Erin Wallace

Malignant melanoma is one of the most common primary tumors to spread to the brain. In close to 50% of patients who have metastatic melanoma, the disease can be found in their brain.

For example, in former President Carter&rsquo;s case, the cancer was first found in his liver and later removed. During his press briefing last month, he announced that the melanoma had metastasized to his brain, and he was beginning treatment with pembrolizumab immediately.

In order to learn more about melanoma metastases to the brain,

interviewed Keith Black, MD, chairman and professor, Department of Neurosurgery, Cedars-Sinai Medical Center, director, Maxine Dunitz Neurosurgical Institute, director, Johnnie L. Cochran, Jr, Brain Tumor Center, and Ruth and Lawrence Harvey Chair in Neuroscience.

What is the best treatment for patients with melanoma and brain metastases?

Treatment is dependent on a number of factors, and those factors include the number of metastases that have spread to the brain, their size, and the condition of the patient, in terms of both his or her overall medical condition, as well as his or her control of systemic cancer outside of the brain. If there are less than three tumors in the brain, and they are very large (ie, greater than 3 cm), then one can certainly consider surgical removal of those tumors, if they&rsquo;re in a surgically accessible area followed by a radiosurgery boost to the tumor margin.

If the tumors are smaller than 3 cm, one can certainly also consider surgery followed by radiosurgery or radiosurgery alone. The results and prognosis are slightly better, if one can remove the tumors, followed by the radiosurgery boost, rather than relying on the radiosurgery alone. If there are more than three tumors, and they&rsquo;re all less than 3 cm, one can consider a radiosurgery treatment to multiple tumor sites, without doing surgery, or one can do sort of a hybrid therapy. If one [tumor] is greater than 3 cm, it needs to be removed, and others can be treated with radiosurgery; that&rsquo;s an option as well. Typically, when they [tumors] get to be more than 5 to 7 cm, radiosurgery tends not to be preferred. One tends to look at the possibility of whole brain radiation, unless one of the tumors is very large and symptomatic and needs to be surgically removed to allow the patient time to get through the radiation therapy. It depends overall on the size of the tumors, their location, whether or not they&rsquo;re surgically resectable, and how well the systemic disease is controlled.

What toxicities are associated with these treatments?

Surgery is invasive, and there will always be a risk. There is also a 3% to 5% risk of getting some radiation necrosis from focus radiation, typically about 9 to 14 months after the treatment, which could cause swelling in the area around the radiation necrosis. Sometimes, that&rsquo;s [the swelling is] limited to a few months, and it can be treated with steroids. In rare occurrences, it gets to a point where the radiation necrosis needs to be removed, in order to control the swelling.

Do you think immunotherapy would be appropriate in this instance?

Yes. It sounds like the systemic disease is limited in President Carter&rsquo;s case. The lesions in the brain have been treated with focus radiation, and using the checkpoint inhibitors has been very successful in treating melanomas, particularly outside of the brain. There&rsquo;s also some evidence that they may be effective within the brain itself. Once a T-cell is activated, it can actually get into the brain and cross the blood-brain barrier and be effective. I think that it&rsquo;s a good choice of treatment for President Carter, and if he gets a response to the radiation treatment, then he has the potential of having that be a very durable response.

Do you think President Carter is at more of a risk because melanoma was found in other parts of his body?

Certainly having systemic spread impacts the prognosis, but if it&rsquo;s only limited to one site, and if that site is under control, then that attenuates that risk to some extent.

What clinical trials are available for patients with melanoma that has spread to their brain?

Well, I think one of the more exciting ones is the use of checkpoint inhibitorsipilimumab and programmed cell death-1 (PD-1) inhibitors. I think they are really showing some of the most promising results.

What do you think is the most significant information for medical oncologists to know, when treating patients with melanoma that has metastasized to the brain?

Melanoma is not particularly radiosensitive, unlike some tumors that are more sensitive to radiation therapy. We prefer using focus radiosurgery or radiation on these tumors to get a high enough dose to be lethal to the tumors within the brain, and we think that&rsquo;s an advantage. We try to defer whole brain radiation, unless we&rsquo;ve exhausted all other options. The approach of combining surgery for some of the larger tumors that are beyond the limit of radiosurgery with treating others that can be treated with radiosurgery is a very compelling strategy, being more aggressive with the number of tumors inside the brain. Typically, in the past, we would limit radiosurgery to one, two, or three tumors, but we&rsquo;re seeing promising results now that are expanding the numbers higher, to potentially five or seven tumors within the brain.

