 has been riding on the coattails of other cancers, reaping the benefits of therapies designed for these diseases, and that’s especially true of cancers related to B-cell lymphoma and leukemia. Waldenstrom, which is a type of non-Hodgkin lymphoma, came to light in 1944 after the Swedish physician Jan Gosta Waldenström determined what distinguishes it from other blood cancers: large amounts of an abnormal protein, immunoglobulin M, that are created by the cancer cells.

With an incidence rate of about three cases per million people a year in the United States, Waldenstrom macroglobulinemia is a rare malignancy, and, therefore, has no widely used screening tools. Diagnosing the disease early and, most important, accurately is the art of medicine that remains to be perfected.

Oftentimes, it’s not found unless a patient presents with symptoms, such as fever, night sweats, nosebleeds, swollen lymph nodes, weakness and weight loss or a person undergoes blood testing for another reason. One unique constellation of symptoms patients can have is due to the large size of immunoglobulin M that causes sludging of the blood, or hyperviscosity syndrome, that can include changes in brain and eye function. Also, some symptoms mimic other types of non-Hodgkin lymphoma. Then there are some cases where a person may have a precursor to Waldenstrom, which is called monoclonal gammopathy of undetermined significance. So, does an oncologist treat it then or wait it out?

Questions like this arise when dealing with this rare cancer. Should treatment, such as chemotherapy, begin right away, possibly subjecting a patient to its toxic side effects like diarrhea, fatigue, infections, nausea and vomiting? Or can active surveillance benefit the person for months or even years?

It is difficult to answer such questions on a rare disease. Nevertheless, researchers are making progress when it comes to the treatment of Waldenstrom macroglobulinemia. Imbruvica (ibrutinib), a targeted therapy that inhibits the function of Bruton’s tyrosine kinase (BTK), was approved by the Food and Drug Administration in 2015. It is the first drug approved for the treatment of Waldenstrom. Other targeted agents and BTK inhibitors are currently being studied to hopefully expand the treatment field. These therapies typically have different side effects than the standard chemotherapy regimen and may be more manageable and tolerable.

Clinical trials continue to provide some of the answers needed to treat Waldenstrom macroglobulinemia, but only time will tell what is really in store for the future of these patients.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Articles

Editor's Page

Success in Cancer Care Doesn't Happen Overnight

Research continues to drive the oncology field.

Investigators are in the lab testing the newest drugs and cuttingedge techniques in hopes of extending the survival of people whose lives have been turned upside down by cancer — maybe one day even finding a cure.

But in a rare cancer, which is defined by the American Cancer Society as fewer than six cases per 100,000 people each year, the challenge becomes studying these diseases because of their rarity. Particularly, this is an issue in 

, cancer of the eye, because the risk factors are still not well defined. Our cover story focuses on refined radiation techniques that allow physicians to save the affected eye and preserve their patient’s vision, as well as drugs and combinations of drugs that are being studied in early-phase clinical trials. Two patients share their very different journeys with uveal melanoma — one woman developing metastasis to her liver and brain &mdash; and how they are doing today.

, we explore the latest innovations in treatment for 

, more commonly known as GBM. Each year in the United States, approximately 12,000 new cases of the rare and aggressive brain cancer are diagnosed. Once considered a disease with a very grim survival rate, patients are living longer thanks to new advances in surgery, drugs and diagnostics.

 to patients with rare pediatric cancers. Recent study findings show a response rate of more than 90 percent in those who harbor a specific fusion of two genes in their tumor when treated with larotrectinib. Having received a metastatic sarcoma diagnosis at 11 years old, one young girl from Texas entered a clinical trial. Two years later, she is back at school with her future goal in mind: moving to New York City to be a fashion designer.

And after brain surgery, radiation, chemotherapy and clinical trials, a 

 reflects on why she believes she is alive and thriving. Jeannine Walston shares her journey, what she has learned and how it has transformed her.

Also in this issue, a new drug approval for rare 

 may affect the survival of patients with anal cancer and recent 

From the Chairman

Driving Research in Rare Cancers

OVER THE PAST SEVERAL decades, the cancer community has celebrated great advances made in the fight against the disease. Some cancers, such as breast cancer, have received a tremendous amount of attention in the public arena and much interest from researchers. As a result, many promising new treatment options exist today for breast cancer, even for some of the most difficult subtypes of the disease.

Unfortunately, not all cancers have had the same widespread level of public interest and attention from researchers that breast cancer has enjoyed. For instance, not much changed in the treatment of sarcomas for more than 30 years. At the forefront are two drugs that did not work very well, Ifex (ifosfamide) and Adriamycin (doxorubicin), and they were given to all patients without distinguishing tumor type. Despite dismal survival outcomes, these drugs were the cornerstone for treatment of advanced softtissue sarcoma.

Sarcoma is a difficult disease to diagnose and treat, partly because sarcomas account for just one percent of all new cancers diagnosed annually in the United States. This represents roughly 10,000 to 15,000 patients each year, making it a rare cancer.

Rare cancers are more likely to be diagnosed at later stages, when they can be more difficult to treat than if found early, according to the American Cancer Society. Additionally, rare cancers usually have fewer treatment options because it is difficult to find enough patients to enroll in the clinical trials that are necessary to advance understanding of these diseases. Sarcomas also include from 50 to 70 histologies, each with a unique molecular biology. The rarity of a disease, large number of diverse histologies and lack of effective treatment options have made this group of cancers very challenging to manage.

Within the past five to six years, several new sarcoma drugs have been approved by the Food and Drug Administration (FDA), providing some headway against the disease. The first among these was Votrient (pazopanib), which was approved in 2012 for second-line treatment of advanced soft tissue sarcoma. When the drug became available, oncologists were very excited to have something new to offer patients rather than the same two drugs with exceedingly poor survival rates that had been around for decades.

In late 2015, Yondelis (trabectedin) was approved by the FDA for the treatment of two subtypes of soft tissue sarcoma, liposarcoma and leiomyosarcoma. It can be used for patients whose cancers are advanced or cannot be removed by surgery and who have been treated with anthracycline-based chemotherapy. Yondelis, a chemotherapy drug, created a lot of optimism, since it is a very novel compound that was well tolerated and provided some patients with a benefit.

By far, the most promising new drug to emerge for sarcoma over the last several decades is Lartruvo (olaratumab), a targeted therapy approved by the FDA in 2016 for the initial treatment of metastatic sarcomas. The monoclonal antibody binds to a receptor for a protein called platelet-derived growth factor. By blocking this protein receptor, the medication may prevent cancer cells from growing. Lartruvo is the first new drug approved for first-line treatment of soft tissue sarcomas since Adriamycin was approved more than 40 years ago. Prior to Lartruvo, the newly approved sarcoma drugs were all for second-line use.

Oncologists are extremely excited about Lartruvo, since it provides a new frontline therapeutic option for patients who previously had few choices and it is very well tolerated. A randomized phase 2 study demonstrated a near doubling of survival (26.5 versus 14.7 months) in patients with advanced or metastatic disease who were randomized to receive Lartruvo plus Adriamycin or Adriamycin alone. This was the single greatest advance for sarcoma treatment in decades and created hope in both patients and oncologists.

