A new study has offered insight into how to predict the long-term effectiveness of multiple myeloma treatments.
Researchers propose using a less-than-one-in-a-million level—or the absence of minimal residual disease (MRD)—as a new standard.
According to the study, MRD status can be used to evaluate patients’ response to therapy at all stages of treatment.
As new treatments for multiple myeloma have extended patient survival—from an average of three years to more than 10 in some cases—physicians and researchers face a new challenge: how to predict a drug’s long-term effectiveness? How to tell, early on, whether one drug is likely to extend patients’ lives more than another?
At Dana-Farber’s Jerome Lipper Multiple Myeloma Center, researchers have identified one such sign. In a study published in the journal Blood, investigators found that, after treatment, patients with no myeloma cells within 1 million bone marrow cells were more likely to have a lengthy remission than those with higher myeloma cell counts. They propose that the less-than-one-in-a-million level—formally known as an absence of “minimal residual disease” (MRD)—be adopted as the new standard for managing myeloma and evaluating myeloma drugs.
“The success of new agents in extending the lives of patients with multiple myeloma has created the need to identify biomarkers of drugs’ effectiveness,” says study senior author Nikhil Munshi, MD, director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center. “Our findings show that MRD status can be such a biomarker—not only in clinical trials of potential new therapies but inpatients treated with standard therapies. It has the potential to change the practice of myeloma treatment.”
The traditional criterion of myeloma drugs’ effectiveness is whether they generate a complete response, defined as an absence of any myeloma cells within 100 bone marrow cells. Even at such low concentrations, however, myeloma is rarely vanquished: Virtually all patients who achieve a complete response eventually relapse, Munshi notes.
With the development of next-generation DNA sequencing, it has become possible to detect myeloma cells at a much deeper level. This September, in fact, the U.S. Food and Drug Administration (FDA) authorized the first test based on next-generation sequencing to detect very low levels of cancer cells in patients with myeloma or acute lymphoblastic leukemia.
Researchers propose that the less-than-one-in-a-million level—formally known as an absence of “minimal residual disease” (MRD)—be adopted as the new standard for managing myeloma and evaluating myeloma drugs.
MRD status versus complete response
The study explored whether MRD status is a better predictor of a long-lasting remission than complete response is. Data for the investigation came from a collaborative study between Dana-Farber and the French Myeloma Group that enrolled 700 patients with multiple myeloma between 2010 and 2012. Patients received either a standard chemotherapy regimen or a shorter, more intense round of chemotherapy followed by a transplant of their own stem cells. Bone marrow samples were collected from all patients at the beginning and end of maintenance therapy—a 12-month period of follow-up treatment intended to prevent or delay the cancer’s return – and were analyzed for MRD.
The analysis showed that 127 of the patients were MRD-negative (had no minimal residual disease) at least once during their maintenance therapy. Researchers found that patients who were MRD-negative were likely to survive for a much longer time before the disease worsened than were patients with the presence of MRD. The overall survival of MRD-negative patients—the percent alive more than two years after finishing maintenance therapy—was far higher, as well.
“We showed that when patients have deep responses to therapy, they have much better outcomes: they relapse later and live longer,” Munshi comments. “The effect is so great, that patients with high-risk myeloma who achieve MRD negativity have essentially the same rate of relapse as patients with standard-risk myeloma.”
MRD status can be used to evaluate patients’ response to therapy at all stages of treatment, he continues—prior to a stem cell transplant (to judge the effectiveness of pre-transplant chemotherapy); after transplant (to gauge the success of the transplant); and during and after maintenance therapy.
“MRD is one of the most promising biomarkers identified to date and has long been used in patients with lymphoma and chronic myelogenous leukemia, Munshi observes. “It will now inform our therapy in myeloma with the eventual goal of achieving MRD-negative status.”
Chemotherapy has long been a mainstay of cancer treatment. But a lot has changed since Sidney Farber, MD, the founder of Dana-Farber Cancer Institute, achieved the first remissions for pediatric leukemia using chemotherapy in the 1940s.
Today, in the era of precision cancer medicine, there are newer treatments and chemotherapy that can more specifically target cancer cells. Researchers have also discovered the effectiveness of using chemotherapy drugs in conjunction with other drugs to pack a more powerful punch. To put it simply: Chemo is a lot better today than it used to be.
Still, there’s a lot of misinformation surrounding this kind of cancer treatment. In this episode, we explore some of the most common myths and misconceptions with Clare Sullivan, MPH, BSN, clinical program manager for Patient Education at Dana-Farber.
MEGAN RIESZ: So, first, can you just kind of explain generally what chemotherapy is and how it’s commonly administered?
CLARE SULLIVAN, NPH, BSN: Sure. Think about what the body does. The body is made up of cells that normally divide and grow and are replaced. Think about how your fingernails grow. Chemotherapy (or chemo, for short) is a group of medicines or drugs that treat cancer and other diseases. Cancer also divides and replicates.
