Immunotherapy in the Elderly

This blog was originally published by Cancer Today by Emma Yasinki here.

Immune checkpoint inhibitors can be effective treatments for elderly people with some types of advanced cancer, but more information is needed on their risks and benefits in this group.

​Photo by graffoto8​ / iStock / Getty Images Plus

CHECKPOINT INHIBITORS, a type of immunotherapy drug, help spur the immune system to kill cancer cells. These drugs can be effective treatments for some patients who otherwise would have few options.

Beginning in 2011, with the approval by the U.S. Food and Drug Administration of the first checkpoint inhibitor, seven of these immunotherapy drugs have come onto the market for treatment of various cancer types.

Enthusiasm for these drugs is widespread, including among elderly patients with advanced cancer. Now, some frail elderly patients who might previously have opted out of chemotherapy are choosing immunotherapy in hopes of achieving a long-term response.

But data on immunotherapy side effects and outcomes are more limited in elderly people than in younger patients. Some doctors worry that all the excitement surrounding checkpoint inhibitors is preventing older patients from getting palliative and hospice care that could be more likely to improve their lives.

Rawad Elias, an oncologist at Hartford Hospital in Connecticut, studies immunotherapy in older patients and presented on the topic at the American Society of Clinical Oncology Annual Meeting in Chicago in June 2019. Cancer Today spoke with Elias about the benefits and risks of checkpoint inhibitors and how their availability may affect treatment decisions for older patients.

Q: Are there common misconceptions among patients and families about checkpoint inhibitors?
A: We’re very excited about [immunotherapy] because it’s an option now other than chemotherapy, [but] it doesn’t work in all cancers. Even in the cancer[s] that it works for, it doesn’t work in all patients. And most patients, in fact, do not respond to checkpoint inhibitors.

We often see patients who … ask us, “OK. How about immunotherapy?” And we’ll have to explain that, unfortunately, in your type of cancer, it doesn’t even work.

Q: What do we know about the efficacy of checkpoint inhibitors in older patients?
A: Unfortunately, older adults are underrepresented in clinical trials. Older adults constitute about 60% of cancer patients, and [in] the clinical trials of checkpoint inhibitors, they [made up] about 40% [of participants]. Also, patients who are enrolled on clinical trials are usually the … fit people with [few] medical complications. So we don’t really understand the clinical profile of these drugs in the real-world population.

We did some work in the past looking … if the efficacy of the checkpoint inhibitors is similar across age groups. We published that in the Journal for ImmunoTherapy of Cancer based on [an] age cutoff of 65. The efficacy of checkpoint inhibitors was considerable in younger and older adults. What we don’t know about, though, is what’s the impact of frailty on these medications? And does that make patients more prone to toxicity? Does it make the efficacy of the drug less?

Q: What are the special considerations older patients need to take into account when considering checkpoint inhibitor therapy?
A: What we don’t know about … is the impact of low-grade toxicity or any toxicity on older adults. We tend to call things like fatigue or a little bit of nausea “low-grade” toxicity, but we don’t know the impact of this low-grade toxicity on an 80-year-old person who already has trouble getting out of the house.

When it comes to older patients with an advanced cancer, this is a really critical thing to discuss: What’s your quality of life during this period of time, and what matters most to you as a person? The goal is not to go and treat the cancer. The goal is to treat you as a person. And it’s only you as a patient who gets to determine: What does that mean?

For example, [one of my patients], even though therapy could have been an option for her, she’s a frail older adult. We talked about [the fact that] the impact of treating her with immunotherapy would be potentially more fatigue and coming to the doctor’s office [more frequently]—coming in once every two weeks or once every four weeks … getting bloodwork, waiting in the waiting room to see the doctor and then getting the infusion, then going back home, then coming back again. So the question is: Does that make sense to you? My patient … decided that doesn’t make sense to her based on what we think … [immunotherapy] is going to achieve.

Q: Why are some people concerned that the increasing popularity of checkpoint inhibitors could hinder access to palliative and end-of-life care?
A: Unfortunately, when we’re treating cancer patients, we’re treating a very hard disease and even small things get us excited. In the hype or the excitement about checkpoint inhibitors, many may skip that conversation [about risks and alternatives like palliative care] and go straight to, “Let’s start you on checkpoint inhibitors and see what happens.” And what’s happening in most patients is that they do not respond, and we forget about palliative care which we know, for sure, makes people have a better quality of life, keeps them outside the hospital, keeps them at home. This is not to say older adults should not be treated, but to say that there are concerns about these drugs. They do not work for everyone.​ ​​

Emma Yasinski​ is a Florida-based freelance science and medical journalist.​

Focusing on Proton Therapy

This blog was originally published by Cancer Today by Sue Rochman here.

Proton therapy, an alternative to standard radiation therapy, is safe and effective. But evidence is lacking that it’s always a better option than standard radiation, and some insurers balk at the higher price tag.

Photo by ​​​​gorodenkoff​ / iStock / Getty Images Plus

IN AUGUST 2017, Ha​uli Sioux Warrior Gray noticed a lump in her left breast. Two months later, after having seen three different health care providers, the then 33-year-old mother of two from Yukon, Oklahoma, learned she had stage IIB breast cancer. In November, she started chemotherapy to shrink the 7-centimeter tumo​r in her left breast and kill the cancer cells that had spread to her lymph nodes. In March 2018, she had a mastectomy. When it was time to start radiation, Gray says, her radiation oncologist at the Integris Cancer Institute in Oklahoma City explained that proton therapy would be a better option than standard radiation therapy because “it would save my heart and lungs.”​

Gray’s doctor sent a treatment proposal for proton therapy to her health insurer. The request was denied. “I didn’t know insurance companies did that,” says Gray. Aided by a media consultant brought in by her doctor, Gray used social media and local news outlets to tell her story. Time was ticking—the first of 34 proton therapy radiation treatments that would target her lymph nodes and any breast tissue remaining in her chest wall was scheduled for May 10, just three weeks away. When her insurer wouldn’t budge, the proton therapy center, ProCure, agreed to front the cost. The same day, says Gray, the Indian Health Service, which also provided her with health benefits, called to say they would cover the cost of the treatment. “I was surprised, shocked and happy,” says Gray. “I had been praying and asking God if this is what needed to be done.”

