NEW DRUG FOR NEUROBLASTOMA

 

The US Food and Drug Administration (FDA) has granted accelerated approval for a new drug for certain patients with neuroblastoma based on response rate results in small open-label trials.

The drug is naxitamab (Danyelza, Y-mAbs Therapeutics), a humanized monoclonal antibody that targets GD2 3F8, a disialoganglioside highly expressed on neuroblastomas.

The product was originally developed at the Memorial Sloan Kettering Cancer Center (MSK) in New York City and licensed exclusively to Y-mAbs. As a result of the licensing arrangement, MSK has institutional financial interests in the product, the company noted.

Naxitamab has been approved for use in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients (children over 1 year old as well as adults) with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.

The accelerated approval was based on results for overall response rate (ORR) and duration of response from two single-arm, open-label trials: Study 201 (NCT 03363373) in 22 patients and Study 12-230 (NCT 01757626) in 38 patients.  

In both studies, patients received naxitamab 3 mg/kg administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m²/day on days -4 to 0 and at 500 µg/m²/day on days 1 to 5.

Some patients also received radiotherapy. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to nontarget bony lesions or soft tissue disease in Study 12-230.

The results showed an ORR of 45% (95% CI, 24% - 68%) in Study 201 and an ORR of 34% (95% CI, 20% - 51%)  in Study 12-230.

Responses were observed in the bone and/or bone marrow, the FDA noted.

Less than a third of patients had a duration of response that lasted 6 months or more (30% of responders in Study 201 and 23% of patients in Study 12-230).  

The FDA noted that continued approval of the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.

It also noted that the drug was granted priority review, breakthrough therapy, and orphan drug designation. In addition, a priority review voucher was issued for the rare pediatric disease product application.

Boxed Warning and Adverse Events

Naxitamab has a boxed warning about serious infusion-related reactions and neurotoxicity.

The product information notes that in clinical studies, naxitamab has been shown to cause serious infusion reactions including anaphylaxis, cardiac arrest, bronchospasm, stridor, and hypotension. Infusion reactions generally occurred within 24 hours of completing an infusion, most often within 30 minutes of initiation. Infusion reactions are most frequent during the first infusion in each cycle.

In order to mitigate these risks, the company recommends premedication with an antihistamine, acetaminophen, an H₂ antagonist and corticosteroid, and close monitoring of patients during and for at least 2 hours after each infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Based on its mechanism of action, naxitamab can cause severe pain, the company notes. It recommends premedication with gabapentin and, for example, oral oxycodone, and recommends treating break-through pain with intravenous hydromorphone or equivalent.

In addition, naxitamab may cause severe hypertension. The onset of hypertension may be delayed, so blood pressure should be monitored both during and after infusion.

The product insert also notes that one case of transverse myelitis (Grade 3) and two cases of posterior reversible encephalopathy syndrome (PRES) have been reported.

The most common adverse reactions (incidence ≥ 25% in either trial) were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common Grade 3 or 4 laboratory abnormalities (≥ 5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.

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THERAPY ASSOCIATED POLYPOSIS-A NOVELSYNDROME

Undergoing cancer treatment at a younger age can put the survivors at risk of developing numerous gastrointestinal polyps, even if they do not have hereditary susceptibility to polyposis.

The acquired condition, therapy-associated polyposis (TAP), has only recently been discovered. Before the current study, TAP had been reported in only eight patients in the medical literature.

More details from another 34 patients are now described in an article published online February 12 in Cancer Prevention Research. 

It reports that these patients with TAP had a median of 32 colorectal polyps, although some patients were found to have more than 50.

Polyposis is a known risk factor for gastrointestinal cancers, note the authors. From this series of 34 patients with TAP, nine patients developed colorectal cancer.

"It is well established that prior exposure to radiation and/or chemotherapy in childhood and young adult cancer (CYAC) survivors is associated with a broad range of late organ effects," write the authors, led by Leah Biller, MD, Dana-Farber Cancer Institute, Boston, Massachusetts.

"This series demonstrates that TAP should be considered in patients with significant polyposis, no known pathologic germline variant and/or family history of gastrointestinal neoplasia, and a history of prior CYAC treatment," they add.

Important Implications

Recognition of a nonhereditary form of polyposis has important implications for the diagnosis of patients and the subsequent management of family members, say the authors.

"Providers may not be aware that polyposis even exists as an acquired phenomenon — it is traditionally presumed to be hereditary, with inherited syndromes such as familial adenomatous polyposis," Biller explained to Medscape Medical News in an email.

Patients who are diagnosed with polyposis, as well as their relatives, are typically advised to undergo increased screening with colonoscopy. Knowing that TAP is not a familial syndrome means that physicians can spare family members unnecessary colonoscopies.

Biller also suggested that physicians consider TAP for cancer survivors who have unexplained polyposis.

"We also think it would be reasonable to consider starting colonoscopies in survivors treated with prior chemotherapy and/or radiation at age 35 or 10 years after receiving treatment ― whichever occurs first," Biller noted.

In addition, given that TAP patients may also have a predisposition for upper gastrointestinal polyps, "it would also be reasonable to consider at least a baseline esophagogastroduodenoscopy (EGD) in these patients," she added.

Investigators also recommended that providers have a low threshold for recommending colonoscopy to any cancer survivor who is symptomatic with abdominal pain or bleeding, regardless of age, given the overall increased risk for polyps and CRC in these patients

Cases Identified From Eight Registries

The team identified TAP cases from registries at eight cancer genetics programs.

"Each TAP case was assessed for clinical features of inherited CRC (colorectal cancer) predisposition syndromes, even though none of the cases...had a known personal diagnosis of any genetically defined syndrome," the investigators explain.

For their analysis, polyposis was defined as a cumulative lifetime incidence of 10 or more gastrointestinal polyps of any type that occurred anywhere along the gastrointestinal tract.

The investigators included patients who had been diagnosed with cancer at age 30 years or younger or who had been diagnosed with CYAC between the ages of 31 and 45 if their first polyp was identified 10 years or more after their initial treatment.

From the eight cancer registries, 34 patients with TAP were identified. Of these, 28 had been previously treated for Hodgkin lymphoma, three for neuroblastoma, and one each for acute myeloid leukemia, medulloblastoma, nephroblastoma, and non-Hodgkin lymphoma.

Some 59% of patients had received an alkylating agent as their initial treatment; 62% had received abdominoplevic radiation; and 35% had received both.

The median age at which gastrointestinal polyposis was first detected was 49 years; the median time after initial cancer treatment was 27 years, the team notes.

For 24% of patients who received prior abdominopelvic radiotherapy, polyps were detected at a younger age than the age at which it is recommended that colonoscopy screening begin, the authors point out.