Different chemotherapy drugs act in various ways. Some chemotherapy drugs can kill the cancer as they divide at critical times during the cell cycle, something that we learned way back in high school. Some chemotherapy can target the cancer’s food supply and kill important hormones and other nutrients it needs to grow. And then some chemotherapies can target the cancer’s genes and prevent it from growing. Then, one of the other interesting areas is that some chemotherapy can prevent the tumor from growing new blood vessels that it needs to grow and spread.
There have been many new and exciting developments in the field of cancer care, and when I say this, I mean chemotherapy, whether you add different combinations or other treatments. So, chemotherapy is still a very important tool for treating many cancers today.
MEGAN: Just to be clear, how is chemotherapy different than immunotherapy, which is something that’s talked about a lot today?
SULLIVAN: Well, immunotherapy has received a lot of attention because of new medications discovered that help treat cancer, but immunotherapy is unlike chemotherapy because of the way that it fights cancer.
Let’s start at the beginning. The immune system is a very complex network of cells and organs that defend against foreign substances, like bacteria or viruses.
Think about when you get a cut. The body’s defenses go into action immediately scanning and will recognize any foreign bacteria and then send out the correct army or navy to wipe out that invader. The immune system is so sophisticated that it can remember that invader, and if it comes again, it will recognize it and protect you from that disease. This is very similar to the chicken pox.
MEGAN: And let’s talk about side effects, which can be big considerations for patients. What are some common side effects that patients experience during chemotherapy?
SULLIVAN: The most common side effects for chemotherapy depend on the drug, the manner it’s given, the dose, and how often you get it, but the number one side effect across the board is fatigue. Then there are a few others that I’ll mention: appetite changes, nausea. But again, remember, there’s a lot of anti-nausea medications that are very effective now. A weakened immune system where you might get bruising or bleeding, and this is because of the way the chemotherapy goes after the cell cycle—it decreases the red blood cell and the white blood cell. Constipation and diarrhea are also another side effect, but again, there are a lot of good medications that are very effective. Then, mouth care—mouth care is really important to prevent mouth sores.
I want to go back to my first symptom, which was fatigue. Fatigue is real. Think about it as tiredness that doesn’t go away with rest. If you take a nap and wake up, you should ordinarily feel refreshed, but fatigue is when you wake up and really feel just as tired as when you went to sleep. So, during your treatment, of course, there will be times that you need to rest, but when possible, the best way to offset a host of issues that can happen when you lay in bed all day is to stay active.
Here are some tips. First, I want to think about those days that you’re most tired, really struggling with fatigue and really just around the house. Every time that you get up to the bathroom, try to move around. Move from the bathroom to the couch for a few minutes to a chair, and then move back to bed and continue that cycle as you get up to the bathroom. Just keep moving. Keep walking, even if it’s around the dining room table and in the middle of the night. If you can carry something like a laundry basket, put some weight in it. If you can carry a carton of milk around the dining room table…something just to help you move. Do some arm or leg stretches when you’re in or out of bed. A tip is that if you’re watching TV, put the exercise channel on and follow along in bed.
On a good day, you’re going to want to put your coat on right over that bathrobe, walk around the block, get a good pair of slippers with some comfortable soles, and you don’t even need to change your shoes.
The tip here for you is that you will find your energy perks up a few days before your next chemotherapy treatment. Use this time wisely. This is when you can really get out of the house. Maybe you might work a half a day. Maybe someone would drive you to work. Maybe you could work around the house. Walk a little further than just around the block. Walk with a little bit of speed. Use your arms. Get off a stop earlier on the train. Take the stairs at work. Take the stairs during your hospital visit. Take the dog for a walk. On your way back, pull a few weeds in the lawn.
If you’re in the hospital and you’re getting your chemotherapy in the hospital, work with the nursing staff on the floor. Measure how many laps it would take around the unit to equal a mile. We have many units over at the Brigham with signs of encouragement for lap walking.
MEGAN: So, patients often wonder if they will lose their hair during chemotherapy. Can you talk about this as well?
SULLIVAN: Sure. There are many other side effects that are specific to the drugs, and the one that I have not mentioned, as you have brought up, is hair loss. Many people associate hair loss with chemotherapy from movies or TV, but this is not as common anymore. When you enter the infusion clinic, you might be surprised to see that many patients have hair. This is not to say that some chemotherapy still causes hair loss, but it is not as common as people think.
MEGAN: So, chemotherapy can be used in a few different ways—curatively or palliative, for example. Can you talk about this?
SULLIVAN: Yes, Megan. What you’re referring to are the three goals of cancer treatment. There are actually three. You may see one of these terms on your initial chemotherapy consent, but most importantly, you may want to confirm with your cancer team what the strategy is for your treatment plan. Starting out on the same page with your team is very important. Remember, this can change as information about your cancer is understood over time by your team.
