Pediatr Blood Cancer 2008;50:1143–1146

Transfer of Complex Frontline Anticancer Therapy to a Developing Country:The St. Jude Osteosarcoma Experience in Chile

Gaston K. Rivera, MD,1,2* Juan Quintana, MD,3,4 Milena Villarroel, MD,3,4 Victor M. Santana, MD,2,5

Carlos Rodriguez-Galindo, MD,1,2,5 Michael D. Neel, MD,6 George Velez, MBA, CAAMA, FACHE,1

Raul C. Ribeiro, MD,1,2,5 and Najat C. Daw, MD2,5

INTRODUCTION

‘‘Twinning,’’ an attractive strategy to improve cure rates for

childhood cancer through partnerships between established centers

in the developed world and selected institutions in developing

countries, has been successfully used in the field of pediatric

oncology [1]. The rationale is to extend therapeutic gains and

organizational skills worldwide, to benefit from shared experiences,

and to create unique opportunities for biomedical research. We

recently reported efforts to improve childhood cancer treatment in

developing countries and encouraged others to follow our lead [2].

A decade ago, an International Outreach Program (IOP) was

initiated at St. Jude with the objective of exporting and sharing

knowledge, technology, and ‘‘know-how’’ to countries with limited

resources through education, professional interaction, and overall

support [3]. In less developed areas, our main focus has been to

reduce treatment-related complications and prevent abandonment

of therapy [4–6]. In countries with established pediatric oncology

programs, the objective has been to refine treatment and improve

patient outcomes for specific diseases. Here we report the St. Jude

IOP experience in conducting a complex frontline protocol for

newly diagnosed, localized osteosarcoma in collaboration with a

pediatric hospital in Chile.

METHODS

Selection of Site

The Chilean Public Health System is sound and well developed,

has experts in the treatment of pediatric cancer, and supports a robust

national cooperative pediatric oncology group (PINDA-National

Pediatric Program for Antineoplastic Agents) that oversees the

treatment of childhood cancer in Chile. Patients are compliant,

abandonment of therapy is virtually nonexistent, and extended

follow-up is the rule. The Calvo Mackenna Hospital (CMH) in

Santiago is a 220-bed public tertiary-care hospital, a member of the

PINDA network, and a teaching hospital associated with the

University of Chile. It is the national center for pediatric cardio-

vascular surgery, bone tumors, and kidney and liver transplantation.

Members of PINDA refer patients with osteosarcoma for treatment

at CMH. The St. Jude IOP had conducted collaborative projects with

CMH since 1999, including the establishment of a national pediatric

hematopoietic stem cell transplantation program [7].

Initial Site Visit and Groundwork

Prior to patient enrollment, St. Jude investigators conducted a

site visit at CMH to evaluate resources and capabilities and to assess

the quality of medical, surgical, and nursing care for osteosarcoma.

The protocol was translated into Spanish and approved by the CMH

Independent Ethics Committee (IEC) and the Chilean Ministry of

Health in 2000. The IEC fulfills the requirements of the International

Conference of Harmonization guidelines for IECs and the U.S.

Department of Health and Human Services Office for Human

Background. A frontline protocol for newly diagnosed osteosar-coma was conducted simultaneously at St. Jude Children’s ResearchHospital (sponsor) and Calvo Mackenna Hospital (CMH, partner), apublic pediatric hospital and national center for the treatment ofbone tumors in Santiago, Chile. Procedure. Of 72 eligible patients,22 (31%) were enrolled and managed in Santiago, without travel toMemphis. Pathology specimens and imaging material were centrallyreviewed at St. Jude. Patients received 12 intensive courses ofsystemic chemotherapy with hematopoietic growth factor supportover 35 weeks, and amputation or limb-salvage surgery as indicatedfor local control. The sponsor assisted the partner site to establish aclinical research infrastructure and obtain hematopoietic growthfactor. Communication among medical and nursing teams wasmaintained throughout the study. Patient-care and protocol issues