Current guidelines from the Children's Oncology Group (COG) recommend initiation of colonoscopy for CYAC survivors who undergo abdominopelvic radiotherapy either at age 30 years or 5 years after they receive radiotherapy, whichever occurs later. Colonoscopy should then be repeated every 5 years.

It is currently recommended that for CYAC survivors, colonoscopy be initiated at age 45 years. For 30% of TAP patients who did not receive abdominopelvic radiotherapy, a polyp was detected at a younger age than 45.

For children and young adults who do not undergo abdominopelvic radiotherapy, COG guidelines recommend that screening colonoscopy begin at the age of 45. Colonoscopy should then be repeated every 10 years.

In the current analysis, nine patients who developed CRC had previously undergone radiotherapy. In this small group of patients, a third were diagnosed prior to the age at which current guidelines recommend that patients start screening colonoscopy.

Colorectal Polyps

"All TAP cases had colorectal polyps, with a median lifetime aggregate of 32 polyps," the investigators report. More than two thirds of the group had a lifetime aggregate of 20 or more colorectal polyps; 35% of patients had 50 or more colorectal polyps, they add.

Some 30% of patients known to have undergone EGD had gastric or duodenal polyps or both. When fundic gland polyps were included in the analysis, almost three quarters of patients who underwent EGD were found to also have upper gastrointestinal polyps.

Almost all patients (94%) had more than one histologic type of colorectal polyp, the researchers note. This is in contrast to persons with hereditary polyposis syndromes; in those patients, all the polyps are generally of the same type.

Moreover, almost three quarters of patients with TAP displayed clinical features that were suggestive of one or more CRC predisposition syndromes.

"TAP appears to be an acquired condition that imitates various familial colorectal cancer syndromes but is biologically distinct from them," senior author Matthew Yurgelun, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, said in a statement.

"The fact that it takes different forms and involves different types of polyps suggests that there may be multiple biological pathways involved in its development," he added.

Biller and Yurgelun have disclosed no relevant financial relationships.

Cancer Prev Res. Published online February 12, 2020.

SARCOMA RISK IN PATIENTS WITH HEREDITARY RETINOBLASTOMA

The risk of bone and soft-tissue sarcoma is markedly elevated in long-term survivors of hereditary retinoblastoma treated with radiation, researchers report.

"We provide novel data that after radiotherapy for hereditary retinoblastoma, if sarcoma develops, it occurs in distinctive patterns by the type of sarcoma and location on the body," Dr. Lindsay M. Morton of the National Cancer Institute, in Bethesda, Maryland, told Reuters Health by email. "These findings provide a potential roadmap for tailoring the screening approach for sarcomas among retinoblastoma survivors."

Radiotherapy is an established cause of sarcoma after hereditary retinoblastoma, but little is known about the long-term risk of sarcoma after hereditary retinoblastoma and whether the risks varied by specific tumor characteristics.

Dr. Morton and colleagues used data from 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed between 1914 and 2006 to quantify sarcoma risk and to analyze risk factors by anatomic location and histologic subtype.

Nearly half of the patients (44%) were also treated with chemotherapy. The median age at sarcoma diagnosis was 15.5 years for bone sarcomas and 33.5 years for soft-tissue sarcomas.

Compared with the general population, these survivors had a more than 2,000 times increased risk of bone sarcomas in the head and neck and a 169-fold increased risk of bone sarcomas in the body and extremities (with 21.7 and 12.0 cases per 10,000 person-years, respectively).

In contrast to patterns in the general population, the risk of bone sarcoma in these survivors decreased with increasing age, the researchers report in the Journal of Clinical Oncology, online October 17.

For head and neck bone sarcomas, the cumulative incidence rose sharply after age 5 years through adolescence and then increased more modestly through 60 years after retinoblastoma. For body and extremity bone sarcomas, the cumulative incidence also increased sharply after age 5 through adolescence but remained stable thereafter.

The risk of soft-tissue sarcoma in the head and neck was 542 times greater in hereditary retinoblastoma survivors than in the general public and was 45.7-fold greater for other regions of the body (with 25.0 and 11.9 cases per 10,000 person-years, respectively).

The risk of body and extremity soft-tissue sarcoma increased substantially with increasing age, but there was no association between attained age for head and neck soft-tissue sarcomas.

In cumulative-incidence analyses, the incidence of head and neck soft-tissue sarcoma rose steadily throughout the entire duration of follow-up, whereas soft-tissue sarcoma in other body regions rarely occurred before the fourth decade of life, at which point the incidence increased steeply.

Patients diagnosed before age 12 months had the highest risks for head and neck soft-tissue sarcoma, whereas age at diagnosis was not associated with the risk of body and extremity soft-tissue sarcoma.

Females were 41% less likely than males to be diagnosed with head and neck soft-tissue sarcoma, but they were twice as likely as males to be diagnosed with body and extremity soft-tissue sarcoma.

Use of chemotherapy, family history of retinoblastoma, and year of retinoblastoma diagnosis did not appear to influence the risk of either bone or soft-tissue sarcoma.

"This report should inform study design in assessing the efficacy of sarcoma screening in this high-risk population," Dr. Morton said. "For example, our data suggest that screening for bone sarcomas in the head should persist for decades following retinoblastoma because of persistently elevated risks, whereas screening for bone sarcomas in the extremities may no longer be needed after adolescence."

"Because no evidence-based screening protocols have been developed for retinoblastoma survivors to date, international collaboration will be essential for advancing research to optimize the long-term health and clinical care for these patients," she said.