The three strategies to cancer treatment are cure, control, and palliation. Cure is when the cancer is completely removed, and the intent is that the cancer will not come back. Control would be the second strategy. That’s when disease cannot be fully removed from the body, but the team can keep it in check for long periods of time. Then the third strategy is what we call palliation. The disease here cannot be successfully removed and may not be controlled for long, but the team is confident that they can minimize any symptoms to help you feel more comfortable.
The word “palliation” can be confusing and even turn some people off from the medical specialty of palliative medicine. Palliative care is a specialized medical care for any cancer patient. It helps patients get relief from pain, symptoms, and the stress of having a serious illness. It can help improve their quality of life, no matter what treatment goal there is. Palliative care can help with fatigue, pain, nausea, shortness of breath, and a whole host of other symptoms that you may have during treatment, where the goal of palliative care is to help you feel more comfortable during your treatment, preserve your dignity, and better communicate with your family and caregivers.
Palliative care can be helpful through all stages of cancer care. Early on, it can help make the treatment more tolerable. Later, it can help you with daily life, can assist you in planning your care, and provide you with an additional layer of support. Think of it as a superhero. Think of it as the superheroes of cancer care.
Often, people mix up the word “palliative care” and “hospice care.” Palliative care is available to any patient with any stage of cancer at any age. Hospice care is for patients also receiving palliative care, but hospice care is typically only given during the final months of life.
MEGAN: Is there anything else you might like to convey to patients who are starting chemotherapy?
SULLIVAN: Sure. There are some tips here that I’d really like to share with you today. For those people who might be going to an infusion clinic or going even to a hospital, it’s OK to ask for a tour. Go and visit the infusion area, or even walk through the hospital ward, just to get familiar with the surroundings. Bring a friend and stay active.
If you don’t understand something that the doctor or nurse says, please ask them to repeat. It’s very important that you understand. Know who to call and when. Keep that information near you at all times, whether it be on your refrigerator, in your wallet, or type it right away in your phone contacts the minute that you get it. Make sure family members have it or close friends know where this information is kept.
When cancer spreads in the body, it is first and foremost due to changes, or mutations, in the DNA of cells. Because of a mutation or other abnormality in a cancer cell’s genome (the DNA stored in its nucleus), the cell may become separated from its neighbors and invade surrounding tissue. Other genomic breakdowns allow the cell to make its way to a nearby blood or lymph vessel, pass through the vessel wall, and ride to another part of the body, where it once again crosses the vessel wall and begins to grow and divide, forming a “secondary” tumor, or metastasis.
The genes that enable tumor cells to break free of their original location and travel to distant sites are part of every cell’s natural endowment. They play a critical role in the early stages of life, allowing cells to move to their assigned positions in the developing embryo or fetus. Eventually, these genes shut down, rendering the cell immobile and helping bind them to their native tissue—be it the lungs, nerves, muscles, or any of the hundreds of other tissue types in the human body. When a mutation or other genetic problem causes the genes to reactivate, tumor cells can gain the ability to move and slip through the spaces between other cells.
Even when cancer cells do break free, their ability to metastasize to other parts of the body is not guaranteed. For one, they may be subject to attack and destruction by elements of the immune system. For another, it takes a variety of genetic alterations to equip tumor cells with the skills needed to pull up stakes and survive in distant tissue: to become unanchored from their home tissue, invade and traverse adjacent tissue, pierce the wall of a blood or lymph vessel, survive a trip in the bloodstream or lymph, make landing downstream, root themselves in a new location, attract blood vessels to draw nourishment, and abide among unfamiliar cells.
Few cancer cells possess all these abilities; most die during their journey through the body. Even when they succeed in settling at a new site, they often remain inactive for many years before beginning to grow again, if at all.
Because metastatic tumor cells have acquired genetic mutations that enable them to survive beyond their place of origin, they may differ, at a molecular level, from cells in the primary tumor. As a result, they may be less vulnerable to drugs that are effective against the tumor. This is one of the main reasons why metastasized cancers are usually more difficult to treat than primary cancers.
The ability to metastasize illustrates cancer cells’ ability to exploit their genetic equipment and surroundings. Genes normally used during fetal development are subverted to enable tumor cells to take up residence outside the original tumor. Blood and lymphatic vessels that carry nutrients, immune system cells, and other critical agents are appropriated by tumor cells as highways to other parts of the body. Substances that normal cells secrete to gain access to blood vessels are hijacked by tumor cells to feed themselves.
Because metastasis involves cancer cells’ ability to make a home in tissue far from the original tumor, a major branch of cancer research seeks to make other tissues inhospitable to breakaway tumor cells. At Dana-Farber, for example, researchers have identified a compound that can potentially prevent multiple myeloma from metastasizing to the bones in animal models. Other research focuses on arming the immune system to prevent metastasis following cancer surgery.
