publication date: Aug. 31, 2018

Clinical Roundup

NCCN publishes first U.S. guidelines for rare cancers associated with pregnancy

The National Comprehensive Cancer Network has released new treatment guidelines for a group of rare cancers that impact women during pregnancy. Gestational trophoblastic neoplasia, also known as gestational trophoblastic disease, can occur when tumors develop in the cells that would normally form the placenta during pregnancy.

It happens in approximately one out of every 1,000 pregnancies in the U.S., though it is more common in many Asian and African countries. Due to the rare nature of this condition, and the small number of specialists worldwide, providers often are not aware of how to provide the best care for people with GTN.

“These guidelines are sorely needed,” explained David Mutch, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, who leads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN. “By compiling expert consensus, we can standardize the way this uncommon disease is treated. When treated properly, GTN can almost always be cured, but deviating from that standard can have severe consequences. Plus, by providing clear instructions for how best to treat GTN, we can streamline the insurance approval process for more efficient care.”

The NCCN Guidelines for GTN details treatments for several variations of the disease. For molar pregnancy (also known as a hydatiform mole, a rare mass that can form inside the womb during early pregnancy, resulting in an abnormal fetus), surgery is the first, and often only treatment required. It is generally performed via suction dilation and curettage.

Low-risk GTN is primarily treated with single-agent chemotherapy, although additional chemotherapy or surgery may be required for persistent disease. With high-risk GTN, treatment typically involves multiagent chemotherapy, with possible radiation therapy for brain metastasis. Surgery can be used for chemotherapy-resistant disease.

Mutch was joined on the GTN Committee by John Lurain, Robert H. Lurie Comprehensive Cancer Center of Northwestern University and R. Kevin Reynolds, University of Michigan Rogel Cancer Center.

The committee is a subset of the larger NCCN Guidelines Panel for Cervical, Uterine, and Vulvar Cancers, of which all three are members.

The NCCN Guidelines for GTN bring the total number of NCCN Guidelines to 72. They are available free-of-charge online at NCCN.org or via the Virtual Library of NCCN Guidelines mobile app for smartphones and tablets.

 

Collection of brain cancer data accessible to global researchers

A cache of brain cancer biomedical data has been made freely available to researchers worldwide, say researchers at Georgetown Lombardi Comprehensive Cancer Center. The dataset, Repository for Molecular Brain Neoplasia Data, also known as REMBRANDT, hosted and supported by Georgetown, is one of only two such large collections in the country.

Information about the brain cancer data collection, which contains information on 671 adult patients collected from 14 contributing institutions, is detailed in Scientific Data, an open-access journal.

Already, thousands of researchers in the U.S. and internationally log on to the data site on a daily basis, and word about the resource is expected to increase its use, says Subha Madhavan, chief data scientist at Georgetown University Medical Center and director of the Innovation Center for Biomedical Informatics at Georgetown Lombardi.

The Georgetown data resource is unique in several ways. One is that it contains genomic information, collected from volunteer patients who allowed their tumors to be sampled, as well as diagnostic (including brain scans), treatment and outcomes data. Most collections contain either one or the other.

“We want this data to be widely used by the broadest audience — the entire biomedical research community — so that imagination and discovery is maximized,” says first author on the paper Yuriy Gusev, associate professor and a faculty member of the ICBI. “Our common goal is to tease apart the clues hidden within this biomedical and clinical information in order to find ways that advance diagnostic and clinical outcomes for these patients.”

The REMBRANDT dataset was originally created at the National Cancer Institute and  funded by Glioma Molecular Diagnostic Initiative led by co-authors Howard Fine, from New York Presbyterian Hospital, and Jean-Claude Zenklusen, from the NCI. They collected the data from 2004 to 2006.

NCI transferred the data to Georgetown in 2015, and it is now physically located on the Georgetown Database of Cancer, a cancer data integration and sharing platform for hosting alongside other cancer studies. G-DOC investigators, led by Madhavan, developed novel analytical tools to process the information anew.