For about a century, radiation therapy has been a mainstay of cancer treatment. Standard radiation systems use photons, or X-rays, to kill cancer cells. Proton therapy uses particles that can be targeted at the tumor more precisely. Studies have shown that proton therapy is safe and effective. Less clear is which patients with which types of cancer should receive it instead of standard radiation. Clinical trials that compare proton and photon therapies are now underway, but enrolling patients hasn’t been easy. And in the years that it takes fo​r the answers to come in, thousands more cancer patients will find themselves in a position similar to Gray’s.

Photons and Protons

Radiation kills a cell by damaging its DNA. The photon beam used in standard radiation therapy travels through normal cells in the body, gets into the cancer cells, and then travels again through normal cells as it comes out the other side of the body. Protons are particles with a different set of physical characteristics. They accelerate and penetrate the skin quickly, explains Steven Lin, a radiation oncologist at the University of Texas MD Anderson Cancer Center in Houston. Then the particles stop at the tumor, where they deposit all their energy at once.

The U.S. Food and Drug Administration (FDA) approved proton radiation as a cancer treatment in 1988. Before the FDA can approve a new cancer drug, clinical trials must show that the treatment is safe and effective for a specific type of cancer. New devices and technologies like proton therapy are held to a different benchmark. They only have to be proved safe and effective overall, not for a specific use. This means “there is no clear indication where proton [therapy] should be the standard treatment,” says Lin. Instead, “every cancer patient who needs radiation is potentially eligible for proton treatment, but not all patients will benefit.”

When there are no specific indications for a treatment’s use, insurance coverage can vary widely. Medicare typically covers the cost of proton therapy, regardless of the type of cancer. But many private insurers do not want to pay for proton therapy when it has not been shown to be more effective than standard radiation therapy and can cost four to 10 times more. A recent study found that two-thirds of patients with private health insurance initially had their requests for proton therapy denied. (On appeal, about 68% of patients initially denied coverage had their treatment approved.)

​Determining the BenefitFor children with cancer, proton therapy is now a routine treatment. “For many pediatric patients, proton therapy offers clear benefits,” says Shannon MacDonald, a radiation oncologist at Massachusetts General Hospital in Boston. When treating children, she explains, “you are treating brain tumors and tumors close to areas that are responsible for future growth.” Before proton therapy was available, some of these children would not have been able to have radiation at all. With proton therapy, she says, they can be treated, and the tissue spared from radiation will continue to grow and develop normally. Proton therapy has also made radiation a possibility for some adults with rare or difficult-to-treat cancers, such as tumors in the central nervous system, brain, head and neck, eye, skull and spine.

In other instances, proton therapy has allowed many patients to avoid some or all of the potential side effects associated with standard radiation therapy, which can include skin problems, pain and swelling, and heart and lung problems. That was the case for Arianne Missimer of Coatesville, Pennsylvania, who was diagnosed in 2015 with a stage III liposarcoma—​a rare cancer that can start in muscle tissue—in her right thigh. The 34-year-old physical therapist, registered dietitian and athlete needed radiation therapy to treat her cancer and was concerned about her potential risk for pain, swelling, weakness and long-term bone damage. Her radiation oncologist explained the difference between photon and proton therapies and then suggested proton therapy at Penn Medicine’s Roberts Proton Therapy Center in Philadelphia. Her insurer was willing to cover it.

A Growing Business

Proton therapy centers are now ​located across the U.S.

​Waiting for Answers

It’s unclear whether proton therapy improves outcomes and reduces side effects in other cancer types, including breast and prostate cancer. The National Cancer Institute (NCI) and the Patient-Centered Outcomes Research Institute (PCORI) have funded seven phase III randomized trials comparing proton therapy and photon therapy in patients with breast, esophageal, liver, lung and prostate cancer and two types of brain tumors, glioblastoma and low-grade glioma. Some of the trials are comparing overall survival; others are looking at reductions in symptoms and side effects.

New Research Sheds Light on Side Effects

When combined with chemotherapy, proton therapy is associated with fewer severe s​ide effects than standard radiation therapy, according to a​ study.

The results of these trials have the potential to inform future treatment guidelines, but finding patients for the studies has been laborious. In 2018, almost two years after it opened, the breast cancer trial had enrolled only 317 of 1,716 patients needed; after five years, the prostate cancer trial, which needs 400 patients, had enrolled only 254. Radiation oncologists point to multiple factors contributing to the slow patient accrual. In some cases, says Lin, doctors may believe proton therapy is better, and they don’t want their patients to participate in a clinical trial where there is a chance they won’t receive the newer approach. In other instances, patients don’t want to take the chance they will be assigned to the treatment arm that doesn’t receive proton therapy.

There is also an insurance barrier. In the major proton therapy trials, insurers are asked to pay for patients’ radiation treatment, whether it’s proton or photon therapy. Justin Bekelman, a radiation oncologist at the Penn Medicine Abramson Cancer Center, says it’s all too common for insurers to say they won’t pay for an unproven treatment when a patient is selected for the proton therapy arm. Bekelman was the lead investigator for the breast cancer trial and a co-lead investigator for the prostate cancer trial.

“Naturally, insurance companies are going to question the value,” says Bekelman. “That’s precisely why we need to run these trials. We want to determine if there are benefits and if there are harms to proton therapy, and in which cancer patients which treatment will be most successful for cancer control and reducing side effects.” But researchers can’t do that if insurers won’t cover that care.

In 2012, the University of Texas MD Anderson Cancer Center launched the NCI-funded clinical trial comparing protons and photons in esophageal cancer, which aimed to enroll 180 patients. Enrollment closed this year with 104. (Another 21 patients enrolled but couldn’t be evaluated because their insurer wouldn’t pay for the proton therapy.) Lin, who is overseeing the study, says some patients declined to enroll when they learned their health insurance covered proton therapy. “We explain to [patients] that the proton therapy is experimental, which is why we are trying to do the study,” he says. “But they say they’ve heard good things about it. Others say, ‘I have money and I don’t want standard treatment. I want the best.’”

