Ellie Leick

Patients with melanoma have reaped the benefits of surgical strategies, targeted drugs and immunotherapies, and their options continue to expand as more medicines and drug combinations enter the marketplace and surgery is applied in new ways.

Targeted drugs are used as first or second-line treatments and provide a survival advantage to patients, even sparking responses in those with disease that has spread to their brains, said Dr. Omid Hamid.

To build on that success, he said, investigators are examining the use of these therapies in combination regimens that pair them with immunotherapies known as checkpoint inhibitors, which rev up the immune system by interfering with the activity of certain proteins. Health outcomes can also be improved by employing surgery at various milestone moments during the course of the disease.

, Hamid, director of the Melanoma Center and phase 1 immuno-oncology program at The Angeles Clinic and Research Institute, discussed emerging treatment approaches, the role of surgery and ongoing research efforts in melanoma.

: What role does targeted therapy play in the modern management of patients with melanoma?

 There is now the idea that some immune activity exists with targeted therapies and (there is an) ability to have a tolerable triplet regimen with immunotherapy and targeted therapy. Future efforts will be dedicated to understanding the benefits we can get with this triplet therapy.

Multiple randomized trials are nearing completion and initial data show a progression-free survival benefit (a longer time until disease progression). For example, the (IMspire150) TRILOGY study of cobimetinib (Cotellic), vemurafenib (Zelboraf) and atezolizumab (Tecentriq) versus cobimetinib and vemurafenib alone has been shown to have a progression-free survival advantage. Other triplets are being investigated in ongoing research efforts.

Despite the emergence of these targeted therapies in recent years, does surgery still have a role in this space?

Absolutely. Surgery is going to help us with predictive and prognostic markers. The tissue (harvested) will help us in the (presurgical) and metastatic settings to figure out what a response really means.

In my practice, I have the pleasure of working with Dr. Mark B. Faries, of The Angeles Clinic and Research Institute, who is a leader in melanoma surgical and (postsurgical) therapy. Through his work in the MSLT-II trial, we've learned that we don't need to (remove the lymph nodes). That’s an important thing for our patients in terms of (avoiding side effects) and it also allows us to move further with (postsurgical) therapy in a more rapid fashion. Additionally, (there’s a role for metastasectomy in those with) progressive disease. This refers to the removal of cancerous tissue in the patient who is either responding except for one area, or who is responding and then progresses in an area where we can surgically remove that tumor and allow future therapy.

In addition, for immunotherapy, it’s important to remember that you need time for an immune response to happen. We have certain patients who have obstructions or areas that are troublesome and don't allow us to get that dose intensity. In these cases, our surgical colleagues can come in, take that area out and allow us to treat those patients until they achieve a response.

What immunotherapies are showing promise?

Obviously, our checkpoint inhibitors are showing significant benefit and long-term survival. Combinations are showing five-year survival (rates) of over 50%. We are understanding dosing and flip dosing in a better fashion, but the next frontier in melanoma is combination regimens that are more tolerable, with less … toxicity. We are also waiting to see what trials examining vaccine approaches and oncolytic therapies will show. (Checkpoint inhibitors that target different proteins) may also have less toxicity. All these regimens are not just in the first-line setting, but also for patients with (recurrent) disease.

In addition, we're now looking (at immunotherapies that use a patient’s own immune cells, multiplied and in some cases engineered to recognize cancer). In melanoma, CAR (chimeric antigen receptor) T-cell studies are opening (that will evaluate) benefits for solid tumors. Adoptive T cell therapy is also becoming more and more available.

Combinations of those therapies are (being evaluated) in clinical trials. For example, one clinical trial is now (examining a type of adoptive T cell therapy called) tumor-infiltrating lymphocyte therapy (paired with checkpoint) inhibition for multiple solid tumors. The ability to take those regimens and utilize them in the frontline and in patients with (treatment-resistant) disease is going to be key.