were discussed frequently between the two centers via scheduledvideoconferences and electronic communications. Auditors moni-tored appropriate study conduct at the international site. Results. Nomajor discrepancies were identified in histologic findings, staging, orimaging studies. Preliminary results demonstrated similar outcomeand treatment tolerance; the 2-year event-free survival estimate was78.5% (95% CI, 51–100%) for patients treated at CMH (medianfollow-up, 1.6 years) and 74.3% (95% CI, 62–87%) for patientstreated at St. Jude (median follow-up, 4 years). Overall per-patientcosts were significantly lower in Chile. Conclusions. Through atwinning mechanism, it is feasible to simultaneously conductcomplex front-line osteosarcoma clinical trials at two institutions incountries with different levels of resources. Pediatr Blood Cancer2008;50:1143–1146. � 2007 Wiley-Liss, Inc.

Key words: collaborative clinical research trial; osteosarcoma; pediatric oncology; surgery

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21444

——————1International Outreach Program, St. Jude Children’s Research

Hospital, Memphis, Tennessee; 2Department of Pediatrics, University

of Tennessee Health Science Center College of Medicine, Memphis,

Tennessee; 3Division of Oncology, Luis Calvo Mackenna Hospital,

Santiago, Chile; 4Chilean National Pediatric Oncology Group

(PINDA), Santiago, Chile; 5Department of Oncology, St. Jude

Children’s Research Hospital, Memphis, Tennessee; 6Department of

Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee

Presented at the American Society of Clinical Oncology Annual

Meeting, June 1–5, 2007.

Grant sponsor: USPHS awards; Grant number: CA 23099; Grant

sponsor: Cancer Center Support Grant; Grant number: CA 21765;

Grant sponsor: American Lebanese Syrian Associated Charities.

*Correspondence to: Gaston K. Rivera, St. Jude Children’s Research

Hospital, 332 N. Lauderdale, MS 721, Memphis, TN 38105-2794.

E-mail: gaston.rivera@stjude.org

Received 9 July 2007; Accepted 16 October 2007

Research Protections. The protocol was activated at CMH in

July 2003.

Patient Evaluation and Enrollment

Patients with previously untreated localized osteosarcoma were

eligible. After informed consent was obtained, the patient was

enrolled and information was reviewed at the central protocol and

data monitoring office at St. Jude. The criteria used for diagnosis,

eligibility, and overall management on St. Jude osteosarcoma

protocols have been reported [8,9]. Pretreatment evaluation,

laboratory testing, diagnostic imaging, and tumor pathology studies

were performed at CMH. Diagnostic imaging studies and pathology

specimens were centrally reviewed at St. Jude.

Protocol Treatment

Therapy comprised 12 intensive cycles of chemotherapy

administered every 3 weeks with hematopoietic growth factor

support for a total of 35 weeks. Surgery for local control was

done after four cycles of neoadjuvant chemotherapy. Orthopedic

surgeons and surgical oncologists determined whether definitive

ablative surgery or a limb-sparing procedure was indicated;

decisions regarding Chilean patients were made by the CMH

surgeons in consultation with St. Jude. Specimens from biopsy,

amputation, and en bloc tumor resection (limb salvage) were studied

at the CMH pathology laboratory and reviewed at St. Jude.Eight

additional cycles of chemotherapy were administered after surgery.

All patients were followed throughout therapy by a physiatrist and

physical therapists. After appropriate training, a psychologist at

CMH periodically assessed quality of life using standard tools and

provided support to parents and patients throughout treatment.

Laboratory and diagnostic imaging studies were done regularly

during therapy and at the completion of therapy. Subsequently,

periodic follow-up assessments were performed until at least 4 years

after completion of therapy.

Conduct of the Study

Principal investigators at St. Jude and at CMH communicated by

telephone and electronic mail frequently. Likewise, orthopedic

surgeons, radiologists, and pathologists in Santiago and Memphis

consulted with their counterparts as necessary. All patients enrolled

in Chile were reviewed at a monthly meeting of the St. Jude and

CMH multidisciplinary osteosarcoma teams. Each patient’s med-

ical history, physical examination, protocol eligibility, imaging

studies, pathology findings, planned surgery, and psychological

profile were discussed. Periodically the principal investigator in

Santiago sent study updates to St. Jude including dates of initiation

and completion of each chemotherapy cycle, responses to therapy,

and treatment complications.