It’s easy to understand why a patient who has pored over a proton therapy center’s website might feel that way. In a study published online March 15, 2018, in Radiation Oncology​, researchers analyzed 46 websites of proton therapy centers—half of which w​ere in the U.S. The analysis found that many centers used language that could lead patients to think that choosing proton therapy would give them a better outcome, says the study’s senior author Alexander Louie, a radiation oncologist and epidemiologist at Sunnybrook Health Sciences Centre in Toronto. “Many of the websites made blanket or generic statements that may not be completely supported by evidence but have some credence potentially or theoretically, blurring the line between evidence and advertising,” he says.

“It’s not as easy as saying if proton therapy is good or bad,” adds radiation oncologist Jeffrey Buchsbaum of the NCI’s Radiation Research Program. “Proton therapy is like a vehicle for getting the patient to a better place. And it has to be used properly.” There are certain situations, he notes, in which patients wouldn’t be alive without proton therapy. “But that doesn’t mean it’s necessary for all cancers.”

Proton Therapy Tips

Follow​ these suggestions​ as you consider radiation therapy options.

​Moving Forward

The American Society for Radiation Oncology has developed model policies for insurers that delineate where there is sufficient evidence to support coverage of proton therapy. Insurers also use National Comprehensive Cancer Network treatment guidelines to support or deny a patient’s treatment with proton therapy. To move research forward, investigators are trying to work with hospitals to find ways to make insurers more amenable to covering the cost of treating patients in randomized clinical trials comparing photon therapy and proton therapy. In some cases, this may include reducing the cost of proton therapy to make it more comparable to that of standard radiation therapy. “The issues happening here are partially the result of the complexity of the health care delivery system,” says Buchsbaum.

But for patients, treatment choices must be made now. Missimer believes that proton therapy helped treat her cancer without sacrificing her athleticism. She is an active member of Penn Medicine’s proton center alumni group, which provides support to patients who are currently receiving or are considering proton therapy. She also appears in an advertisement for Penn Medicine’s proton therapy center, and an article about her experience is included on the cancer center’s website.

Missimer’s treatment began with chemotherapy, which she admits slowed her down. But during her proton therapy, which started in July 2015, she joined a ninja gym. And as she recovered from the surgery and additional chemotherapy that followed the radiation, she kept going. In May 2016, Missimer competed in the Philadelphia regional American Ninja Warrior competition. “I lost my brother to cancer,” she says. “He had radiation and had significant complications. The only thing I get is a little stiffness. But as long as I keep moving, my leg is good.”

Gray completed her proton beam treatment in June 2018, about a year after she’d first felt the lump in her breast. Skin damage is a common side effect of both types of radiation therapy. Gray says her doctor told her that her skin did well during the proton therapy. “But if that was well,” she says, “I can’t imagine what worse would be like. My chest looked like burnt hot-dog skin. And I still have a dark scar from the burn that might not ever go away.” After being out of work for a full year, Gray returned to her job as an educational specialist for Native American youth in October 2018, and she slowly started back at the gym. She wears a compression sleeve and a glove to manage lymphedema that developed in her arm—caused by either the surgery or radiation—and deals with nerve pain in her arm and chest. None of it has been easy, but, she says, “my faith has gotten me through.”​ 

Sue Rochman is a contributing editor for Cancer Today.​

The Right Dose

This blog was originally published by Cancer Today by Kate Yandell here.

Researchers want to find out when cancer patients can benefit from receiving lower doses of drugs or radiation, shortening treatment or skipping certain treatments altogether.

​​​

OVER A SPAN OF 15 YEARS, ​Liza Bernstein was diagnosed with three separate primary, early-stage breast cancers. Even though she was treated by the same oncologist throughout, the treatments she received varied with each diagnosis.

​Bernstein, who lives in the Los Angeles area, was first diagnosed with hormone receptor-positive breast cancer in 1994, when she was 29 years old. She recalls that her doctors were pleased to be able to do a lumpectomy, only removing part of the breast, instead of a mastectomy as would once have been standard. However, her surgeon removed about 20 lymph nodes from her armpit, and she received both radiation and chemotherapy.

In the course of receiving her second diagnosis, a hormone receptor-positive cancer in her opposite breast, in 2005, Bernstein underwent a sentinel lymph node biopsy, a less invasive procedure that requires surgeons to remove only a few lymph nodes in areas where the cancer is most likely to have spread.

Bernstein was also able to get testing with a product called Oncotype DX, which measures gene expression in breast tumors and helps estimate the likelihood that chemotherapy will prevent an early-stage, hormone receptor-positive cancer from recurring. The test, released in 2004, helped Bernstein and her oncologist make the difficult decision to skip chemotherapy in 2005, due to little predicted benefit. Bernstein received a lumpectomy, radiation and the hormone therapy tamoxifen. Conversely, when she was diagnosed with another hormone receptor-positive cancer in 2009, genomic tumor testing helped them decide to include chemotherapy, along with a double mastectomy and tamoxifen, in her treatment.

Advances in cancer research can mean making patients’ treatment more onerous and complex. But some of the changes in Bernstein’s breast cancer treatment over the years reflect de-escalation—the process of decreasing the intensity or duration of a treatment, thus reducing side effects and cost, while maintaining the treatment’s effectiveness.

Today, researchers are investigating whether they can identify patients—using genomic tumor testing, imaging of the cancer or other methods—who can receive less intense treatment. Treatment de-escalation aims to spare patients the burden of unnecessary treatments and side effects.

“The key is we want to give people the right treatment that they need without treating them excessively, which just produces too much toxicity,” says Eric Winer, a medical oncologist and chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute in Boston.

Treating the Right Patients

Treatment de-escalation has been successful primarily in cancers where the survival rate is high. “When you have a situation where mortality from a given malignancy is high, then it’s pretty hard to think about backing off [from treatment],” Winer explains.

