About 12,400 children under 20 years old in the United States are diagnosed with cancer each year.¹ The SEER Pediatric Monograph explains that "Childhood cancer is not one disease entity, but rather is a spectrum of different malignancies.¹" While the 5-year relative survival rate for pediatric cancers was about 78.2% from 1996-2003, survival statistics for various childhood sarcomas ranged from 59.2% to 68.5%.² Sarcomas are among the most life-threatening cancers that children face.

The Cancers that Affect Children

In order to best advocate for families dealing with pediatric sarcomas, it is important to understand the types of childhood cancers and the sources of funding for those cancers.

Each year, about 5047 cases of childhood cancer are leukemias and lymphomas, 2071 cases are brain and central nervous system (CNS) tumors, and 1612 cases are sarcomas.¹ The remaining cases include tumors of the sympathetic nervous system, retinoblastomas, renal cancers, hepatatic cancers, germ cell cancers, carcinomas, and other tumors.^{Note 1}

NCI Research Funding for Cancers that Affect Children

When we look at the National Cancer Institute’s research expenditures,³ we find that funding for sarcoma research is disproportionately low compared to research into the other common childhood cancers.⁴

Based on the prevalence of the cancers in Figure 1, one would expect to see NCI investing about 1/3 of the amount of money into sarcomas as they do leukemias and lymphomas. The fact is, sarcomas receive only 1/9 of the amount of research funding as leukemias and lymphomas do. There is a similar issue when comparing funding for brain and central nervous system tumors and sarcomas. Though a similar number of children are affected by these cancers, brain and CNS tumors receive four times the funding as sarcomas do.

We can look at this data another way by calculating the amount of NCI annual spending on a particular type of cancer research per child diagnosed with that cancer.

Not only do leukemias, lymphomas and brain tumors affect a significant portion of children who are diagnosed with malignancies, but they also affect more adults than sarcomas do. This creates more support for medical research into these cancers at the public and private level.

Private Funding for Support and Research

A look at private charitable funding indicates the support services available to pediatric cancer patients and their families, as well as the private research funds invested in cancers that affect children. The major childhood cancer organizations like St. Baldrick's Foundation and St. Jude Children's Research Hospital do not provide a breakdown of their budget according to cancer type. Thus, the graph below uses a sample of charities dedicated to specific types of cancer.^{Note 2} The graph can be used to understand the difference between private funding of specific childhood cancers. One would expect that each total figure is increased by several million dollars when general "childhood cancer" charitable funds are included and distributed.

Organizations like the Leukemia & Lymphoma Society illustrate the power of private collaborative effort. Their expenditures on patient services, advocacy and research topped $193 million in 2007. This one organization has an annual budget that is nearly 60% of the NCI budget for leukemia and lymphoma. In order to accomplish so much, the Leukemia & Lymphoma Society must have found a way to unite families of pediatric and adult patients, as well as those who are affected by several types of leukemia and lymphoma.

We can look at private funding another way by calculating the estimated funds that are spent on each type of cancer per newly-diagnosed child with that cancer.

Discussion

The statistics presented in this piece provide good reason for parents of children with sarcoma to unite in order to fill the gap in funding for sarcomas. The numbers clearly show that there is much less public research funding per child for sarcomas than the more common cancers. There is also significantly less private funding per child that is used for sarcoma patient services, support, advocacy and research. In addition, children with sarcomas have a lower chance of survival than most children with cancer.² These facts are a clear call for parents and families to:

1. Advocate for more government funding of sarcoma research or for a fairer distribution of funds.
2. Work in partnership to support and create fiscally responsible organizations that fund sarcoma patient services and sarcoma research.

Consider what we can do to improve the lives of children with sarcoma. Notice the parents and families who are joining Team Sarcoma, hosting events and raising money for support and research into the sarcomas that affect thousands of children around the world.

As families of children with sarcoma work together, they realize that some of their greatest allies are people of all ages with sarcoma. People with sarcomas face a difficult situation with an often aggressive cancer. The distance from one patient to another, regardless of age or type of sarcoma, is not as far as it appears. And even though the statistics in this article come from the United States, people around the world share these same challenges. What we do for children with sarcomas can improve the lives of hundreds of thousands of people worldwide.

This article had its genesis in a discussion on an on-line sarcoma support group. Adult sarcoma patients often suggest to new group members that they seek out sarcoma centers, institutions with teams of sarcoma specialists. This recommendation is echoed in "A Roadmap for Sarcoma Research," a report of the National Cancer Institute’s Sarcoma Progress Review Group. The rationale is the rarity of sarcoma, which comprises less than one percent of adult cancers. Thus, an oncologist who is not at a sarcoma center might see only a handful of sarcoma patients during a career, and is unlikely to be familiar with the latest diagnostic and treatment methods. In contrast, sarcoma centers would have teams of medical oncologists, pathologists, surgeons, and radiation oncologists who had seen dozens or even hundreds of sarcoma patients. 

