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Adolescent and Young Adult Cancer Care
by
Karen Albritton, MD Chief, Adolescent and Young Adult Oncology Program Assistant Professor, Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute and Harvard Medical School Nearly ninety percent of the patients seen at pediatric centers or by pediatric oncologists are less than 15 years old; likewise more than 90% of all patients seen by medical oncologists or at adult hospitals are greater than 40 years of age. Yet each year in the United States, 70,000 individuals between the age of 15 and 40 are diagnosed with cancer. This means that adolescents and young adults (AYA) are not the focus of care given by, or research done by either system. The current binary system of medicine, divided arbitrarily and not biologically (and not even reproducibly between centers) between age 16 and 21 does a disservice to those patients at the overlap. This is evidenced by the lack of progress in survival statistics for this population; although younger children and older adults with cancer has benefited from a steady improvement in 5-year survival of over 1.5% per year, AYA patients have had no change in survival rates in 20 years (Figure 1).
Figure 1: Improvement in 5-Year Survival Invasive Cancer, 1975 to 1997, Courtesy: A. Bleyer, SEER data. Click on the figure to see a larger image of it.
Their enrollment in clinical trials is much lower than that of pediatric cancer patients and among the lowest of adult patients too, see Figure 2.
Figure 2: AYA Participation in US Clinical Trials, Courtesy: A. Bleyer, NCI data. Click on the figure to see a larger image of it.
Who should care for these patients is problematic. The ideal physician to care for any cancer patient would meet the following criteria:
For many AYA patients, they must compromise (often unknowingly) on one or more of these criteria. They may be a 15 year old with melanoma, referred to the expertise of a medical oncologist who gives very appropriate medical management but is less than fully able to deal with parental involvement, developmental needs of teenager; the child is ineligible for most melanoma protocols because they have lower age limit of 18, and the child must go to adult clinics and hospitals that feel intimidating. Alternatively, the 25 year old with rhabdomyosarcoma might best be served by a pediatric oncologist with more experience in sarcoma, but would likewise feel out of place with the Disney on the wall of a pediatric center, a potentially paternalistic care system, and less likely recognition of needs such as fertility, missed work, social calendar.
Specifically for Ewing’s sarcoma, the data is very controversial. In virtually all retrospective studies, it has appeared that older adolescents and young adults with Ewing’s do worse than those < 15 years of age (Rosito and Nesbit). Indeed, SEER (Surveillance, Epidemiology, and End Results) data for all Ewing's patients found that between 1985-1994, those age 5-9 had a 71% 5-year OS, and those 10-14 and those 15-19 both had a 56% 5-year OS (Smith). Unpublished SEER data on adult Ewing's sarcoma 1988-1998 show a 45% 5-year OS for ages 20-39. The reason for this disparity may be due to a difference in disease biology (larger tumors, more axial location), in patient substrate (difference in drug metabolism, difference in drug dosing due to m2, more concomitant medications) or in patient care (more delays in therapy, more patients stopping therapy early). Indeed in a large analysis of Ewing's patients (aged 8 months to 47 years), the age group >=15 had a significantly higher proportion of pelvic primaries and greater tumor volumes (Cotterill).
Recently, it has become more common to include adults on Ewing's clinical therapeutic trials. Verrill's group in England treated all Ewing's patients age 16-48 identically with an intensive regimen and found age did not influence survival, but volume of tumor did (Verrill). This was corroborated in the German CESS 86 study (Paulssen), which intensified treatment for patients with large volume tumors and did not find any impact of age on survival. However, other reports of adults on "pediatric" trials continue to find an inferior outcome for patients above 15 years (Cotterill, Grier, Craft, and Bacci). One of these (Grier), the recent POG experience, found that the inferior outcome in those >18 years of age (relative risk of recurrence 2.5) was not explained by differences in dose intensity between age groups; however, multivariate analysis was not performed to determine if the differences in outcome was due to higher tumor volume, pelvic primary, or male sex, all of which independently had inferior survival. Interestingly, this study found that the addition of ifosfamide and etoposide to standard treatment with Vincristine, Adriamycin and Cyclophosphamide improved survival in children, but not in patients aged 15-30 years. It remains speculative if this reflects different tumor biology between younger and older Ewing’s sarcomas.
Even when treated on the same protocol, data from the EICESS trials show evidence that adolescents may fare worse when treated in medical oncology compared to pediatric institutions (Paulussen). 1426 ET patients were recorded on trials CESS81-EICESS92. Patients aged <15 years fared better than older patients (Figure 3).
Figure 3: Outcome of Ewing Patients on CESS81-EICESS92 by Age, Paulessen, ASCO Educational Book 2004. Click on the figure to see a larger image of it.