The effects of treatment can last long after chemotherapy or radiation is completed. For example, 87% of people in the U.S. diagnosed with Hodgkin lymphoma, which until the 1960s was usually fatal, live five years or more. “The issue for this group of people, who are often diagnosed in their 20s and 30s, is that they have a long life ahead of them,” says Peter Johnson, a medical oncologist who specializes in lymphoma at University Hospital Southampton in England. The radiation and chemotherapy typically given for Hodgkin lymphoma can result in serious side effects, including heart disease, second cancers and infertility.

Over time, doctors have adopted techniques for delivering radiotherapy to Hodgkin lymphoma patients that increasingly spare normal tissues from damage, Johnson says. Most recently, researchers have learned that they can perform a form of imaging, called 18F-fluorodeoxyglucose PET, to determine early on whether a patient’s Hodgkin lymphoma is responding to chemotherapy. If the scan indicates a good response, the patient may be able to skip later radiation therapy or receive a less intensive chemotherapy regimen.

“In some ways, it’s a reflection of how successful modern oncology has been that we’re thinking about these things,” Johnson says of the topic of de-escalation.

The rise of genomic testing, among other factors, has contributed to a decline in chemotherapy use for patients with early-stage breast cancer whose disease is driven by hormones. With Oncotype DX and similar tests, patients with hormone receptor-positive, HER2-negative breast cancer can learn how likely they are to benefit from chemotherapy. Their score can help determine whether their drug treatment after surgery should include both chemotherapy and hormone therapy or whether just hormone therapy is enough.

Researchers are investigating de-escalation strategies for patients with early-stage HER2-positive breast cancers as well. These patients are often treated with HER2-targeted therapy and a multidrug chemotherapy regimen. Winer’s research shows that patients with small HER2-positive cancers that have not spread to the lymph nodes can safely use a de-escalated ​chemotherapy regimen that includes just one drug, paclitaxel, alongside targeted therapy.

Challenges of Stepping Back

Despite some successes in de-escalation, it can be easier to intensify treatment than to take treatment away. This is partly because it is difficult to prove that taking away treatment is not going to harm patients—a different statistical challenge than showing that a therapy is significantly better than standard care.

For example, in 2004, researchers discovered that patients with stage III colon cancer lived longer if oxaliplatin was added to their chemotherapy regimen. The additional chemotherapy drug can lead to peripheral neuropathy, and the effects are cumulative as therapy continues. An international consortium of researchers published a study in the New England Journal of Medicine​ on March 29, 2018, pooling the results of six randomized clinical trials that included 12,834 participants. The trials investigated the practice of shortening chemotherapy after surgery from six to three months for these patients.

“We thought with such a large number it would be very easy and we’d get a clear answer, [but] we haven’t got as clear an answer as we thought we would,” says Timothy Iveson, a medical oncologist at University Hospital Southampton who co-authored the study.

The study did not meet pre-specified statistical benchmarks to determine that a shorter period 
of chemotherapy was not worse than standard chemotherapy for the patients in the trial in general. However, the survival difference between patients using shorter versus longer chemotherapy (six months versus three months) was small, Iveson says, and the decrease in side effects with shorter chemotherapy was large. And for some patients, treatment for three months was sufficient. Cancer treatment guidelines now recommend the shorter chemotherapy regimen as an option for certain patients with low-risk stage III colon cancer.

New information about cancer subtypes can also spur de-escalation. But even when it’s clear that de-escalation is necessary, it can take time to settle on the right strategy, as shown by the experience of researchers trying to back off treatment for head and neck cancer caused by the human papillomavirus (HPV). “There’s been an epidemic of oropharyngeal cancers that are related to HPV,” explains Joshua Bauml, a medical oncologist at the Hospital of the University of Pennsylvania in Philadelphia. “These cancers have a much higher cure rate, and that’s wonderful, but the issue is that our treatment paradigm is still based upon older cancers with a different biology.”

Standard treatment for patients with advanced head and neck cancer—originally developed for patients with smoking- and alcohol-associated cancers—involves some combination of surgery, radiation and chemotherapy. But these treatments can cause troubling side effects, including difficulty swallowing, dry mouth, problems with speech and changes in taste.

One approach for reducing toxicity of chemotherapy for these patients was to replace the chemotherapy drug cisplatin with the targeted therapy Erbitux (cetuximab), in an attempt to spare patients the side effects that cisplatin can cause when combined with radiotherapy. However, recent clinical trial res​ults have shown that patients with HPV-positive oropharyngeal cancer treated with Erbitux have shorter survival than those treated with cisplatin and have similar rates of side effects, indicating that this is not a good de-escalation strategy.

Early trials of approaches to reduce doses of radiation ​or chemotherapy for patients with HPV-related oropharyngeal cancer have shown promise, Bauml says. However, he urges clinicians to wait for further data before adopting new protocols for HPV-related oropharyngeal cancer. “If a head and neck cancer metastasizes, it is incurable,” he says. “It’s really essential that when we move towards treatment de-escalation, this is done through robust clinical trials.”

Getting Targeted

The term de-escalation is used most often to describe efforts to reduce harms from old modes of therapy, including surgery, radiation and chemotherapy. But researchers are also working to understand the right doses of medication for patients being treated with newer targeted therapies and immunotherapies.

A study in the July 2018 issue of Cancer, for instance, showed that Sprycel (dasatinib), a type of targeted therapy called a tyrosine kinase inhibitor, is effective at a reduced dose in treating chronic myeloid leukemia (CML). The lower dose appears to cause fewer dangerous side effects, such as buildup of fluid near the lungs, and costs around half as much. Other tyrosine kinase inhibitors have also been shown to be effective in treating CML at reduced doses, says study co-author Hagop Kantarjian, an oncologist who specializes in leukemia at the University of Texas MD Anderson Cancer Center in Houston.

Traditional methods of determining doses for cancer drugs aren’t always ideal for dosing targeted therapies, Kantarjian explains. Clinical trials for chemotherapy ramp up doses in people until the highest dose with acceptable side effects is found, a measure known as maximum tolerated dose. Targeted therapies, in contrast, can be effective at doses much lower than the maximum tolerated dose. Researchers are still trying to find the best strategies for determining dosing of targeted therapies.