The genomic data includes the specific genes within individual tumors that are either over-expressed or under-expressed as well as the number of times that gene is repeated within a chromosome. The data collection also includes information on RNA.

REMBRANDT includes genomic data from 261 samples of glioblastoma, 170 of astrocytoma, 86 tissues of oligodendroglioma, and a number that are mixed or of an unknown subclass. Outcomes data include more than 13,000 data points.

Additional co-authors of the work are Krithika Bhuvaneshwar, from Georgetown and Lei Song, from the National Cancer Institute.

Georgetown has filed a patent application related to G-DOC technology.  Madhavan is the named inventor of the intellectual property protected.

The project was funded by the Georgetown Lombardi cancer center support grant (P30 CA51008) and a contract from the NCI to migrate the Rembrandt dataset to G-DOC.

 

Comprehensive CAR T-cell therapy pediatric guidelines developed

Almost one year after FDA approval of chimeric antigen receptor T-cell therapy for children with acute lymphoblastic leukemia, researchers at MD Anderson Cancer Center and the Pediatric Acute Lung Injury and Sepsis Investigators Network published treatment guidelines for managing the treatment in the online issue of Nature Reviews Clinical Oncology.

These guidelines outline lessons learned by leading experts in various fields to identify early signs and symptoms of treatment-related toxicity and detail ways in which to manage it.

The FDA approved the first CAR T-cell therapy for children and young adults with ALL last year. Ongoing research aims to expand its use for other cancers.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL, yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said Kris Mahadeo, associate professor of Pediatrics and Chief of Stem Cell Transplant and Cellular Therapy at MD Anderson. “This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

As CAR T-cell therapy becomes more widely used, treatment guidelines, comprehensive training of multi-disciplinary staff, and other measures should facilitate the appropriate management of toxicities that may occur following this new treatment, Mahadeo said.

MD Anderson’s CAR T-cell-therapy-associated Toxicity program collaborated with PALISI and its Hematopoietic Stem Cell Transplantation sub-group in creating the comprehensive guidelines for treating children with cancer receiving CAR T-cell therapy.

By bringing together experts from many areas, including pediatric intensivists, pharmacy, neurology, and translational immunotherapy research, the guidelines offer key learnings to providers and aim to help improve the patient experience and outcome.

“CARTOX, which oversees care for MD Anderson CAR T-cell therapy patients, is the first stand-alone immune effector cellular therapy program to earn accreditation from the Foundation for the Accreditation of Cellular Therapy,” said Elizabeth Shpall, professor of Stem Cell Transplantation and Cellular Therapy and one of the senior authors on the Natures Reviews Clinical Oncology paper. “The program provides oversight for more than 20 active immune effector cell research protocols and two approved standard of care therapies at MD Anderson, and it is clear these new guidelines will serve as an important new model for care of CAR T-cell patients.”

In 2017, MD Anderson’s CARTOX Program published guidelines in Nature Reviews Clinical Oncology on management of adult patients receiving CAR T-cell therapy. However, early signs and symptoms of toxicity in children brought attention to pediatric-specific monitoring including escalation of care based on parent and caregiver concerns.

Some examples of the recommendations include:

  • Monitoring for cytokine release syndrome using pediatric normal ranges for organ function.

  • Promptly addressing parent and/or caregiver concerns as early signs or symptoms of CRS can be subtle and best recognized by those who know the child best.

MD Anderson team members who collaborated on development of the guidelines included Elizabeth Shpall; Katy Rezvani; and Partow Kebriaei; all of the Department of Stem Cell Transplantation and Cellular Therapy; Sattva Neelapu, of the Department of Lymphoma and Myeloma; Sajad Khazhal; David McCall; Demetrios Petrepolous; Joan O’Hanlon Curry; Sarah Featherston; Jessica Fogelsong; Lisa Hafemeister; Cathy Nguyen; Rodrigo Mejia; and John Slopis; all of the Division of Pediatrics; and Alison Gulbis; and Maria Mireles; of the Department of Pharmacy.