In addition, the multidisciplinary teams in Memphis and

Santiago met via videoconference every 4–6 months to present

patient updates, address protocol topics, and ensure appropriate

study conduct. A bilingual senior pediatric oncologist at St. Jude

with extensive clinical trials experience served as liaison physician,

facilitating communications between principal investigators and

among other team members, overseeing study compliance, and

traveling to Santiago approximately every 4 months. A data

manager was hired at CMH and trained at St. Jude, and a clinical

research nurse was added to the team. They prepared case report

forms for submission to the protocol data manager at St. Jude and

assisted the local principal investigator with regulatory compliance

and the timely submission of serious adverse event reports to the

local IEC and the St. Jude principal investigator; the latter in turn

submitted these reports to the St. Jude Institutional Review Board

(IRB).

Regulatory Compliance

Serious and unexpected adverse events were reported by both

St. Jude and CMH. The principal investigators submitted annual

continuing review reports to the St. Jude IRB and to the IEC at CMH.

To ensure patient safety and study compliance, protocol progress

was also reviewed by the St. Jude Data Safety Monitoring Board

twice yearly. A contract research organization was hired by St. Jude

to evaluate study conduct and protocol compliance at the partner

site, and a St. Jude research nurse traveled yearly to Santiago to

assist the local team with study conduct.

RESULTS

Initial Site Visit

The outpatient oncology department had recently been remod-

eled and surgical suites had been constructed 3 years previously. The

diagnostic imaging department offered computed tomography

scans but magnetic resonance imaging studies were performed

at the University of Chile Clinical Hospital, 15 miles away.

Rehabilitation facilities were available at the CMH and at the Centro

de Rehabilitacion Infantil Teleton, a center of excellence for

rehabilitation 20 miles away.

Physician and nurse staffing were adequate but clinical trial

support staff was insufficient. A pediatric oncologist with ample

osteosarcoma experience was selected as principal investigator in

Santiago. The roles of other investigators, including data collection

and management, were specified. The oncology staff included three

additional pediatric oncologists and two senior registered nurses.

Positions for a data manager and a research nurse were created with

salary support from St. Jude IOP.

Diagnosis, Patient Evaluation, and Results of Treatment

Between 1999 and 2006, 72 eligible patients with resectable

localized osteosarcoma were enrolled on the protocol. Of these, 22

were enrolled at CMH (July 2003–May 2006) and 50 were enrolled

at St. Jude (n¼ 48) or at a collaborating site in the U.S. (n¼ 2).

Therefore, 31% of the protocol patients were enrolled at CMH. The

eligibility of all Chilean patients was verified by the St. Jude central

protocol and data monitoring office, and no significant diagnostic

discrepancies were observed in imaging studies or tumor histology.

No Chilean patient was required to travel to Memphis.

The results of treatment in Memphis and Santiago were similar.

No important differences were observed between the two patient

cohorts in toxicity or response to chemotherapy. Details of treatment

outcome, adverse events, surgical procedures, and psychological

outcome will be reported separately. The majority of patients with

extremity tumors underwent limb-salvage surgery; this procedure

had been previously performed in Santiago. Techniques of surgical

resection and reconstruction used for protocol patients were similar

at both institutions, and the endoprostheses utilized for reconstruc-

tion of joint resections were made by the same manufacturer.

Pediatr Blood Cancer DOI 10.1002/pbc

1144 Rivera et al.

Although median follow-up at CMH is only 1.6 years post-

enrollment, preliminary results suggest that event-free survival is

similar at CMH and at St. Jude (median follow-up, 4 years post-

enrollment; Fig. 1).