Researchers are also investigating whether they can reduce the time that patients are on targeted therapies and immunotherapies. For instance, “there are no clear, specific guidelines on exactly how long to treat patients with immune therapy in cancer,” says Michael Postow, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City who treats patients with melanoma.

Scientifically, it makes sense that patients who respond to immunotherapy drugs might be able to stop taking them at some point, says Janet Dancey, scientific director of the Canadian Cancer Trials Group and a medical oncologist at Queen’s University in Kingston, Ontario.

Most cancer drugs work by directly killing or inhibiting the growth of cancer cells. In contrast, immunotherapies work by stimulating the immune system to attack cancer. It’s possible that once the immune system has been activated, continued administration of the drugs isn’t necessary.

Dancey’s organization is currently enrolling patients for the STOP-GAP study, a randomized trial looking into whether melanoma patients who have responded to a class of immunotherapy drugs called PD-1 inhibitors can stop treatment or whether they would benefit from staying on treatment indefinitely.

There are multiple reasons to stop treatments, says Postow. “People would want to stop mostly to get their lives back to themselves, for flexibility in travel and work. … And I think the idea of being under treatment is still a reminder that there is something wrong with the patient.”

There are also financial implications: Checkpoint inhibitors have generally debuted with list prices of $150,000 per year or more. And treatment comes with other costs like time taken off from work, Postow says.

Currently, Postow works with his patients to make individual decisions on whether to stay on immunotherapy after all evidence of active cancer disappears or after two years of improvement on the treatment. He hopes further research will make choices easier for patients. “As you can imagine, there is a lot of emotional decision-making around this issue, too, which is reasonable in a setting where we don’t have strong science to specifically guide us,” he says.

A Lower Dose of 
Financial Toxicity

Researchers are​ looking into whether some drugs are just as effective when taken at a reduced​ dose.

​A Shared Decision

Whether patients are considering skipping chemo​therapy or stopping immunotherapy, having thoughtful discussions about benefits and risks of treatments is key. That includes helping patients understand side effects, says Iveson, who studied shortening chemotherapy for colon cancer patients. For instance, rather than telling patients they might experience peripheral neuropathy, doctors should explain this can mean not being able to button a shirt or feel one’s feet.

“The challenging part is that, for both doctors and patients, there’s a tendency to be risk averse,” Winer notes. People don’t like to feel they are leaving potential benefits of treatment on the table. Doctors sometimes underestimate side effects and overestimate treatment benefits, he says, and “nobody wants to be judged as having done something wrong by backing off if there’s a bad outcome.”

For Bernstein, the lengthy decision-making process that came with skipping chemotherapy after her second cancer diagnosis was difficult because there wasn’t a clear-cut answer of what to do, at least until she got the Oncotype DX test results. But she says she ultimately was glad to have had in-depth discussions with her doctor. Despite progress in treatment de-escalation, Bernstein hopes more can be done both to eliminate unnecessary treatment and to treat cancer more effectively.

“Over time there have been strategies that have come into play and have helped, in a sense, to do less harm, but by no means do they do no harm,” Bernstein says. “I want to make that clear.”​ 

Kate Yandell is the digital editor of Cancer Today.

 

A How-To On Reading Scientific Papers

“Be skeptical. But when you get proof, accept proof.” – Michael Specter

That quote is from Denialism: How Irrational Thinking Hinders Scientific Progress, Harms the Planet, and Threatens Our Lives, where New Yorker staff writer Michael Specter examined the distrust of science that’s turned discussion of scientific topics into a potential minefield. Some good examples of that minefield are climate change, and childhood vaccinations.

Anyone interested in scientific progress – full disclosure, I’m in that group – needs to understand the ideas being explored in scientific papers, the dispatches from the front lines of scientific thinking and discovery. To arrive at that understanding, you have to be able to understand what you’re reading, and I’ll be the first to admit that isn’t easy.

Scientific papers are written by scientists, for scientists, and follow a set of rules and formal structures that can feel like they’re designed to prevent any understanding by the average Joe/Jane “just plain human.” In this post, my goal is to help anyone interested in, but not formally trained in, science tackle reading – and understanding! – an article in any scientific journal.

10 steps to scientific (article) understanding

  1. Check the source

    • What journal is publishing the article? Check Beall’s List, and if the journal appears there, you can stop reading – it’s a fake journal.
    • Who is the lead author, and what organization or institution is s/he affiliated with? If it’s an established university or research institute (University of Chicago or Scripps Institute, for example), keep reading.
  2. Read the introduction first, not the abstract

    • The introduction will reveal the Big Question, the one that the research project worked to reveal the answer to. For instance, an article in the Christmas 2017 issue of The BMJ reports on research into the effects of pet ownership on human biomarkers of ageing; the introduction clearly lays out the Big Question as “ we examined the prospective link between pet ownership and a selected range of objective biomarkers of ageing proposed for use in large scale population based studies of older people.”
  3. Write out your own summary of what the research was examining

    • This will give you a grasp of why the researchers wanted to ask the Big Question, and a framework for assessing what their answers to that question are.
  4. Identify the null hypothesis

    • The null hypothesis could really be better termed the “nullifiable” hypothesis, since the purpose of the research project is to nullify the hypothesis that there are no differences in possible answers to the Big Question.
    • An example of a null hypothesis is “the world is flat,” which is what Copernicus worked to scientifically disprove a while back. He was successful, but there are some people who still reject his conclusions. (Warning: opening that link might be hazardous to your sanity.)
  5. Look at the approach, and the methods, used in the research study or experiment(s)

    • What did the researchers do to answer the Big Question? What specific experiments did they run?
    • Sketch out diagrams of each experiment or data crunch.
  6. Read the results section of the article

    • Look at the written results, as well as all charts and figures related to those results.
    • What are the sample sizes? Really small sample sizes are a red flag.
    • What results are listed as “significant,” and what as “non-significant”? If you want to totally geek out on this topic, this post will make your geeky day.
  7. Do the results actually answer the Big Question?