Unfortunately, adjuvant therapy — additional treatment given after the primary treatment to lower the risk that the cancer will come back &mdash; for sarcoma is still poorly defined. Not much headway has been made, and that probably will not change in the near future. The data for adjuvant therapy is exceedingly poor, and we have no better data today than we did five years ago. Plus, no major studies are in progress, so for the near term, adjuvant therapy remains a locked box for oncologists.

After years of no significant advancements, great progress in sarcoma treatment has been made in the last few years — but survival rates remain dismal. Although these rates are spread depending on the subtype of the disease, on average, overall survival is around 12 to 18 months. There is still a lot of work to be done. Massive change for the better may be on the horizon for sarcoma treatment on several fronts. New developments are coming down the pike looking specifically at the molecular and biological characteristics of sarcoma tumors. Researchers are beginning to differentiate the tumors, rather than just calling all of them “sarcomas,” and physicians are trying to treat them according to the subtype, with drugs approved for a specific subtype. Researchers are making progress in identifying where these drugs may be effective and, more important, where they most likely will not work well.

There is a new focus on targeting mutations, using genetic sequencing and next-generation sequencing analysis to see if there are any target mutations that could enlarge the therapy pool for sarcomas. For instance, PD-L1 (a type of protein found on cells in the body) expression status and what role immunotherapy can play are being examined.

Although emerging data exist on all of the new immunotherapy drugs, they are still largely experimental. Some have produced limited responses, and researchers are trying to sort that out, much like what has been done with other cancers. Several large ongoing immunotherapy clinical trials for synovial cell sarcoma and other sarcoma subtypes, at various institutions, will hopefully provide valuable data to guide further development of therapies. Because of the rarity of sarcoma tumors, more and more data concerning sarcomas and the use of immunotherapies will likely be seen in the future.

In the past, it was difficult to be optimistic about sarcoma, since, compared with the breast cancer world, it has largely been lost in the wind. Finally, however, for the first time in decades, oncologists have new quality data, exciting clinical trials that could lead to new therapies and promising new drugs to offer patients. Let’s hope the momentum continues.

ALEX SPIRA, M.D., PH.D., FACP, is co-director of the Virginia Cancer Specialists Phase 1 Research Program and co-director of The US Oncology Network Thoracic Oncology Program. A graduate of Harvard University, Spira earned his medical degree from the New York University School of Medicine. He then went on to complete his internship and residency at the Hospital of the University of Pennsylvania, and he completed his medical oncology fellowship at Johns Hopkins Hospital.

Speaking Out

New clinical trials have oncologists excited about potential new therapies for patients.

Progress in Sarcoma Treatment, But Still a Long Journey Ahead

PETER DeNARDIS ignored his doctor's first recommendation to be checked out. A blood test, biopsy and PET scan later revealed Waldenstrom macroglobulinemia. - PHOTO BY SARAH TORTOREA

In 2003, during a routine check on Peter DeNardis’s blissfully quiet Crohn disease, his gastroenterologist noticed something off in the bloodwork. He gave DeNardis a phone number, which he, of course, ignored. “I didn’t follow up,” he confesses, until his doctor called back to check on him. “It’s really important you follow up on that,” he recalls his doctor telling him.

DeNardis realized later he’d been downplaying his nosebleeds and generally rundown feeling. “Maybe it’s just sinuses,” he had thought. “I tend to have nosebleeds, but not like I was having at the time.” Chastened, he called the number — a hospital hematology department &mdash; and before long was booked for more extensive blood work, a bone marrow biopsy and a PET scan.

The tests revealed Waldenstrom macroglobulinemia, which is a rare cancer of the lymphatic system. Only about 1,500 cases are diagnosed in the United States each year — about 2 percent of all blood cancers. Also called lymphoplasmacytic lymphoma, it was lumped with multiple myeloma until 1944 when the Swedish physician Jan Gosta Waldenström described its uniqueness: increased viscosity (thickness) of blood as a result of high levels of a large protein, which is known as immunoglobulin M (IgM).

Waldenstrom macroglobulinemia is twice as common in men as in women, more common among Caucasians, and typically emerges in the mid-60s. DeNardis was 43 at the time. “Not only was I lucky enough to get it,” he says dryly, “but also I got it at an earlier age than normal.”

Lymphomas often develop from the misfiring of natural immune processes. For example, if you were to inhale a particle of flu virus, your B lymphocytes — white blood cells that are part of your immune system &mdash; would recognize the virus as foreign, triggering the lymphocyte to transform into a plasma cell that would make an antibody to the virus. “IgM is the first line of defense against any foreign protein,” explains Stephen M. Ansell, M.D., Ph.D., a hematologist at Mayo Clinic in Rochester, Minnesota. “In Waldenstrom macroglobulinemia, that process gets stuck.”

The result is a bunch of very active cells that proliferate in the bone marrow, crowding out healthier cells and making a very sticky antibody that gums up sensitive tissues, like nerve sheathes and the retina.

When a rare cancer is diagnosed at a community hospital, the doctor in charge does not usually have firsthand experience with it. Physicians try, but the first thing DeNardis heard was that he and his wife should put his affairs in order and delay treatment. He sought a second opinion. At a larger research hospital in Pittsburgh, his next doctor took a more aggressive line: Begin treatment immediately, using the common combination of fludarabine, cyclophosphamide and Rituxan (rituxumab).

“I tolerated it pretty well. I got a little fatigued, but I was still able to work every day,” DeNardis says.

Cyclophosphamide and fludarabine are classic chemotherapy agents, developed in 1953 and 1968, respectively. Rituxan was in the first wave of the next generation of targeted therapy; these drugs take aim at the unique genetics of each tumor and patient. In 1997, Rituxan was the first-ever Food and Drug Administration (FDA)-approved targeted cancer drug for use in patients with B-cell non-Hodgkin lymphoma that no longer responded to other treatment.

Because it is an antibody that targets a receptor on immunoglobin-producing B-cell lymphocytes, Rituxan was already being tried as Waldenstrom treatment, borrowed from other lymphoma regimens. DeNardis sought out the International Waldenstrom’s Macroglobulinemia Foundation (IWMF) online support groups, which buzzed with debate about the new drug. And the combination worked, giving him a six-year break from symptoms.

Now the IWMF channels are abuzz, as the targeting strategies pioneered with Rituxan are maturing. In 2015, Imbruvica (ibrutinib) became the 

 for Waldenstrom macroglobulinemia. Several other drugs using similar targeting strategies are in promising trials, and other agents using different targets are moving forward.

“The results are getting better and better, and the prognosis for patients actually has improved substantially,” says Ansell. “The key question then becomes what’s the best strategy when you have a long road to travel. It’s now clearly a marathon, not a sprint.”

One of the challenges in treating rare cancers is getting enough people into clinical trials to generate meaningful results. The flip side of this problem is that doctors can be somewhat creative in their approach. With no obvious treatment options until Imbruvica’s approval, Waldenstrom macroglobulinemia treatments over the last few decades borrowed liberally from a range of lymphoma treatments.

In 1999, Steven Treon, M.D., Ph.D., was a young oncological researcher working in multiple myeloma, where he had worked on the development of monoclonal antibody therapy. One afternoon in Boston, he met with a Waldenstrom support group and was surprised when more than 100 patients showed up. Many wanted to know more about Rituxan.