TANDEM STEM CELL TRANAPLANTATION FOR NEUROBLASTTOMA

Tandem autologous stem-cell transplant (ASCT) may provide better event-free survival (EFS) in patients with high-risk neuroblastoma, compared with single ASCT, a new clinical trial shows.
"Although it was our hypothesis that tandem transplant would decrease risk for recurrence, we were surprised by the positive results, including the magnitude of the difference, and that tandem transplant improved EFS and overall survival (OS) even for those patients who received postconsolidation immunotherapy," Dr. Julie R. Park from Seattle Children's Hospital told Reuters Health by email.
Patients with high-risk neuroblastoma are typically treated with multiagent chemotherapy induction and surgical resection, consolidated high-dose chemotherapy with ASCT, posttransplant radiotherapy, and postconsolidation treatment with biological agents and immunotherapy. Despite this intensive therapy, 50% to 60% of patients relapse and more than 90% of those who relapse die of the disease.
Dr. Park and colleagues from 142 Children's Oncology Group centers in five countries investigated whether intensifying consolidation treatment with tandem transplant (two transplants six to 10 weeks apart) could improve EFS versus a single transplant in their study of 355 patients with high-risk neuroblastoma.
Among the 652 patients who had been eligible for randomization, the three-year EFS was 51.1%. The three-year EFS from the time of randomization was 54.9% for the 355 enrolled patients.
The three-year EFS from the time of randomization was significantly higher in the tandem-transplant group than in the single-transplant group (61.6% vs. 48.4%, P=0.006), the team reports in the August 27 issue of JAMA.
There were 17 deaths due to toxicity (seven during induction and 10 during consolidation therapy).
The three-year OS from the time of randomization did not differ significantly between the tandem transplant group (74.1%) and the single transplant group (69.1%).
Among patients who went on to receive isotretinoin plus anti-GD2 chimeric antibody and cytokines (immunotherapy) in two other trials, three-year ESS and OS from the time of initiating immunotherapy were significantly higher in the tandem transplant group (73.3% and 84.0%, respectively) than in the single transplant group (54.7% and 73.5%, respectively).
"Patients who meet the criteria outlined in our article (adequate organ function, no evidence of progressive disease) should be considered for tandem transplant using the regimen we report," Dr. Park said. "Intensification of therapy beyond induction therapy is required to achieve the best state of minimal residual disease to enter postconsolidation immunotherapy."
She added, "Therapy for high-risk neuroblastoma is intense and places patients at risk for late effects of therapy. While we are pleased with the continued improvement in survival for these patients, it is paramount that we continue research into novel targeted thera
A linked editorial notes that the results "clearly demonstrate a benefit to dose intensification with tandem high-dose chemotherapy with autologous stem cell transplant within the studied patient population with high-risk neuroblastoma."
But it cautions, "The ANBL0532 trial does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization."
"A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials," write Dr. Rochelle Bagatell of Children's Hospital of Philadelphia and Dr. Meredith S. Irwin from The Hospital for Sick Children in Toronto, Canada.
"The findings of this randomized clinical trial have changed current practice in North America and are expected to affect the care of children with neuroblastoma in the decades to come," they conclude.
Dr. Ami V. Desai of the University of Chicago Comprehensive Cancer Center, who recently evaluated toxicities after single versus tandem ASCT in high-risk neuroblastoma, told Reuters Health by email, "While acute toxicities were similar between those who received a single versus tandem ASCT on this study, it will be important to continue to assess both the short- and long-term toxicities associated with tandem ASCT. As alluded to by the authors, it will also be important to continue to identify the subgroups of patients with high-risk neuroblastoma who benefit the most from intensification of therapy with tandem ASCT."
"New advances in immunotherapy and targeted approaches may ultimately lead to treatments for children with high-risk neuroblastoma that prove to be effective and less toxic than tandem ASCT," she said. "However, future prospective clinical trials will be needed to determine if these alternative approaches will result in superior survival compared to tandem ASCT."
SOURCE: https://bit.ly/2UbWu7B and https://bit.ly/2NI15wK
pies (molecular or immunological) that will improve efficacy and hopefully limit late effects."

CANCER SURVIVORS AND HEART RISK

Childhood cancer survivors' risks for heart problems may be broader than what was previously recognized, researchers say.
It's been known for years that some treatments for childhood cancer increase the risk of heart failure. But in a new study of more than 43,000 children, Canadian researchers found young cancer survivors had as much as a three-fold increased risk of developing a variety of other cardiovascular problems, too, according to the report online August 26 in Circulation.
The new findings suggest that survivors of childhood cancers should focus on improving modifiable heart disease risk factors, such as high blood pressure and diabetes, said study coauthor Dr. Paul Nathan, a professor of pediatrics and health policy, management and evaluation at the University of Toronto and a staff oncologist at The Hospital for Sick Children.
There's a chance that there will be new cancer treatments that are less toxic to the heart, Nathan said.
"However, we can't eliminate use of these (cardio-toxic) treatments completely because they are needed to cure cancer," Nathan said in an email. So, it's important to make "sure survivors and their doctors are aware of the risks and (know) what to look out for."
The heightened risks also mean that childhood cancer survivors should be screened for heart disease so it can be caught early, Nathan said.
To take a closer look at the impact of childhood cancer therapies on the heart, Nathan and his colleagues turned to a pediatric cancer registry called the Pediatric Oncology Group of Ontario Networked Information System, along with health data from the general public collected by The Institute for Clinical Evaluative Sciences (ICES) a nonprofit corporation.
The researchers focused on the 7,289 cancer survivors who had been diagnosed before age 18, treated at a pediatric cancer center between 1987 and 2010, and survived at least 5 years. Each of those survivors was matched in age, gender and postal code to 5 cancer-free individuals from the general population, for a total of 36,205 individuals in the control group.
Half of the patients were tracked for more than 10 years. During follow-up, 203 survivors (2.8%) experienced one or more cardiac events as compared to 331 of those in the control group (0.9%).
When the researchers analyzed their data, they found that even at relatively young ages, cancer survivors had a three-fold increased risk for any type of heart event and as much as a ten-fold increased risk for heart failure compared to their peers.
Childhood cancer survivors also appeared to be at increased risk of metabolic conditions such as diabetes, hypertension and high cholesterol. And those conditions increased the risk of heart disease.
Cancer survivors diagnosed with diabetes were more than three times more likely to develop cardiovascular disease and more than 4 times more likely to develop heart failure compared with nondiabetic survivors. Similarly, those diagnosed with high blood pressure were 3 times more likely to develop heart failure compared to non-hypertensive survivors.
This study is a useful reminder to not overlook traditional risk factors and more common types of cardiovascular disease in childhood cancer survivors, said Dr. Prashant Vaishnava, a cardiologist at The Mount Sinai Hospital in New York City. "This is becoming a recurring theme in medicine as patients are able to survive diseases that once may have been quickly fatal. The treatment paradigm for these survivors shifts to management of those conditions which are ubiquitous in the general population."
These days many pediatric cancer centers follow survivors of childhood cancers for possible heart damage, said Dr. Kirsten Rose-Felker, a pediatric cardiologist at UPMC Children's Hospital of Pittsburgh.
While many will just need to be monitored for the rest of their lives, some children suffer severe damage to their hearts from the cancer treatments, Rose-Felker said. "We've taken care of patients who needed a heart transplant," she added. "The damage can be so bad that it completely destroys the heart muscle."
The number of children who will need to be watched for heart problems is on the rise, Rose-Felker said. "There are half a million childhood cancer survivors in the U.S. and that number continues to grow as treatments get better," she added.
The good news, Rose-Felker said, is that this is "something we can actually affect."

