Clinicians strive to meet needs of ‘underserved’ AYA population

Adolescents and young adults with cancer historically have fallen through the cracks between pediatric and adult oncology practices.

Approximately 70,000 adolescent and young adults (AYAs) — defined by the NCI as those aged 15 to 39 years — are diagnosed with cancer each year. Many of these cancers are unique to this age group, and those that are not unique to AYA patients often differ biologically from those diagnosed in children or older adults.

Yet, a lack of clinical trial data specific to AYA cancers has left two key questions — how and where these patients should be treated — open to debate.

“These patients are an underserved population,” Wendy Stock, MD, professor of medicine at the University of Chicago Medicine, told HemOnc Today. “There is less knowledge about clinical outcomes in these patients because they have been less likely to participate in clinical trials, in part because of referral base and in part because there have not been clinical trials necessarily focused on this population. I hope that this is now changing with the recent focus on this population and the increased access to care and clinical trial enrollment.”

AYA patients with cancer also may have psychosocial needs that typically are not addressed in pediatric or adult oncology settings.

Some cancer centers are establishing AYA clinics to address these challenges and better serve this patient population.

“There is a great opportunity for pediatric and medical oncologists to work together,” Stock said. “By working together, we can capitalize on both the clinical expertise and the psychosocial resources that are available in each of these settings.”

HemOnc Today spoke with several oncologists to learn more about the challenges unique to the AYA population, the stagnating survival curves in this demographic and the steps being taken in the clinical community to better fulfill these patients’ needs.

Setting of care

One of the greatest challenges is determining the appropriate setting of care for AYA patients with cancer.

“Adolescents and young adults in general slip through the cracks, medically, because they have a set of unique problems that don’t fit into pediatrics and don’t particularly fit into internal medicine,” Michael P. Link, MD, professor of pediatrics at Stanford University School of Medicine and past president of ASCO, said in an interview. “Besides having unique stage-of-life problems, they also have a set of cancers which are not typically pediatric, not typically adult, but which tend to cross the boundaries.”

Leukemia, lymphoma, testicular cancer and thyroid cancer are the most common malignancies in patients aged 15 to 24 years, according to data from the NCI. Breast cancer and melanoma are the most common malignancies in those aged 25 to 39 years.

This diversity of cancers observed in AYAs complicates the effort to determine the most appropriate care setting.

“The initial site of referral or diagnosis influences a lot where the patient goes,” Stella M. Davies, MBBS, PhD, MRCP, director of bone marrow transplantation and immune deficiency at Cincinnati Children’s Hospital Medical Center, told HemOnc Today. “There is no absolute right or wrong for where these patients should be treated. It depends on local resources and what kind of cancer it is.”

For instance, an AYA aged 26 years with breast cancer is likely to be treated in an adult setting due to the familiarity and expertise medical oncologists have with the disease. However, someone of the same age with neuroblastoma may be more appropriately treated in a pediatric setting.

Typically, however, AYAs with cancer may be more commonly referred to pediatric centers because of the availability of resources and lower volume of patients at these centers.

“These patients face these difficult diseases at a pivotal time in their lives, and they often do not have the support network that many of our older or younger patients have,” Stock said. “It becomes specifically important in this population to have as many onsite resources as possible, which pediatric centers tend to have.”

Not every AYA patient may prefer these extra resources.

“We peel their grapes for them in contrast to adult practices,” Davies said. “We have a lot of services that aren’t provided to adults: art, massage and music therapists, a therapeutic recreation specialist to take them out on trips. A mature 22-year-old can find that annoying. For others, it’s a huge plus, and they won’t transition to adult care because they won’t have those things.”

Still, the availability of these resources still may not address the specific needs of an AYA population.

“In pediatric centers, we are very concerned about our patients going to kindergarten, and in adult centers they are worried about their jobs, but what about people in college?” Link said. “What about fertility issues, which older patients may not care about? The issues that would be of key importance to AYAs are not necessarily addressed very well in pediatric or adult centers.”