The question was asked on-line as to whether pediatric sarcoma centers exist as well, and if they do whether children with sarcomas should be treated at those centers. I gave my opinion, which is that to the best of my knowledge, there are no pediatric sarcoma centers in the same sense that there are adult centers. But I do not see that as a problem. Most pediatric sarcoma patients will get appropriate treatment at many institutions, for reasons given below.

Current State of Pediatric Sarcoma Treatment

Although childhood cancer fortunately is a relatively rare disease with about 13,000 children in the U.S. diagnosed annually, sarcomas make up a much higher percentage than in adults. Sarcomas account for about 15 percent of pediatric cancers. Thus the average pediatric oncologist is likely to see a couple of sarcomas each year, instead of a couple of sarcomas in a career.

In addition, almost all pediatric oncologists are associated with pediatric hospitals. These hospitals are tertiary care facilities that provide a specialized team of health care providers with the skills to image, sedate, draw blood, administer chemotherapy, and operate on children.

Perhaps most importantly, pediatric oncology clinics are centers of research. Most pediatric hospitals in the U.S. and Canada are members of the Children’s Oncology Group (COG), the cooperative group that designs and implements clinical trials for pediatric cancers. Membership in COG guarantees that the institution has met group requirements for expertise in treatment of childhood cancer. A newly-diagnosed child being treated at any of over 240 member institutions will have access to the same treatment protocols, whether or not her pediatric oncologist is a pediatric sarcoma specialist. 

Children’s hospitals in other countries also frequently are members of COG or other cooperative groups with similar research goals. Membership in a cooperative group fosters a collegial atmosphere in which pediatric oncologists know and consult with one another. For example, my daughter’s primary pediatric oncologist is a lymphoma expert, but we consulted with many sarcoma specialists during the course of her treatment.

The close intertwining of research and treatment means that most children with cancer are enrolled on clinical trials. This produces a high level of standardized care. Central pathology review is required for enrollment on COG sarcoma clinical trials, so a mistake in diagnosis is corrected before or soon after the start of treatment. Patients are closely monitored for treatment success and side effects, which helps improve outcome. And the treating physician must contact the study chair (a sarcoma specialist) if there are any questions or if treatment deviates from protocol. Therefore, sarcoma experts are involved in the treatment of many children on these clinical trials, even if they are at a distant facility.

The nature of childhood cancer makes it unlikely that most families would travel to a sarcoma center, even if they existed. Childhood cancer means serious disruption to family routine and finances, and most families choose to have their children treated at the nearest pediatric oncology facility. Consequently, newly-diagnosed pediatric sarcoma patients typically are scattered among many hospitals.

Does that mean that every hospital is the same? Absolutely not. But I would always recommend finding the right doctor rather than a sarcoma center for children with sarcomas. For example, surgery is an important part of sarcoma treatment, and although one surgeon deems a tumor inoperable, another with different expertise might successfully remove it. Similarly, the experience of radiation oncologists and the type of equipment may vary from one hospital to another. A family might opt to travel to a hospital that has a newer generation of radiation equipment capable of reducing damage to healthy tissues, such as IMRT or proton beam. Some institutions run their own clinical trials, so the family of a child who has an unusual sarcoma or who has relapsed might search out a specialist. But for most childhood sarcomas, almost any pediatric oncology clinic can provide the same front-line chemotherapy treatment. If the family likes and trusts the pediatric oncologist, specialty doesn’t matter that much.

As a result of a generation of research, standard treatments have been developed that have good success for some of the more common childhood sarcomas. I know the most about rhabdomyosarcoma (RMS), the cancer my daughter had. Overall, about 70 percent of children with RMS are considered to be "cured", up from about 25 percent 30 years ago. But this rate varies greatly by stage and tumor site. Stage 1 orbital RMS has close to 100 percent cure rate, while Stage 4 (metastatic) RMS as a terrible outcome of about 20 percent survival at 5 years. 

Gaps in Research

There are other problems besides the abysmal results for metastatic children. In the December 2004 ESUN newsletter, Dr. Karen Albritton described the lack of progress that has been made in improving survival for adolescent and young adult (AYA) cancer patients, or the "teen gap." While survival rates for younger and older patients have increased at the rate of 1.5 percent per year over the last 20 years, there has been no increase in survival rates for AYA patients. As Dr. Albritton points out, these patients fall between the territories of the pediatric and adult oncologists. Pediatric oncologists and their adult counterparts belong to different professional societies, attend different conferences, often practice at different hospitals. Therefore, the opportunity for collaboration has been sharply limited, resulting in very little research focused on this age group.