Other participating institutions included the Keck School of Medicine, University of Southern California, Los Angeles; University of Pennsylvania Perelman School of Medicine, Philadelphia; University of Washington Seattle Children’s Hospital; George Washington University and Children’s National, Washington D.C.; Baylor College of Medicine, Houston; Dana-Farber Cancer Institute, Harvard University, Boston; Weill Cornell Medical College Presbyterian Hospital, New York; University of Minnesota Masonic Children’s Hospital, Minneapolis; Duke Children’s Hospital, Duke University, Durham, N.C.; Nationwide Children’s Hospital, Ohio State University, Columbus; St. Jude’s Children’s Research Hospital, Memphis, Tenn.; and Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, N.Y.

 

University of Maryland scientists to conduct first FDA-approved study of focused ultrasound to open blood-brain barrier

In the first such clinical trial in the United States, physician-scientists with the University of Maryland School of Medicine are investigating the use of MRI-guided focused ultrasound to open the blood-brain barrier. The trial will be conducted with patients undergoing brain cancer surgery at the University of Maryland Medical Center.

While this network protects the brain, it also limits doctors’ ability to deliver effective doses of disease-fighting drugs to the brain, particularly in the case of brain tumors, which are notoriously treatment-resistant. This safety and feasibility study is a first step in attempting to overcome a major hurdle in treating these often-deadly cancers.

“The ability to temporarily disrupt the blood-brain barrier without causing tissue damage has the potential to dramatically alter the landscape of drug delivery to the brain for many diseases,” said Graeme Woodworth, principal investigator, professor of neurosurgery at UMSOM and director of the Brain Tumor Treatment and Research Center at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center at UMMC.

“If successful, this approach would allow us to use chemotherapy and other therapies in the brain in ways that are currently not possible,” said Woodworth, noting that 98 percent of currently approved drugs don’t enter the brain because of the blood-brain barrier. “If we can selectively open the blood-brain barrier, then in the future we could give a much lower dose of powerful drugs, which would likely reduce toxic side effects and make treatments safer and more effective for patients.”

The process involves injecting microscopic inert gas-filled bubbles into a patient’s bloodstream and then oscillating the microbubbles with highly targeted sound waves, stretching the blood vessel walls to create temporary openings.

FDA approved the clinical trial in October 2017 after a lengthy review process. Although there are similar research studies in Canada and other countries, this was the first time the FDA approved a clinical study using this promising technology and approach.

Within a few months, University of Maryland researchers expect to open another FDA-approved clinical trial in which newly diagnosed glioblastoma patients will undergo blood-brain barrier opening prior to treatment with standard chemotherapy, temozolomide. This new ultrasound-augmented approach would target the areas where tumor recurrence would be most likely to occur.

In the initial study, researchers plan to enroll up to 15 patients with suspected glioblastoma, an aggressive brain cancer, who will undergo surgery at UMMC to remove their tumor.

The morning of the scheduled surgery, patients will undergo a standard magnetic resonance imaging scan as part of the preoperative planning process. Guided by this MRI, doctors will target a precise region within the tumor with ultrasound, while the injected microbubbles are circulating within the bloodstream.

The microbubbles will oscillate within the ultrasound field, causing temporary openings in the walls of the brain blood vessels, and allowing the MRI contrast agent, gadolinium, to pass into the brain tissue. The MRI scan will then be completed, documenting the extent to which the blood-brain barrier was disrupted.

The data from the MRI will be used in a system called intraoperative stereotactic neuro-navigation – an advanced 3D-guidance system that accurately localizes the tumor within the brain. After the surgery, researchers will also rigorously examine the tissue that was removed to study the potential therapeutic and other effects from the focused ultrasound procedure.

In this initial trial, the increased amount of contrast enhancement within the tumor provided by the focused ultrasound procedure may help the 3D navigation during the surgery, according to Woodworth. “The standard of care is not changing in regard to the surgical procedure. We are functionally increasing the amount of navigation data available to the surgeon,” he says.