Novel Therapies Expand Options in Melanoma, But Surgery Retains Role

Articles

Dr. Omid Hamid discusses combining targeted drugs and immunotherapy, the role of surgery and ongoing research efforts in melanoma.
 

Combining Novel Drugs and Using Surgery at Key Moments Defines Modern Melanoma Treatment

Women with breast cancer — as well as the health care professionals who treat them – often wonder about the origin of their cancer-related cognitive impairment (CRCI), often referred to as “chemobrain.” This side effect can include difficulties with memory, attention and information processing.

The causes of CRCI are varied and complex, and medical, psychological and demographic factors can play a role. To shed more light on subject, researchers at the University of Rochester Medical Center’s Wilmot Cancer Institute embarked on the largest study to date, with a focus on when and why the condition occurs, who is most likely to develop it, and whether age, education, race and menopausal status, among other factors, have an effect.

Their findings: the condition known as “chemobrain” is a pervasive — and persistent &mdash; problem in women with breast cancer.

Michelle C. Janelsins, Ph.D., an assistant professor of Surgery in Wilmot’s Cancer Control and Survivorship program, looked at the cognitive difficulties of 581 patients with breast cancer recruited from community oncology clinics across the United States. Results were compared to those of a control group of 364 healthy individuals, some of whom were friends or family of patients or unrelated. The groups were balanced in age, ethnicity and marital status.

Both groups were assessed using the FACT-Cog tool, which examines perceived cognitive impairment, cognitive abilities, impact of cognitive impairment on quality of life and cognitive impairment as perceived by others. In addition to separate scores for each category, investigators generated an overall cognitive function score. Researchers conducted the FACT-Cog at three different points: seven days before chemotherapy, within four weeks of chemotherapy completion and six months after the second assessment.

In addition to the FACT-Cog, researchers also assessed participants’ reading ability and depressive symptoms, the latter, with an item from the Multidimensional Fatigue Symptom Inventory where participants responded to the statement “I feel depressed” using a scale ranging from “not at all” to “very much.”

Before chemotherapy began, patients with breast cancer had lower FACT-Cog scores than their healthy counterparts. Investigators found that when compared with participants who did not have cancer, FACT-Cog scores of women with breast cancer exhibited 45 percent more impairment. In fact, over the period of nearly one year from diagnosis and prechemotherapy to the postchemotherapy follow-up at six months) 36.5 percent of women reported a decline in scores compared with 13.6 percent of the healthy women, according to the study.

“Our study suggests that perceived CRCI is a complex, multifactorial problem for patients with breast cancer and that it is likely that a combination of demographic, medical and psychological factors plays a role in predisposing someone to CRCI,” study authors wrote.

 “Before any chemotherapy, patients reported lower FACT-Cog scores than did controls; however, we found this effect was influenced by age, race, cognitive reserve, and higher anxiety and depressive symptoms, as our results became a trend after including these covariates.”

Overall, the study found that predictors of perceived cognitive impairment included:

Increased baseline levels of anxiety and depressive symptoms,

Additionally, women who underwent hormone therapy and/or radiation treatment following chemotherapy had similar cognitive problems as women who solely received chemotherapy.

“Our study, from one of the largest nationwide studies to date, shows that cancer-related cognitive problems are a substantial and pervasive issue for many women with breast cancer,” explained Janelsins, in a statement.

“We are currently assessing these data in the context of objective cognitive measures and to understand the role of possible biologic mechanisms that may confer risk to cognitive problems in patients."

A large study at the University of Rochester Medical Center’s Wilmot Cancer Institute sought out to get to the root of the causes of cancer-related cognitive impairment and who may be at risk.

Study Examines Factors Contributing to "Chemobrain" in Patients With Breast Cancer

Patients diagnosed with prostate cancer sometimes allow their feelings of distress and anxiety to influence their treatment choices, which can potentially lead to unnecessary procedures, according to researchers at the University of Buffalo.

For men with low-risk prostate cancer, active surveillance may be considered the best treatment option in their situation. However, many in this population choose to undergo surgery or radiation, largely due to the anxiety they feel.

