The Leukemia Study Group of India met in Delhi for one of its early planning sessions (April 2001).

Because the patterns of cancer, the available resources and the cultural settings differ greatly around the world, the development of effective strategies for cancer control in developing countries must be based upon valid evidence obtained from clinical research studies conducted in these countries. Such studies will generally be closely linked to the provision of health care, so that benefits to patients begin to accrue immediately. Moreover, the requirement for relevant knowledge, skills and discipline in the conduct of clinical research (e.g., accurate diagnosis, effective delivery of care and patient support, and the collection of high quality data) requires that such studies are associated with education and performance monitoring. Thus, they provide highly effective "on-the-job" training in addition to a foundation of knowledge on which future studies or policies can be based. INCTR is collaborating with institutions in many countries in Latin America, Africa and Asia on research studies that are providing valuable disease-specific information while building effective prevention and treatment programs. These studies are focused predominantly on cancer in women and children as well as leukemias and lymphomas, consistent with its policy of giving the highest priority to preventable or curable cancers.

The Clinical Trials Office coordinates the activities of the Clinical Research Program, including the organization of INCTR Strategy Group meetings, the management of clinical research studies and the administration of the INCTR Ethical Review Committee. A major part of its work is also education and training in all aspects of clinical research.

Strategy Groups

Strategy groups, comprised of investigators from developing countries working closely with INCTR staff, shape clinical research programs as well as promote public and professional awareness about specific cancers. At present there are strategy groups devoted to acute lymphoblastic leukemia, African Burkitt lymphoma, breast cancer, uterine cervical cancer, lymphoma, osteosarcoma and retinoblastoma. Members of these strategy groups represent institutions in Argentina, Peru, Brazil, Bolivia, Mexico, Nigeria, Kenya, Tanzania, Uganda, Egypt, Kuwait, Saudi Arabia, Pakistan, India, Nepal, China, Philippines and Vietnam. It is anticipated that the number of countries and institutions participating in strategy group activities, as well as the number of strategy groups, will expand in the coming years, although the focus in 2005 will be to complete the design of several protocols currently in the planning stages. Ongoing and planned clinical research studies are described in the context of the activities and programs of each strategy group.

Breast Cancer

Breast cancer is the most common cancer in women worldwide. Unfortunately, there is relatively little published information about the disease in developing countries. INCTR's Breast Cancer Strategy Group has therefore decided to conduct a retrospective survey of breast cancer patients in participating institutions. The survey captures hospital registry information about the total numbers of patients with breast cancer seen, and patient data, including basic demographic information, social, reproductive and family history, risk factors such as pathological features, disease stage, treatment administered and treatment outcome. This survey will also provide information on the effectiveness of
follow-up. Data collection is already underway in institutions in India and Pakistan and will begin in 2005 in Egypt and Peru. It will be expanded to institutions in other countries - Argentina, Mexico, Tanzania, Kuwait and Nepal after a preliminary analysis of the data.

In addition to the survey, the group is in the process of writing a treatment protocol for patients with locally advanced breast cancer in order to evaluate the role of neoadjuvant chemotherapy in these patients. It is anticipated that the protocol will be implemented towards the end of 2005.

African Burkitt Lymphoma

A major goal of the African Burkitt Lymphoma Strategy Group is to try to improve treatment results and patient follow-up through the conduct of a standard chemotherapy protocol, feasible in equatorial African countries. The protocol entitled "The Treatment and Characterization of Burkitt Lymphoma in Africa" has been approved by both the INCTR Ethical Review Committee and by four institutions in three African countries - Kenya, Nigeria and Tanzania. It is estimated that the primary treatment regimen (first-line treatment) would cost approximately $150 to $200 per patient - a tiny fraction of the treatment cost in affluent countries. In August 2004, a training meeting on protocol and data management procedures was held for the investigators and data managers involved in the care of these patients. Patient enrollment began in late 2004. It is anticipated that 200 children will be treated in this study each year.

Before treatment.

After treatment.

Two new studies in Burkitt lymphoma are in development. The first is an evaluation of liposomal ara-C for intrathecal use in patients with recurrent disease in the central nervous system. SkyePharma has generously agreed to supply the drug free of charge. The second study is a Phase II study of Fluoxetine (Prozac), which is active against Burkitt lymphoma cell lines at concentrations known to be achievable with conventional doses. Investigators in the strategy group believe the effectiveness of this treatment could be investigated in the African setting in patients in whom all other treatment has failed.

