Enrollment in Clinical Cancer Trials: How Are We Doing and What Are the Obstacles to Improving Enrollment Rates? A 2-Year Retrospective Review of Pediatric Cancer Trial Enrollment in New Zealand Andrew J. Dodgshun, MBChB (Dist), DCH,*w Mandy P. De Silva, MBChB, DCH,z Peter Bradbeer, MRCPCH, FRACP, FRCPA,z and Siobhan Cross, FRACP, FRCPA*
Summary: Clinical trials contribute to the establishment of the best therapy for children with cancer. This study looks at rates of enrollment in therapeutic clinical trials over a 2-year period in New Zealand and examines the reasons for nonenrollment. All new diagnoses of cancer in children aged 16 or younger over the period of 1 January, 2009 to 31 December, 2010 were identiﬁed through the New Zealand Child Cancer Registry. Clinical trial enrollment status was identiﬁed from the medical records. For those not enrolled, the reason for nonenrollment was ascertained. A total of 28% of children diagnosed with cancer who received chemotherapy with curative intent in this time period were enrolled on clinical trials. The 2 most common reasons for nonenrollment in this study were that no study was open locally in which to enroll children (27%) or that previously open-clinical trials were closed to accrual at the time of the child’s diagnosis (20%). In New Zealand, enrollment rates on clinical trials for children with cancer are lower than expected. Key Words: clinical trials, pediatric oncology, enrollment
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urvival from childhood cancer has increased steadily over the past 40 years.1 A major reason for this improvement is multicenter randomized clinical trials to compare the eﬃcacy of treatment strategies. Child cancer research internationally has advanced through successive clinical trials and survival beneﬁt has been observed through successive trials for the majority of childhood cancers.2 There are several advantages to enrolling children on therapeutic clinical trials, both for the child enrolled and for children diagnosed with cancer in the future. The ﬁrst and most obvious is the determination of the most eﬀective and least toxic therapy for cancer types and subtypes for children treated in the future. The second is gaining access to research medications for the child enrolled, which would otherwise be unavailable for use. The third is gaining access
Received for publication September 14, 2013; accepted January 15, 2014. From the *Children’s Haematology and Oncology Centre, Christchurch Hospital, Christchurch; zStarship Blood and Cancer Centre, Starship Children’s Hospital, Auckland, New Zealand; and wChildren’s Cancer Centre, Royal Children’s Hospital, Vic., Australia. The authors declare no conﬂict of interest. Reprints: Andrew J. Dodgshun, MBChB (Dist), DCH, Children’s Cancer Centre, Royal Children’s Hospital, 50 Flemington Road, Parkville 3052, Vic., Australia (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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to standardized testing, central pathologic review, and central radiologic review. Investigational agents that prove to have superior eﬃcacy in phase 3 trials take time to go through complex regulatory requirements before they are commercially available. This process can often be slower in pediatrics due to the relatively small pharmaceutical market. An example of this is the chimeric antibody Ch14:18, which is used for all patients enrolled on trials treating high-risk neuroblastoma. Initial results indicate that when used in combination with immunomodulatory drugs, early disease-free survival rates are improved by 20%.3 The antibody is currently only available on clinical trials although there will be availability commercially in the near future. There has been conﬂicting data on the survival beneﬁt for individuals participating in clinical trials in adults.4,5 Recent data from Seattle Children’s Hospital suggested that in their institution there was no survival beneﬁt for children with ALL.6 There is, however, undoubted beneﬁt of clinical trials for children diagnosed with cancer in the future.7 A small study demonstrated that, for families being asked to be enrolled on clinical trials, 80% to 90% of children and their parents rated helping other children with cancer as “pretty important” or “very important” in their decisionmaking process.8 Despite these advantages many children are not enrolled on clinical trials. There have been a small number of studies examining reasons for nonenrollment of adolescents and young adults,9,10 but very few researching reasons for nonenrollment of children.11 There are 2 studies to our knowledge in the literature looking at rates of clinical trial enrollment and reasons for nonenrollment. The ﬁrst looked at children under the age of 3 diagnosed with brain tumors across Canada over a 15year period. The authors report that 21% of patients who received further therapy after surgery were enrolled in a therapeutic clinical trial. They report that the reason for nonenrollment in 53% of the nonenrolled patients was trials being closed to accrual, and in a further 20% was trials not being open in their institution.12 The other study was a single-center experience comparing clinical trial enrollment in children under 15 years, with adolescent and young adult patients aged 15 to 22 years. The authors report that 36% of their patients under 15 years were enrolled in a therapeutic clinical trial, compared with 27% of the older age group. The predominant reason for nonenrollment in both groups was that a clinical trial was not available, but they did not specify whether this was at an institutional or group-wide level.13
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New Zealand, with a population of 4.4 million, has recently moved to 2 tertiary Pediatric Oncology units and approximately 150 new cases of cancer are diagnosed in children 16 years and younger in New Zealand annually. All new cases of pediatric malignancy are notiﬁed to the New Zealand Children’s Cancer Registry (NZCCR). This study aims to quantify enrollment in clinical trials in New Zealand using a complete dataset and to attempt to ascertain reasons for nonenrollment in our population.
