Fewer cases of melanoma among people taking vitamin D supplements

Fewer cases of melanoma were observed among regular users of vitamin D supplements than among non-users, a new study finds. People taking vitamin D supplements regularly also had a considerably lower risk of skin cancer, according to estimates by experienced dermatologists. The study, conducted in collaboration between the University of Eastern Finland and Kuopio University Hospital and published in Melanoma Research, included nearly 500 people with an increased risk of skin cancer.

Vitamin D plays a key role in the normal function of the human body, and it may also play a role in many diseases. The link between vitamin D and skin cancers has been studied abundantly in the past, but these studies have mainly focused on serum levels of calcidiol, which is a metabolite of vitamin D, and its association with skin cancers. Findings from these studies have been inconclusive and even contradictory at times, as serum calcidiol levels have been associated with both a slightly higher and with a slightly lower risk of different skin cancers. This may, in part, be explained by the fact that serum calcidiol analyses do not provide information on the metabolism of vitamin D in the human skin, which can express enzymes that generate biologically active vitamin D metabolites or inactivate them.

The new study, conducted under the North Savo Skin Cancer Programme, took a different approach: 498 adult patients estimated to have an increased risk of a skin cancer, such as basal cell carcinoma, squamous cell carcinoma or melanoma, were recruited at the dermatological outpatient clinic of Kuopio University Hospital. Experienced dermatologists at the University of Eastern Finland carefully analysed the patients' background information and medical history and examined their skin. The dermatologists also classified the patients into different skin cancer risk classes, namely low risk, moderate risk and high risk. Based on their use of oral vitamin D supplements, the patients were divided into three groups: non-users, occasional users and regular users. Serum calcidiol levels were analysed in half of the patients and found to correspond to their self-reported use of vitamin D.

A key finding of the study is that there were considerably fewer cases of melanoma among regular users of vitamin D than among non-users, and that the skin cancer risk classification of regular users was considerably better than non-users'. Logistic regression analysis showed that the risk for melanoma among regular users was considerably reduced, more than halved, compared to non-users.

The findings suggest that even occasional users of vitamin D may have a lower risk for melanoma than non-users. However, there was no statistically significant association between the use of vitamin D and the severity of photoaging, facial photoaging, actinic keratoses, nevus count, basal cell carcinoma and squamous cell carcinoma. Serum calcidiol levels were not significantly associated with these skin changes, either. Since the research design was cross-sectional, the researchers were unable to demonstrate a causal relationship.

Other relatively recent studies, too, have provided evidence of the benefits of vitamin D in melanoma, such as of the association of vitamin D with a less aggressive melanoma.

"These earlier studies back our new findings from the North Savo region here in Finland. However, the question about the optimal dose of oral vitamin D in order to for it to have beneficial effects remains to be answered. Until we know more, national intake recommendations should be followed," Professor of Dermatology and Allergology Ilkka Harvima of the University of Eastern Finland notes.

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Patient's own immune cells effective as living medicine for melanoma

A patient's own immune cells, multiplied into an army of billions of immune cells in a lab, can be used as a living medicine against metastatic melanoma, an aggressive form of skin cancer, as the TIL trial has shown. The TIL trial is the world's first comparative phase 3 trial looking into the effect of T cell therapy in melanoma, and solid tumors in general. Now that the results have come in , the Dutch National Health Care Institute will assess whether TIL therapy () could become a standard treatment, meaning that it will be covered by basic health insurance. The results are published in The New Engeland Journal of Medicine (NEJM) on December 8. The trial was headed by the Netherlands Cancer Institute in collaboration with the National Center for Cancer Immune Therapy in Copenhagen.

Powerful immunotherapy for metastatic melanoma

Medical oncologist John Haanen from the Netherlands Cancer Institute, who is leading the TIL trial, is very happy with the results: "Remember: these are patients with metastatic melanoma. Ten years ago, melanoma was so deadly that I would be seeing an entirely new patient population every year. Now I've been seeing some patients for ten years. This is largely due to the discovery of immunotherapy, which has revolutionized treatment for melanomas. But we still find that about half of people diagnosed with metastatic melanoma lose their lives within five years, so we're still not where we want to be -- not by a long shot. The TIL trial has shown that cell therapy using the patient's own immune cells is an extremely powerful immunotherapy for metastatic melanoma, and that this therapy still offers a high chance of improvement, even if other immunotherapies fail.'