Where do you hope to see the treatment paradigm progress for melanoma metastases to the brain?

Using strategies to get therapies across the blood-brain barrier is particularly appealing. The use of immune approaches where we&rsquo;re seeing good systemic results outside of the brain, applying those approaches to tumors within the brain, is also very compelling.

Memorial Sloan Kettering Cancer Center. About metastatic brain tumors.

https://www.mskcc.org/cancer-care/types/brain-tumors-metastatic/about-metastatic-brain-tumors

Articles

Malignant melanoma is one of the most common primary tumors to spread to the brain.

Melanoma Brain Metastases: Q&A With Keith Black, MD

A sarcoma study arm of the phase II portion of the multiarm PembroPlus clinical trial that combines immunotherapy with chemotherapy has commenced at Cancer Treatment Centers of America (CTCA), Western Regional Medical Center, Goodyear, Arizona. The clinical trial is the first of its kind to use pembrolizumab, a programmed cell death-1 (PD-1) inhibitor, combined with chemotherapy in patients who have advanced small cell lung cancer, pancreatic cancer, and sarcomas.

The purpose of this arm was to target sarcomas, and the multifaceted study was named in accordance with the usage of chemotherapy plus pembrolizumab. Other chemotherapies used in combination with pembrolizumab in PembroPlus include gemcitabine, docetaxel, nab-paclitaxel, vinorelbine, and irinotecan.

&ldquo;There is growing evidence that the use of immunotherapies, like those in our PembroPlus clinical trials, could enhance the ability to fight cancers," said Glen Weiss, MD, MBA, director of clinical research and a medical oncologist at CTCA at Western, in a press release.

&ldquo;We will be testing this new arm for sarcoma patients to determine its effectiveness and safety.&rdquo;

By using pembrolizumab, CTCA Western investigators hope to activate the body&rsquo;s immune system, in order to combat sarcomas and test whether or not results can be improved with the combination treatment, as opposed to using chemotherapy alone.

The study authors plan to enroll around 140 patients who meet the clinical trial criteria.

Patients must be at least 18 years old, with definitive histologically or cytologically confirmed metastatic solid tumor, as well as one or more metastatic tumors measurable by CT scanor PET/CT, if the patient is allergic to CT contrast media. Additionally, investigators will assign patients to the appropriate treatment arm with the following requirements: patients must not have had prior progression or intolerance on the single agent chemotherapy and then enrolled on an arm that has the same single agent chemotherapy plus pembro, and chemotherapy on the arm selected must be considered standard of care or listed within the NCCN guidelines (www.nccn.org) for that cancer type. Lastly, the patient enrolled must have recovered from acute toxicities of previous treatment.

Patients who have metastatic sarcoma will be enrolled in the non-randomized and open label clinical trial within the following four arms: pembro plus gemcitabine, pembro plus gemcitabine and docetaxel, pembro plus gemcitabine and vinorelbine, and pembro plus liposomal doxorubicin. Those with metastatic pancreatic adenocarcinoma will be enrolled in the pembro plus gemcitabine and nab-paclitaxel arm. Patients who have extensive-stage small cell lung cancer will be enrolled in the pembro plus irinotecan arm.

Outcome measures include frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03, response rate by irRC and response evaluation criteria in solid tumors (RECIST), characterization of changes in circulating tumor DNA in enrolled patients, and textural changes identified on imaging that is completed per routine practice.

Study authors plan to determine the overall survival (OS) and progression-free survival (PFS) as well.

On April 23, a patient with triple-negative breast cancer was the first to receive treatment in the clinical trial.

&ldquo;Each year, nearly 14,000 Americans are newly diagnosed with some form of sarcoma, which are often difficult to treat, especially in advanced stages," said Vivek Khemka, MD, medical oncologist, CTCA Western and PembroPlus Principal Investigator, in a press release.

