the new knowledge, and the diagnostic method described in the study will enable oncologists to pay closer attention to any side-effects, in which case it may be possible to reduce the dosage or change medications.

Thomas Wiebe also finds that Swedish healthcare needs to focus more on the growing group of childhood cancer survivors. Only a third of them are completely free from side-effects, while the rest experience anything from mild to severe effects from their treatment.

Today, childhood cancer patients are monitored in paediatric clinics until they turn 18, but after that there is insufficient follow-up. We have introduced a ‘delayed effect clinic’ here in Lund, but it lacks sufficient resources, and the rest of the country has even less resources!“, he says.

Because the survivors of childhood cancer may experience problems not only with their balance and vision, but also with for instance cardiovascular diseases, fertility, growth and cognition, they presumably turn to various forms of care in search of help. If there was a good system for diagnosis and follow-up, they could receive the support they need right away.

When it comes to balance and visual disturbances, there is an exercise programme that can significantly minimise problems. Simply being diagnosed is also valuable so you don’t have to wonder why you are experiencing things such as dizziness and fainting“, says Professor of Otorhinolaryngology Måns Magnusson.

Einarsson et al. Oculomotor deficits after chemotherapy in childhood. PLoS ONE. 2016; 11(1): e0147703. doi:10.1371/journal.pone.0147703 [Article]

Chemoradiation may increase survival for a subset of elderly head and neck cancer patients

The addition of chemotherapy (CT) to radiation therapy (RT) improves survival rates among a subset of elderly head and neck cancer patients, specifically those ages 71 to 79 with low comorbidity scores and advanced disease stage, according to University of Colorado Cancer Center research presented at the 2016 Multidisciplinary Head and Neck Cancer Symposium. While previous research has demonstrated the efficacy of combining CT with RT to improve survival for HNSCC patients, this improvement had not been shown in patients older than 70 years.

Elderly patients have been underrepresented in prospective clinical trials that have defined standards of care for head and neck cancer,” said Sana Karam, MD, PhD, CU Cancer Center investigator, assistant professor of radiation oncology at the University of Colorado School of Medicine, and senior author on the study. “Our study drew on nationwide data to assess more comprehensively how combined therapy impacts this population.”

The authors queried the National Cancer Data Base (NCDB) for records of patients older than 70 years who were treated for non-metastatic oropharyngeal, laryngeal and hypopharyngeal cancers between 1998 and 2011. The NCDB is a jointly-sponsored project of the American College of Surgeons and the American Cancer Society that aggregates data from more than 1,500 facilities accredited by the Commission on Cancer. Sixty-eight percent of the patients received RT alone, and 32 percent received CRT.

​Compared with RT alone, CRT was associated with improved survival in patients age 79 and younger with advanced disease but without comorbid conditions. Collaborators included Dr. Arya Amini, first aurthor on the study, and Drs. Bernard Jones, Antonio Jimeno, Jessica McDermott, David Raben, Debashis Ghosh and Daniel Bowles as co-authors on the study.

Patients who did not see an OS benefit from CRT tended to be age 80 or older, had a comorbidity score of two or greater, presented with less advanced disease, or were treated with three-dimensional RT. Patients age 80 or older with multiple comorbidities trended toward worse OS with CRT, though the difference was only marginally significant.

Findings may aid clinicians in discussing treatment options with their elderly HNSCC patients. Moreover, results of this study could guide future prospective trials to confirm the benefit of multimodality treatment in elderly patients, not only for head and neck cancer but for other cancer sites, as well.

Because the toxicity of concurrent chemoradiation is greater than radiation alone for definitive HNSCC treatment, many clinicians have reservations about offering CRT for elderly head and neck cancer patients,” said Karam. “However, in the era of improved radiation techniques, improved systemic therapy and better supportive care, we find that CRT does, in fact, improve survival for a large segment of this population.

The abstract, “Does Age Matter? Survival Outcomes with the Addition of Concurrent Chemotherapy for Elderly Head and Neck Cancer Patients Undergoing Definitive Radiation Using the National Cancer Data Base,” will be presented in detail as a poster presentation at the 2016 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Arizona.

Multidisciplinary Head and Neck Cancer Symposium, 2016, Scottsdale, Arizona, USA.

Racial disparity lies at the intersection of HIV and Hodgkin lymphoma

A new study finds a significant racial disparity within a doubly troubled population of patients: those with HIV and Hodgkin lymphoma. In such cases, blacks are at significantly higher risk than whites of not receiving treatment for the cancer that in many cases would be effective.

Black patients have higher rates of not receiving treatment,” said lead author Dr. Adam Olszewski, associate professor of medicine in the Alpert Medical School of Brown University and a physician in the Cancer Center of Memorial Hospital in Pawtucket, R.I. “Hodgkin lymphoma is generally believed to be highly curable. We have an expectation to cure over 90 percent of early stage patients and even 70-80 percent of quite advanced cases.”