World's first phase 3 study T cell therapy for melanoma

A melanoma is an aggressive form of skin cancer with a high rate of occurrence Ten years ago, a diagnosis with metastatic melanoma would almost certainly lead to death within the same year. In early clinical trials, cell therapy using the patient's own T cells as a "living drug" showed promising results. However, a comparative phase 3 trial would be necessary to include TIL therapy in the arsenal of regular treatments, and no such trial had ever been conducted. Medical oncologist John Haanen from the Netherlands Cancer Institute decided to take on this task by initiating an international trial in 2014: the TIL trial, which compared TIL therapy to standard immunotherapy with the checkpoint inhibitor ipilimumab. The results of the TIL trial will now be presented at the annual conference of the European Society for Medical Oncology.

Metastases smaller in half of the patient group

In almost half (49%) of the patients with metastatic melanoma who received TIL therapy, the metastases had shrunk. In 20% of patients, the metastases had even disappeared completely. This also proved to be the case in patients who had already received another treatment prior to their trial participation. These percentages were significantly higher than those among the patient group receiving standard immunotherapy (ipilimumab). In the latter group, metastases had shrunk in 21% of patients, while 7% saw a disappearance of the condition.

Progression-free survival after six months is 53%

The progression-free survival, which refers to the percentage of patients who do not experience disease progression after a specified time period, was 53% after six months for patients receiving TIL therapy, and 21% in the control group. At a median follow-up time of 33 months for all patients, the median progression-free survival of patients who had received TIL therapy was significantly better (7 months) than that of patients treated with ipilimumab (3 months).

Quality of life: return to professional life

While assessing a treatment's efficacy, more clinical trials nowadays also consider the patients' quality of life. Patients treated with TIL scored better in this area than those treated with ipilimumab. This applied to their general physical and emotional functioning as well as symptoms like fatigue, pain, or insomnia. "We also looked at whether they could resume their careers and noticed that people were going back to work," says physician-scientist Maartje Rohaan, who coordinated the trial. "That's wonderful to see." The differences in quality of life between the TIL patients and the control group were still visible after 60 weeks. As an added bonus, TIL therapy is much more cost-effective than immunotherapy with ipilimumab.

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Compared to checkpoint inhibitors

The trial compared TIL therapy to a different type of immunotherapy using checkpoint inhibitor ipilimumab, which is a drug that reactivates the body's T cells that have been thwarted by the tumor so they can continue to kill the tumor cells. In 2014, when the TIL trial started, this was the only registered immunotherapy for patients with metastatic melanomas. Research leader Haanen: "We have to remember that this form of immunotherapy has also experienced a lot of development in recent years, with more and more research looking to find more effective treatments for metastatic melanoma, even for patients who have already received treatment without the desired effects. The results of the TIL trial are a good addition to this. We have shown that treatment using the patient's own T cells that have been multiplied outside the body, can be very effective in patients with metastatic melanoma, even if previous systemic treatment failed." read more about the different types of immunotherapy

Not an easy treatment

The TIL therapy itself, a one-time treatment, is not easy on the patient. All TIL patients experienced side effects to some degree, as did 96% of patients treated with ipilimumab. The side effects of the TIL therapy are usually not caused by the T cells themselves, but rather by the chemotherapy pre-treatment, which is required to make room for the billions of T cells, and by the rapidly successive post-treatments with growth factor interleukin-2, which ensures rapid growth of the T cells. This can lead to high fevers and chills. Haanen: "In the future we would like to find a way to avoid the use of high dose interleukin-2 by developing a more precise form of the treatment by using a growth factor that causes fewer side effects."

What do these results mean for patients with metastatic melanomas?

Now that the phase III trial has concluded with positive results, the researchers want the treatment to be covered by basic health insurance, making it accessible to patients in the Netherlands. The Dutch National Health Care Institute (Zorginstituut Nederland) is currently assessing whether TIL therapy meets the requirements (in terms of science and clinical practice as well as cost-effectiveness) so it can be included as a standard treatment in the basic health insurance package.

Patients in the Netherlands can participate in the TIL trial until the end of 2022, through a referral by their practicing physician. Treatment as part of this trial will be covered by basic health insurance. Now that the TIL therapy is proven to be effective, patients will no longer be randomized, meaning that all patients automatically receive TIL therapy if they meet certain criteria.

EMA

One thing that makes T cell therapy unique, is that this 'living medicine', the patient's own T cells, is produced at the Netherlands Cancer Institute itself, and not, as is often seen, at a pharmaceutical company. This is also known as 'academic pharma'. T cell therapies must be produced under extremely strict, hygienic conditions. To facilitate this, the Netherlands Cancer Institute has set up a special Biotherapeutics Unit. In order to be able to produce TIL for the European market following the results of the trial, the EMA, European Medicines Agency, must first give its approval. The way in which production is to take place outside the Netherlands will also be examined.