“Up to that time, there was very little for Waldenstrom. What little we had borrowed very heavily from other diseases, predominantly multiple myeloma, and those therapies were not working,” he says. Sometimes the therapy was worse than the disease, and patients died.

The IWMF boosters encouraged him, and they raised research money to ensure his commitment. In 2005, the Bing Center for Waldenstrom’s Macroglobulinemia, for which Treon serves as director, was officially formed at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston. Among its major accomplishments has been the identification of the MYD88 mutation seen in more than 90 percent of patients with Waldenstrom. The gene helps doctors tell Waldenstrom macroglobulinemia from similar B-cell disorders and is now used as a diagnostic marker for the disease.

Next came the discovery of the CXCR4 mutation, which occurs in up to 30 percent of patients with Waldenstrom. Both genes have a clear effect on the disease when mutated and lowered treatment response.

KLEPAC was told she had two years to live in 2001 following a Waldenstrom macroglobulinemia diagnosis. - PHOTO BY SARAH TORTOREA

Following the cellular signaling pathway mediated by MYD88 led Treon and his colleagues to Bruton’s tyrosine kinase (BTK), a piece of cellular biochemistry that — no surprise &mdash; plays a critical role in B-cell maturation. This was precisely the research needed for targeted therapy. The gene had been discovered in 1993, while a molecule designed to shut it down had been lurking on lab benches since the late ‘90s. Treon led a clinical trial of the BTK inhibitor Imbruvica in 63 previously treated patients with Waldenstrom macroglobulinemia. The drug delivered a 91 percent overall response rate &mdash; 77 percent with a major response. The study published in the New England Journal of Medicine supported the approval of Imbruvica for Waldenstrom in 2015.

Marcia Klepac had six years to prepare for her Waldenstrom macroglobulinemia diagnosis. In 1995, a routine blood test picked up an anomaly, and her doctor said she had monoclonal gammopathy of undetermined significance (MGUS), often a precursor to Waldenstrom or multiple myeloma.

“MGUS is quite challenging because many (patients) actually never develop a malignant process. One has to be very careful not to tell them they have a lymphoma when they don’t,” says Ansell. “Indolent disease can be even trickier, smoldering in the background for years. You could treat them and be patting yourself on the back for a fantastic result and have got that result anyway from just observing.”

That was Klepac’s dilemma when her Waldenstrom macroglobulinemia diagnosis became official in 2001. Her diagnosing physician wanted to treat, while the second opinion suggested waiting. She waited, and it was another year before the disease turned aggressive: nosebleeds, extreme fatigue, night sweats, day sweats. Her first treatment, cladribine with Rituxan — now used for hairy cell leukemia &mdash; went poorly. Her disease flared in response to the Rituxan, and she began to bleed from the eyes. “I knew something was drastically wrong,” she recalls. “My eyes were engorged with blood.”

Her doctor next suggested cyclophosphamide, doxorubicin, vincristine and prednisone plus Rituxan (R-CHOP), a standard treatment for non-Hodgkin lymphoma. But she wanted nothing more to do with chemotherapy and made an appointment in Boston to meet Treon. He also suggested R-CHOP first, then a trial for Campath (alemtuzumab), which failed. Then she found a trial for Genasense (oblimersen), another targeted drug that still hasn’t been approved.

It stabilized her disease at first, but then she relapsed. This was in 2003, and over the next 11 years, Klepac participated in multiple clinical trials — eight in total. Among the treatments she tried: Velcade (bortezomib), Velcade plus Rituxan, enzastaurin, Farydak (panobinostat) and Afinitor (everolimus) plus Rituxan plus Velcade. Throughout these, the best response she ever achieved was minimal &mdash; a 25 percent reduction in disease burden. “It’s amazing that you can keep going,” she says. “My quality of life was OK.”

By the time the Imbruvica trials opened, she knew she wanted it, but she had done too many trials to qualify. Instead she found another BTK inhibitor, spebrutinib, being tested at Cleveland Clinic in Ohio. It worked for a time, but then her disease grew very aggressive. Imbruvica still hadn’t been approved by the FDA for Waldenstrom, but her oncologist could prescribe it, and in early 2014 she began treatment. Finally, she experienced a good partial remission. Her IgM dropped significantly in just a few weeks, and it continues to drop. Her white blood cell and platelet counts also soared. “I couldn’t believe those were my real blood tests,” she says.

She’s still on it, four years later. In 2001, the best guesses gave her two years. “I was prepared to die,” says the now 73-year-old. “I just feel like it’s surreal that I’m even here.” Is it ironic that after so many trials, she wasn’t even on the trial that made the difference? That’s not how she sees it. “I was very, very involved with every decision that was made with treatment because I just could not leave that up to somebody else,” Klepac says. “I had to buy into and feel good about it or otherwise I couldn’t go through with it. I would feel helpless.”

“In a short period of time, we have giant leaps forward. And if you look at Waldenstrom it really is an example of how we are winning the war on cancer,” says Treon. Imbruvica continues to impress. Five years after the trial, the progression-free survival numbers continue to improve. In June, the FDA granted a priority review for Imbruvica in combination with Rituxan as a treatment option across all lines of therapy for patients with Waldenstrom macroglobulinemia. This was based on the phase 3 iNNOVATE trial, which showed that the combination lowered the risk of disease progression or death by 80 percent versus Rituxan alone.

And there are many BTK inhibitors in the pipeline. Zanubrutinib (BGB-3111) and Calquence (acalabrutinib) are both in clinical trials. Calquence was approved last year for mantle cell lymphoma.

Judith Trotman, M.D., director of the Clinical Research Unit in the Hematology Department at Concord Hospital in Sydney, Australia, gives zanubrutinib a glowing review after watching it act in a phase 2 trial. “That was quite a phenomenal experience, as a clinician, to see these patients get so well, so quickly. And, I believe, with minimal side effects,” she says. If it achieves final regulatory approval, it could have other beneficial effects. “I hope they jolly well get to market and drive these prices down,” Trotman adds.

Among the promising results, oncologists are particularly curious about the head-to-head trial of zanubrutinib and Imbruvica. Whereas zanubrutinib is very tightly focused on BTK, Imbruvica acts on a slightly broader level, shutting down related processes as well. “I think we’re going to find out if a very targeted BTK inhibitor is a better or a less good thing (compared with) a targeted — but maybe not quite as clean &mdash; inhibitor such as Imbruvica,” says Ansell.

“Even within BTK inhibitors, I think it’s important for all of us to recognize that there are going to be potentially fundamental differences in their mechanisms of action,” agrees Treon.

But that’s not all. Treon is running a trial of Imbruvica with ulocuplumab, a CXCR4 inhibitor, hoping to close the gap for patients who don’t respond well to Imbruvica because of their CXCR4 status.

And then there is Venclexta (venetoclax), a B-cell lymphoma 2 inhibitor that targets the suicide mechanisms of cancer cells. Approved in 2016 for use in a subset of patients with chronic lymphocytic leukemia, it also shows promise in Waldenstrom macroglobulinemia in combination with Imbruvica.