    • Using your own judgment, do you think the study authors have answered the question asked in the introduction?
    • Do this before you read the paper’s conclusion.
  8. Does the conclusion make sense, in light of everything you’ve read and evaluated while going through the paper?

    • Do you agree with the conclusion?
    • Can you identify an alternative explanation for the results in the article?
    • What are the next steps the authors see emerging from their research?
  9. Read the abstract at the beginning of the paper

    • In light of the work you did in Steps 1 through 8, does the abstract line up with what the authors said their research purpose was?
    • Does it fit with your own interpretation of the paper?
  10. What are other scientists saying about the paper?

    • Have other scientists written about this paper?
    • What other research is referenced in the paper?
    • Have the authors of that research weighed in on the paper you’re evaluating?

Reading, and understanding, scientific papers takes practice. It’s also fun, if you’re a science nerd, or just interested in new scientific discoveries. And it’s work worth doing, because the more you know, the more likely it is that you yourself might make a discovery that makes a difference.

Paying It Forward: Volunteering for Clinical Trials

Editor’s Note: This blog and video is from the Alliance for Aging Research. The Alliance for Aging Research is dedicated to accelerating the pace of scientific discoveries and their application to vastly improve the universal human experience of aging and health.

Getting medical discoveries from the research lab to patients depends on clinical trials and the people who volunteer to participate in them.   Volunteering in a trial may help society at large by bringing new treatments one step closer to patients, and could help a loved one if you have a genetic disease or condition.  Volunteering may also give you access to a cutting-edge treatment and medical team that carefully monitors your health.  But clinical trials can’t happen without volunteers, and 37% of trials don’t enroll enough patients to move forward.  Clinical trials need volunteers like you so watch this short film to find out more about why they are important, how to get involved, and what it means to participate.

How to Read and Understand a Scientific Paper

In a previous article, How to Read Beyond the Headline: 9 Essential Questions to Evaluate Medical News, I recommended you should always try to read an original study (if cited) to evaluate the information presented. In this follow-on article, you will learn how to read a scientific research paper so that you can come to an informed opinion on the latest research in your field of interest.  Understanding research literature is an important skill for patient advocates, and as with any skill, it can be learned with practice and time.

Let’s start by looking at what exactly we mean by the term “scientific paper”. Scientific papers are written reports describing original research findings. They are published in peer reviewed journals, which means they have been refereed by at least two other experts (unpaid and anonymized) in the field of study in order to determine the article’s scientific validity.

You may also come across the following types of scientific papers in the course of your research.

•       Scientific review papers are also published in peer reviewed journals, but seek to synthesize and summarize the work of a particular sub-field, rather than report on new results.

•       Conference proceedings, which may be published in a journal, are referred to as the “Proceedings of Conference X”. They will sometimes go through peer review, but not always.

•       Editorials, commentaries and letters to the editor offer a review or critique of original articles. They are not peer-reviewed.

Most scientific journals follow the IMRD format, meaning its publications will usually consist of an Abstract followed by:

•       Introduction

•       Methods

•       Results

•       Discussion

 

Let’s look at each of these sections in turn.

(a) Introduction  

The Introduction should provide you with enough information to understand the article. It should establish the scientific significance of the study and demonstrate a relevant context for the current study.  The scope and objectives of the study should be clearly stated.

When reading the Introduction, ask yourself the following questions:

·       What specific problem does this research address?

·       Why is this study important?

(b) Methods

The Methods section outlines how the work was done to answer the study’s hypothesis. It should explain new methodology in detail and types of data recorded.

As you read this section, look for answers to the following questions:

  • What procedures were followed?
  • Are the treatments clearly described?
  • How many people did the research study include? In general, the larger a study the more you can trust its results. Small studies may miss important differences because they lack statistical power. Case studies (i.e. those based on single patients or single observations) are no longer regarded as scientific rigorous.
  • Did the study include a control group? A control group allows researchers to compare outcomes in those who receive a treatment with those who don’t.

 (c) Results

The Results section presents the study’s findings.  It should follow a logical sequence to answer the study hypothesis.  Pay careful attention to any data sets shown in graphs, tables, and diagrams. Try to interpret the data first before reading the captions and details.  If you are unfamiliar with statistics, you will find a helpful glossary of terms hereClick here for an online guide to help you understand key concepts of statistics and how these concepts relate to the scientific method and research.

Consider the following questions:

  • Are the findings supported by persuasive evidence?
  • Is there an alternative way to interpret these findings?

(d) Discussion 

The Discussion places the study in the context of the broader field of research. It should explain how the research has moved the body of scientific knowledge forward and outline the next steps for further study.

Questions to ask:

•       Does the study have any limitations? Limitations are the conditions or influences that cannot be controlled by the researcher.  Any limitations that might influence the results should be mentioned in the study’s findings.

  • How are the findings new or supportive of other work in the field?
  • What are some of the specific applications of the study’s findings?

The IMRD format provides you with a useful framework to read a scientific paper. You will need to read a paper several times to understand its findings. Consider your first reading of the study as a “big picture” reading.  Scan the Abstract for a summary of the study’s principal objectives, the methods it used and the principal conclusions. A well-written abstract should allow you to identify the basic content of an article to determine its relevance to you.  In describing how she determines the relevance of a study, research RN, Katy Hanlon, focuses on “key words and phrases first. Those that relate to the author/s base proposal as well as my own interests”.  Medical writer, Nora Cutcliffe, also scans upfront “to gauge power and relevance of clinical trial data”. She looks for “study enrollment (n), country and year”. It’s important to note the publication date to determine if this article contains the latest findings or if there is more up-to-date research available. Cutcliffe also advises you should “note author affiliations and study sponsors”.  Here you are looking out for any potential bias or vested interest in a particular outcome.  Check the Acknowledgments section to see if the author(s) declare any financial interests in the research which might bias their findings. Finally, check if the article is published in a credible journal.  You will find reputable biomedical journals indexed by Pubmed and Web of Science.