A literature review conducted by Tai and colleagues — published in 2014 in Pediatrics — found the rate adolescents were treated at pediatric centers varied from 14% to 47% depending on cancer type. Adolescents with classic “adult” cancers, such as melanoma or germ cell tumors, were more often treated at adult centers.

Yet, this division between typical “adult” vs. “pediatric” cancers fails to acknowledge the complexity of AYA cancers.

“There is a lot of variability within the biology of the disease that we are just learning about,” Stock said. “A whole new subset of acute lymphoblastic leukemia has been discovered that seems to be more common just at the time when people come into adolescence.”

Survival lag

The unique biology of AYA cancers may make the diseases more difficult to treat, worsening the prognosis for these patients.

“Even in diseases that are the same as younger pediatric disease — such as rhabdomyosarcoma or leukemia, which are common pediatric cancers — AYAs have not benefited to the same extent as younger patients,” Link said. “Part of it is just that they tend to present with more unfavorable biologic features. If you look at virtually every disease that we treat, once somebody hits 10 years of age, the prognosis gets worse.”

A study by Bleyer and colleagues, published in 2009 in Seminars in Oncology, revealed a considerable survival gap among AYA patients with cancer.

Using SEER data, researchers found AYA patients experienced much smaller conditional survival improvements from 1973 to 2002 compared with younger or older age groups. Patients aged 20 to 29 years fared the worst, as conditional survival in that age group was 45% below the mean.

“This age group has had the least improvement in outcome in looking at the fall of cancer mortality rates,” Link said. “We can cure the majority of children with cancer aged younger than 15 years, and there has been great progress made in older adults with cancer. But AYAs have been an underserved, complex population.”

Several factors appear to be driving the survival gap. One example is delayed diagnosis.

“We have seen some of our patients who have been in multiple ERs with complaints of fatigue, fever, etc, who were treated for viral respiratory infections and sent out, and several weeks or months later they have presented with ALL,” Stock said. “I think it has to do in part with a lack of continuity of care for these patients, as often they haven’t yet established adult care. There is also a lack of awareness of AYA cancers. They often show up in an ER or urgent care clinic, have a very cursory exam and are sent out.”

Receipt of inappropriate initial treatment is another important variable.

Potosky and colleagues evaluated whether 504 AYAs with ALL, Hodgkin’s or non-Hodgkin’s lymphoma, germ cell cancer or sarcoma received appropriate initial treatment based on guidelines and literature.

The results — published in 2014 in Journal of the National Cancer Institute — showed 25% of patients evaluated in the study did not receive appropriate initial therapy. When male patients with stage I germ cell cancer were excluded, the percentage of patients who failed to receive appropriate initial therapy increased to 32%.

The lack of clinical trial participation among AYA patients with cancer also may limit survival improvements.

A SEER analysis performed by Parsons and colleagues, published in 2011 in Journal of Clinical Oncology, showed only 14% of AYAs were enrolled on clinical trials. Trial participation varied significantly by treatment setting. Seventy percent of AYAs treated by pediatric oncologists were enrolled on clinical trials, compared with 11% of those treated by hematologists/oncologists (P < .001).

Health insurance — or the lack thereof — can contribute to the problem, too.

Data from Rosenberg and colleagues, published in 2014 in Cancer, showed 7% of AYAs lacked insurance and 15% had Medicaid. Patients aged 25 to 39 years were more likely to present with late-stage disease if they lacked insurance (OR = 2.4; 95% CI, 2.1-2.6) or had Medicaid (OR = 3.2; 95% CI, 3-3.5) than those with private insurance. These patients also faced a greater risk for death (stage I/II cancer, HR = 2.9; 95% CI, 2.2-3.9; stage III/IV cancer, HR = 1.7; 95% CI, 1.5-1.9).

Further, a study by Smith and colleagues — published in 2013 in JAMA Surgery — indicated that AYAs with breast cancer who experienced a treatment delay of more than 6 weeks were less likely to achieve 5-year survival than those treated within 2 weeks of diagnosis (80% vs. 90%; P = .005). Treatment delays were more common in AYAs with public or no insurance vs. private insurance (17.8% vs. 9.5%) and in patients with low vs. high socioeconomic status (17.5% vs. 7.7%).