As exciting as Imbruvica is for the typical patient with Waldenstrom, it’s not enough. “We want to be pushing the envelope in terms of combinations for younger patients," argues Trotman. “Taking a tablet every day and waiting until your disease progresses years down the track is not an appealing solution. Should we be trying to get these patients a sustained complete response and, ideally, the ability to stop therapy?”

Ansell, as excited as he is about Imbruvica, agrees the tradeoffs for different patient groups are real.

“We actually have a number of frontline therapeutic options which are usually very successful in treating the disease,” he says. “However, the treatments are expensive.”

With Imbruvica, for example, the patient takes a pill every day for the foreseeable future, at a price tag of about $150,000 per year. Treanda (bendamustine) and Rituxan, meanwhile, runs about $120,000 for a four- to six-month course of treatment.

“You get similar outcomes when these drugs are used as the first treatment that are now approaching five-plus years,” says Ansell. Treanda and Rituxan are considerably cheaper and may offer a significant treatment holiday as well, he adds.

There are risks that go with the rewards. Immunotherapy is another hot field, with lots of excitement around checkpoint inhibitors, such as Opdivo (nivolumab) and Keytruda (pembrolizumab).

Trotman’s group was running a trial combining zanubrutinib with an investigational PD-1 inhibitor called tislelizumab (BGB-A317). The result was nearly disastrous for two patients, who developed reactions to standard blood transfusions. Both patients developed life-threatening uncontrolled hemolytic anemia, where red blood cells are destroyed faster than they can be replaced.

“This was quite a profound immune response that was triggered by the addition of the PD-1 inhibitor in both patients,” Trotman says. “We latched on to it quickly because they were treated contemporaneously at one institution.” They have no explanation, but published the event quickly to raise a warning flag.

The mysterious challenges of cancer are redoubled in rare cancers. If Waldenstrom macroglobulinemia was a common cancer, there might be a pattern in the rare events. But in rare cancers, the rare events are so unique that they can be inscrutable.

That’s true for DeNardis again. His disease is back, sometimes. Sort of. The doctors can’t find testable traces of Waldenstrom in his blood or his bone marrow, yet solid tumors keep recurring in his body. They know they need to treat it, but will the new agents coming out of the lab do the trick?

“The pace of development, especially for our disease, is amazing and it continues to surprise me,” says DeNardis. “I don’t know if it’s going to help me because I have unusual manifestations of an already unusual disease.”

Features

This incurable rare cancer of the lymphatic system has seen improvements, but what is the best strategy for treating patients with the disease?

Waldenstrom Macroglobulinemia: The Discovery and What Lies Ahead

EARLY ON IN HIS career, Andrew Chi, M.D., Ph.D., chief of neurooncology and co-director of the Brain Tumor Center at NYU Langone Health in New York City, learned to be careful in how to introduce his new patients with glioblastoma multiforme (GBM) to palliative care; that is, care that does not seek to cure but to improve pain management and quality of life.

“(The) current consensus is to, ‘Start talking about palliative care early. Be realistic.’ But if you don’t approach those topics carefully with new patients, they may not come back,” Chi explains. “If you’re a young man in your 40s with kids, and you’ve just been diagnosed, most likely you want to talk about fighting, not looking to ease suffering.”

After several patients failed to return for a second visit, Chi changed the way he talked about this issue. “During my initial visits, I often call it ‘supportive oncology,’ instead of palliative care,” he says. “I advise our patients with GBM to see our palliative care practitioners early to talk about social support, depression, pain management, help at home.”

Chi emphasizes that the provider’s role is palliative care. He deemphasizes the association with hospice care, instead focusing on palliation, or alleviation of suffering. Unfortunately, the term palliative care, which nearly all doctors say, has been linked in the public’s mind to hospice and end of life. This leads many patients to fear the concept.

A December 2017 study in Current Oncology found that when patients learned that palliative measures can complement curative treatments, most of them expressed interest in these services.

GBM poses many challenges for patients: Abilities often decline quickly after diagnosis, and treatments can be aggressive.

Neither patients nor their loved ones and caregivers feel they have time to consider social support, mental health and so on when they are dealing with an avalanche of medical information and fighting for life. But doing so can reduce stress and increase quality of life, experts say. Even patients who do well from a standpoint of cancer may continue to live with physical and emotional distress.

“We consider palliative care one of the essential pillars of caring for patients with glioblastoma,” says Vinai Gondi, M.D., director of research and education at Northwestern Medicine Chicago Proton Center in Warrenville, Illinois. “There are a wide range of initiatives seeking to give these patients access to supportive care, how best to help support needs at home.”

Many patients with GBM are too ill to attend support groups and meet with counselors outside the home, explains Richard Dickens, MS, LSW-R, director of client advocacy for CancerCare, a nonprofit organization that provides counseling, education and other support to patients with cancer.

Dickens suggests that patients with GBM join a telephone or online support group to connect with others in a similar situation. CancerCare offers these groups for both patients and caregivers. Online services to coordinate a group of caregivers also are available from other groups, such as Lotsa Helping Hands.

“Patients with GBM have big issues,” explains Sean Grimm, M.D., director of neuro-oncology at Northwestern Medicine Cancer Center, also in Warrenville. “They go from working to not working, they suffer from depression, they need help at home. They need help getting disability. They have neurologic symptoms that require rehab and physical therapy. They need help with nutrition. All (of) these things are important. Palliative care includes all (of) these things.”

The approach used in discussing palliative care can play a role in whether a patient seeks help.

Power in the Words: Discussing Palliative Cancer Care

JESSE WALDINGER'S tumor was found during an eye exam. Fortunately, it was discovered early and his vision was saved. - PHOTO BY AMBER BAUHOFF

Jesse Waldinger had been putting off his annual eye exams because his vision wasn’t changing. He just didn’t think it was necessary to see an optometrist. When his vision started declining in 2017, he booked an eye exam, where he was stunned to learn he had a tumor in his right eye. The diagnosis was uveal melanoma.

Waldinger underwent plaque brachytherapy — a procedure that involves putting a temporary implant in the eye that delivers a concentrated dose of radiation to the tumor. There is no detectable cancer in his eye today.

“My vision is not back to normal. I cannot easily keep both eyes open when I read. But I can drive,” says Waldinger, 71, who also had a follow-up laser procedure to remove dead tumor tissue from his eye. “I am really lucky,” he says of his experience with uveal melanoma. “I had a tumor that was caught early.”

The uveal tract is made up of three regions, all of which are susceptible to melanoma. The first is the iris, the circular pigmented structure that governs how much light reaches the retina. Then there’s the ciliary body, which includes the muscles that help shape the lens. The third element is the choroid, a layer of the eye that contains veins and connective tissue.

Tumors that form in any of these regions are not related to skin melanoma, although both emerge from melanocytes, which are cells responsible for producing pigment.

The risk factors for uveal melanoma are still largely unknown. About 2,500 adults in the United States are diagnosed each year, most of whom are light-skinned individuals, according to the Ocular Melanoma Foundation. Men face a slightly higher risk. Most cases, including Waldinger’s, emerge from the choroid and appear out of the blue. But because uveal melanoma has been reported to run in some families, studies have been launched to identify genetic mutations that may be responsible for the disease.