BRCA2 AND PEDIATRIC LYMPHOMA RISK

For the first time, a pediatric cancer has been added to the "BRCA2 family."
Researchers at St. Jude Children's Research Hospital in Memphis, Tennessee, revealed that BRCA2 mutations were five times more common in children with non-Hodgkin lymphoma compared to a control group.
The study was published online on July 25 in JAMA Oncology.
Although this may seem like bad news, in fact it provides medicine with an unprecedented opportunity to head adult cancers off at the pass, according to study author Zhaoming Wang, PhD.
Identifying BRCA2 mutations early could give a head start to healthcare professionals whose job it is to follow these young patients into adulthood, he added.
Genetic counseling and BRCA2 testing of all survivors of childhood non-Hodgkin lymphoma is crucial, Wang said, especially in cases in which there is a family history of cancers suggesting BRCA2 involvement.
"There is a high chance [the patient] will test positive," he said. "Survivors whose test results are positive for these mutations can be offered surveillance for BRCA2-associated cancers, such as breast cancer and ovarian cancer, and consults for risk-reduction strategies."
For their study, Wang and colleagues used whole-genome sequencing for 1380 survivors of pediatric or adolescent lymphoma treated at St. Jude Hospital and compared the results to those for cancer-free adults in the Genome Aggregation Database. They found that BRCA2 mutations were five times more common in the childhood survivors of non-Hodgkin lymphoma.
Wang said, "In the general population, you might expect to see [a BRCA2 frequency of] 1 in 1000. We saw a fivefold increase, so this really is a telling enrichment of the mutation compared to the controls."
Although non-Hodgkin lymphoma runs in families, this is the first time that researchers have put a name to a genetic mutation associated with the disease.
"I was excited to see this," Wang told Medscape Medical News. "To the best of my knowledge, BRCA2 seems to be the first predisposition gene identified for non-Hodgkin lymphoma, and it may explain the familial non-Hodgkin lymphoma we observed [in the patient's families]."
Wang stressed that healthcare professionals need to be aware that BRCA2 cancers now include childhood non-Hodgkin lymphoma. "We're basically adding one new member into the BRCA2-associated cancers, along with breast, ovarian, prostate, pancreatic, and melanoma," he said.
As well as the implications for better surveillance, Wang said that BRCA2 testing during or after pediatric non-Hodgkin lymphoma could open the door to personalized approaches to treatment.
"I'm just speculating," he said, "but if BRCA2 is really a gene important for development of lymphoma, PARP [poly (ADP-ribose) polymerase] inhibitors could be one of the [treatment] options. And, more importantly, when these survivors grow up into adults and develop some other adult cancer, treatment can be tailored, and PARP inhibitors would certainly be a choice."
Wang acknowledged that the study shows an association, not causality. His team is currently investigating the genetic alterations in tumor samples from non-Hodgkin lymphoma survivors. "We need to understand how pathogenic BRCA2 mutations lead to lymphoma development," he said.

TARGETED TREATMENT FOR PEDIATRIC CANCERS

The investigational oral therapy entrectinib (Genentech/Roche) produced "striking, rapid, and durable" objective responses in children with recurrent/refractory central nervous system (CNS) and solid tumors harboring a range of target gene fusions, said Giles Robinson, MD, pediatric neuro-oncologist, St Jude Children's Research Hospital, Memphis, Tennessee.

The median age of these patients was 7 years old.

Robinson discussed "very promising" phase 1/2 study results with entrectinib with reporters during a press-cast that precedes presentation of the trial at the upcoming American Society of Clinical Oncology (ASCO) 2019 meeting in Chicago, Illinois.

During the press-cast, he showed scans from four study patients with high-grade gliomas, which are "universally fatal."

"It gives me great pleasure as a pediatric brain tumor doctor to show you intracranial responses to this medicine," he said.

"You can watch these tumors basically disappear or at least reduce significantly in size," he observed while displaying a series of progressive scans.

Entrectinib is an oral inhibitor of tropomyosin receptor kinase (TRK), ROS1, and ALK tyrosine kinases, which penetrate the central nervous system (CNS).

It's been established in the last few years, said Robinson, that these fusions act as "drivers" in some cancers, generating proteins that are "locked in the on position" and continuously drive tumor cell proliferation.

In the trial, responses to entrectinib were seen in 12 of the 28 evaluable patients. The 12 responses were among patients who had fusions in NTRK1/2/3, ROS1, or ALK genes (11 patients) or an ALK mutation (one patient). No responses were seen in tumors lacking aberrations in target fusions, a key insight that has led investigators to proceed in only enroling new patients with those fusions.

Median duration of therapy for confirmed fusion-positive responders was 10.5 months (3.8 to 17.7 months), and median time to response was 1.9 months (1 to 1.9 months).

The variety of solid tumors that responded, which included high-grade gliomas, three types of sarcoma, as well as a CNS embryonal tumor and a melanoma, is a source of satisfaction, suggested an expert.

The results are "yet another example of tumor-agnostic precision medicine therapy," said Monica Bertagnolli, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and ASCO president. She hopes that eventual final results will reflect what has been seen in this early study.

The variety of targetable tumors was thrilling for investigator Robinson.

"What got us really excited as pediatric oncologists was that a variety of pediatric cancers harbor these fusions and mutations," he said.

But there is more good news: the list of potentially treatable tumors is growing as investigators do next generation sequencing outside the trial in a widening number of cancers.

These fusions are coming out in tumors that we didn't expect to see before," he said.

Entrectinib belongs to the same class of drugs as larotrectinib (Vitrakvi, Bayer/Loxo Oncology), which has activity that is limited to NTRK1/2/3 but has nevertheless been hailed as a "game changer" for patients with tumors with those fusions.

Which drug would be better for patients with NTRK1/2/3 fusions?

Vivek Subbiah, MD, pediatric oncologist, MD Anderson Cancer Center, Houston, Texas, said that's not currently known.

"It is difficult and not appropriate to make cross-trial comparisons given that this is an early phase trial, with different dosing levels and different eligibility in heterogeneous populations," said Subbiah, who is not involved with these studies, when asked for comment.

Study Details

The new data on entrectinib come from the STARTRK-NG trial, an open-label dose-escalation and expansion study evaluating the safety and efficacy of the agent in children and adolescents with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1, or ALK fusions.

Entrectinib was well tolerated, said investigators. Dose-limiting toxicities were elevated creatinine, dysgeusia, fatigue, and one incidence of pulmonary edema.

In terms of complete and partial responses (CR and PR), in CNS tumors (n = 6), all were high-grade with gene fusions: one patient achieved a CR (ETV6-NTRK3); three achieved a PR (TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); one achieved an unconfirmed PR (GOPC-ROS1); and one has yet to be evaluated (KANK1-NTRK2).

