|
|
              
 |
Correlation of Lack of Participation on Clinical Trials and Lack of Progress in Bone Sarcoma Published
by
Archie Bleyer, MD St. Charles Medical Center Bend, Oregon
“If more teens and young adults with cancer took part in clinical trials, it might improve that age group's chances of survival.”, Miranda Hitti, WebMD News release, John Wiley & Sons, Inc.
U.S. cancer patients 15 to 45 years of age have been found to have had less survival prolongation and a lowered mortality rate reduction during the past quarter century than either younger or older patients (Refs. 1-2). As reviewed elsewhere, there are multiple explanations for the lack of progress in young adults in the U.S. with cancer.
We have also previously noted an age-dependent correlation between outcome improvement, as measured by improvement in survival over time periods, for all invasive cancers analyzed in aggregate and the rate of clinical trial participation in the age subgroups (Ref. 3). This observation suggested that a major reason for the deficit in outcome improvement in young adults was their relative lack of inclusion and participation in clinical trials and the associated lack of scientific advancement and discovery of more effective therapies.
In the U.S., sarcomas account for 9.1% and 2.9% of all invasive cancers in 15- to 29-year-olds and 30- to 44-year-olds, respectively (U.S. Surveillance, Epidemiology, and End-Results data; see SEER Data below). In these age groups, soft-tissue sarcomas predominate, including synovial cell sarcoma, malignant fibrous histiocytoma, peripheral primitive neuroectodermal soft-tissue tumors, rhabdomyosarcoma and Kaposi’s sarcoma. The remainder are bone tumors, primarily osteosarcoma and Ewing’s sarcoma. A comparison in Australia among young adult and older adolescents with bone sarcomas suggested that survival and clinical trial activity were correlated (Ref. 4). We therefore evaluated clinical trial participation as an explanation for an observed relative lack of outcome improvement in young adults with sarcoma.
Methods For this study, we evaluated the 5-year survival in young adults in the U.S. who were diagnosed between 1975 and 1998 to have a sarcoma and followed by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute. Survival data was available on 38,144 patients less than 45 years of age, of which 33,618 had sarcomas of soft-tissue and 4,326 had bone sarcomas. The SEER Program currently collects and publishes cancer incidence and survival data from 14 population-based cancer registries and three supplemental registries covering approximately 26 percent of the U.S. population
The U.S. NCI Cancer Therapy Evaluation Program (CTEP) requires that all of its sponsored clinical trial sites submit accrual data electronically on a quarterly basis. Accrual data was therefore obtained from CTEP on 2,242 patients with soft-tissue (2,295) and bone sarcomas (947) entered on national sarcoma treatment trials from 1997 to 2002. The accrual proportion was expressed as the ratio of accruals on national treatment trials to the number of new cases of cancers diagnosed during the interval of accrual estimated from the SEER incidence rate and the 2000 U.S. census for each age group analyzed.
The yearly change in five year survival rates, averaged over the 23 years studied (the average annual percent change), was compared with accrual and accrual proportion as a function of patient age. Only those age groups that had at least 100 patients in each 5-year age group were analyzed. The histopathology types were based on to the International Classification of Childhood Cancer (ICCC) system. Note that this classification scheme separates Ewing's Sarcoma (EWS) occurring in soft tissue (peripheral primitive neuroectodermal tumors) from EWS of bone. Gynecologic sarcomas (sarcomas of the uterus and ovary) were not included since they did not meet the minimum criteria of 100 patients per age group in the majority of age intervals analyzed.
Results: Survival Depends on Age at Diagnosis and Type of Sarcoma For all bone and soft-tissue sarcomas except Kaposi’s sarcoma (KS), the least progress in improving the 5-year survival during 1975-1998 occurred for patients between the ages of 20 and 40. For patients with soft-tissue sarcomas (inclusive of KS), the average annual percent change in survival was actually negative for 1975-1998, meaning that the 5 year survival for all soft tissue sarcoma (STS) together was worse in 1998 than in 1975. This was due to decreases in 5-year survival among young adults with sarcomas in ICCC categories IX(b) (rhabdomyosarcoma and embryonal sarcoma) and IX(d) (synovial cell sarcoma, malignant fibrous hystiocytoma, peripheral primitive neuroectodermal soft-tissue tumors including malignant peripheral nerve sheet tumor, and related tumors).
Among patients with bone sarcomas, the least improvement occurred between 25 and 35 years of age (Figure 1, solid bars). The greatest improvement in five-year survival was seen in people with KS, particularly those aged 30-44.