METHODS All children diagnosed with cancer in New Zealand in the 2-year period from 1 January, 2009 to 31 December, 2010 identiﬁed through the NZCCR were included. Where completed, data from the clinical trials ﬁeld of NZCCR was used to identify children enrolled on clinical trials. Where this information was not available, records from the clinical research associates (who collect all clinical trial data) from the 2 institutions were contacted to complete the dataset. Both institutions are members of the Children’s Oncology Group (COG) and actively participate in clinical trials through COG, in addition to a limited number of trials under other international groups such as the International Society of Paediatric Oncology (SIOP) and the Australia New Zealand Child Cancer Study Group (ANZCCSG). The availability of clinical trials was individually determined for each child at the time of diagnosis. The clinical research associates hold records of trial availability and closures due to temporary suspensions. COG holds a register of all clinical trials which was also examined to determine availability. All protocols were viewed and eligibility criteria recorded. For children not enrolled on clinical trials, medical records were obtained and the reason for nonenrollment ascertained. Where this was not documented in the clinical notes and an open trial was available, the primary consultant was approached and the reason for nonenrollment documented. These data were retrospectively entered into NZCCR. Children who were not enrolled on a clinical trial were then categorized depending on the reason for nonenrollment:
Disease Factors Palliative Children who received no active treatment or palliative chemotherapy from diagnosis.
No Chemotherapy Therapy with curative intent did not involve chemotherapy.
Rare Tumor A rare malignancy or combination of rare factors, meaning it is very unlikely a patient would be eligible for a clinical trial.
Emergency Treatment Emergency treatment was required before enrollment which led to the child being ineligible for enrollment
Technical Insuﬃcient samples of tissue available to enroll on a current clinical trial. r
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Trial Availability Nontrial Unit For a period of the study a small number of children were treated at a third unit that was not involved in clinical trials.
No Trial Open Locally A group-wide international trial was active at the time of diagnosis but not open in the Primary Oncology Centre where the child was treated.
Closed to Accrual A clinical trial for which the child would have been eligible had been open and active in the Primary Oncology Centre but was closed to accrual at the time of diagnosis.
Administrative Decision Because of lack of administrative support, enrollment in clinical trials was temporarily suspended.
Patient/Physician Physician Decision: Treatment The treating physician elected for a treatment strategy that was other than a current clinical trial.
Parental Decision Parents or guardians declined to enroll on clinical trial or declined randomization.
Physician Decision: Compliance The treating physician decided it would be unlikely the child and family would manage the rigor required on a clinical trial.
Breach Protocol breach meant the child was removed from the clinical trial. Occasionally patients fell into >1 category. Patients who began on trial and were then removed for breach of protocol or parental declination were assigned the categories which caused them to be removed from participation in the trial. If a trial was unavailable either because it was closed to accrual or never open in the Primary Oncology Centre in which the child was treated then these were the categories assigned regardless of other factors such as technical issues or physician judgments about likely compliance.
RESULTS A total of 289 patients were registered on NZCCR during the time period of 1 January, 2009 to 31 December, 2010. Of these children, 226 received chemotherapy with curative intent as part of treatment. Of 226 children receiving chemotherapy, 8 patients were treated in a nontrial center and excluded from further analysis. Of the remaining 218 children, 60 were enrolled on a clinical trial, 158 were not enrolled, giving a total percentage of patients enrolled on trial of 28%, with 72% not enrolled (Fig. 1) The reasons for nonenrollment are detailed in Table 1. Comparison of the 2 centers revealed a slightly higher enrollment rate for children in Auckland of 29% compared with Christchurch at 23%. Other diﬀerences between centers were minor other than a higher percentage of patients with rare tumors being treated in Christchurch (Table 2). www.jpho-online.com |
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TABLE 2. Number of Children Enrolled in Clinical Trials and Reasons for Nonenrollment: Differences Between Treating Centers
n (%) Reasons
Enrolled on clinical trial No trial open locally Closed to accrual Rare tumor Physician decision: treatment Technical Parental decision Physician decision: compliance Emergency treatment Breach of protocol Administrative decision Total
The table shows children receiving chemotherapy with curative intent: comparison of 2 treating centers.