The five-year survival rate for uveal melanoma that’s confined to the eye is 80 percent, according to the American Cancer Society (ACS). Radiation treatments like plaque brachytherapy are popular because they can be delivered straight to the tumor, sparing healthy tissue and preserving vision. Brachytherapy discs containing tiny radioactive seeds are implanted in the eye and then removed four to seven days later, according to the ACS, depending on the size of the tumor and strength of the radiation source.

“Plaque brachytherapy offers a greater than 90 percent likelihood of controlling the disease in the eye,” says Jasmine Francis, M.D., an ophthalmic oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City. “It used to be that only the smallest tumors were eligible for radiation, but now we’re treating eyes with larger tumors, up to a maximum of about 22 millimeters in diameter.” Proton therapy and other external-beam radiation techniques are also used in some patients. Side effects can include eyelash loss, dry eye and cataracts, and some patients have vision loss in the treated eye months or years after treatment.

The ongoing refinement of radiation techniques is allowing more and more patients to avoid “enucleation,” the technical term for the removal of the affected eye. But patients with large tumors may be urged to have the entire eye surgically removed and replaced with a prosthesis. Some oncologists will try shrinking the tumor with radiation before surgery.

Half of patients with diagnosed uveal melanoma develop metastatic disease, which can be treated with chemotherapy given intravenously or directly in the eye. But in patients whose disease has spread, the five-year survival rate is just 15 percent. That’s why so much of the research in uveal melanoma is focused on treating and preventing metastasis.

About 90 percent of patients with metastatic uveal melanoma have tumors in their livers, which can be directly targeted with a variety of treatments. They include radiation, implanted beads that deliver the chemotherapy drug Adriamycin (doxorubicin), and transarterial chemoembolization, a procedure that involves cutting off the blood supply to liver tumors by inserting a material such as gelatin sponge into the arteries that feed them. A recent study of more than 600 patients treated over the last 45 years at Thomas Jefferson University in Philadelphia found that patients who received liver-directed therapies survived on average for 5.1 years — significantly longer than the 3.3-year overall survival (OS) rate of those who underwent intravenous chemotherapy.

Several drugs that stimulate the immune system to recognize and attack uveal melanoma are being developed, and some are showing promise in early studies. IMCgp100 is a “bi-specific” drug that combines two elements: The first is a T-cell receptor — a molecule on the surface of immune cells &mdash; that’s designed to home in on the antigen gp100, which is prevalent on uveal melanoma cells. The second is an antibody fragment that binds to cancer-killing T cells. “The drug binds to the cancer and it brings T cells within the cancer right next to the tumor cell. By doing that it causes tumor lysis, or cell death,” says Richard Carvajal, M.D., director of experimental therapeutics at Columbia University’s Herbert Irving Comprehensive Cancer Center in New York City and one of the clinical trial investigators for the drug.

In a phase 1/2 study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June, patients with metastatic uveal melanoma who were treated with IMCgp100 had a one-year OS rate of 74 percent, with the median OS not reached and a median follow-up time of over 19 months. Sixty-six percent of patients survived for one year without seeing their disease progress.

In this trial, “the percentage of patients who were alive after a year was almost double what we would expect, based on historical controls,” says Carvajal. “So we’re seeing this really intriguing signal in terms of overall survival benefit, which we’ve not seen before with other drugs.” A randomized pivotal phase 2 trial is currently underway to confirm this benefit.

Another promising treatment for uveal melanoma is called adoptive T-cell therapy. This procedure involves taking tumor-infiltrating lymphocytes (TILs), which are immune cells that have a natural ability to recognize and kill tumor cells; growing them in a lab; and re-infusing them into patients. In a phase 2 trial published in 2017 in The Lancet Oncology, seven of 20 patients who had the procedure saw their metastases shrink. Liver tumors in one of the patients disappeared, with no signs of recurrence 21 months after the therapy. Another phase 2 study of TILs in metastatic uveal melanoma is underway at the University of Pittsburgh.

The University of Texas MD Anderson Cancer Center in Houston has started a phase 2 study of an adoptive T-cell therapy that involves removing T cells from patients’ blood and engineering them so they can target melanoma cells. Patients receive the T cells along with the chemotherapy drug cyclophosphamide and the blood protein interleukin- 2, which “is like Miracle-Gro for the T cells,” prompting them to make copies of themselves so they will continue to recognize and attack cancer should it recur, says Sapna Patel, B.A., M.D., assistant professor of melanoma medical oncology at MD Anderson. Although it’s designed to be a one-time treatment, patients who relapse may be eligible to receive a second dose of T cells, she adds.

Several trials are underway combining different methods of attacking uveal melanoma. For example, an experimental drug called indoximod that blocks indoleamine 2,3-dioxygenase — a checkpoint that normally prevents the immune system from recognizing and targeting cancer cells &mdash; is being tested with Keytruda (pembrolizumab), a programmed cell death protein 1 inhibitor approved by the Food and Drug Administration for other indications. A phase 2 trial examined the combination in 102 patients, 15 of whom had the ocular form of the disease. Data presented at ASCO showed an overall response rate of 55.7 percent to the combination, which was an improvement over the reported 33 percent overall response rate to Keytruda alone.

Treatments that target certain proteins that are prevalent in uveal melanoma are also being investigated, although they have mostly been disappointing so far. Carvajal recently led a phase 3 trial of the experimental drug selumetinib, which inhibits the enzymes MEK1 and MEK2, commonly found in uveal melanoma and other tumors. The trial concluded that adding the drug to the chemotherapy treatment dacarbazine did not improve progression-free survival for patients with metastatic disease. Carvajal is hopeful ongoing studies of the drug with different dosing schedules or other types of chemotherapy will produce better results.

Additional studies underway are investigating methods for limiting metastasis and preventing recurrence in uveal melanoma. For example, the lung cancer drug Xalkori (crizotinib), which addresses a defect in a gene called ALK, is in phase 2 trials in patients whose uveal melanoma is confined to the eye but who are deemed to be at high risk for metastatic disease.

Another trial is investigating the potential in patients at high risk for metastatic disease of the drug Sutent (sunitinib), which inhibits multiple cancer-promoting proteins.

KATIE DOBLE and her dog, ALICE, have matching eyes. Doble's eye color changed to brown after a series of procedures related to her cancer. - PHOTO BY RYAN DEARTH

The proliferation of clinical trials in metastatic uveal melanoma has benefited patients like Katie Doble, who received her diagnosis in 2013. After multiple metastases were found in her liver in 2014, she participated in one trial of a MEK inhibitor, another combining two immunotherapies, and a third of an antibody called glembatumumab vedotin, which targets a protein called glycoprotein NMB that’s found in abundance in multiple tumor types, including uveal melanoma. Doble’s cancer didn’t improve as a result of the experimental treatments, so she received two treatments with radioembolization — radioactive particles delivered straight to the liver.

“I feel that the clinical trials bought me some time,” says Doble, 36, a vice president at an executive recruiting firm in Denver. Doble was married in 2015 and has screening images taken every three months. She took a break from therapy, but after metastases showed up in her brain in May 2018, she underwent gamma knife radiation to treat them.