“This has to do with the resilience of youth, that people tend to be well until they are incredibly ill, and often they don’t seek attention in the right fashion because they don’t have the means or established routine to do so,” Stock said. “They have lost the umbrella of their parents’ coverage, or the coverage of the state, and they are kind of lost.”

Pediatric vs. adult protocols

Treatment protocols also may affect the survival gap. One of the greatest challenges physicians face is whether to treat AYA patients on an adult or pediatric protocol.

Stock and colleagues evaluated trial data from two entities — the Children’s Cancer Group, which uses pediatric protocols, and Cancer and Leukemia Group B (CALGB), which uses adult protocols — to assess whether either approach demonstrated an association with survival among AYAs aged 16 to 20 years with ALL.

Results, published in 2008 in Blood, showed patients in Children’s Cancer Group trials demonstrated significantly better 7-year EFS (63% vs. 34%; P < .001) and 7-year OS (67% vs. 46%; P < .001).

A study by Woods and colleagues, published in 2013 in Cancer, yielded similar findings. In a cohort of patients aged 16 to 21 years with acute myeloid leukemia, those treated on Children’s Oncology Group trials demonstrated superior 10-year EFS (38±6% vs. 23±6%; P = .006) and OS (45±6% vs. 34±7%; P = .026) compared with those treated on CALGB and Southwest Oncology Group trials.

Yet, these data do not necessarily indicate that the pediatric regimens themselves improved outcomes.

“Medical oncologists are used to treating older patients, so they may not be willing to push the envelope on treatment for fear of toxicity,” Link said. “In pediatric cancer, we’re not looking to extend someone’s life by 2 years, we’re looking for a cure. There is a much more aggressive approach and we tend to downplay acute toxicities in the interest of the larger goal.”

Link referenced a 2003 Journal of Clinical Oncology editorial written by Charles A. Schiffer, MD, of Karmanos Cancer Institute, to exemplify this difference.

“Pediatricians administer these treatments with a military precision on the basis of a near-religious conviction about the necessity of maintaining prescribed dose and schedule come hell, high water, birthdays, Bastille Day or Christmas,” Schiffer wrote.

Still, there are diseases — such as acute promyelocytic leukemia — for which adult regimens may offer more promise for AYA patients, Stock said.

“Some adult regimens have been more successful than pediatric regimens in some of the diseases,” Stock said. “It can go both ways.”

‘A fine line’

Adolescents or young adults with testicular cancer epitomize many of the overall challenges faced by the AYA population.

Although incidence of testis cancer is generally increasing across the board, men aged 20 to 34 years account for more cases (48.9%) than any other age group, according to data from the NCI. A study conducted by Chien and colleagues, published in 2013 in Cancer, showed incidence of testicular germ cell tumors increased 58% in Hispanic AYAs and 7% in non-Hispanic white AYAs between 1992 and 2010.

“Culturally, the Hispanic population has not always sought early medical attention, so they might be diagnosed later, requiring more aggressive treatment,” David C. Smith, MD, professor of medicine and urology in the division of hematology/oncology at the University of Michigan, told HemOnc Today. “There are also language and cultural barriers, and you have to be more sensitive as to where they are in terms of thinking about their illness.”

The incidence rate of testicular cancer peak rises sharply after puberty, and post-pubertal germ cell tumors in males are different from the germ cell tumors of early childhood, which are mostly extragonadal, Timothy Gilligan, MD, a medical oncologist at Cleveland Clinic who specializes in cancers of the testicles, bladder, prostate and kidneys, said in an interview.

“If a 15-year-old sees a pediatric oncologist for testicular cancer, and he is treated the way a prepubertal boy with a germ cell tumor is treated, then he is going to receive a very different treatment plan than a 19-year-old with testicular cancer seeing an adult oncologist,” Gilligan said. “Teenage boys with testis cancer are at risk of being treated inappropriately because they are being clumped with the wrong group of patients. They should be treated as young men rather than old boys.”

Smith has observed a similar trend.