Next, circle or take note of any scientific terms or keywords you don’t understand and look up their meaning before your second reading. Scan the References section – you may even want to read an article listed here first to help you better understand the current study.

With the second reading you are going to deepen your comprehension of the study. You’ll want to highlight key points, consult the references, and take notes as you read.  According to the scientific publisher, Elsevier, “reading a scientific paper should not be done in a linear way (from beginning to end); instead, it should be done strategically and with a critical mindset, questioning your understanding and the findings.”  Scientist, Dr Jennifer Raff, agrees. “When I’m choosing papers to read, I decide what’s relevant to my interests based on a combination of the title and abstract”, she writes in How to read and understand a scientific paper: a guide for non-scientists. “But when I’ve got a collection of papers assembled for deep reading, I always read the abstract last”. Raff explains she does this “because abstracts contain a succinct summary of the entire paper, and I’m concerned about inadvertently becoming biased by the authors’ interpretation of the results”.

When you have read the article through several times, try to distill it down to its scientific essence, using your own words. Write down the key points you have gleaned from your reading such as the purpose of the study, main findings and conclusions. You might find it helpful to develop a template for recording notes, or adapt the template below for use. You will then have a useful resource to find the correct reference and to cross reference when you want to consult an article in the future.

In the example below I have taken an article published in 2015, as an example. You can read the paper Twitter Social Media is an Effective Tool for Breast Cancer Patient Education and Support: Patient-Reported Outcomes by Survey on PubMed.

Template for Taking Notes on Research Articles

 

 

Further reading

Nothing About Us Without Us: Patient Involvement in Research

Until recently, patient participation in research was limited to their involvement as subjects enrolled in research studies, but there is a shift occurring as funding bodies increasingly look for evidence of patient and public involvement (PPI) in research proposals. The rationale for this is increasing evidence that PPI in the provision of healthcare leads to improved outcomes and better quality of care.

Assumptions are made every day about patients; assumptions which may lead to a failure to deliver optimum care. When these assumptions extend to research, quite often there is a mismatch between the questions that patients want answers to and the ones that researchers are investigating. As an example, the research priorities of patients with osteoarthritis of the knee, and the clinicians looking after them, were shown in a study to favor more rigorous evaluation of physiotherapy and surgery, and assessment of educational and coping strategies. Only 9% of patients wanted more research on drugs, yet over 80% of randomized controlled trials in patients with osteoarthritis of the knee were drug evaluations. PPI recognizes that patients bring a unique perspective and experience to the decision-making process in research. It is paternalistic and patronizing to rely on speculation about patient experience. By considering the actual experience of patients, researchers can make more informed research decisions. Involving patients is an important step in ensuring that the real life experiences of patients are considered when it comes to setting research priorities. This in turn will increase the relevance of research to patients and improve research quality and outcomes.

As an advocate you may be asked to become involved in a research project, so it is important to have a clear understanding of what PPI is – and what it isn’t. PPI is not about being recruited as a participant in a clinical trial or other research project, donating sample material for research, answering questionnaires or providing opinions. PPI describes a variety of ways that researchers engage with people for whom their research holds relevance. It spans a spectrum of involvement which may include any of the following:

  • Being involved in defining the research question
  • Being a co-applicant in a research proposal
  • Working with funders to review patient-focused section of applications
  • Being an active member of a steering group for a research study
  • Providing your input into a study’s conception and design
  • Contributing to/proofing of documentation
  • Assisting in the implementation and dissemination of research outcomes
  • Improving access to patients via peer networks and accessing difficult-to-reach patients and groups

Effective PPI transforms the traditional research hierarchy in which studies are done to, on, or for participants into a partnership model in which research is carried out with or by patients.  PPI should always involve meaningful patient participation and avoid tokenism. The Canadian Institutes of Health Research Strategy for Patient-Oriented Research (SPOR) describes PPI as fostering a climate in which researchers, health care providers, decision-makers and policy-makers understand the value of patient involvement and patients see the value of these interactions. Underpinning this framework are the following guiding principles for integrating patient engagement into research:

  • Inclusiveness:Patient engagement in research integrates a diversity of patient perspectives and research is reflective of their contribution.
  • Support:Adequate support and flexibility are provided to patient participants to ensure that they can contribute fully to discussions and decisions. This implies creating safe environments that promote honest interactions, cultural competence, training, and education. Support also implies financial compensation for their involvement.
  • Mutual Respect:Researchers, practitioners and patients acknowledge and value each other’s expertise and experiential knowledge.
  • Co-Build:Patients, researchers and practitioners work together from the beginning to identify problems and gaps, set priorities for research and work together to produce and implement solutions.

Derek Stewart, a patient advocate and Associate Director for Patient and Public Involvement at NIHR Clinical Research Network, sees a growing momentum of actively involving patients and public in research gathering pace worldwide. “It is really pleasing to hear researchers saying how valuable it has been to involve patients and the public in their work”, he says. “It has equally improved the quality of the research and enriched their own thinking and understanding.”

Earlier this year, PCORnet, the National Patient-Centered Clinical Research Network, announced its first demonstration study which reflects PCORnet’s aims of patient engagement and open science. ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness) will compare the effect of two different aspirin doses given to prevent heart attacks and strokes in high-risk patients with a history of heart disease. Seeking input at every critical step, from consent design and protocol development, through dissemination of final study results, the project represents a new research paradigm. Unprecedented in the design of clinical trials, the final consent form and protocol were shaped with input from patients, local institutional review boards, physicians, and study coordinators.

Another noteworthy example of PPI can be found in the Metastatic Breast Cancer Project a direct-to-patients initiative launched at the Broad Institute of MIT and Harvard last October. Corrie Painter, an angiosarcoma patient and Associate Director of Operations and Scientific Outreach at Broad Institute, explains that “the project seeks to greatly accelerate the pace of biomedical research by empowering patients to directly contribute to research and was built in lock step from design to consent language with dozens of patients.”