In extracranial solid tumors (n = 8), six patients had a fusion, of whom one achieved a CR (DCTN1-ALK) and five achieved a PR (TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3).

In neuroblastoma (n = 15), one patient achieved a CR (ALK^F1174L ). Median duration of therapy was 85 days for all patients, 56 days for nonresponders, and 281 days for responders.

The "take-away point" about the responses is that those with tumor shrinkage stayed on study much longer than those who did not have shrinkage, said Robinson.

The FDA recently granted priority review for entrectinib for pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have progressed following prior therapies or as initial therapy when there are no acceptable standard therapies, and for metastatic ROS1-positive nonsmall cell lung cancer.

The study was sponsored by and received funding from Roche. The study design and conduct were also supported by Alex's Lemonade Stand Foundation Center of Excellence. Robinson has reported serving as a consultant/advisor for Eli Lilly and receiving research funding from Novartis, Genentech/Roche, and Novartis. Study authors include employees of Roche.

American Society of Clinical Oncology (ASCO) 2019 Annual Meeting. To be presented June 2, 2019. Abstract 10009.

MITOXANTRONE CARDIOTOXICITY

In pediatric cancer patients, mitoxantrone appears to be at least ten times as cardiotoxic as doxorubicin therapy, while daunorubicin therapy may be less so, according to a large cohort study.

"With 5-year survival of childhood cancer now reaching nearly 85%, balancing the potential long-term adverse effects of otherwise effective cancer treatments is an important consideration," researchers write in JAMA Oncology, online January 31.

In children, "a doxorubicin to mitoxantrone substitution rule of 4:1 has been commonly accepted for both anti-tumor efficacy and toxicity," add Dr. Eric J. Chow of Fred Hutchinson Cancer Research Center, in Seattle, and colleagues.

To provide more robust evidence, the team studied more than 28,000 childhood cancer survivors (median age at diagnosis, 6.1 years), including 9,330 treated with doxorubicin, 4,433 with daunorubicin, 342 with epirubicin, 241 with idarubicin, and 265 with mitoxantrone.

After adjusting for factors including chest radiotherapy and age at cancer diagnosis, the risk of severe, life-threatening or fatal cardiomyopathy by age 40 was evaluated via agent-specific Cox proportional hazards models.

After a median follow-up of 20 years, there were 399 cases of cardiomyopathy. Relative to doxorubicin, the agent-specific cardiomyopathy equivalence ratio was 0.6 for daunorubicin, 0.8 for epirubicin and 10.5 for mitoxantrone.

"In contrast to the commonly used 4:1 (mitoxantrone to doxorubicin) and 1:1 (daunorubicin to doxorubicin) ratios for late cardiomyopathy, the ratios we found were more like 10+:1 and about 0.5:1, respectively,” Dr. Chow told Reuters Health by email.

"These findings may impact the choice of anthracyclines/anthraquinones in future treatment protocols," he said.

In particular, he and his colleagues conclude, "our findings may . . . allow for better personalization when regimens with equivalent anticancer efficacy may be evaluated more accurately with respect to their long-term cardiotoxicity risk."

SOURCE: https://bit.ly/2Dxj1Up

JAMA Oncol 2019.

BRAIN RT MAY HAMPER NEW MEMORIES IN SOME CHILDREN

Children who've undergone radiotherapy for medulloblastoma or ependymoma might easily remember things that happened to them before their treatment, but struggle to remember what happens to them afterwards, researchers in Canada report.

While lifesaving, radiotherapy is known to be linked with reduced hippocampal volume and neurogenesis, and it can disrupt brain development, Dr. Melanie J. Sekeres of the Hospital for Sick Children and the University of Toronto and colleagues note in The Journal of Neuroscience, online August 20.

"These finding have significant implications for these patients' quality of life," Dr. Sekeres told Reuters Health by email. "The ability to form and retain detailed personal memories of important events in one's life is a big part of what gives our lives rich meaning."

Dr. Sekeres and her colleagues investigated thirteen 7- to 18-year-old survivors of posterior fossa tumors (PFTs) through the brain tumor program at one pediatric hospital, as part of a larger clinical research study; 12 were treated for medulloblastoma and one for ependymoma.

Complete Children's Autobiographical Interview (CAI), standardized memory testing, and neuroimaging data were available for all participants.

The children had undergone surgical resection of the tumor followed by radiotherapy and chemotherapy at least one year before taking part in the study, and they were age-matched with nine healthy controls. An additional 19 age-matched healthy controls were recruited for the CAI section of the study through ads in the hospital and community.

The researchers asked the participants to recall two separate memories: an event from the previous month and one from as far back in time as they could remember. They then used the CAI to retrospectively evaluate the patients' memories for events that either preceded or followed their treatment.

Compared to the healthy controls, the patients treated for brain tumor recalled fewer details, such as time and place, from their recent memory; but the patients and controls recalled the a similar amount of detail from their pre-treatment memory.

The authors acknowledge that the results may be affected by treatment effects linked with anesthesia and chemotherapy and by mechanisms including effects on white matter, glia, vasculature, synaptogenesis and neuroinflammation.

"Obviously, the clinician's primary concern is choosing a course of treatment that will increase the likelihood of patient survival, and consideration of potential side effects on cognition are secondary concerns," Dr. Sekeres said. "When deciding on treatment options, clinicians need to consider that standard treatment methods may impair their patient's ability to form new autobiographical memories."

Dr. Kevin F. Ginn, a neuro-oncologist and the director of the Brain Tumor Program at Children's Mercy Kansas City, in Missouri, said by email, "We know from multiple studies and from our clinical care of these patients that their memory can be significantly affected by therapy."

"Attempts to reduce craniospinal radiation in young low-risk medulloblastoma patients have not been successful," explained Dr. Ginn, who was not involved in the study. "But radiation is currently essential to cure most patients with medulloblastoma, so new therapeutic approaches are desperately needed."

"These findings won't affect patient care but they may lead to better understanding of the deficits and mechanism of those deficits in pediatric patients who have had cranial radiation," he added. "This information gives us more reason to work towards reduction or avoidance of cranial radiation in patients."

Dr. Ginn would like to see further related research. "The patient numbers in this study are small, so many important clinical factors are not powered sufficiently to reach statistical significance," he said. "Having larger groups of patients so as to better determine impact of age, radiation dose, or other clinical factors would add significantly to this work."

Co-author Dr. Donald J. Mabbott, also of the Hospital for Sick Children and the University of Toronto, told Reuters Health that the research team is now conducting clinical trials to examine the impact of various drugs and activities on hippocampal neurogenesis and memory recovery.