No Trial Open Locally
FIGURE 1. Data ascertainment from the New Zealand Child Cancer Registry, exclusion criteria, and numbers for final analysis.
Enrollment by diagnosis showed stark diﬀerences in enrollment rates between diagnostic categories. There were very low enrollment rates for lymphomas and neurooncology tumors with relatively high enrollment rates for other solid tumors and acute lymphoblastic leukemia (Table 3).
DISCUSSION This study shows that only 28% of children with cancer in New Zealand are enrolled on clinical trials. This number is lower than the authors had expected and is slightly lower than the 1 similar previously published report.13 By categorizing the patients who were not enrolled, we have begun to address the reasons for their nonenrollment.
TABLE 1. Number of Children Enrolled in Clinical Trials and Reasons for Nonenrollment
Reasons Enrolled on clinical trial No trial open locally Closed to accrual Rare tumor Parental decision Physician decision: treatment Technical Physician decision: compliance Emergency treatment Administrative decision Breach of protocol Total
The table shows children receiving chemotherapy with curative intent.
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A total of 27% of children on this study were not enrolled as there was no trial open locally, despite a trial being open and available from 1 of the 3 cooperative groups mentioned (COG, SIOP, or ANZCCSG). There are multiple potential reasons for this. There is a great deal of administrative and research eﬀort required for opening and maintaining an international clinical trial. The number of children with cancer diagnosed in New Zealand is relatively small compared with tertiary centers in many other countries. Combined with the huge variety of childhood cancers and the multitude of current open trials, this means that some degree of pragmatism must be adopted when electing which clinical trials to open in New Zealand. Treating physicians at a clinical trial center must also feel comfortable that the therapeutic options available on a clinical trial are in the best interests of their patients. Different international groups may have diﬀerent strategies for treating some types of cancers and individual treating physicians’ preferences vary. In New Zealand for a given cancer subtype if a COG trial is open and acceptable to the majority of clinicians, it is considered “ﬁrst choice” to open. If either there is no COG trial available group wide or if an alternative group approach is preferred and open, then this trial will be opened if it is possible to do so. The range of conditions which fell into this category of “No trial open locally” were varied. For the majority of conditions, fewer than 1 child per year diagnosed in the country would be eligible for entry into the appropriate TABLE 3. Number of Children Enrolled on Clinical Trials by Diagnosis
group-wide open trial. The exceptions to this were lowgrade glioma, high-risk medulloblastoma, and bilateral Wilms tumor. This highlights one of the diﬃculties for smaller centers in enrolling a high percentage of children on openclinical trials. The breadth of diagnoses in pediatric oncology and the huge number of diﬀerent treatment protocols requires a certain critical mass of new diagnoses per year to justify the medical, nursing, and administrative support required to open and maintain clinical trials. It is diﬃcult to improve enrollment rates in these small patient groups without a higher level of recognition of the importance of therapeutic clinical trials in this area by hospital executives and a correspondingly higher budget for staﬃng. There is a contrast between COG and some European trials groups regarding the separation of protocols based on risk stratiﬁcation. Whereas COG often have separate trials for the various risk stratiﬁcations within tumor classes, European groups tend to have a broader range of risk stratiﬁcations enrolling on 1 trial. An example of this would be in Wilms tumor, where there are 3 COG protocols open compared with only 1 protocol by SIOP. This suggests that if administrative and funding support is minimal, there may be more value in opening trials enrolling a broader range of patients. There were 3 situations where multiple new cases of a condition were diagnosed each year. These were of low-grade glioma, bilateral Wilms tumor, and high-risk medulloblastoma. For low-grade glioma, the national approach was to treat using the SIOP approach despite the COG low-grade glioma trial being available group wide. The SIOP low-grade glioma trial was open to European countries only. Bilateral Wilms tumor is a rare condition and the COG trial has since been opened in both centers. For high-risk medulloblastoma, there were varied approaches across the units without this necessarily reﬂecting strong treatment preferences. This highlights the need for a coordinated approach when selecting trials to open. In New Zealand this has since been addressed with the formation of a National Children’s Cancer Network, which meets regularly to discuss protocol priorities across the units.