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Protecting the ozone layer is delivering vast health benefits

An international agreement to protect the ozone layer is expected to prevent 443 million cases of skin cancer and 63 million cataract cases for people born in the United States through the end of this century, according to new research.

The research team, by scientists at the National Center for Atmospheric Research (NCAR), ICF Consulting, and U.S. Environmental Protection Agency (EPA), focused on the far-reaching impacts of a landmark 1987 treaty known as the Montreal Protocol and later amendments that substantially strengthened it. The agreement phased out the use of chemicals such as chlorofluorocarbons (CFCs) that destroy ozone in the stratosphere.

Stratospheric ozone shields the planet from harmful levels of the Sun's ultraviolet (UV) radiation, protecting life on Earth.

To measure the long-term effects of the Montreal Protocol, the scientists developed a computer modeling approach that enabled them to look to both the past and the future by simulating the treaty's impact on Americans born between 1890 and 2100. The modeling revealed the treaty's effect on stratospheric ozone, the associated reductions in ultraviolet radiation, and the resulting health benefits.

In addition to the number of skin cancer and cataract cases that were avoided, the study also showed that the treaty, as most recently amended, will prevent approximately 2.3 million skin cancer deaths in the U.S.

"It's very encouraging," said NCAR scientist Julia Lee-Taylor, a co-author of the study. "It shows that, given the will, the nations of the world can come together to solve global environmental problems."

The study, funded by the EPA, was published in ACS Earth and Space Chemistry. NCAR is sponsored by the National Science Foundation.

Mounting concerns over the ozone layer

Scientists in the 1970s began highlighting the threat to the ozone layer when they found that CFCs, used as refrigerants and in other applications, release chlorine atoms in the stratosphere that set off chemical reactions that destroy ozone. Concerns mounted the following decade with the discovery of an Antarctic ozone hole.

The loss of stratospheric ozone would be catastrophic, as high levels of UV radiation have been linked to certain types of skin cancer, cataracts, and immunological disorders. The ozone layer also protects terrestrial and aquatic ecosystems, as well as agriculture.

Policy makers responded to the threat with the 1987 Montreal Protocol on Substances that Deplete the Ozone Layer, in which nations agreed to curtail the use of certain ozone-destroying substances. Subsequent amendments strengthened the treaty by expanding the list of ozone-destroying substances (such as halons and hydrochlorofluorocarbons, or HCFCs) and accelerating the timeline for phasing out their use. The amendments were based on Input from the scientific community, including a number of NCAR scientists, that were summarized in quadrennial Ozone Assessment reports.

To quantify the impacts of the treaty, the research team built a model known as the Atmospheric and Health Effects Framework. This model, which draws on various data sources about ozone, public health, and population demographics, consists of five computational steps. These simulate past and future emissions of ozone-destroying substances, the impacts of those substances on stratospheric ozone, the resulting changes in ground-level UV radiation, the U.S. population's exposure to UV radiation, and the incidence and mortality of health effects resulting from the exposure.

The results showed UV radiation levels returning to 1980 levels by the mid-2040s under the amended treaty. In contrast, UV levels would have continued to increase throughout this century if the treaty had not been amended, and they would have soared far higher without any treaty at all.

Even with the amendments, the simulations show excess cases of cataracts and various types of skin cancer beginning to occur with the onset of ozone depletion and peaking decades later as the population exposed to the highest UV levels ages. Those born between 1900 and 2040 experience heightened cases of skin cancer and cataracts, with the worst health outcomes affecting those born between about 1950 and 2000.

However, the health impacts would have been far more severe without the treaty, with cases of skin cancer and cataracts rising at an increasingly rapid rate through the century.

"We peeled away from disaster," Lee-Taylor said. "What is eye popping is what would have happened by the end of this century if not for the Montreal Protocol. By 2080, the amount of UV has tripled. After that, our calculations for the health impacts start to break down because we're getting so far into conditions that have never been seen before."

The research team also found that more than half the treaty's health benefits could be traced to the later amendments rather than the original 1987 Montreal Protocol. Overall, the treaty prevented more than 99% of potential health impacts that would have otherwise occurred from ozone destruction. This showed the importance of the treaty's flexibility in adjusting to evolving scientific knowledge, the authors said.

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