As genetic sequencing technology advances, discoveries of mutations that drive uveal melanoma could point to new therapies. Some genes that drive the disease have already been identified, including BAP1, EIF1AX, GNA11, GNAQ and SF3B1. While being treated at MSK, Waldinger was tested for abnormalities in BAP1. He tested negative. “I have no doubt this was genetic” Waldinger says. “Even though they haven’t yet figured out what genes cause it and to what it extent, I believe it is hereditary.”

Clinical trials seek to discover new ways to attack the disease, limit metastasis and prevent recurrence.

Advances and Combinations Raise Sights on Uveal Melanoma

ANNE MURRAY, with her son, BRENDAN. - PHOTO BY MICHELLE BABYAK

Six years ago, Anne Murray, an occupational therapist, visited John Andrew Boockvar, M.D., vice chair of the department of neurosurgery, and director of the Brain Tumor Center at Lenox Hill Hospital, a member of Northwell Health, the largest health care system in New York state. Murray had received a diagnosis of glioblastoma, often referred to as GBM — one of the most aggressive forms of brain cancer.

With her prognosis dire and worried about her then 9-year-old son, she consulted with Boockvar, who was an attending physician at Weill Cornell Medical Center at the time, about a clinical trial of an experimental treatment using intra-arterial drug delivery in which the tumor blood vessel-inhibiting drug Avastin (bevacizumab) would be administered directly to her tumor, as opposed to systemic therapy (intravenously). She responded so well to this one-time treatment that she felt as if a fog had cleared when she woke up. “I went in to the procedure pretty confused,” says Murray, now 48. “But when I woke up, I knew where I was. I knew that my husband was waiting for me in the ICU step down unit. I knew what I had just been through. I asked the nurse, ‘This is crazy, but could this have already worked?’”

In the months that followed, Murray’s tumor, which had been growing out of control, shrunk back to a manageable size. Murray now goes for regular MRIs, but doesn’t take any medication. She also works a few hours a week. She feels her positive attitude has come from the support she receives from her caregivers, friends, the community and her church, St. Rose of Lima.

“The fact that I got to celebrate my son’s 15th birthday was such a gift,” says Murray, who lives with her son and husband in Newtown, Connecticut. “I didn’t know if I was going to be around. We do a lot of celebrating around here.

I’ve set a new goal: I want to dance at my son’s wedding.” This sense of hope wasn’t always the case in this disease type. “If you read glioblastoma textbooks, this type of response shouldn’t happen,” says Boockvar. “We used to be nihilistic, just do a needle biopsy and that’s it. We thought there was nothing we could do to prolong the lives of patients with GBM. Now, there’s optimism in the field. My slogan now is ‘strive for five.’ We can keep 5 percent of patients with glioblastoma alive for five years. Then we can hope that during those five years, another treatment will come along and that will allow us to keep patients alive for another five years.”

GBM remains incurable, a devastating malignancy. However, Boockvar points out that 30 percent of patients will survive two years. Of those that make it to two years, half will make it to three years. And then there are the five-year survivors. A 2009 study found that as many as 10 percent might make it this far. Some live even longer: Boockvar has a patient diagnosed at 20 years old who is now nine years out, getting on with his life and going to college.

Brain cancer specialists emphasize that these long-term survivors are outliers. A generation ago, only the very rare patient with glioblastoma survived this long and the median survival after diagnosis was nine months. Now, that median survival figure, taking into account the whole range of outcomes, has crept up to 14.6 months. Meanwhile, advances in surgical and radiation techniques, new drugs, better diagnostics, and a newly energized research community seem to indicate that the outlook will continue to improve. “We’re not just looking for random outliers,” explains Andrew Chi, M.D., Ph.D., chief of neuro-oncology and the co-director of the Brain Tumor Center at NYU Langone Health in New York City. “We’re looking to learn from those outliers. Maybe we can unlock the keys as to why those patients survive so long.”

Gliomas are a malignancy of the brain’s supportive tissue, or glial cells, from the Greek word for glue. Astrocytomas, a type of glioma, arise from one kind of glial cell, called astrocytes because the cells are star-shaped. GBM is the highest grade of glioma (grade 4) and is the most malignant form of astrocytoma. About two-thirds of gliomas are GBM. In the United States, approximately 12,000 new cases of GBM are diagnosed each year.

As brain tumors grow, they often crowd out or interfere with normal brain structures and functions, creating symptoms such as headaches, seizures, memory loss and behavior changes. Experts say that several things make GBM particularly challenging: First, it occurs in the brain — that limits how much of a tumor can be taken out or irradiated. In addition, this malignancy grows behind the blood-brain barrier, which is a wall of specialized cells that keeps most compounds from migrating from the bloodstream into the brain. That makes it difficult to deliver drugs to GBM tumors.

As if that weren’t enough, GBM tumors are diffuse, tentacle like spreading through the brain rather than concentrating in one or several places like most breast or lung tumors. And spidery GBM is always aggressive, changing and morphing to escape from immune cells and other enemies. One part of a tumor may have different genetics in different areas. Often, when these tumors recur, the genetics have completely changed, making them an entirely new adversary to the medical team.

“One of the biggest challenges of this disease is that it is so heterogenous. That is, it’s so different in every patient, and not every part of the tumor is the same. You’re playing whack-a-mole, trying to kill all (of) the different kinds of GBM cells,” explains Linda Liau, M.D., Ph.D., M.B.A., director of the Brain Tumor Program at the University of California Los Angeles.

One of the most profound advances has been the Food and Drug Administration’s (FDA) approval of two medications specifically for the treatment of GBM: In 2005, Temodar (temozolomide) received full FDA approval for the treatment of adult patients with newly diagnosed GBM concomitantly with radiotherapy and then as maintenance treatment. The medication works by damaging the DNA of tumor cells, leading to cell death. Then, in 2009, the FDA granted accelerated approval to Avastin for GBM that occurs after prior therapy. Last year, it received full approval. Avastin can control swelling caused by the cancer, or by treatment, thus decreasing dependence on corticosteroids that can have serious side effects. However, it has not been proved to improve survival outcomes.

Researchers continue to look for new drugs, or new combinations of old drugs, that may be effective, such as BiCNU (carmustine), Gleostine (lomustine), Gliadel wafer (biodegradable discs infused with BiCNU), Temodar, cisplatin, carboplatin, etoposide and irinotecan are examples of cytotoxic drugs that kill tumor cells. They may be given as a single agent or in combination. For instance, two commonly used combinations in GBM include procarbazine, Gleostine and vincristine, as well as carboplatin/etoposide, according to the American Brain Tumor Association. Not all of these drugs have been approved by the FDA. Only BiCNU/Gleostine, Avastin, Gliadel wafer and Temodar are approved for the treatment of high-grade gliomas. Others are approved for the treatment of different cancers, and must be prescribed off label for brain tumor use. “There are probably nine off-label drugs for glioblastoma that probably work,” explains Boockvar. “But we’re waiting on the data.”