It appears to happen more readily than we once believed
Cells, the units of life that compose our bodies, are able to make copies of themselves to help us grow, fight disease and recover from injuries. Cells have built-in mechanisms that maintain the fidelity of transmission of genetic information from one generation to the next, and to control cell division in a timely manner, allowing our bodies to build or rebuild various tissues.
But as cells divide to generate new cells, errors known as mutations can arise. And if a cell accumulates enough mutations in the genes that control cell growth and maintain the fidelity of the genome from one generation to the next, known as tumor suppressors and oncogenes, it loses its stability and starts dividing faster than normal, which leads to cancer. Some of these genes can mutate to accelerate the speed at which mutations arise (a phenomenon known as genetic instability).
Genetic instability genes may be relics of a time when single-celled organisms needed to adapt to rapidly changing environments; it is possible that these genes evolved secondary functions that are important for multicellular organismal development, and are therefore essential, despite their role in instability.
In the early 1950s, scientists proposed that it took a double hit of mutations to trigger cancer—because we have two copies of each gene, one from our mothers and one from our fathers. Destruction of the tumor suppressors, or mutation of the oncogenes genes that directly cause cancer, is therefore unlikely; both copies would have to be damaged for cancer to arise. But that idea was contradicted by the high rates of cancer incidence we actually see.
Now, however we have discovered that cancer might arise more easily than previously thought. By doing experiments on both yeast cells and on human cells in culture, my colleagues and I have been able to show that just a single mutated gene suffices to accelerate cancer. The experiments mimic an early event during cancer development—the acquisition of genetic instability—which is characterized by a faster accumulation of mutations, and by genomic changes which can themselves disrupt cancer tumor suppressor genes or activate oncogenes.
So far it has been difficult to identify when and where genetic instability arises, either because tumor samples represent a late stage of cancer development and thus carry many different mutations, or because studies with model organisms are focused on inactivation of specific genes. This new work started from a provocative question posed to me by my mentor, Andrew Murray: “If we let cells choose, how do stable cells evolve into cancer cells?” Catching the initial transition from genetic stability to instability was the crucial goal, and this was done by selecting cells that are able to survive different drugs, each survival step requiring the inactivation of a “tumor suppressor” gene.
Mimicking two important aspects of cancer development, the inactivation of cancer suppressors and the acquisition of drug-resistance, we allowed the cells to choose how to evolve accelerated mutation rates. Surprisingly, instead of the predicted two-hits, a single heterozygous mutation (a mutation in one of the two copies of a gene) was the favorite route to evolve instability. This means that, similar to the famous anime show One-Punch Man, where the hero defeats his enemies with a single hit, cancer might start with a single mutation.
This contradicts the prevailing thinking in the field, which, as I noted, states that two inactivating mutations are required for cancer onset. And since a heterozygous mutation in a single gene suffices to trigger genetic instability, and we predict that human cells have 300 such genes, it is very probable that cells turn on the ability to mutate faster. As a result, the chance of hitting tumor suppressors and oncogenes, and genes that favor metastasis or drug resistance, becomes much higher, accelerating cancer development.
Hence, this work suggests that a single heterozygous mutation, in one of a large number of genes, is an easy way for cells to acquire a “super-mutator” power that allows cancer to progress faster. From the basic scientific standpoint: similar to what was shown in bacteria, which dial up their mutation rates in adverse environments, for instance to survive antibiotics, eukaryotic cells also have pedals (genes) that accelerate the speed of evolution, allowing them to escape growth control.
In collaboration with a research group lead by Ricardo M. Pinto at the Center for Genomic Medicine at Massachusetts General Hospital, we were able to test if the homologs of instability genes we found in yeast worked similarly in human cells. They did: five out of six of the genes tested gave rise to genetic instability when they inactivated. We found a total of 57 human instability genes, 47 of which have not been previously implicated in cancer and require further studies. Moreover, many of these genes do not have a known direct function in genome maintenance, which reveals that other cellular pathways, such as metabolism and protein quality control, can be compromised to cause instability.
Another idea, which I will explore in the future, is that different types of cancer require different instability types (and genes) during different stages of development. Since not all tissues express the same genes, I hypothesize that different targets act locally to initially start cancer, and later during metastasis and treatment resistance.
To test this hypothesis, I will develop experimental evolution systems in organoids (cellular arrays that recreate tissues and organs) and animal models, where I can test the role of instability in different cancers, elucidating for which stages instability is more relevant and how it interferes with different cancer treatments.