Costs

A retrospective cost study was performed as part of the overall

assessment of the protocol. Cost allocation was performed strictly

on actual direct and indirect costs with minor adjustments made due

to fluctuating monetary exchange rates between the U.S. Dollar and

Chilean Peso throughout the study. The estimated average cost to the

Chilean government for the treatment of a patient with osteosar-

coma at CMH was $45,000. St. Jude funding was required for

prostheses (average, $7,000 each) and MRI (average, $3,000 per

patient). The cost of GM-CSF could not be quantified, as it was

donated to the patients in Chile. The estimated average cost of

treatment of a patient with osteosarcoma at St. Jude was $457,000.

Study Conduct

The regularly scheduled videoconferences provided an oppor-

tunity for in-service presentations on study monitoring and good

clinical practices as well as case management discussions. At all

times, communication among principal investigators and team

members was excellent. During the course of the study, data

managers in Santiago submitted 260 case report forms and 11

serious adverse event reports to the St. Jude central protocol and data

monitoring office.

Regulatory Compliance

ClinAudits, L.L.C., a contract research organization hired by

St. Jude, performed an investigator site audit at CMH in May 2004,

focusing on medical care, protocol compliance, and compliance

with regulatory requirements of good clinical practice. Auditors

found that patient care was excellent and that the majority of study-

related activities adhered to the protocol and to international

standards. Minor deficiencies were identified and appropriately

resolved through a corrective plan. ClinAudits concluded that

patients were receiving therapy as specified on the protocol and that

the IEC was well supported by the institution.

The St. Jude Vice President for Clinical Research visited CMH in

October 2004 to assure compliance with the audit recommenda-

tions, conduct a study monitoring site visit, and provide information

on regulatory requirements. The visit established that patient

accrual was brisk, that the staff was highly motivated, that the IEC

met U.S. standards, and that the principal investigator had good

knowledge of the protocol. Problems identified were related

primarily to clinical research infrastructure. For example, the data

manager did not have a designated office space, and equipment such

as a computer and photocopier was lacking. The Santiago team was

found to be committed to the conduct of high-quality research.

Infrastructure deficiencies were corrected and an adequately

equipped office in the oncology outpatient area was provided.

Subsequently, site audits were conducted at regular intervals with

good results. Figure 2 provides a chronology of the most significant

study events.

DISCUSSION

Our results demonstrate the feasibility of conducting a complex

front-line clinical therapy trial in collaboration with a partner

institution in a developing country. On the basis of this twinning

program experience, we offer a series of recommendations to guide

similar collaborations. First, the Public Health System in the ‘‘twin’’

country should be well organized. Second, the national government

must be committed to and engaged in public health support [10]. The

Chilean Ministry of Health has funded medical care for children

with cancer for almost 20 years. Encouraged by this support,

pediatric oncologists founded the national cooperative group

PINDA and introduced nationwide treatment protocols for all

pediatric oncology patients [11]. Recently approved legislation in

Chile dictates that treatment must be initiated within 7 days after

a diagnosis of childhood leukemia and within 30 days after a

diagnosis of pediatric solid tumor. Our success also reflects genuine

collegiality among team members in Memphis and Santiago, who

participated equally in study and patient-care decisions and were

similarly invested in the program.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Preliminary event-free survival distributions for patients

treated on the osteosarcoma protocol at CMH and at St. Jude. The

2-year event-free survival estimate was 78.5% (95% CI, 51–100%) for

patients treated at CMH and 74.3% (95% CI, 62–87%) for patients

treated at St. Jude. Median follow-up post-enrollment was 1.6 years at

CMH and 4 years at St. Jude.

Fig. 2. Chronology of the most important study events. CMH, Calvo

Mackenna Hospital; IEC, Independent Ethics Committee; CRO,

contract research organization.

Osteosarcoma Twinning Program 1145

The organizational skills of PINDA group investigators and the

involvement of the Chilean government were pivotal reasons for

selecting Chile as a partner country. The CMH was selected because

it is the national referral center for pediatric bone tumors and its

physicians and nurses are experienced in the treatment of these

patients. Moreover, the physician/nursing team had shown excep-

tional commitment in an earlier collaboration on hematopoietic

stem cell transplantation, which produced encouraging results [7].