As an example of the lack of collaboration, the National Cancer Institute has sponsored a series of State of the Science symposia on different cancers, and in 2002 a symposium was held on sarcoma. This would have been an ideal opportunity to encourage more interaction between adult and pediatric oncologists, as the SOTS leukemia meetings have done. But only a handful of COG members were invited to attend, and most of the big names in pediatric sarcoma research and treatment were missing. 

The lack of collaboration is reinforced by another gap, that between sarcomas that typically occur in adults and those that typically occur in children. For example, leiomyosarcoma—the smooth muscle sarcoma—is an "adult" sarcoma, while rhabdomyosarcoma—the skeletal muscle sarcoma—is a "pediatric" sarcoma. The same doctors will not know both tumors equally well, contributing to the difficulty that children with LMS or adults with RMS sometimes have in finding the right doctors and treatments.

These two gaps—teen and tumor—have conspired to produce very few clinical trials designed for all patients with a particular type of sarcoma. For example, most adult clinical trials have a minimum age of 18, while pediatric oncology clinical trials until recently were limited to patients under the age of 21. The age limits in general make sense, as children are not just small adults. There are strict rules about research on children, and there are medical, physical and emotional needs of ill children and their families that children’s hospitals may be uniquely qualified to fulfill. But the good reasons also deny patients access to some treatments, based on age alone.

Within the last few years, the gaps have begun to close. COG clinical trials for sarcomas now are open to patients up to age 50, and for the first time adults in their 20s, 30s, and 40s are being enrolled in the same clinical trials as children. Similarly pediatric and adult cooperative groups are beginning to jointly sponsor clinical trials for synovial sarcoma, MPNST, and other "adult" sarcomas that also occur in children, as Dr. Albritton mentioned in her article. 

What About the Future?

In my opinion, it is crucial to close the teen and tumor gaps if sarcoma treatment is to progress as quickly as possible for all patients, not just for the underserved AYA patients. Children make up about 20 percent of all sarcoma patients, and thus are a sizeable portion of the sarcoma community. Because of the relatively large number of sarcomas in children and the relatively small number in adults, and because children get adult sarcomas and adults get pediatric sarcomas, closing the gaps results in a larger patient population for clinical trials of new treatments. And more patients can result in more trials and faster trial results.

Closing the gaps also produces a larger and more attractive subject for research. I have no doubt that the next generation of cancer treatment will be targeted drugs like imatinib mesylate (gleevec) designed to attack the particular genetic mistakes that cause a normal cell to become cancerous. The long-promised "magic bullet" that homes in on the unique metabolism of cancer cells while sparing healthy cells will become a reality, but each bullet will be designed for one cancer.

In a perfect world, sarcomas should be among the first cancers for which targeted drugs are developed, as many of them have known genetic mistakes, often a single chromosomal translocation. Unfortunately, the world is not perfect. It takes a boatload of research to get from the translocation unique to Ewing’s sarcoma to a targeted treatment. Sarcomas are rare and diverse, two characteristics that make it unlikely that pharmaceutical companies will spend their resources on this category of cancer. It falls to government and private funding to make sure that researchers are not ignoring sarcomas in their quest for magic bullets. 

Our voices must be heard to keep that funding coming. If pediatric and adult sarcoma voices are united, our message will be stronger still. And when effective targeted drugs have been developed, maybe all sarcoma patients will be able get appropriate treatment everywhere and we will no longer need to urge anyone to seek out sarcoma centers. 

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).

Their enrollment in clinical trials is much lower than that of pediatric cancer patients and among the lowest of adult patients too (Figure 2).

Who should care for these patients is problematic. The ideal physician to care for any cancer patient would meet the following criteria:

• Board certified in general medical care of a patient that age
• Experienced in care of that tumor in that age group
• Ability to meet psychosocial needs of patient that age
• Ability to enroll on clinical trials for that tumor in that age group
• Ability to care for patient in an outpatient and inpatient setting that feels comfortable and suitable to the patient

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).

Patients registered in pediatric institutions fared better than those in medical or other institutions (Figure 4).

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:

• A clinical care coordinator that assesses medical, educational and psychosocial needs of AYA patient and links them up to appropriate services and advocates for needs during therapy
• Educational materials geared to AYA patients addressing topics such as fertility, dating/ intimacy, insurance, vocation, schooling, parental involvement
• AYA "support groups" with AYA social workers/psychologists
• Clinical trials, especially in leukemia, lymphoma, brain tumors, sarcomas, thyroid cancer and testicular cancer specifically geared to AYA patients
• Collection of tumor specimens from AYA patients to further biologic understandings
• Research clarifying the pathways to care for AYA patients
• Fellowship program that cross-trains young oncologists in both medical and pediatric oncology
• Research on infertility and fertility preservation
• Parallel 8-12 bed inpatient oncology units at Children’s Hospital (age 15-30) and Brigham and Women’s (age 20-40) that bring together patients with similar needs and issues with experienced staff and age-appropriate décor.

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.