Trial Closed to Accrual A total of 20% of children in the study were not enrolled on a clinical trial as no trial was available due to closure to accrual. It is likely that the overall enrollment rate would have been higher if the study period had not fallen over a permanent closure in the COG standard-risk ALL trial. At present the majority of trials under the COG are sequential. After accrual targets are reached a trial is closed to further enrollment until the subsequent trial is opened by COG, often leaving a period where there is no trial open for enrollment. For example, in Standard Risk ALL, AALL0331 closed in May 2010 and the subsequent trial, AALL0932 was not opened in New Zealand until January 2011—it opened group wide in September 2010. The delay in opening this trial locally was largely due to the process of obtaining local ethics approval. Inevitably there will be some disease types for which data from previous trials has not yet matured and new clinical questions are not yet appropriate to ask, as there are no new agents or combinations with suﬃcient early phase data to support their routine use. As of November 2013, there are no open-COG clinical trials for several r
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tumor types, including osteosarcoma, renal tumors, rhabdomyosarcoma, and retinoblastoma. Phase I and II trials are vital for advancing the evidence base of pediatric oncology but there are very few phase I and II trials open in New Zealand at present due to small patient numbers. The focus of this review was phase III trials for newly diagnosed patients.
Rare Tumors A total of 9% of children had rare tumors or common tumors with unusual features that made them ineligible for clinical trials. Examples included plasmacytoid dendritic cell leukemia, B-cell lymphoblastic lymphoma (although this is now eligible for COG ALL trials), undiﬀerentiated sarcoma, and desmoplastic small-round cell tumor. For the majority of these children it is unlikely an international trial would be speciﬁcally designed and opened for these rare tumors. Some international groups do run registries where such tumors can be recorded so that knowledge about potential treatment options can be recorded even without speciﬁed treatment protocols.
Emergency Treatment Emergency treatment, given before enrollment can be pursued, can preclude enrollment onto clinical trials. There are some exceptions, for example, pretreatment with steroids is allowed on some studies of children with T-cell disease and all-trans retinoic acid is allowed before enrollment on some studies for acute promyelocytic leukemia. Enrollment in clinical trials requires informed consent to be sought after suﬃcient time to read and consider information and discuss it with family and friends. This is nearly impossible where treatment must be given very rapidly after diagnosis when the family is often very distressed and unable to provide suﬃciently informed consent.
Patient/Physician Factors The percentage made up by patients in these categories was only 7%, which suggests that in the majority of cases where a clinical trial is open and available, every eﬀort is made to oﬀer enrollment to families. There were some cases with unusual patient factors where the treating oncologist had strong preferences for a particular therapeutic approach which was not in line with treatment on the open-clinical trial. It is recognized that in a minority of cases, families will be unlikely to be able to comply with trial requirements for social, geographical, or other reasons. Parental declination either of enrollment or randomization made up a surprisingly small percentage of nonenrollment. Almost half of these patients had a standard-risk medulloblastoma and declined randomization for standard radiotherapy versus reduced-dose conformal radiotherapy to the posterior fossa. There are ethical considerations and potential risks involved in enrolling children in clinical trials, which children and their families consider carefully. Parents may feel that the risk of a reduction in treatment resulting in higher relapse rates outweighs any potential beneﬁt in sideeﬀect proﬁle.
Technical It can be diﬃcult to obtain suﬃcient diagnostic samples from children to enroll in clinical trials. The most common situation in which this arises is children with ALL whose marrow is replaced by lymphoblasts. Physical characteristics of these cells can make diagnostic aspiration very www.jpho-online.com |
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diﬃcult. There are allowances by COG for peripheral blood only to be sent if bone marrow is not able to be obtained, but only where the peripheral blood blast count is >1 109/L. This means that a group of patients with low blast counts and diﬃcult marrow aspiration are unable to be enrolled on trial even though it is feasible to process bone marrow trephine biopsy specimens for the required tests. It is essential that a health care professional very experienced in bone marrow aspiration and familiar with trial protocol be present during the diagnostic bone marrow aspiration and able to utilize alternative methods of sample obtainment if necessary.
Nontrial Unit A third Paediatric Oncology Unit was operational for a short time during the study period. This unit had never been part of the COG and during the study period was not running any open-clinical trials. This unit has since become a secondary center and these 8 patients in the unit were excluded from further analysis.