“I have seen patients who probably would have been best served being observed getting fairly aggressive adjuvant therapy in the pediatric setting,” Smith said. “I have also seen patients getting their treatment almost entirely as an inpatient, when in fact outpatient treatment is appropriate for testis cancer.”

Some of these variations in care may stem from a lack of consensus in the field as to whether patients with stage I disease should be observed after surgery, Smith said.

“The reality is that a vast majority of these men are diagnosed with early-stage disease and they are cured by their initial surgical procedure,” Smith said. “Given that we can cure them if they relapse, it makes sense to err on the side of limiting treatment so you don’t cause patients the side effects of chemotherapy down the road.”

The line between over- and under-treatment is extremely important in AYA testicular cancer.

“It is exciting that testicular cancer is very curable and we have a lot of data to guide our treatment patterns,” Gilligan said. “But if we undertreat, we may not cure some of those who could have been and then they die. If we overtreat they will be exposed to lifelong toxicities they didn’t need to have. This affects AYA patients if they are seeing a pediatric oncologist who does not see a lot of testis cancer.”

Difficulties adhering to treatment — a common issue for this age group — also pose challenges for young men with testicular cancer.

“In this realm, the challenge is getting them to adhere to the surveillance schedule,” Smith said. “The biggest risk for relapse is in the first 2 years, and the patient’s commitment to keep a surveillance schedule sometimes influences our decision-making when it comes to whether we are going to recommend surgery in hopes of preventing problems down the road.”

Hodgkin’s lymphoma is another condition that typically affects the AYA population, and for which different treatment approaches have emerged from the pediatric and adult oncology communities.

Adults with Hodgkin’s lymphoma now typically receive chemotherapy regimens that do not include extensive alkylating agent or steroid therapy, and that have reduced the extent and dose of radiation therapy. These treatment approaches are aimed to minimize potential late toxicities of treatment, including the risks of second cancers and impaired fertility.

Trials in pediatric Hodgkin’s lymphoma often still include relatively extensive alkylating agent exposure, as well as high doses of corticosteroid.

“From time to time, I see patients in my clinic who previously received treatment for Hodgkin’s lymphoma on pediatric protocols and who have significant late toxicities, including infertility and avascular necrosis of the hip. These are late toxicities that we no longer typically see in the treated adult population,” said John Sweetenham, MD, senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah, and HemOnc Today’s Chief Medical Editor for Hematology.

As in testicular cancer, there is “a fine line” between overtreatment and undertreatment, and the AYA population is especially vulnerable to both, Sweetenham said.

Specialized AYA clinics

In order to address challenges unique to the AYA population, many larger cancer centers are establishing AYA cancer clinics. These clinics — which can be staffed by both pediatric and adult oncologists — may consider adult and pediatric treatment approaches to optimize treatment. They also include additional resources and specialists to address psychosocial needs specific to AYA patients.

Stock and her colleagues set up such a clinic at the University of Chicago medicine for AYAs with hematologic malignancies. Preliminary results from patient surveys indicate that compliance may be improved in this setting.

“So far, we’ve found that some AYAs who had been treated on the adult side much prefer the environment and more focused care that is available in this clinic compared to the standard adult clinic,” Stock said.

Psychosocial support is a critical part of these clinics.

“Most patients with cancer are in their 60s and 70s, so the world isn’t really set up to accommodate the 20-year-old with cancer,” Gilligan said. “These patients are not at a psychological stage in life where they can be dealing with a life-threatening crisis. It can be really overwhelming, and this is an opportunity for many cancer centers to do better.”

The formation of such clinics also might enhance AYA participation in clinical trials.

“If AYA patients are concentrated in places where we know we have plenty of patients who can be studied, that would be an impetus to study them,” Link said. “Further, if community oncologists collaborate with or refer patients to AYA centers, that would give them access to clinical trials.”

These clinics also would allow for more collaboration among pediatric and adult oncologists.

“We draw an arbitrary boundary between adolescents and adults,” Gilligan said. “The big challenge is to get pediatric and adult oncologists to talk to each other more, to enhance communication between those two worlds and break down the divides between them.” – by Alexandra Todak

References:

Bleyer A, et al. Semin Oncol. 2009;doi:10.1053/j.seminoncol.2009.07.004.