"We are examining the role of exercise in promoting hippocampal growth and improved memory in these patients," Dr. Mabbott said by email. "We are also interested in the impact of drugs such as metformin, which is known to promote neurogenesis, on memory recovery."

SOURCE: https://bit.ly/2PgwoMW

J Neurosci 2018.

BONE MARROW TRANSPLANT AND LONG TERM MORTALITY RISK

Recipients of donor blood or marrow transplants (BMTs) during childhood remain at increased risk of premature death for 25 years or more after the procedure, researchers say.

"We found that, conditional on surviving the first two years after BMT, the probability of surviving an additional 20 years approached 80%," Dr. Smita Bhatia of the University of Alabama at Birmingham Comprehensive Cancer Center told Reuters Health.

"Overall, the cohort was at a 14-fold greater risk of dying as compared with the general population (of similar age and sex)," she said by email. "Further, this excess risk remained elevated even among those who had survived 25 years."

"On a positive note," she added, "the risk of late mortality has continued to decline over the past three decades."

Dr. Bhatia and colleagues studied 1,388 individuals (about 60% men) who underwent allogeneic BMT at a median age of 14.6 and survived at least two years.

As reported online July 26 in JAMA Oncology, the overall survival rate was 79.9% at 20 years after BMT. Leading causes of death were infection and/or chronic graft-vs-host disease (49.6%); primary disease such as acute lymphoblastic leukemia, acute myeloid leukemia or myelodysplastic syndrome (24.6%); and subsequent malignant neoplasms (18.4%).

As Dr. Bhatia noted, the group had a 14.4-fold increased risk for death compared with the general population and relative mortality remained elevated at 25 years or more after BMT (standardized mortality ratio, 2.9). The absolute excess risk for death from any cause was 12.0 per 1,000 person-years, and the cumulative incidence of non-relapse-related mortality exceeded that of relapse-related mortality throughout follow-up.

Further, the 10-year cumulative incidence of late mortality decreased over time: 18.9% before 1990; 12.8% from 1990-1999; 10.9%, 2000-2010. The decrease remained statistically significant after adjustment for demographic and clinical factors, with hazard ratios compared with the referent group (<1990 0.49="" 0.64="" and="" of="" p="">

"The key practice-changing message," Dr. Bhatia said, "is that there is a need to follow BMT survivors closely long-term and to develop strategies to be vigilant in anticipating and effectively addressing infections several years after BMT, as well as screening for new cancers in this population."

"The long-term risk (of early mortality) is elevated in adults undergoing BMT, as well," she added.

David Loeb, Division Chief of Pediatric Hematology/Oncology and Marrow and Blood Cell Transplantation at the Children's Hospital at Montefiore in New York City, commented, "BMT for children has only been around since the mid-1980s, and so long-term follow-up of the kind described in this study could not have been performed previously. The description of what happens to our patients as they move through adulthood is very important."

The fact that excess mortality has declined over time "probably reflects advances in our ability to perform BMT and manage the toxicities of the procedure over time," he said in an email to Reuters Health.

However, "this study does not compare the experience of patients who had what we now call 'full intensity' or 'myeloablative' transplants and those who had 'reduced intensity conditioning,'" he noted.

"The increased use of less toxic treatment regimens is likely a contributor to the decrease in excess mortality seen in patients transplanted in the 21st century, and as these regimens become even more commonly used, excess mortality should decrease," he said. "We and others are actively working on developing less toxic BMT regimens, and hopefully this will address the concern raised by this paper."

"It is important to recognize that the patients who underwent BMT had immediately life-threatening conditions, and if they had not undergone transplant, would almost all have died," he added. "Thus, the overall survival of this group of patients is better than if none had had a transplant, despite the excess mortality they are experiencing now."

"The long-term toxicities faced by transplant patients, including excess mortality, are important considerations to discuss with potential transplant patients, but this does not mean that transplant is bad - just that we need to continue to work to make the procedure safer, and this information needs to be part of the process of informed consent for the procedure," Dr. Loeb concluded.

SOURCE: http://bit.ly/2OBPFJ8

JAMA Oncol 2018.

LOW DOSE RADIATION AND LEUKEMIA RISK

 Cumulative exposure to low levels of ionizing radiation is associated with an increased risk of developing leukemia, according to a new analysis.

There is substantial evidence linking moderate or high doses of ionizing radiation, particularly in childhood, to leukemia risk, write Dr. Mark P. Little of the National Institutes of Health, in Bethesda, Maryland, and colleagues in The Lancet Haematology, online July 16.

To examine whether this might also be true of low doses, the team studied data on more than 262,000 people enrolled in nine cohorts between 1915 and 2004. All had been exposed to less than 100 mSv and were younger than 21 years at first irradiation.

The mean follow-up was 19.63 years and the mean cumulative estimated individual active bone marrow dosage was 19.6 mSv.

There were 154 myeloid malignancies and 40 cases of acute lymphoblastic leukemia. The grouped categories used for comparisons, included 139 cases of acute leukemia and 221 cases of all leukemia, excluding chronic lymphocytic leukemia because there is "little evidence" of its association with radiation.

The fitted relative risk at 100 mSv was 3.09 for acute myeloid leukemia and myelodysplastic syndromes combined. It was 2.56 for acute myeloid leukemia and 5.66 for acute lymphoblastic leukemia. Moreover, for acute myeloid leukemia and myelodysplastic syndromes combined, as well as acute lymphoblastic leukemia, the risk continued to be significantly increased at doses of less than 50 mSv.

Overall, the researchers write, there were "were few indications of between-cohort heterogeneity or departure from linearity."

These findings, Dr. Little told Reuters Health by email, "suggest that there is risk of leukaemia associated with low-level exposure to radiation. Since most exposures to workers and the public are from low doses, the present study, among others, suggests that the current system of radiological protection is prudent and not overly protective."

The results "also add weight to efforts already underway (such as by the Image Gently Campaign) to minimize the use of diagnostic radiological imaging, particularly in children, wherever possible."

Dr. Christopher S. Hourigan, also of the National Institutes of Health in Bethesda, who co-wrote an accompanying editorial, told Reuters Health by email, "While we continue to look for better ways to treat acute leukemia, we are also extremely interested in understanding inherited and acquired factors that may be helpful in preventing these blood cancers."

"This new work," he concluded, "provides important evidence in support of efforts over the past decade to minimize radiation exposure to children during essential medical procedures."