Meanwhile, a new era in which genetic sequencing — analyzing the genetic code of tumors &mdash; has become faster and less expensive and has led to the identification of many potential genetic and metabolic targets that might lead to breakthrough treatment. It has also made more fine-grained diagnosis possible that combines genetic information and how tumor cells look under a microscope. Doctors use both genetic sequencing and imaging techniques, such as MRI with contrast dyes to make the tumor cells stand out and CT scans to diagnose the disease and characterize it.

For instance, based on genetics, GBM has been divided into two major subgroups: IDH wild-type (90 percent) and IDH-mutant (10 percent). IDH wild-type GBM tends to be more malignant, so knowing the subtype helps physicians decide how aggressively to design treatment. In addition, GBM tumors with an inactive gene called methylated MGMT, found in 50 percent of GBM cases, predicts longer survival.

Genetic mutations, changes in what proteins are produced under the direction of those genes, point to other potential GBM markers. For instance, many growth factor receptors — epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor &mdash; are either mutated or overexpressed in GBM, thus removing the cellular brakes and allowing the tumor cells to go into overdrive. Ongoing clinical trials are now testing treatments that could inhibit these growth factors. One clinical trial is testing a DNA vaccine, INO-5401, that seeks out three markers overexpressed in GBM. Other trials are examining AG-120, an oral drug that inhibits the IDH1 mutation.

“We’ve learned a lot of biology in the last 10 years,” says Chi. “We need to study each one of these subgroups, both in terms of biology and in terms of what works in the clinic. We will be able to treat one subgroup eventually, and it will take off from there.”

“There is just a ton of research going on right now. There’s real ferment,” says Sean Grimm, M.D., codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center in Warrenville, Illinois.

Most experts caution that it will take time to figure out ways to design and deliver drugs that can reach those various targets, and to figure out what works. Various research groups are working on myriad ways to get around the blood-brain barrier.

They are using gold nanoparticles, viruses (polio, adenoviruses or herpes virus), specially engineered genes, antibodies and stem cells, combining viruses with oral drugs. In a sense, these delivery mechanisms, or vectors, act like specialized smart bombs that can get around the brain’s defenses and deliver treatments where they need to go.

Other methods in clinical trial are more mechanical: Some teams spray chemotherapy agents into the surgical site. Others leave radioactive beads or biodegradable wafers to deliver a high dose of local radiation. Convectionenhanced delivery employs a pump to slowly drip anti-tumor agents into the site. In another method, a biodegradable Gliadel wafer that cannot be removed is left in the tumor cavity after surgery to release a chemotherapy drug into the tumor tissue.

In tandem with drug development, GBM surgery has been making strides. GBM cells spread like tentacles, as previously mentioned, and usually cannot be totally removed, surgeons say. Additionally, brain tumors are not always visible, nor are they always easy to access. A century ago, surgeons would remove half of a brain hemisphere in a patient with GBM in an attempt to get every last tumor cell. Eventually, surgeons found that method didn’t help: Removing that much of the brain eliminated much of the patient’s abilities and personality, and tumors still eventually grew in the remaining half of the brain. Today, neurosurgeons have to balance on a knife’s edge: They try to remove as much of the tumor as they can while avoiding damage to abilities such as movement, sensation or speech. Computerized brain mapping, much like GPS, makes it possible for surgeons to find their way more accurately.

Performing MRI scans while the patient is still in the operating room (intra-operative MRI) does as well. Stereotactic computerized surgical equipment also improves accuracy. In some cases, surgeons use a local anesthetic so they can perform awake craniotomies, asking for patient feedback as they remove tissue so as to avoid too much damage. And when a tumor recurs, surgeons now can do minimally invasive, MRI-guided biopsies so that the medical team can evaluate whether this is a new tumor or tissue damage from treatment. After surgery, the standard of care in GBM is usually radiation five days a week for five or six weeks. A kind of local radiation, which more precisely targets larger doses of radiation, may be used, such as stereotactic radiosurgery, proton beam therapy or image-guided radiation therapy.

CARMEN MIRANDOLA on vacation with his wife, JULIE, daughter, ALEXA, and son, NICO, following surgery and treatment in March 2018. - PHOTO BY COURTESY CARMEN MIRANDOLA

Although results from earlier studies have showed no benefit to continuing radiation beyond six weeks, researchers today are looking at whether new more precise methods can increase the dose or the duration of radiation to better effect. Carmen Mirandola, a sales area manager from suburban Chicago, was on a business trip to Colorado in February 2017 when he suddenly started to have strange symptoms, small seizures and tremors. Colleagues took him to the local emergency department, where a scan found a small mass in the right frontal lobe of his brain. When he returned home, a biopsy confirmed a GBM diagnosis. Mirandola’s surgeon at Northwestern Medicine Central DuPage Hospital was able to remove all of the tumor, often not possible in GBM. After that, Mirandola participated in a clinical trial in which he received proton radiation therapy and Temodar. After more than a year of treatment, he says, his medical team has told him that he may be one of those lucky patients who may survive a decade or more.

“It feels like I’ve been given a second, third and fourth chance. I feel so grateful to Northwestern and my team there,” says Mirandola, 51. “I believe in miracles, the power of prayer and proton radiation.”

Radiation causes DNA damage that leads to the death of tumor cells. Temodar enhances this. Some studies’ findings suggest that radiation doses and timelines can increase as much as 30 percent and improve GBM survival post Temodar. When the timing of radiation and Temodar doses are coordinated, early results from the ongoing CATNON study also showed benefit. Other teams are investigating whether radiation or proton therapy can be used when a GBM tumor recurs.

The FDA has also approved electric field therapy for GBM: Optune is a wearable device that delivers continuous electric pulses to the tumor, through adhesive patches — transducer arrays &mdash; applied to the scalp and connected to the device and a battery. The Optune device must be worn for at least 18 hours a day.

Although FDA approved, Optune remains controversial among neuroscientists. Some sharply criticize the lack of a sham device to the clinical trials that led to its approval. Others say they’re concerned that it remains unclear what biological mechanism makes the treatment work.

“Although trials show some efficacy, most feel that the impact is not dramatic enough that it will become a mainstay of brain tumor therapy,” explains Theodore Schwartz, M.D., professor of minimally invasive neurosurgery at Weill Cornell Medicine in Manhattan.

Further out on the research edge, GBM investigators are trying to determine if an exciting new area of cancer research, immunotherapy, may work for these aggressive brain tumors. Cancer vaccines attack GBM cells by using genetically engineered cells to stimulate the immune system and cause a response. Some teams are looking at chimeric antigen receptor T-cell therapy, which re-engineers a patient’s own immune cells so that they target specific receptors on tumor cells. Other trials are looking at checkpoint inhibitors, which block normal protective proteins on cancer cells, allowing the immune system to target them. So far, trials with checkpoint inhibitors haven’t seemed to make a difference in GBM, but experts say there’s still work to be done here and with Optune.

“There are so many highly trained, smart, qualified researchers devoting their lives to tackle this disease. Patients should feel hopeful,” says Schwartz. “We are making progress. It’s slower than we would like, and patients would like, but look for leaps and bounds of innovation in the coming years.”

Innovations in drug development, surgery, radiation and clinical trials have investigators hard at work in glioblastoma.

Turning the Tide in Glioblastoma

BRIANA AYALA, 13, benefited from a larotrectinib clinical trial led by THEODORE LAETSCH, M.D.