Genetic instability also has implications on cellular aging: it is known that as a cell divides, the speed at which its genetic material mutates, as well as chromosomes shorten and structural rearrangements occur, increases. However, the causality of these events is not well established: is it that instability is a consequence of cellular aging and the cellular inability to repair itself, or is instability triggering aging? During my doctoral work I discovered that unicellular organisms are able to replicate without exhibiting aging, and it might be that further studying how these cells maintain genetic stability is key.
Therefore, I plan to establish my own research group using experimental evolution systems to explore genetic instability in the context of aging and cancer development, which are two fast-increasing human malignancies with a heavy individual and societal burden. In the long term, findings on what controls the speed of cellular evolution might lead to targeted therapies that delay genetic instability in specific cancer types and prolong human healthy lifespan.
Results from the phase 3b/4 CheckMate 511 trial suggest that a dosing regimen of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) is associated with improved safety but similar efficacy compared with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) for patients with unresectable stage III/IV melanoma.
Why this matters
These results suggest a superior safety profile for NIVO3+IPI1.
Patients treated with NIVO3+IPI1 had lower incidence of grade 3-5 treatment-related adverse events (TRAEs) compared with patients treated with NIVO1+IPI3 (33.9% vs 48.3%; P=.006; primary endpoint).
NIVO3+IPI1 and NIVO1+IPI3 were associated with similar objective response rates (45.6% vs 50.6%, respectively; P=.35).
NIVO3+IPI1 and NIVO1+IPI3 were associated with similar median PFS (9.92 vs 8.94 months; HR, 1.06; 95% CI, 0.79-1.42) and OS (not reached for both; HR, 1.09; 95% CI, 0.73-1.62).
360 patients with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for 4 doses.
6 weeks after the last combination dose, patients received NIVO 480 mg once every 4 weeks until progression or unacceptable toxicity.
Funding: Bristol-Myers Squibb and ONO Pharmaceutical Company.
Study not designed to formally demonstrate noninferiority for efficacy endpoints.
The FDA has approved a subcutaneous formulation of trastuzumab that strikingly reduces administration time in human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
Subcutaneous trastuzumab consists of trastuzumab plus hyaluronidase, an enzyme used to hasten absorption. Administration takes 2-5 minutes, according to an FDA news release, instead of 30-90 minutes with intravenous (IV) trastuzumab, according to a Genentech news release.
Why this matters
Subcutaneous trastuzumab is a new, more efficient treatment option.
Subcutaneous trastuzumab carries the same indications as the IV formulation for adjuvant treatment of HER2+ breast cancer and metastatic breast cancer, but is not indicated for metastatic gastric cancer.
The recommended dose is 600 mg trastuzumab and 10,000 units hyaluronidase once every 3 weeks.
Approval of subcutaneous trastuzumab was based on 2 trials, HannaH and SafeHER.
HannaH (N=596) showed noninferior pharmacokinetics and pathologic complete response with subcutaneous vs IV trastuzumab.
SafeHER (N=1864) was a nonrandomized trial assessing safety of a 600-mg fixed dose of subcutaneous trastuzumab. The most frequent adverse events (in ≥10% of patients) included fatigue, arthralgia, diarrhea, and injection site reaction, according to the FDA news release.
Men with early stage testicular cancer can safely receive one course of chemotherapy or radiotherapy after surgery without it having a long-term effect on their sperm count, according to a study published in the leading cancer journal Annals of Oncology  on February 25.
Although it is known already that several rounds of chemotherapy or high doses of radiotherapy given to men with more advanced testicular cancer can reduce sperm count and concentration, it has been unclear whether a single cycle of chemotherapy or radiotherapy would have a similar effect in men with stage I disease.
Dr, Kristina Weibring, a cancer doctor at the Hospital in Stockholm, Sweden, who led the study, said: “We wanted to examine in more detail if postoperative treatment, given to decrease the risk of recurrence after the removal of the tumorous testicle, would affect the sperm count and sperm concentration long term in testicular cancer patients with no spread of the disease. To our knowledge, no such study has been done before.
“This is important to find out, since treatment with one course of postoperative chemotherapy has been shown to decrease the risk of relapse substantially, thereby reducing the number of patients having to be treated with several courses of chemotherapy.”
Testicular cancer is the most common cancer in young men between the ages of 15 and 40. When it is diagnosed, all patients have the testicle containing the tumour removed, a surgical procedure called orchiectomy.
In this study, 182 men aged between 18 and 50, diagnosed with stage I testicular cancer and who had had an orchiectomy within the past five years, took part in the study between 2001 and 2006. They were treated either in Stockholm or Lund. After surgery, they received radiotherapy (14 fractions of 1.8 Gy each, up to a total dose of 25 Gy) or one course of chemotherapy, or were managed by surveillance, meaning there was no postoperative treatment. They provided semen samples after orchiectomy but before further treatment, and then six months, one year, two years, three years and five years thereafter. From 2006 onward, radiotherapy was no longer used as a standard treatment in Sweden because of the risk of causing secondary cancer.