Figure 1
Clinical Trials Rarely Include Young Adults Sarcoma patients aged 20-44 had the lowest rate of participation in national treatment trials monitored by the NCI. Among patients with soft-tissue sarcomas, the average annual accrual rate ranged from a high of 33% (61 of an estimated 183 available patients <5 years of age) to a low of 0.3% (4 in 1,513 25- to 29-year-old patients. Above age 35 the accrual proportion increased to 0.7%. Among patients with bone sarcomas, the average annual accrual proportion was inversely proportional to age, ranging from a high of 6 of 11 patients among those <5 years of age to 0 of 183 available patients among 40- to 44-year-olds (Figure 1, hatched bars). In both soft-tissue and bone sarcoma patients, a precipitous decrease in the number and proportion of patients with sarcoma accrued to clinical trials occurred above age 20.
Kaposi Sarcoma was An Exception Among the soft-tissue sarcoma patients, the vast majority of treatment trial entries between 25 and 45 years of age were in patients with Kaposi’s sarcoma (KS). When considered as a separate group, KS patients had their peak participation at age 35 to 39, in both absolute accrual (average of 21 patients per year) and accrual proportion (1.8%). This age-dependent pattern is the reverse of that seen in the other soft-tissue sarcomas and in the bone sarcomas.
Correlations Between Survival Improvement and Clinical Trial Participation Patients with the least improvement in survival had the lowest rate of participation and the patients with the greatest survival improvement also had the highest participation in NCI-sponsored clinical trials. For bone sarcomas, the reduction in mortality rate mirrored the average annual percent change in 5-year survival, with no significant improvement among 20- to 34-year-olds from 1975 to 1999 (Figure 2).
Figure 2
There was a statistically significant age-dependent correlation between survival improvement and clinical trial participation rates whether or not the type of sarcoma evaluated had a rate decline in young adults (non-KS soft-tissue sarcomas and bone sarcomas, Figure 1) or a peak (KS sarcomas, Figure 3).
Figure 3
This rate-pattern independence is consistent with a cause and effect relationship. Moreover, reversing the national accrual trend in KS was temporally associated with a reversal in the survival trend, further supporting a cause and effect relationship. Thus, a possible, practical solution to improving survival in young adults with sarcoma is to increase their participation in clinical trials that are dedicated to the development and study of new therapies.
Recent Trends in Sarcoma Treatment Trial Accruals and Comparison with Cancer Trial Accruals in General This study also compared the clinical trial participation of all cancer patients with the participation of patients with non-KS sarcomas on national trials. Except for 25- to 34-year-olds (Figure 4), participation in sarcoma trials is lower in all age groups.
Figure 4
From age 25 up, the proportion is less than 30% of the proportion in all cancer. This means that except for Kaposi sarcoma, the U.S. is not entering sarcoma patients onto clinical trials as well as it is on cancer in general.
Trends in Clinical Trial Participation in Last Decade: From 1997 to 2003, accrual to sarcoma trials among 15- to 44-year-old patients groups has not had sustained increases (Figure 5). In comparison, the number of treatment trial entries by adults over 45 years of age increased 40% from 1997-1998 to 2003-2004.
Figure 5
Summary and Conclusions In the study, we found that improvement in cancer survival was less for patients aged 15-44 in the U.S. with sarcomas, and that this may have been a result, at least in part, of their relative lack of participation in clinical trials.
This supports the concept that clinical trials are one of the critical pathways to improved outcomes for cancer patients. It should be stressed that this data does not prove that the individual patient participating in a clinical trial is benefiting per se. Whereas this may happen for other reasons, the study and its finding apply to populations of patients and should not be applied directly to an individual patient. Clinical trials can help patients of the future, and current patients enjoy the benefits provided by prior patients who entered clinical trials.
Although there are no easy solutions to the accrual dilemma, the recent improvement in the overall cancer treatment trial participation rate by adults over 45 years of age and the specific experience with KS demonstrate that the obstacles can be overcome. Reversing the deficits among young adults and older adolescents with sarcomas will require broad support and cooperation to increase clinical trial availability, access, and participation. Non-KS soft-tissue sarcomas should require special emphasis since among the types of sarcoma that occur in young adults they have shown the least progress and they represent half of all sarcomas. Intergroup and cancer center collaboration is paramount to overcoming the deficits in young adults and older adolescents with sarcoma.
To this end, the Children’s Oncology Group (COG) formalized an Adolescent and Young Adult (AYA) program in 2000, with an initial focus on sarcomas. In 2002, an adult-pediatric intergroup sarcoma clinical trial collaboration was initiated under the auspices of the Southwest Oncology Group. This has led to the formation of the Intergroup Consortium Against Sarcoma (ICAS), which has representation from each of the adult and pediatric cooperative groups in the U.S., as well as the National Cancer Institute of Canada. The fact that the most recent year, 2003, had the greatest accrual of non-KS sarcomas since 1997 (Figure 4) may be the first sign of success of the COG and ICAS initiatives.
References
V2N3 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative
|