Given these opportunities and strengths, we reasoned that a complex

protocol could be conducted in the medical and academic environ-

ment of CMH. Professional resources were in place, including an

experienced clinical investigator and well-trained surgeons and

pathologists. Moreover, high-quality diagnostic imaging, rehabil-

itation, psychology, and nursing services were available.

All protocol chemotherapy agents were available in Chile at

no cost to patients. To ensure that treatment in Santiago paralleled

that in Memphis, expensive items such as GM-CSF and surgical

prostheses had to be provided through the sponsor institution. The

support of the manufacturers of GM-CSF and limb prostheses was

crucial in making state-of-the-art anticancer therapy available to the

Chilean cohort.

Importantly, there were no significant discrepancies in patient

eligibility, diagnostic imaging studies, or tumor histology findings

throughout the study. Further, preliminary treatment results obtain-

ed in Memphis and Santiago were similar. Clinically important

adverse events were recognized and reported in a timely manner

to further safeguard research participants. These results demon-

strate that when international partner sites are adequately

selected and supported, clinical trials may be conducted jointly

with success.

The mean per-patient cost of treatment of osteosarcoma,

including chemotherapy, hospitalization, neutropenia, surgery,

imaging studies, pathology, rehabilitation, and long-term follow-

up, was significantly higher at St. Jude than at CMH. Key cost

elements that differed between the two sites included salaries for

medical and nursing staff, medications, imaging studies, and

laboratory evaluations in private versus publicly financed healthcare

settings. However, length of stay of hospitalization and other patient

care activities such as nurse to patient ratio did not appear to

contribute to the cost differences. In view of the rarity of pediatric

cancer, collaboration with institutions like CMH may be of practical

importance in planning future trials.

The main weakness identified early was compliance with

regulatory requirements. This problem, which was adequately

resolved, may reflect insufficient preliminary education of the

partner participants by the sponsor institution. In our case, the lack

of a clinical trials infrastructure at CMH, including secretarial

support and trained data managers, resulted initially in delayed

compliance with regulatory requirements. Further training and

support for data managers and research nurses resolved the problem.

Also helpful were the appointment of a senior St. Jude pediatric

oncologist as a liaison physician who was readily available to study

investigators, as well as periodic site visits by St. Jude staff.

Importantly, the auditors considered patients to be well cared for at

all times, and the deficiencies were satisfactorily corrected. Sub-

sequently, the contract research organization found study conduct to

be excellent.

We have demonstrated that it is feasible and practical to treat

pediatric cancer patients simultaneously at a well-equipped center,

such as St. Jude, and at a selected international partner site, such as

CMH. This clinical research model allows the timely completion of

clinical investigations designed for patients with rare tumors, such

as pediatric tumors; in our case, the osteosarcoma protocol was

completed approximately 3 years early, and at a reduced total cost.

This approach also delivers state-of-the-art therapy to a larger

number of children, enhances professional development at partner

sites, allows the identification of additional research opportunities,

and benefits all participants at both sites.

ACKNOWLEDGMENT

The Chilean Public Health System provided funding for patient

care at CMH, a PINDA associated institution. St. Jude arranged for

the donation of GM-CSF for Chilean patients by an American

pharmaceutical company. For this, we are indebted to Berlex

Laboratories of Seattle, Washington. Research imaging studies were

funded by St. Jude. We are also grateful to Wright Medical

Company of Arlington, Tennessee for providing prostheses at a

reduced price for Chilean patients. We acknowledge the valuable

contributions of Myriam Campbell, MD (Chair, PINDA), of Jesse

Jenkins, MD, Bhaskar Rao, MD, and Dana Hawkins, RN, BSN,

CCRC, all of St. Jude, and of Juan Jose Latorre, MD, Jesus Ortega,

MD, and Emma Concha, MD, all of CMH, to the conduct of the

study. We thank Sharon Naron for constructive editorial advice.

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