“We found no clinically significant detrimental long-term effect in either total sperm number or sperm concentration, irrespective of the type of postoperative treatment received,” said Dr Weibring. “Among men who received radiotherapy, there was a distinct decrease in average sperm number and concentration six months after treatment, though not in those who received chemotherapy. However, sperm number and concentration recovered in the radiotherapy group after six months, and continued to increase in all groups up to five years after treatment.
“I am very excited to see these results as I wasn’t expecting sperm to recover so well after postoperative treatment. I didn’t expect as negative an effect as if the patient had received many courses of chemotherapy, since it is much more toxic, but I was not sure how much the sperm would be affected by one course.
“With the results of this study we can give the patients more adequate information on potential side effects from postoperative treatment. Testicular cancer patients are often young men wanting to father children at some point, and we find, in many cases, that the patients are afraid of the potential risk of infertility caused by chemotherapeutic treatment. These findings should provide some reassurance to them.”
A well-known problem for men diagnosed with testicular cancer is an impaired ability to create sperm. A condition called testicular dysgenesis syndrome, characterized by poor semen quality among other things, may play a role in this and is also associated with a higher risk of developing testicular cancer. In addition, the orchiectomy and the cancer itself may also affect sperm quality. The removal of one testicle does not necessarily affect a man’s sperm count and concentration as the remaining testicle can compensate.
Dr Weibring concluded: “Our results are promising but more studies are needed, and we still recommend sperm banking before orchiectomy as a number of patients may have low sperm counts at the time of diagnosis that persists after postoperative treatment. In addition, the type of testicular cancer and whether or not it will need further treatments are unknown factors before the orchiectomy. Assisted reproductive measures may be necessary for these patients regardless of any treatment given.”
Editor-in-chief of Annals of Oncology, Professor Fabrice André, Professor in the Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France, commented: “This study, together with other research efforts, explores the paths to recovering a normal life after cancer. The finding that one course of chemotherapy has minimal impact on sperm count offers hope for thousands of patients worldwide, but we all must keep in mind that these data are preliminary and will require validation before we can use them in clinics. The next step will be to establish how to predict the toxic effects on sperm count of different chemotherapy regimens.”
 “Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment”, by Kristina Weibring et al. Annals of Oncology. doi:10.1093/annonc/mdz017
The research was supported by grants from the Swedish Government Funding for Clinical Research, the Swedish Cancer Society, Gunnar Nilsson’s Cancer Fund, Malmo University Hospital Foundation for Cancer Research and Foundation for Urological Research, and King Gustaf V’s Jubilee Fund for Cancer Research.
Lead author Dr. Amar Kishan, assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and researcher at the UCLA Jonsson Comprehensive Cancer Center.
A new UCLA-led study shows that men with low- or intermediate-risk prostate cancer can safely undergo higher doses of radiation over a significantly shorter period of time and still have the same, successful outcomes as from a much longer course of treatment.
This type of radiation, known as stereotactic body radiotherapy, is a form of external beam radiation therapy and reduces the duration of treatment from 45 days to four to five days. The approach has been in use since 2000, but has not yet been widely adopted because of concerns over how safe and effective this approach would be in the long term.
“Most men with low- or intermediate-risk prostate cancer undergo conventional radiation, which requires them to come in daily for treatment and takes an average of nine weeks to complete,” said lead author Dr. Amar Kishan, assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and researcher at the UCLA Jonsson Comprehensive Cancer Center. “That can be very burdensome on a patient and be a huge interruption in their life. With the improvements being made to modern technology, we’ve found that using stereotactic body radiotherapy, which has a higher dose of radiation, can safely and effectively be done in a much shorter timeframe without additional toxicity or compromising any chance of a cure.”
The UCLA research team analyzed data from 2,142 men with low- or intermediate-risk prostate cancer across multiple institutions who were treated with stereotactic body radiotherapy for prostate cancer between 2000 and 2012.
The men were followed for a median of 6.9 years. Just over half of the men had low-risk disease (53 percent), 32 percent had less aggressive intermediate-risk disease and 12 percent had a more aggressive form of intermediate-risk disease.
The recurrence rate for men with low-risk disease was 4.5 percent, the recurrence rate for the less aggressive intermediate-risk was 8.6 percent, and the recurrence rate for the more aggressive intermediate-risk group was 14.9 percent. Overall, the recurrence rate for intermediate-risk disease was 10.2 percent. These are essentially identical to rates following more conventional forms of radiation, which are about 4 percent to 5 percent for low-risk disease and 10 percent to 15 percent for intermediate-risk disease.
“What is remarkable about this very large study is how favorably stereotactic body radiotherapy compares to all other forms of radiation treatments, both in terms of effectiveness and side effects,” said senior author Dr. Christopher King, professor of radiation oncology and scientist at the UCLA cancer center. “With such long-term follow-up data, we can now offer this approach to patients with full confidence.”