Patients registered in pediatric institutions fared better than those in medical or other institutions (Figure 4).
Figure 4: Outcome of 15-20 year old Ewing patients on CESS81-EICESS92 by treatment center, Paulessen, ASCO Educational Book 2004. Click on the figure to see a larger image of it.
This was mainly due to the patients aged >15 to 20 years, as patients aged above 20 fared equally (inferiorly) in both institutions. Thus, as yet unexplained differences of care between pediatric and medical oncology institutional settings, (perhaps a reflection of experience with the disease) seem to contribute to differences in outcome of adolescent patients, but other issues may also have import in the uniformly inferior outcomes of young adults.
To improve the care and outcomes of AYA patients, several initiatives have begun nationwide. The Children’s Oncology Group and several of the adult cooperative trial groups have begun collaborative clinical trials for tumors that occur in both children and adults (already available for acute promyelocytic leukemia, melanoma, and Ewing’s sarcoma and soon to be available for acute lymphoblastic leukemia and malignant peripheral nerve sheath tumor, synovial sarcoma and gastrointestinal stromal tumor). Research is underway to study many issues unique to this population, including the biology of tumors that cross the spectrum, factors influencing the referral patterns of primary care providers, issues of adherence, fatigue, depression and coping, and factors influencing survival in given tumor types (such as further evaluation of the Ewing’s data reported above).
Some institutions are looking to start AYA oncology programs to more appropriately and systematically meet the needs of these patients. The Dana Farber Cancer Institute (DFCI) at Harvard University is in the process of launching such an Adolescent and Young Adult Program. This will be multi-disciplinary, full-service program bridging the research and patient care resources of the faculty and clinics of Dana-Farber Cancer Institute, Children’s Hospital of Boston and Brigham & Women’s Hospital. The AYA Program seeks to provide multidisciplinary, holistic, patient-centered and biology-driven care with access to clinical and research expertise throughout an academic institution unfettered by any age-restrictions or institutional walls. The belief is that such a programmatic approach will improve survival and quality of life for these patients, as well as advance our understanding of cancer in this age group.
Special goals of the program include:
Hopefully, between better access to appropriate clinical care, elucidating research on biology of cancer, and education and training of providers, the outcomes of all AYA patients, including those with Ewing’s sarcoma, will improve in the next 20 years.
References Bacci, G., Ferrari, S., Bertoni, F., et al: Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J. Clin. Oncol. 2000; 18:4-11.
Cotterill, S. J., Ahrens, S, Paulussen, M, et al: Prognostic Factors in Ewing's Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing's Sarcoma Study Group. J. Clin. Oncol. 2000; 18:3108-3114.
Craft, A., Cotterill, S, Malcolm, A., et al: Ifosfamide-containing chemotherapy in Ewing's sarcoma: The Second United Kingdom Children's Cancer Study Group and the Medical Research Council Ewing's Tumor Study. J. Clin. Oncol. 1998; 16:3628-3633.
Grier, H. E., Krailo, M. D., Tarbell, N. J., et al: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N. Engl. J. Med. 2003; 348:694-701.
Nesbit, M. E., Jr., Gehan, E. A., Burgert, E. O., Jr., et al: Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. J. Clin. Oncol. 1990; 8:1664-1674.
Albritton, K., Stock, W., and Paulussen, M.: Cancer at the Interface of Pediatric and Medical Oncology: Striving to Understand and Improve Outcomes, ASCO Educational Book, pp. 587-64, 2004.
Paulussen, M., Ahrens, S, Dunst, J., et al: Localized ewing tumor of bone: final results of the cooperative Ewing's sarcoma study CESS 86. J. Clin. Oncol. 2001; 19:1818-1829.
Paulussen, M., Ahrens, S., Juergens, H. F.: Cure rates in Ewing tumor patients aged over 15 years are better in pediatric oncology units. Results of GPOH CESS/EICESS studies. Proc. Am. Soc. Clin. Oncol. 2003; 22: 816 (Abstract 5 3279).
Rosito, P., Mancini, A. F., Rondelli, R., Abate, M. E., Pession, A., Bedei, L., Bacci, G., Picci, P., Mercuri, M., Ruggieri, P., Frezza, G., Campanacci, M., Paolucci, G.. Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer. 1999 Aug 1;86(3):421-8.
Smith, M. et al In Ries, L. A. G. et al., Editors, Cancer Incidence and survival among children and adolescents, NIH Pub. No. 99-4649, 1999.
Verrill, M. W., Judson, I. R., Harmer, C. L., et al: Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children? J. Clin. Oncol. 1997; 15:2611-2621.
V1N6 ESUN Copyright © 2004 Liddy Shriver Sarcoma Initiative
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