, the study followed 1,531 patients with localized prostate cancer (36 percent low-risk, 49 percent intermediate-risk and 15 percent high-risk). Researchers evaluated the emotional distress of the patients soon after diagnosis and after a treatment decision. This evaluation was done using the Distress Thermometer, an 11-point scale that ranges from zero (no distress) to 10 (extreme distress). The aim was to discover if a man’s level of distress could predict his treatment choices.

Among all participants, men who felt more anxiety at diagnosis were more likely to choose surgery over active surveillance. Similarly, men who were more distressed around the time they made the treatment decision were likely to choose surgery over active surveillance, as well as surgery over radiation.

The researchers said of this pattern, “Importantly, this was true among men with low-risk disease, for whom active surveillance may be a clinically viable option and side effects of surgery might be avoided.”

According to the American Cancer Society, prostate cancer is a major disease in the United States, but its diagnosis is not synonymous with death. The organization says there are nearly three million prostate cancer survivors alive today.

Despite these facts, many patients feel distress strong enough to influence decisions that could lead to overtreatment. Surgery and radiation have side effects such as erectile dysfunction and incontinence, which can have an effect on patients’ quality of life. These side effects can be safely avoided for men with low-risk cancer by choosing active surveillance, which is used to closely follow the potential progression of cancer. Treatment can still be considered later if the cancer becomes more concerning.

To help men make treatment decisions that are more preference and value driven, it is important they receive all information pertinent to their situation, including the side effects of all treatments.

Lead author on the study, Heather Orom, Ph.D., said, “If distress early on is influencing treatment choice, then maybe we help men by providing clearer information about prognosis and strategies for dealing with anxiety.”

Additionally, physicians should take time to understand the reasoning behind their treatment decision and address any negative motivators, such as anxiety, to make sure patients do not receive treatment they don’t need and might potentially regret.

A team of researchers at the University of Buffalo investigated the role that patients' stress and anxiety plays in deciding on treatment. 

Patient Anxiety Influences Prostate Cancer Treatment Decisions

While new and emerging therapies have the potential to change the treatment landscape for myeloproliferative disorders such as as chronic myeloid leukemia (CML), polycythemia vera (PV), Michael J. Mauro, M.D., stated that researchers in the field still have a significant amount of work ahead of them.

“It's still a battle for patients,” said Mauro. “They still have long journeys, side effect management, a lot of decision making with multiple medications and new drugs on the horizon. However, this is a very good ending to what was really the breaking story of targeted therapy in cancer.”

What are some of the pivotal studies for CML?

In an interview during the meeting, Mauro, a hematologist and leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses the major questions regarding the current state of CML, as well as explorative options for patients with PV and myelofibrosis.

The EURO-SKI trial looked at the success of treatment-free remission in a very large number of patients — over 700 &mdash; from Europe. Part of the most innovative findings was learning patients need to be on TKI or in deep remission for about 5.8 years for it to be the most successful. That was the dividing line where success was higher versus lower.

What do you imagine the landscape of CML looking like in five to 10 years?

What are the optimal ways of managing some of these side effects?

What is important to highlight regarding myeloproliferative neoplasms (MPNs)?

We are starting to shape the picture of what a patient with CML might need to look like before they can think about treatment-free remission, from the EURO-SKI trial.

For myeloproliferative disorders — CML specifically &mdash; we're getting better and better targeted therapies. We're really coming “full circle” in that we're not only putting a high fraction of patients in remission without what people consider conventional chemotherapy, but we are really talking about a functional cure, which plenty of people didn't think was possible. That is great news.