&ldquo;We believe that, even though these types of cancer pose a significant challenge, researchers are developing powerful new tools that eventually may give cancer patients additional answers and renewed hope.&rdquo;

1. Cancer Treatment Centers of America. Cancer Treatment Centers of America at Western Regional Medical Center launches phase II of innovative &lsquo;PembroPlus&rsquo; clinical trial.

http://www.cancercenter.com/press-center/press-releases/ctca/2015/04/Cancer-Treatment-Centers-of-America-at-Western-Regional-Medical-Center-Launches-Phase-II-of-Innovative-PembroPlus-Clinical-Trial/

2. Cancer Treatment Centers of America. Cancer Treatment Centers of America at Western Regional Medical Center launches next phase of immunotherapy clinical trial aimed at soft-tissue cancers.

http://www.cancercenter.com/press-center/press-releases/ctca/2015/09/Western-Regional-Medical-Center-Launches-next-phase-of-immunoterapy-clinical-trial-aimed-at-soft-tissue-cancers/

3. ClinicalTrials.gov. ClinicalTrials.gov Identifier: NCT02331251.

A sarcoma study arm of the phase II portion of the multiarm PembroPlus clinical trial that combines immunotherapy with chemotherapy has commenced at Cancer Treatment Centers of America (CTCA), Western Regional Medical Center, Goodyear, Arizona

Immunotherapy and Chemotherapy Trial Arm for Sarcoma Commences

The study authors chose an intention-to-treat analysis. For each amendment, researchers adjusted the sample size so that the study would have 80% power to discover a 33.3% difference in median OS between the ADT plus docetaxel group and ADT-alone group, with the use of a stratified log-rank examination at a one-sided alpha level of 2.5%.

The trial included a total of 790 patients, 397 for the combination group and 393 for the ADT-alone group, with a median age of 63 years. Men with mHSPC received either ADT plus docetaxel at a dose of 75 mg/m

of body-surface area every 3 weeks for 6 cycles, or ADT alone.

Median OS was 13.6 months longer with the combination therapy compared with ADT alone, after a median follow-up of 28.9 months (57.6 months vs 44.0 months; combination group HR for death, 0.61; 95% Cl, 0.47-0.80;

Median time to biochemical, symptomatic, or radiographic progression was 20.2 months for the ADT plus docetaxel group compared with 11.7 months in the ADT-alone group (HR, 0.61; 95% Cl, 0.51- 0.72;

<.001). A prostate-specific antigen level of less than 0.2 ng/mL at 12 months was 27.7% for the combination group and 16.8% for the ADT-alone group (

For the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, 2.3% for grade 3 or 4 infection with neutropenia, and 0.5% for grade 3 sensory neuropathy and grade 3 motor neuropathy.

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

Administering 6 cycles of docetaxel at the beginning of androgen-deprivation therapy (ADT) to patients with metastatic, hormone-sensitive prostate cancer (mHSPC) resulted in a significantly longer overall survival (OS) than ADT alone.

Significant OS Benefit Seen With Docetaxel and ADT in Hormone-Sensitive Prostate Cancer

that supports an association between Agent Orange exposure and multiple myeloma.

The goal of the study was to examine the relationship between MGUS and exposure to Agent Orange, including its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in veterans from the Vietnam War.

Previous occupational studies have shown that other pesticides, such as insecticides and herbicides, are linked with excess risk of multiple myeloma and MGUS, according to Landgren et al, but there are no known studies that have uncovered an association with veterans from the Vietnam War.

This prospective cohort, conducted from 2013 to 2014, tested for MGUS in the serum specimens of veterans that were previously collected and stored by the Air Force Health Study (AFHS).

The AFHS included veterans from Operation Ranch Hand who were exposed to Agent Orange and TCDD, as well as those who participated in similar duties within Southeast Asia but did not come in contact with any herbicides (comparison veterans).

The cohort study chose to include 479 of the exposed US Air Force Vietnam War veterans in the first group and 479 comparison veterans in the second.

Findings from this study reported a crude prevalence of overall MGUS of 7.1% (34 of 479) in the first group and 3.1% (15 of 479) in the second, following an adjustment of age, race, and BMI in 2002, as well as difference in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44;

Ultimately, it was discovered that the veterans exposed during the herbicide spray missions (ie, Operation Ranch Hand) have a significantly increased risk of MGUS, which supports the theory regarding the association between Agent Orange exposure and multiple myeloma.

Landgren O, MD, PhD, Shim YK, PhD, Michalek J, PhD, et al. Agent Orange exposure and monoclonal gammopathy of undetermined significance: an Operation Ranch Hand veteran cohort study.

US Veterans, including former Air Force personnel who participated in Operation Ranch Hand, have a 2.4-fold increased risk of multiple myelomaâ€™s precursor state, MGUS, 

Erin Wallace | Authors

Articles

Melanoma Brain Metastases: Q&A With Keith Black, MD

Immunotherapy and Chemotherapy Trial Arm for Sarcoma Commences

Significant OS Benefit Seen With Docetaxel and ADT in Hormone-Sensitive Prostate Cancer

Agent Orange Associated With Multiple Myeloma