Tumor Types The disparity between enrollment rates for diﬀerent tumor types is multifactorial. It is clear that for neurooncology tumors, there were favored treatment approaches by clinicians which were not allowed for in open-clinical trials. The same is true for Hodgkin disease where the Euronet approach was selected as standard approach in both treating centers despite group-wide COG trials being open at the time. Clearly it is futile to open a clinical trial onto which clinicians will not enroll their patients in favor of an alternative approach. There are several limitations to this study. As a smaller country it is unclear how relevant our ﬁndings may be to larger centers, although it did allow us to capture a complete data set across a population which would be more diﬃcult elsewhere. The study was limited in the numbers of adolescents about whom data was ascertained as the upper limit of age studied was 16 years. Only 38 patients aged 13 to 16 years were included in the analysis and of those, 9 were enrolled in a clinical trial, giving a ﬁgure of 23% enrollment which is similar to the rate overall. That only 28% of patients receiving chemotherapy with curative intent in New Zealand are enrolled on clinical trials is surprising to ﬁnd. It is, however, consistent with the only published research in this area.12,13 The reasons for nonenrollment are varied but there is certainly scope to improve enrollment rates in some areas. This may be achieved by continuing to identify patient groups for whom there are no locally open-clinical trials and seeking to open appropriate trials for which they would be eligible. A small number of children with bone marrow samples which are diﬃcult to obtain at diagnosis may beneﬁt from the most experienced operator performing the procedure to maximize the yield. A signiﬁcant number of children were not able to enroll in a clinical trial as it had closed to accrual and the subsequent trial had not yet opened. This number would be able to enroll if groups running clinical trials used
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a strategy where enrollment in trials overlapped one another ensuring an open-clinical trial at all times. Clinical trials are vital to the advancement of knowledge in pediatric oncology. The potential beneﬁts to children enrolled have been described, but the primary purpose is to inform the treatment of children diagnosed in the future with cancer. Optimizing enrollment rates is challenging, especially in smaller units, but we have identiﬁed areas where this can be improved. ACKNOWLEDGMENT The authors thank Dr Michael Sullivan, the New Zealand Child Cancer Registry, Starship Blood and Cancer Centre, and Christchurch Clinical Research Associate teams for their assistance in this study. REFERENCES 1. Stiller C. Childhood Cancer in Britain: Incidence, Survival, Mortality. Oxford: Oxford University Press; 2007. 2. Stiller CA, Kroll ME, Pritchard-Jones K. Population survival from childhood cancer in Britain during 1978–2005 by eras of entry to clinical trials. Ann Oncol. 2012;23:2464–2469. 3. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–1334. 4. Peppercorn JM, Weeks JC, Cook EF, et al. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet. 2004;363:263–270. 5. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001;54:217–224. 6. Koschmann C, Thomson B, Hawkins DS. No evidence of a trial effect in newly diagnosed pediatric acute lymphoblastic leukemia. Arch Pediatr Adolesc Med. 2010;164:214–217. 7. Bleyer WA. Cancer in older adolescents and young adults: epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Med Pediatr Oncol. 2002;38:1–10. 8. Varma S, Jenkins T, Wendler D. How do children and parents make decisions about pediatric clinical research? J Pediatr Hematol Oncol. 2008;30:823–828. 9. Shaw PH, Boyiadzis M, Tawbi H, et al. Improved clinical trial enrollment in adolescent and young adult (AYA) oncology patients after the establishment of an AYA oncology program uniting pediatric and medical oncology divisions. Cancer. 2012;118:3614–3617. 10. Downs-Canner S, Shaw PH. A comparison of clinical trial enrollment between adolescent and young adult (AYA) oncology patients treated at affiliated adult and pediatric oncology centers. J Pediatr Hematol Oncol. 2009;31:927–929. 11. Read K, Fernandez CV, Gao J, et al. Decision-making by adolescents and parents of children with cancer regarding health research participation. Pediatrics. 2009;124:959–965. 12. Johnston DL, Keene D, Bartels U, et al. Patterns of enrollment of infants with central nervous system tumours on cooperative group studies: a report from the Canadian Pediatric Brain Tumour Consortium. J Neurooncol. 2010;99:243–249. 13. Shaw PH, Ritchey AK. Different rates of clinical trial enrollment between adolescents and young adults aged 15 to 22 years old and children under 15 years old with cancer at a children’s hospital. J Pediatr Hematol Oncol. 2007;29:811–814.
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