Chien FL, et al. Cancer. 2013;doi:10.1002/cncr.28684.

NCI. A snapshot of adolescent and young adult cancers. Available at: www.cancer.gov/researchandfunding/snapshots/adolescent-young-adult. Accessed Feb. 6, 2015.

NCI. SEER stat fact sheets: testis cancer. Available at: seer.cancer.gov/statfacts/html/testis.html. Accessed Feb. 6, 2015.

Parsons HM, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2011.36.2954.

Potosky AL, et al. J Natl Cancer Inst. 2014;doi:10.1093/jnci/dju300.

Rosenberg AR, et al. Cancer. 2014;doi:10.1002/cncr.29187.

Schiffer CA. J Clin Oncol. 2003;21:760-761.

Smith EC, et al. JAMA Surg. 2013;doi:10.1001/jamasurg.2013.1680.

Stock W, et al. Blood. 2008;doi:10.1182/blood-2008-01-130237.

Tai E, et al. Pediatrics. 2014;doi:10.1542/peds2014-0122C.

Woods WG, et al. Cancer. 2013;doi:10.1002/cncr.28344.

For more information:

Stella M. Davies, MBBS, PhD, MRCP, can be reached at Cincinnati Children’s Hospital, 3333 Burnet Ave., Cincinnati, OH 45229; email: stella.davies@cchmc.org.

Timothy Gilligan, MD, can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195; email: gilligt@ccf.org.

Michael P. Link, MD, can be reached at Lucile Packard Children’s Hospital of Stanford, Pediatric Hematology-Oncology, Mail Code 5798, 1000 Welch Road, Suite 300, Palo Alto, CA 94304-1812; email: mlink@stanford.edu.

David C. Smith, MD, can be reached at University of Michigan, Internal Medicine Oncology, Cancer Center Floor B1 Reception D, 1500 E. Medical Center Drive, SPC 5913, Ann Arbor, MI 48109; email: dcsmith@med.umich.edu.

Wendy Stock, MD, can be reached at The University of Chicago Medicine, 5841 S. Maryland Ave., Chicago, IL 60637; email: wstock@medicine.bsd.uchicago.edu.

John Sweetenham, MD, can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Davies, Gilligan, Link, Smith, Stock and Sweetenham report no relevant financial disclosures.

Should AYA patients with ALL receive a pediatric protocol?

AYA patients should receive pediatric protocols, but they may be treated by either an adult or a pediatric hematologist/oncologist.

The treatment of AYAs with acute lymphoblastic leukemia has been a focus of research during the last decade. Two pivotal retrospective trials — one conducted in France and one conducted in the United States — demonstrated superior outcomes for AYAs treated on pediatric cooperative group trials (DFS of 60% to 70%) compared with those treated on adult cooperative trials (DFS of 30% to 40%). Multiple other investigators replicated these results on an international level. This raised the question of why these outcomes are different. Are the outcomes related to the treating physician (pediatrician vs. adult hematologist/oncologist), the differences in treatment regimen (more vincristine, steroids, asparaginase and intrathecal therapy in the pediatric regimens), a slightly different patient population (younger patients and better-risk cytogenetics in the pediatric trials) or patient compliance (patients treated by pediatricians are typically still living at home with their patients and have help/support with transportation/medications)?

The adult U.S. cancer intergroup conducted a prospective clinical trial, C10403, to address this question. Newly diagnosed patients with ALL aged 16 to 39 years were treated by adult hematologists/oncologists using the standard arm of the Children’s Oncology Group (COG) AALL0232. Researchers enrolled 318 patients. The median age at diagnosis was 24 years, although 22% of patients were aged 30 to 39 years. The 2-year EFS was 66%, which is comparable to results achieved by the pediatric groups in this AYA population. This is particularly encouraging given the older patient population in this trial and validates the treatment of AYA patients by adult hematologists/oncologists.