The research team at UCLA had previously found that stereotactic body radiation therapy was more cost effective because of the fewer treatments involved. Other research has also suggested psychological benefits such as less regret about undergoing treatment. The current study now provides long-term data regarding the safety and clinical efficacy of this approach.
Kishan said the data show that the majority of the men followed are free of prostate cancer seven years after treatment. He added that there was no evidence that this therapy caused worse toxicity in the long term. “In fact,” Kishan said, “we not only confirm that this method is both safe and effective, but we provide significant evidence that this could be a viable treatment option for men with low- and intermediate-risk of prostate cancer.”
Cardio-oncology is a specialty increasing in importance in the 21st century, a tribute to advances in cancer treatment that cure patients or significantly extend survival outcomes. However, many treatments are not without risk, especially regarding the heart. They can cause arrhythmias, coronary artery disease (CAD), venous thromboembolism, valvular heart disease, and/or heart failure. While many of these conditions are caused by chemotherapy drugs, radiation therapy treatments can also be damaging.
St. Jude Children’s Research Center reports that by 2020, there will be an estimated 500,000 pediatric cancer survivors in the United States, an increase of almost 30% since 2011. The American Cancer Society estimates that in the United States, there were approximately 15.5 million cancer survivors in 2016 and will be 20.3 million by 2026. This increase, and a growing concern about cardiotoxicity, has created the relatively new field of cardio-oncology, which focuses, in part, on identifying side effects and providing optimum multidisciplinary care.
In a recent article in the International Journal of Cardiology, physicians from the West German Heart and Vascular Center of University Hospital Essen review the many potential cancer treatments that cause cardiotoxicity and recommend strategies for management, including selection criteria for survivors to be referred to a cardiologist or cardio-oncology unit.
The most common radiation dose-dependent adverse effects are ischemic heart disease (especially for breast cancer patients), valvular heart disease, cardiomyopathy, and congestive heart failure, notes co-author Tienush Rassaf, MD, professor of cardiology and the center’s clinical director, and colleagues. Breast cancer patients undergoing radiation therapy treatment have an estimated risk of developing ischemic heart disease by 7.4% per Gy mean heart dose for up to 20 years.1 These patients also were more likely to experience heart failure and valvular disease.
Patients with Hodgkin lymphoma who received mediastinal radiation therapy also are at risk for valvular heart disease. The authors note that excess relative risk increases by 2.5% per Gy for doses < 30 Gy, and up to 24% per Gy for doses > 30 Gy.2 The median time interval for the up to 70% of Hodgkin lymphoma survivors before developing valvular heart disease is approximately 23 years.
The authors also state that high-dose radiation therapy in the region of the heart can increase intima-media thickness in large arteries such as the carotid artery. Because this occurs rapidly, often within 3 months of treatment, patients should be followed with ultrasound and frequent surveillance.
The West German Heart and Vascular Center’s cardio-oncology unit includes clinicians representing oncology, hematology, radiation oncology, dermatology, gynecology, and bone marrow transplantation in addition to cardiovascular specialists. The unit maintains a close collaboration with the hospital’s imaging institutes of radiology and nuclear medicine. It has established referral protocols for cancer survivors, which can include baseline diagnostics that include magnetic resonance imaging (MRI) and positron emission tomography (PET)/MRI for individualized diagnostic assessment.
Applied Radiation Oncology talked with Melissa M. Hudson, MD, a pediatric oncologist and the director of the Cancer Survivorship Division at St. Jude Children’s Research Hospital. She said that when radiation exposure to the heart and other organs at risk is unavoidable, “periodic monitoring of cardiovascular function (if exposure has reached a threshold deemed at risk for injury) should be considered. Patients and their parents should be counseled regarding the importance of controlling all comorbid conditions that affect cardiovascular disease risk, such as hypertension, dyslipidemia, diabetes, and/or obesity, and adhering to a healthy lifestyle.”
MEDIRAD EARLY HEART Study
One European clinical study recruiting patients is the MEDIRAD EARLY HEART study (NCT03297346).3 Launched in July 2017, it is a 5-center prospective cohort study of 250 women undergoing radiation therapy following breast conservation surgery. It will “combine cardiac imaging information regarding potential early myocardial dysfunction, anatomical coronary changes, and changes in a large panel of circulating cardiac damage biomarkers occurring within the first 2 years of RT, based on a precise cardiac dosimetry, allowing [researchers] to analyze the effect of not only mean heart dose but also doses absorbed by specific heart structures, which better reflect the heterogeneity of dose absorbed by the heart,” according to Sophie Jacob, PhD, of the Pôle Santé-Environnement (PSE-SANTE) of the Institut de Radioprotection et du Sûreté Nucléaire in Fontenay-aux-Roses, France, and co-investigators. These researchers will also develop risk models to estimate individualized risk for patients and to enhance knowledge for primary and secondary prevention.