Decision making for patients with CML takes some thought and finesse. First, TKI therapy is based on patients' profiles and perhaps their comorbidities. Comorbidities play an important role in CML. They may have more of an impact than CML responses shown in a recent paper by Germans in the 

. The side effect management encompasses knowing what a patient's comorbidities are and thinking TKI may be best for them. When you're looking at resistant disease, you're obviously going to think a little bit differently about comorbidities. However, they need to be managed. The most important breaking story is likely cardiovascular or vascular risk. Patients need to have a good base on cardiovascular assessment, like they should have in primary care—or maybe at the direction of the oncologist to see a specialist to know what their comorbidity really is. They need to manage that as they navigate through TKI therapy, as well as drugs with vascular risk. 

Here, we are a little further behind CML. However, we are really making nice progress. One important thing in 2016 was the update of the World Health Organization's (WHO) definitions of MPNs. What used to be called masked polycythemia vera (mPV) is now identified, which means we've lowered the bar and recognized patients with PV. Patients who have lower but still elevated hemoglobin levels may have PV and should be evaluated and diagnosed as such.

We've recognized a prefibrotic form of myelofibrosis, which was always tough to separate from thrombocytosis or overt myelofibrosis. It's now a category in WHO. We've received some nice clarification of what were the trickier forms of MPNs to diagnose.

We've also seen the first appearance of guidelines for MPNs from the NCCN. We don't have the full set of treatment guidelines. What we have now for myelofibrosis is some direction on how to treat our patients based on their risk. There was an important notification that patients should have their symptoms assessed by a symptom-assessment scale—a tool that's been validated and published. We shouldn't forget about autologous transplant with such patients.

When we think about therapeutics, there have been some big questions in the field and thinking about PV and thrombocytosis for ET. There is a large trial that has accrued and is asking this question for high-risk patients without previous therapy: is interferon versus hydroxyurea—which tends to be the standard&mdash;more effective? What's the real benefit? It’s too early to say.

At the 2016 ASH Annual Meeting, through the MPN consortium, we saw a presentation of this important study that is showing pretty equal results with regards to hematologic response, bone marrow and molecular response. The thinking is that you will probably need to wait a little longer to see that data mature to fully assess it.

Also at the meeting, with regard to myelofibrosis, we've had Jakafi (ruxolitinib) approved for many years and have been looking for competition. Can there be a different JAK inhibitor that could offset some of the anemia we see with Jakafi? What about patients with low platelets? They're hard to treat. There are updated data from studies of pacritinib, which is a JAK inhibitor, with the possibility to be useful in patients with low platelets.

Who are the most appropriate patients to receive Jakafi?

Not presented at ASH, but in the background, is updated data on momelotinib, another JAK inhibitor with a probable ability to offset anemia. Some of its trials showed that it could hold its ground and offer some of the similar benefits of Jakafi, but not as complete as we thought. We are soon going to have alternative JAK inhibitors that allow us to treat patients with more difficult blood count imbalances.

It's important to identify the patient that can benefit from JAK inhibitor therapy. It's going to be the patient with symptoms and high-risk disease. The main benefits of Jakafi are going to be spleen size reduction and symptom management. These patients, by default, are often some of the higher-risk patients, particularly with enlarged spleens. It's remarkable to see the symptom control and the improvement in quality of life. Even the improvement in survival is probably due to global reduction of complications such as thrombosis and comorbid complications from the burden of advanced myelofibrosis. 

Jakafi has been approved for PV for a while now. It probably stands on the middle ground as the drug we would think of after some initial therapy—whether or not it's hydroxyurea. I mentioned that interferon and hydroxyurea are battling for first place in the higher-risk PV patient. Jakafi offers the ability to render someone's phlebotomy independent and show spleen size reduction and good symptom improvement, similar to how we see it in myelofibrosis. It's an improved drug for the patient who doesn't respond to hydroxyurea.

Michael J. Mauro, M.D., discusses advances in treating myeloproliferative disorders. 

Ellie Leick

Combining Novel Drugs and Using Surgery at Key Moments Defines Modern Melanoma Treatment

Study Examines Factors Contributing to "Chemobrain" in Patients With Breast Cancer

Patient Anxiety Influences Prostate Cancer Treatment Decisions

Expert Looks Ahead in the Treatment of MPNs

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