Therefore, the critical issue is using an appropriate regimen (pediatric or “pediatric-like”), and appropriate knowledge of the toxicities and support of the patient. Collaboration between pediatricians and adult hematologists/oncologists in this AYA population also is crucial in understanding the “best” regimen, as well as understanding the differences in biology and toxicity along the continuum of age. Such collaboration led to the finding of the Ph-like signature in 28% of patients on the C10403 trial. This signature had a higher incidence in this AYA population as compared with the pediatric population, and it has prognostic and therapeutic implications. Future trials in this AYA population will continue to be performed on a collaborative basis.

 

References:

Boissel N, et al. J Clin Oncol. 2003;21:774-780.

Larsen EC, et al. J Clin Oncol. 2011;20:suppl 3.

Stock W, et al. Blood. 2008;doi:10.1182/blood-2008-01-130237.

Stock W, et al. Abstract 796. Presented at: ASH Annual Meeting and Exposition; Dec. 5-9, 2014; San Francisco.

For more information:

Anjali Advani, MD, is a staff physician in the department of hematologic oncology and blood disorders and director of the Inpatient Leukemia Program at Taussig Cancer Institute at Cleveland Clinic. She can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195; email: advania@ccf.org. Disclosure: Advani reports research funding from EUSA and Sigma-Tau.

It depends on the type of ALL.

I routinely use a pediatric-inspired regimen for AYAs with ALL, with one notable exception: the relatively uncommon circumstance of a young patient with Philadelphia chromosome-positive ALL. In that circumstance, I think an adult-inspired regimen is appropriate because that tends to be more of an adult disease. For Ph+ALL, we tend to use the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) regimen, along with an oral tyrosine kinase inhibitor. We use a traditional four-drug induction and Berlin-Frankfurt-Munster (BFM)-style consolidation — the specific regimen is the C10403 regimen that was reported at last year’s ASH meeting by Wendy Stock, MD — for the Ph-negative AYAs with ALL.

Much of current opinion regarding adult or pediatric regimens for AYAs is based on research that compared cooperative group studies in primarily, if not exclusively, patients who are Ph-negative. An analysis by Stock and colleagues, published in Blood in 2008, compared adult and pediatric regimens. Of the approximately 300 patients included in that analysis, only seven patients had Ph+ALL. The challenge is that, although ALL is more common in younger people, the proportion of those cases that are PH+ is quite small. In contrast, Ph+ALL is a larger piece of the pie in older adults. Trying to find enough patients in the AYA age range who are Ph+ is relatively difficult, because PH+ disease may comprise only about 10% of AYA patients with ALL.

The data that do exist comparing adult with pediatric treatments in this age group are so provocative that it begs the question: Would we see similar differences for Ph+ALL as we see primarily with PH-negative ALL? It would be a very challenging study to conduct because of the relatively small number of patients. As the landscape of treating PH+ALL has changed so much in the last 10 to 15 years with the routine use of oral TKIs in initial treatment, the outcomes have gotten substantially better. To muddy the water even further, should these patients all be transplanted in first remission? It is a controversial area, but that controversy expands beyond the question of a pediatric vs. adult chemotherapy backbone. Is there a TKI that is clearly better than another? What is the role of transplantation? There are a lot of potential areas of interest in terms of teasing out these paradigms.

How a pediatric regimen vs. hyper-CVAD — probably the most widely used ALL treatment in the U.S. in adults — compares is unclear, as none of these adult-to-pediatric historical comparison trials looked at that regimen as the comparator. There aren’t any data to say that hyper-CVAD is inferior to a pediatric regimen even in a retrospective analysis, which is what most of these data are.

 

References:

Ravandi F, et al. Blood. 2013;doi:10.1182/blood-2012-11-466482.

Stock W, et al. Blood. 2008;doi:10.1182/blood-2008-01-130237.

Stock W, et al. Abstract 796. Presented at: ASH Annual Meeting and Exposition; Dec. 5-9, 2014; San Francisco.

For more information:

Ryan Cassaday, MD, is an assistant professor in the division of hematology at the University of Washington School of Medicine. He can be reached at University of Washington, 825 Eastlake Ave. E, Box 358081, Mailstop G6075, Seattle, WA 98109; email: cassaday@uw.edu. Disclosure: Cassaday reports research funding from Pfizer.