To what extent you may wish to be involved in PPI will depend on several factors. Do you have professional experience (e.g. project management, clinical experience, etc.) which would be useful? Are you happy to work as part of a team? Or would you prefer to work on your own? You should also take into consideration your other work or family commitments. For instance will you need to take time off work to attend meetings? Consider also at what point you are in your own health journey. Will participation in research place an added burden on your treatment or recovery? In making the decision to become involved in research, you should always balance your own health needs with the desire to be supportive of research and the research process.

 

Useful links

PCORI www.pcori.org

PCORnet www.pcornet.org

Metastatic Breast Cancer Project www.mbcproject.org

#WhyWeDoResearch www.whywedoresearch.weebly.com

How to Read Beyond the Headline: 9 Essential Questions to Evaluate Medical News

Ben Goldacre writing in Bad Science classified science reporting as falling into three categories – wacky stories, scare stories and breakthrough stories; the last of which he views as ”a more subtly destructive category of science story”. Whether you get your news through digital or traditional means, you can’t fail to notice the regularity with which journalists report on the latest medical breakthroughs. Some of these reports are sensationalist (“coffee causes cancer”) and fairly easy to dismiss; but do you know how to separate fact from fiction when it comes to less sensationalist headlines?

The foundation of empowered patient-hood is built on reliable health information. This means not only knowing where to find medical information, but being able to evaluate it and knowing how it can be applied to your own, or your loved-ones’ particular circumstances. Headlines often mislead people into thinking a certain substance or activity will prevent or cure chronic disease. As patient advocates we must learn to read beyond the headlines to filter out the good, the bad, and the questionable. The following questions are designed to help sort the signal from the noise next time you read the latest news story heralding a medical breakthrough.

1. Does the article support its claims with scientific research?

Your first concern should be the research behind the news article. If an article contains no link to scientific research to support its claims, then be very wary about treating those claims as scientifically credible.

2. What is the original source of the article?

If the article cites scientific research you should still treat the findings with caution. Always consider the source. Find out where the study was done. Who paid for and conducted the study? Is there a potential conflict of interest?

3. Does the article contain expert commentary to back up claims?

Look for expert independent commentary from doctors or other healthcare providers to explain the findings (there should be an independent expert source quoted – someone not directly connected with the research).

4. Is this a conference presentation?

Journalists frequently report on research presented at large scientific meetings. It’s important to realize that this research may only be at a preliminary stage and may not fulfill its early promise.

5. What kind of clinical trial is being reported on?

If the news relates to results from a clinical trial, it’s important you understand how, or even if, the results apply to you. Quite often, news publications report on trials which have not yet been conducted on humans. Many drugs that show promising results in animals don’t work in humans. Cancer.Net and American Cancer Society have useful guides to understanding the format of cancer research studies.

6. What stage is the trial at?

Research studies must go through several phases before a treatment can be considered safe and effective; but many times journalists report on early phase trials as if these hold all the answers. The testing process in humans is divided into several phases:

  •  Phase I trials: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
  • Phase II trials: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
  • Phase III trials: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

Source: ClinicalTrials.gov

7. How many people did the research study include?

In general, the larger a study the more you can trust its results. Small studies may miss important differences because they lack statistical power.

8. Did the study include a control group?

A control group allows researchers to compare outcomes in those who receive a treatment with those who don’t. The gold standard is a “randomised controlled trial”, a study in which participants are randomly allocated to receive (or not receive) a particular intervention (e.g. a treatment or a placebo).

9. What are the study’s limitations?

Many news stories fail to point out the limitations of the evidence. The limitations of a study are the shortcomings, conditions or influences that cannot be controlled by the researcher. Any limitations that might influence the results should be mentioned in the study’s findings, so always read the original study where possible.

Useful Resources

  • Gary Schweitzer’s Health News Review website provides many useful resources to help you determine the trustworthiness of medical news. To date, it has reviewed more than 1,000 news stories concerning claims made for treatments, tests, products and procedures.
  • Sense about Science works with scientists and members of the public to equip people to make sense of science and evidence. It responds to hundreds of requests for independent advice and questions on scientific evidence each year.
  • Trust It or Trash is a tool to help you think critically about the quality of health information (including websites, handouts, booklets, etc.).
  • Understanding Health Research (UHR) is a free service created with the intention of helping people better understand health research in context. It gives clear and understandable explanations of important considerations like sampling, bias, uncertainty and replicability.

Heading Off Cancer Growth on the Cellular Level

Cancer cells are like all the cells in our body, in that they need certain basic building blocks – amino acids – in order to reproduce. There are 20 amino acids found in nature. The amino acid serine is often found in abundance in patients with certain types of breast cancer, lung cancer, and melanoma. The overproduction of this amino acid is often required for the rapid and unregulated growth characteristic of cancer.

Scientists at the Scripps Research Institute (TSRI) wondered if there was a way to take advantage of the relationship between cancer cell proliferation and serine. Amy GrayThey examined a large library of molecules -numbering 800,000 – to find an enzyme that inhibited serine production. After much research, the group found 408 contenders that could possibly work. This list was again narrowed down to a smaller set of seven, ending with one promising candidate. This molecule, 3-phosphoglycerate dehydrogenase (PHGDH), seemed to inhibit the first step in a cancer cell’s use of serine to reproduce itself.

Luke L. Lairson, assistant professor of chemistry at TSRI and principal investigator of cell biology at the California Institute for Biomedical Research remarked, “In addition to discovering an inhibitor that targets cancer metabolism, we also now have a tool to help answer interesting questions about serine metabolism.”

What does this mean for cancer patients in the future?

Discovering an enzyme that inhibits serine production means that a key process in cancer cell proliferation can be slowed down or even stopped.   Interfering with cancer cell metabolism could be a pathway to treatment. Potentially, adding the molecule PHGDH to cancer cells disturbs the basic need of cancer cells to divide and reproduce rapidly. Obviously this finding points to years of further research and drug development. But discovering this key relationship between serine over-production and a molecule that slows it down could be a model for new cancer treatments in the future.

 

References:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989988/

http://medicalxpress.com/news/2016-03-team-approach-curbing-cancer-cell.html