“MEDIRAD EARLY HEART results will allow for the optimization of RT protocols, leading to personalized treatments with increased therapeutic efficacy, and will, therefore, contribute to improve the radiation
protection of breast cancer patients,” write the authors. “Additionally, it should improve the prediction and prevention of potential lesions to normal cardiac tissues surrounding tumors and ultimately enhance patients’ care and quality of life.”
The clinical study is supported by the European Community’s Horizon 2020 Programme, and includes participating hospitals in Germany, the Netherlands, Portugal, Spain and France. Expected completion is 2021.
Totzeck M, Schuler M, Stuschke M, et al. Cardio-Oncology – strategies for management of cancer-therapy related cardiovascular disease. Int J Cardiol. Published online January 11, 2019. doi: 10.1016/j.ijcard.2019.01.038.
Cutter DJ, Schaapveld M, Darby SC, et al. Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst. 2015;107(4).
Walker V, Crijns A, Langendijk J, et al. Early detection of cardiovascular changes after radiotherapy for breast cancer: protocol for a European multicenter prospective cohort study (MEDIRAD EARLY HEART Study). JMIR Res Protoc. 2018;7(10):e178.
Zytiga May Up Mortality Risk in Prostate An increased risk of early death was observed in men with pre-existing cardiovascular disease (CVD) starting abiraterone acetate (Zytiga) for advanced prostate cancer, a registry study found.
Among abiraterone-treated patients, increased mortality ranged from 21.4% for those with ischemic heart disease to 25.6% for those with acute myocardial infarction (MI), compared with 15.8% for those without a heart condition, reported Grace Lu-Yao, PhD, MPH, of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.
“Our data show that patients with existing cardiovascular conditions experience significantly higher 6-month mortality than those without CVD,” Lu-Yao said during a media briefing ahead of the American Association for Cancer Research (AACR) meeting, to be held here March 29-April 3.
Of the 2,845 patients in the study, 67.6% had a pre-existing heart condition (n=1,924). Patients with atrial fibrillation, congestive heart failure, and stroke had increased mortality risks of 24.4%, 23.4%, and 22.1%, respectively, within these first 6 months.
“Typically clinical trials do exclude people who have significant medical problems,” said AACR President Elizabeth Jaffee, MD, of Johns Hopkins Medicine in Baltimore. “I think this has been rationalized as a safety measure by both investigators and sponsors.”
In her presentation, Lu-Yao highlighted that roughly 40% of prostate cancer patients have uncontrolled hypertension. These patients, plus those with a history of major heart conditions, are usually excluded from clinical trials. In the STAMPEDE study, for instance, exclusion criteria included those with a history of severe angina or heart failure, and those with a recent MI.
Jaffe noted that testing new agents in the healthiest patients does not provide the real-world data physicians need.
The researchers used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data to look at prostate cancer patients treated with abiraterone from 2011 to 2014.
The study also found an increased risk of hospitalizations by examining hospital use in the 6 months before and after starting abiraterone treatment. Risk of hospitalization was increased for patients without a history of CVD for incidence rate ratios (IRR) 1.43 (95% CI 1.30-1.57), as well as for those with pre-existing CVD:
Acute MI: IRR 1.44 (95% CI 1.12-1.86)
Congestive heart failure: IRR 1.35 (95% CI 1.21-1.51)
Stroke: IRR 1.30 (95% CI 1.07-1.57)
Atrial fibrillation: IRR 1.27 (95% CI 1.09-1.48)
Ischemic heart disease: IRR 1.22 (95% CI 1.01-1.48)
The study captured the period from when abiraterone was first approved by the FDA in 2011 for use in late-stage castration-resistant prostate cancer after prior treatment with docetaxel, and when it was then expanded in 2012 to also include use before chemotherapy. In the study, roughly 20% of the patients had received prior chemotherapy (n=586), with the rest being chemotherapy naive. Lu-Yao said that regardless of prior chemotherapy use, the patterns for both early mortality and hospitalization were “quite similar.”
Jaffee noted that while the study is retrospective, it still provides important data, similar to that of a phase IV study.
“Once a drug’s approved, all physicians can administer these drugs, and we don’t really have a handle on who may have worse side effects from these drugs,” she said. “We know that all therapies have side effects, and we need to be able to predict early, screen early, so we can at least monitor for these side effects and intervene at an early stage before patients have severe consequences from these drugs.”
Study limitations included the possibility of misclassification of patients’ CVD, the fact that treatment efficacy could not be assessed, and that there was no control group to look at expected survival for this patient population. A lack of clinical data also meant that the researchers could not compare the study population against the pivotal trials of abiraterone acetate.