Woodworth notes that the disruption in the blood-brain barrier is not permanent, lasting about four to six hours.

The clinical trial is sponsored by InSightec, which has developed the MRI-guided focused ultrasound technology that will be used in the study. Neurosurgeons at UMMC are also using this technology to treat patients with neurological conditions, such as essential tremor and Parkinson’s disease, the latter as part of a clinical research study.

 

Liquid biopsy could ease the way to immunotherapy for lung cancer

Researchers at UC Davis, Genentech, and Foundation Medicine are the first to show that a blood-based test to assess tumor mutational burden accurately identifies non-small cell lung cancer patients who could benefit from immunotherapies called checkpoint inhibitors.

The blood test offers a much less invasive and more repeatable alternative to tissue testing. The study was published online today in Nature Medicine.

“We wanted to know if we could transfer this TMB assay from tissue to blood,” said David Gandara, who directs the Thoracic Oncology Program at the UC Davis Comprehensive Cancer Center and is first author on the paper. “We succeeded, establishing a TMB level in blood that correlates well with similar levels in tissue and was associated with favorable patient outcomes.”

Checkpoint inhibitors take the molecular brakes off T cells, allowing them to attack tumors.

However, they work best in patients who exhibit certain tumor biomarkers. One of these is the PD-L1 protein. More recent is tumor mutational burden – the number of mutations found in specific genomic sequences in tumor cells of an individual patient. Patients with higher TMB are often better candidates for immunotherapy.

Translating these findings into clinical practice is now feasible. The initial laboratory research methods used to identify these biomarkers, such as exome sequencing, take a long time and are not always scalable for clinical care. In addition, as many as 30 percent of NSCLC patients have too little tumor tissue to facilitate these tests. A fast, minimally invasive blood test would be the ideal solution.

“There are patients for whom the biopsy is inadequate from the start, or the tissue is used for routine pathology and we don’t have enough tissue left to do either genomic testing or tissue TMB,” Gandara said. “If we can do it in blood in one test, that offers many advantages for patients who have had an inadequate biopsy.”

In addition, because it’s much less invasive, a blood test could be repeated to determine if a treatment is effective or provide an additional option for patients who might not tolerate a traditional biopsy in the first place.

To determine whether blood could produce TMB results as well as tumor tissue, the researchers examined more than a thousand blood samples from patients with advanced NSCLC (two or more lines of treatment) in two studies, OAK and POPLAR.

This retrospective study compared these blood samples with tumor tissue and found a strong, though not perfect, TMB correlation between the two. This was not unforeseen, as tumor tissue is heterogeneous, and the blood test is actually more sensitive.

Despite these differences, the blood test performed well, consistently predicting which patients would benefit – with improved response and progression-free survival – from the PD-L1 inhibitor atezolizumab (Tecentriq). The assay proved both accurate and reproducible.

This blood-based approach seems poised to move rapidly into the clinic. Foundation Medicine is now seeking FDA approval to incorporate it into their FoundationACT liquid biopsy. In addition, interim data from the prospective BFIRST study presented at the recent ASCO conference confirmed that blood samples are a viable way to test TMB.

Other authors included: Sarah Paul, Marcin Kowanetz, Erica Schleifman, Wei Zou, Yan Li, Lukas Amler, Todd Riehl, Craig Cummings, Priti Hegde, Alan Sandler, Marcus Ballinger and David Shames at Genentech; Achim Rittmeyer at Lungenfachklinik Immenhausen; Louis Fehrenbacher at Kaiser Permanente Medical Center, Vallejo, California; Geoff Otto, Christine Malboeuf, Daniel Lieber, Doron Lipson, Jacob Silterra and David Fabrizio at Foundation Medicine; and Tony Mok at State Key Laboratory of Southern China.

This research was funded by F. Hoffmann-La Roche.

Copyright (c) 2018 The Cancer Letter Inc.