Olszewski’s study in the journal AIDS, conducted with Dr. Jorge Castillo of Dana-Farber Cancer Institute, identified the racial disparity in data from nearly 2,100 cases in the National Cancer Data Base between 2004 and 2012.

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​While the disparity is clear, Olsewski said, the root cause of it is not. Several closely entangled epidemiological, socioeconomic, and medical factors are at play.Heading into the study, researchers knew that people with HIV have a risk of Hodgkin lymphoma that is five to 20 times greater than people who do not have HIV. They also knew that HIV incidence has remained relatively high among blacks, while it has dropped significantly for whites. As a result, the new study found that between 2004 and 2012, blacks surpassed whites as the largest racial group with simultaneous HIV infection and Hodgkin lymphoma, making up 49 percent of such cases in 2012.

Meanwhile, doctors have had a muddy sense of whether HIV-positive people with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. Many HIV-positive patients didn’t tolerate an older treatment regime for the lymphoma, Olszewski said, but chemotherapy treatment has vastly improved in more recent years. While some small studies, particularly in Europe, have found that HIV status makes no difference to survival, observations in the U.S. population suggest that being HIV-positive makes survival less likely.

The new study, the largest to date, may reconcile that conflict. It shows that in the United States the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

Specifically, the study ostensibly showed that HIV-negative people had an 80 percent Hodgkin lymphoma survival rate five years after diagnosis, but HIV-positive people survived at a rate of only 66 percent over the same timeframe. But among HIV-positive patients, 16 percent went untreated. Among people in the study who did get lymphoma treatment, HIV-positive people were statistically just as likely to survive as HIV-negative people. The results apply to the majority of cases in which the subtype of Hodgkin lymphoma is determined.

Importantly, further statistical analysis showed that one of the main risk factors for an HIV-positive person going untreated was being black. Statistically adjusting for possibly confounding factors, HIV-positive blacks were 67 percent more likely than HIV-positive whites to go untreated for the lymphoma. Other risk factors, which are often related to race, were low income and lacking health insurance. Another was being over 60 years of age.

Olszewski acknowledged it’s not clear how the racial disparity arises. It could correlate with more advanced or poorly controlled HIV infection. It could also be a lingering assumption that HIV-positive patients (who are increasingly likely to be black) won’t tolerate the treatment well. Some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself. Another possibility is that the often-related socioeconomic status of being black and poor and uninsured makes it hard for patients to remain connected to care after diagnosis.

For patients who have HIV and Hodgkin lymphoma, treatment can be effective and tolerated, especially when the lymphoma subtype is known, Olszewski said, but doctors should understand that some patients many need extra assistance or attention to ensure they connect with that care.

To date, this study suggests, it’s apparent that some people who should get treatment aren’t getting it.

Olszewski et al., Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy: analysis of the National Cancer Data Base. AIDS, 2016; doi: 10.1097/QAD.0000000000000986 [Abstract]

New smart robot accelerates cancer treatment research

A new smart research robot accelerates research on cancer treatments by finding optimal treatment combinations. 

Complex diseases like cancer are almost exclusively treated by combining several different drugs. These combinations are typically composed from drugs that show an effect on their own, but do not necessarily constitute the best possible combinations. The new robot system finds optimal treatment combinations and was developed by a research group led by Dr Mats Gustafsson, Professor of Medical Bioinformatics at Uppsala University.

We have built a robot system that plans and conducts experiments with many substances, and draws its own conclusions from the results. The idea is to gradually refine combinations of substances so that they kill cancer cells without harming healthy cells‘, says Dr Claes Andersson, also a leading scientist in the project.

Instead of just combining a couple of substances at a time, the new lab robot has the ability to handle on the order of a dozen drugs simultaneously. The aim for the future is to be able to handle many more, preferably hundreds.

We are now one among the few laboratories in the world with this type of lab robot. However, so far researchers have only used the systems to look for combinations that kills the cancer cells, not taking the side effects into account‘, says Mats Gustafsson.

The next step in the development is to make the robot system more automated and smarter. The current version still involves a few manual steps that could be automated. The scientists also want to build more prior knowledge into the guiding algorithm of the robot, for example, prior knowledge about drug targets and disease pathways.

For patients with the same cancer type returning multiple times, sometimes the cancer cells develop resistance against the pharmacotherapy used. The new robot systems may also become important in the efforts to find new drug compounds that make these resistant cells sensitive again.

An article about the robot system was presented today in Scientific Reports, and is part of a doctoral thesis on drug combinations, recently defended by Dr Muhammad Kashif.

Kashif et al. In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index. Sci Rep. 2015;5:14118. doi: 10.1038/srep14118 [Article]