SOURCE: https://bit.ly/2v0tOmi and https://bit.ly/2KdBXbR

ENDOCRINE DISORDERS IN CHILDHOOD CANCER SURVIVORS

To address a growing risk of endocrine disorders among childhood cancer survivors, the Endocrine Society has published the “Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline,” advising health-care providers on the long-term screening of survivors of childhood cancers at risk for treatment-related problems, including growth disorders, pituitary hormone deficiencies, and early puberty, and how to diagnose and manage these conditions. The guideline by Sklar et al is published in The Journal of Clinical Endocrinology & Metabolism.

Due to improvements in childhood cancer treatment and supportive care over the past several decades, the 5-year survival rate for patients diagnosed with childhood cancers is more than 80%. However, because of their disease and treatment, especially radiation exposure to endocrine organs, these survivors are at an increased risk for developing serious health conditions, including growth disorders. Recent data show that between 40% and 50% of childhood cancer survivors will develop an endocrine disorder during their lifetime, increasing the importance of lifelong surveillance in this population. 

Clinical Practice Recommendations

An Endocrine Society–appointed guideline-writing committee consisting of six medical experts and a methodologist formulated the clinical practice guideline recommendations in the diagnosis, treatment, and management of endocrine-related conditions. The recommendations include the long-term screening of childhood cancer survivors who underwent radiation therapy to key endocrine organs, including the hypothalamus, pituitary, thyroid, and gonads, and calls for the screening of growth disorders, pituitary hormone deficiencies, and early puberty.

According to the recommendations, if a condition is diagnosed, in most cases, clinicians should treat these survivors with the same approaches as other patients who develop endocrine conditions. The recommendations cover six areas of concern in childhood cancer survivors, including:

1. Diagnosis and monitoring of short stature/impaired linear growth
2. Growth hormone deficiency and its treatment
3. Central precocious puberty
4. Hypogonadotropic hypogonadism 
5. Central hypothyroidism/thyroid-stimulating hormone deficiency
6. Adrenocorticotropic hormone deficiency

“Childhood cancer survivors have a high risk of developing endocrine disorders,” said Charles A. Sklar, MD, a pediatric endocrinologist at Memorial Sloan Kettering Cancer Center, New York, and Chair of the writing committee that developed the guideline. “Our new guideline addresses the growing risk of endocrine disorders among childhood cancer survivors and suggests best practices for managing pituitary and growth disorders commonly found in this population. The guideline stresses the importance of lifelong screening of these survivors for earlier detection and optimal patient care.” 

Dr. Sklar is the corresponding author of the Endocrine Society’s cinical practice guideline. The Endocrine Society provided funding for this guideline.

For full disclosures of the guideline authors, see the Appendix of the clinical practice guideline.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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ASCO 2018-PROGRESS IN RHABDOMYOSARCOMA TREATMENT

The trial enrolled patients with pathologically proven high-risk RMS from 108 centers across 14 countries. Enrollment required that patients have no evidence of metastasis and that they had received no treatment for their disease.

Patients were aged 6 months to 21 years and had N0 alveolar RMS or had undergone incomplete resection (group II or III) of embryonal RMS arising in an unfavorable site (eg, the head) and/or N1 complete resection.

All patients received standard intensive therapy, which consisted of nine cycles of high-dose chemotherapy (a combination of ifosfamide, vincristine, and actinomycin D with or without doxorubicin), followed by radiotherapy and surgery.

"Ninety percent of patients achieve complete remission with this approach. Of the others, about a third relapse and will die," Bisogno said. "Some persistent residual disease is a major obstacle to increase cure rates in these patients," he added.

The purpose of the trial was to see whether low-dose chemotherapy given as maintenance therapy was effective against minimal residual disease that was still present after the conclusion of standard chemotherapy, he explained. That is why patients with no evidence of tumor were randomly assigned to receive no treatment (n = 186) or 6 months of maintenance treatment (n = 185).

Maintenance therapy consisted of weekly vinorelbine 25 mg/m² given intravenously on day 1, 8, and 15 every 28 days; daily cyclophosphamide 25 mg/m² was given orally daily. Patients received a total of six cycles of maintenance therapy.

Median follow-up was 5 years.

Study Results

The 5-year DFS was 77.6% for patients who received maintenance therapy; it was 69.8% for those who received standard therapy alone (azard ratio [HR], 0.68; P = .06)

Five-year overall survival was 86.5% for the patients who received maintenance therapy vs 73.7% for the those who received standard therapy (HR, 0.52; P = .01).

Compared with standard therapy, maintenance therapy was associated with less anemia, neutropenia, and thrombocytopenia, less infection episodes, and no cardiac, hepatic, gastrointestinal, or renal toxicity.

Bisogno pointed out that future EpSSG trials will study alternate maintenance regimens and different durations of maintenance therapy. He also indicated that, given these data, this approach merits consideration in other solid childhood malignancies.

Team Should Be Congratulated

The discussant for the study, Douglas S. Hawkins, MD, chief of the Division of Hematology/Oncology at Seattle Children's Hospital, Washington, provided context to the EpSSG trial and speculated on why this intervention improved outcomes. He also discussed who should receive maintenance chemotherapy in the future.

"The EpSSG should be congratulated. They conceived, conducted, and completed a randomized study in an exceptionally rare population of patients — pediatric rhabdomyosarcomas," he said. The EpSSG study is only the third positive study of pediatric RMS to be reported in the past 40 years.

He suggested that improvement in outcomes in the EpSSG study may be due to the activity of vinorelbine (Navelbine, Pierre Fabre), which has yielded response rates of 36% and 50% as single agent in relapsed/refractory RMS. Similar responses have been seen with the combination of cyclophosphamide and vinorelbine. In the maintenance phase, patients received 18 doses of vinorelbine, which perhaps accounts for the outcomes reported, he noted.

Hawkins also weighed in on the duration of therapy. He pointed out that, compared with the total of 51 weeks of treatment that patients in the maintenance arm received in this study, the duration of standard therapy in the US Children's Oncology Group (US COG) study is 42 weeks, and it does not include maintenance therapyCHICAGO — After 30 years, a significant advancement has been reported on how outcomes can be improved for patients with rhabdomyosarcoma (RMS).

In this rare childhood disease, which is diagnosed in 350 children in the United States every year, 6 months of low-dose maintenance therapy after standard treatment increased 5-year disease-free survival (DFS) by ~8% and improved overall survival by 13%.

The new data come from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) and were presented here at a plenary session of the American Society of Clinical Oncology (ASCO) 2018 annual meeting.

"This study establishes the new standard of treatment for patients with high-risk rhabdomyosarcoma, at least in Europe," said lead author Gianni Bisogno, MD, of the University Hospital of Padova, Italy.

ASCO Expert Warren Chow, MD, clinical professor at City of Hope, Duarte, California, agreed. "The study established maintenance chemotherapy after standard chemotherapy as the standard of care in the European consortium," he said.