A DRUG THAT TARGETS a fused gene frequently found in some rare pediatric cancers has shown great promise in a clinical trial of patients ranging in age from 1 month to 21 years, according to researchers from the University of Texas Southwestern Medical Center in Dallas.

The phase 1/2 study, published in The Lancet Oncology, included 24 patients and was conducted from December 2015 to April 2017 at eight U.S. sites. Larotrectinib, a tropomyosin receptor kinase (TRK) inhibitor, was administered to patients twice daily.

“Every patient who had a TRK fusion had their tumor shrink with this therapy,” Theodore Laetsch, M.D., an assistant professor of pediatrics at the Harold C. Simmons Comprehensive Cancer Center and leader of the Experimental Therapeutics Program at Children’s Health in Dallas, told CURE® in an interview. “Almost all of them decreased in size enough to qualify as an objective response by our preset criteria.”

All patients had been diagnosed with locally advanced or metastatic solid tumors or central nervous system tumors that had relapsed, progressed or were nonresponsive to available therapies, regardless of TRK fusion status. The 17 patients whose tumors harbored TRK fusions had primary diagnoses of cancers such as infantile fibrosarcoma, other soft tissue sarcomas and papillary thyroid cancer.

Researchers were able to evaluate 22 patients. Of the 15 who harbored TRK fusions, all but one showed an objective response by investigator review. Four patients saw no signs of cancer (complete responses) and 10 saw their tumors shrink (partial responses). One patient’s initial partial response became stable disease at a later assessment. Independent radiology review confirmed objective responses in 14 (93 percent) patients with two complete and 12 partial responses. The seven patients without TRK fusions had progressive disease as best response.

“The TRK fusion is like an engine that’s always turned on, and it’s turned on because two genes are stuck together,” Laetsch said. “One gene is supposed to be turned on as a normal gene in your cell. The TRK gene is supposed to be turned off. But they’re stuck together, so that first gene turns on the TRK gene, so it’s continually active and driving the cells to grow and become cancerous.

This drug blocks the activity of that TRK gene, so it turns off the signaling that drives the cancer.” Briana Ayala of El Paso, Texas, is one of the study participants who has had a great response to larotrectinib. In 2016, she received a diagnosis of metastatic sarcoma and underwent surgery, but surgeons couldn’t remove the entire tumor. She had failed to respond to other types of chemotherapy, so her medical team was out of options. Laetsch then conducted genetic testing of her tumor, which revealed she had a TRK fusion. “Briana has had a great and prolonged response to this drug with very minimal side effects,” he said, “and that’s really what we have seen in the vast majority of patients.”

Within weeks, the girl’s tumor shrunk significantly. Now 13 years old and back in school, Ayala tells CURE® she is feeling much better but was hesitant about returning to her friends. “When I first went back to school, I was glad — and a little nervous because I had changed a lot in my appearance,” she said.

Ayala spends her days drawing — she aspires to be a fashion designer in New York City &mdash; and walking her miniature poodle, Goofy. She credits her faith with helping her through the tough days and shared that message with a young girl who was crying during a visit to the clinic. “I told her that she needs to act positive so she can fight her disease. I told her, ‘Don’t worry, God is with you. Don’t fear,’” she said.

Because Ayala remains on the clinical trial, she has an exam and lab testing done every month, plus scans every three months to make sure her tumors are doing well. “For a long time, we have been hoping that using the genomics of cancer, or the specific gene changes, may be able to allow us to target therapy and give patients specific drugs that block those gene changes,” Laetsch said. “This is one of the best examples of where that sort of form of precision medicine or targeted therapy has really been successful at helping the vast majority of patients with these rare fusions.”

The researchers noted that 21 of the 24 total patients experienced side effects, but only four were grade 3 treatment-related.

Larotrectinib has been submitted to the Food and Drug Administration for approval based on the findings of this trial, as well as those of a study published in the New England Journal of Medicine that showed a 75 percent response rate in 55 adult patients.

Because the results have been so dramatic, a phase 3 trial is unlikely, Laetsch said. He hopes to study larotrectinib in patients who haven’t failed prior therapies, he said: “Do it up front and look at the efficacy of this drug in newly diagnosed patients with TRK fusion-positive cancers, so we don’t subject these patients to all the chemotherapy and side effects that come with it.”

Pipeline

Early study results show response to therapy in more than 90 percent of patients.

Larotrectinib May Offer a New Way to Treat Children With Rare Cancers

ALTHOUGH TREATMENTS FOR ANAL cancer are often effective and even curative, patients with the disease who live in areas with a low median-household income are at increased risk of early death, according to the results of a recent study published in Cancer, a peer-reviewed journal of the American Cancer Society (ACS).

The lifetime risk of receiving a diagnosis of this rare form of cancer is about 1 in 500, according to the ACS, which estimates that over 8,500 cases, mostly in women, will be diagnosed in 2018.

“Patients with anal cancer who live in areas of poverty are more likely to die overall, but even more likely to die from their anal cancer,” Daniel J. Becker, M.D., of NYU Langone Health’s Perlmutter Cancer Center in New York City, said in an interview with

“So, there is something about poverty that is associated with them doing worse with their anal cancer.” The study included 9,550 patients with squamous cell carcinoma of the anus. The researchers used patients listed in the U.S. Surveillance, Epidemiology, and End Results registry from 2004 to 2013. Patients were a median age of 58 years, and most had non-metastatic disease; 85 percent were white, 63 percent were women and 38 percent were married. Incomes ranged from $46,840 or less to $70,820 or greater.

The findings showed that patients living in areas with a lower median household income had worse overall and cancer-specific survival compared with patients in highestincome areas. From the lowest to the higher income levels, the risk of dying was 31 percent. The increased risk of cancer-related death ranged from 34 to 22 percent for the lowest to higher incomes.

Worse cancer-specific survival was seen in male, older, African-American and unmarried patients. Earlier year of diagnosis, higher-grade and late-stage disease also played roles in cancer-specific survival. “The overall goal is to determine which factors (we can) change to make sure that how much money you have does not predict how you do with anal cancer,” Becker said. “As a community, we don’t believe that should be the case. Everyone should have access to complete care.”

Some small tumors can be surgically removed; sometimes chemotherapy and radiation therapy are needed afterward. In cases where surgery cannot be performed, standard treatment involves radiation therapy combined with chemotherapy.

Income did not play a role in the likelihood of a patient initiating radiation therapy, the researchers noted. “It is impressive that they start radiation therapy, but (it) requires a lot of resources to be able to go to radiation daily and be able to continue your chemotherapy,” Becker said. “There’s a lot of sort of social support and other sort of network support that goes into allowing people to complete that therapy.”

Research like this can help identify which patients are at high risk so that they can have access to more resources, such as case managers, transportation or additional social support, Becker said. “Anal cancer is a hopeful cancer. With early recognition and intensive therapy with chemoradiation, we cure the majority of cases now,” he said. “It’s a tough road, and it takes a lot of support for the patients and their caregivers. It’s a hard therapy, but there is a very good chance of cure.”

A recent study found that socioeconomic status can play a role in survival for patients with anal cancer.

Rare Cancers Special Issue | CURE