"By keeping the pressure on this cancer longer with maintenance therapy, we are giving patients two wins — we are boosting cure rates by preventing relapses, and doing so with few side effects," Chow said.

Chow pointed out that this trial was limited to patients younger than 21 years. It is yet to be determined whether this approach can be applied to patients older than 21 years, who are considered to be at high risk because of their age, he noted.

This is the first significant advance in this cancer in more than 30 years.Dr Warren Chow

"Even with the caveats, this is the first significant advance in this cancer in more than 30 years. No doubt, this trial was a home run," Chow said.

However, another expert not involved in the study questioned whether these new results would change clinical practice in the United States. The duration of the initial chemotherapy given in the United States is longer (45 weeks vs 27 weeks in Europe), noted Leonard H. Wexler, MD, pediatric oncologist who treats RMS at Memorial Sloan Kettering Cancer Center, New York City. "Results without maintenance treatment in the US are similar to what the EpSSG study reported with maintenance therapy. Whether we can further reduce metastatic disease recurrence by adding maintenance therapy is currently not known," he told Medscape Medical News.

Study Details

Because of the rarity of this cancer, the EpSSG study (called RMS2005 Maintenance study) took 11 years to complete. The first patient was enrolled in April 2006, and the study was completed in December 2016.

As to who should receive treatment, he noted that low-risk patients, who constitute a third of patients, were excluded from the study. Hawkins pointed out that, of the high-risk patients, only those who demonstrated radiographic remission at week 27 were eligible for maintenance therapy. "Patients with the highest risk were not studied in this study," he said. In particular, treatment outcomes for patients who did not achieve complete remission and were excluded from the study were not reported.

Also, patients with alveolar RMS with regional lymph node involvement (N1) and those with distant metastases — the highest-risk group — were not included in the study.

Hawkins identified reasons why extrapolation of these data to those from the US COG can be challenging. He noted that the standard treatment in the US COG is 42 weeks, which is longer than the 27 weeks in the EpSSG trial. "It is not certain that adding maintenance treatment will improve the outcome," he said. Secondly, he noted that the backbone chemotherapy differs in significant ways in the first 27 weeks. He also indicated that strategies for local control are not identical.

He also indicated that US COG and EpSSG risk stratification do not overlap. Comparisons cannot be made without some adjustments, he said.

Limited Impact in the United States

A press statement from ASCO indicated that findings from this trial have been shared by investigators with soft tissue study group institutions in 14 countries and that the protocol used in this trial is now standard in Europe.

Asked at the press conference about the study's impact on clinical practice in the United States, Chow indicated that it is unusual to use maintenance chemotherapy for pediatric sarcomas. "So this is a paradigm shift," he said.

However, Chow also noted that this approach needs to be tested with US protocols before it can be standard of care in the United States.

He explained that in the United States, US COG uses irinotecan (Camptosar, Pfizer) on the backbone of vincristine, actinomycin D, and cyclophosphamide, but no maintenance therapy.

Medscape Medical News approached sarcoma experts in the United States who were not associated with the study. All experts acknowledged that the results of this study are not likely to change practice in the United States.

Dr Wexler explained that there is a population of children with newly diagnosed RMS whose tumors have not spread visibly; for these patients, the risk for recurrence is between 30% and 40%. Treatment failure occurs because the tumor is not eradicated at the primary site, appears at other sites, or both.

He also noted that that treatment approach is common in the United States. "There is a near uniform treatment for this disease," he said. Wexler explained that patients are given 3 months of preradiation chemotherapy, followed by concurrent chemotherapy and radiotherapy. Some patients may undergo surgery prior to or after radiotherapy. This approach is designed to achieve local control, he pointed out.

After radiotherapy, patients receive 20 to 22 weeks of chemotherapy, which is expected to achieve systemic control and kill any tumor cells in parts of the body secondary to the primary site. "The entire process takes from 40 to 45 weeks," he noted.

When recurrence occurs, it is either at the primary site or at other sites. The pattern of recurrence indicates whether the tumor is resistant to radiotherapy or chemotherapy. Recurrence at the primary site indicates resistance to radiotherapy; in such cases, providing additional chemotherapy will not benefit the patient. If the tumor recurs at secondary sites, the disease is resistant to chemotherapy, which means that not enough chemotherapy was given initially.

"The purpose of maintenance therapy is to get rid of tumors that are chemoresistant, ie, occur at secondary sites," Wexler said.

In the EpSSG study, all patients were randomly assigned to receive maintenance therapy or no treatment after complete response at week 27, he further explained. Although it is helpful to know that risk for recurrence was reduced, it would be better to know the pattern of recurrence. "What was not shared in the presentation was whether maintenance treatment reduced metastatic recurrence or local recurrence," Wexler said. One would expect all benefit would be at secondary sites, since the purpose of systemic therapy is to reduce the development of metastatic disease.

Margaret von Mehren, MD, chief of the Division of Sarcoma Medical Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, treats adults with RMS in her practice.

"Overall, it is a chemosensitive disease, and we can cure a lot of patients by giving the right-intensity regimen for the right patient," she said.

"This study group [EpSSG] has done a tremendous amount of work in getting meaningful data and getting it right. The results of this study are intriguing and look like maintenance therapy can have a meaningful impact on the disease," von Mehren told Medscape Medical News.

"Chemotherapy is better tolerated in children. Could we give this to adults, and is it feasible in high-risk adults?" von Mehren questioned.

"In the US, pediatric oncologists are a more disciplined group and look for clear guidance from trial data before changing practice. These results will have to be replicated in clinical trials before maintenance chemotherapy can be the standard of care in the US," von Mehren told Medscape Medical News.

Alberto Pappo, MD, director of the Solid Tumor Division at St. Jude's Children's Research Hospital in Memphis, Tennessee, said the new results are exciting, but he needed to see more. "We do not have all the data," he said.

In particular, he noted a discrepancy between the event-free survival, which was the primary endpoint and was not significant, and OS. "As standard treatment, we also do not know how many patients got surgery and how many got radiation or both," he said.

Pappo concluded that, from the abstract, patients who received standard chemotherapy were also randomly assigned to receive doxorubicin or not to receive it. "We do not know whether the patients who received doxorubicin did better," he said.

Given these uncertainties, Pappo indicated that he would not adopt maintenance therapy for his patients in the United States.

Dr Bisogno reports consulting with Clinigen Group and that his travel, accommodations, and expenses are paid by Jazz Pharmaceuticals. Dr Hawkins has received travel expenses from Bayer, Bristol-Myers Squibb, Celgene, and Loxo.

American Society of Clinical Oncology (ASCO) 2018. Abstract LBA2, presented June 3, 2018.