INCTR staff and African colleagues meet at the Ocean Road Cancer Center in Tanzania to implement the Burkitt lymphoma project.

Cervical Cancer

An important goal of INCTR is to expand population coverage for the detection and treatment of CIN (cervical intraepithethial neoplasia) i.e., benign lesions that can evolve into invasive cervical cancer. Demonstration programs using well-established approaches to the detection and treatment of CIN are planned for small selected populations located in close proximity to regional cancer centers that have existing programs for cervical cancer detection. Existing health care infrastructure such as smaller health centers or their equivalents, family practitioners and general hospitals will be used as screening points. Regional cancer centers will provide training and coordination, as well as treatment for women detected with invasive cancer. Success of the screening programs will be measured by the number of women screened expressed as a fraction of women at risk, CIN/cancer detection rates and treatment rates. Professional education about cancer prevention will be provided by the regional cancer centers for medical students, nurses, health assistants, gynecologists and family practitioners. Community involvement will be widened through public awareness campaigns and attempts will be made to enlist local and regional governmental support.

INCTR presently supports demonstration programs for early cervical cancer detection and treatment that are located in Nepal and Tanzania in collaboration with the International Agency for Research on Cancer. To date more than 20,000 women have been screened at four sites.

INCTR is providing off-site data management services for a clinical trial in the treatment of locally advanced cervical cancer. The trial is sponsored by Eli Lilly and is being conducted by ten centers in eight developing countries. Patient accrual has now been completed and over 500 patients have been enrolled in the study.

Burkitt Lymphoma in Africa Burkitt lymphoma was first recognized in Africa as a tumor of the jaw occurring at high frequency in children; the first medical report of a probable case came from the first missionary hospital in Uganda, founded in 1897. Studies conducted in many University Hospitals, subsequently established in various equatorial African countries, revealed a high frequency of tumors of the jaw and orbit in children. Definitive descriptions by Denis Burkitt and Greg O’Conor of the clinical features and pathology, respectively, date to the late 1950s and early 1960s. Burkitt lymphoma accounted for over 50% of the childhood cancers prior to the AIDS epidemic (now, in some African countries, Kaposi’s sarcoma occurs more frequently). Many lessons have been learned from the study of this tumor in Africa, including its apparent relationship to the distribution of malaria, its association with Epstein-Barr virus, and the presence of certain characteristic molecular abnormalities in the tumor cells. It was also one of the first tumors shown to be curable by chemotherapy alone (in some cases by a single dose of a cytotoxic drug!). Quite simple, inexpensive combinations of cytotoxic drugs, manageable in the African setting, were shown to result in the cure of approximately half of all patients with this disease in the early 1970s. Unfortunately, little progress has been made in Africa since that era, and today, many patients do not even complete their treatment so that presently achieved survival rates in most countries are largely undocumented. In contrast, in affluent countries, newer, more intensive chemotherapy regimens, combined with improvements in the ability to support patients undergoing intensive regimens, have resulted in cure rates of approximately 90% in children. The cost and toxicity of such treatment protocols in Africa, however, is prohibitive – even if affordable, such regimens would probably result in many deaths from the treatment itself.

Leukemia Study Group of India

INCTR and the Leukemia Study Group of India - a strategy group dedicated to the treatment and characterization of acute lymphoblastic leukemia (ALL) in children, adolescents and young adults - implemented a new treatment protocol in August 2004. The study is being conducted in four major centers in three major cities in India - Chennai, Delhi and Mumbai - and includes a more prolonged period of intensive therapy with higher total doses of asparaginase. The primary objective is to identify prognostic factors - in the previous protocol, factors common to all participating centers have, surprisingly, not been identified. It is also hoped that survival will be improved and serious toxic complications reduced. Over 60 patients have been enrolled since August 2004 and we anticipate that 150 patients will be entered on the protocol each year. The study is partially supported by a grant of $250,000 (over three years) from the Sir Ratan Tata Trust. INCTR is seeking additional funding or gifts-in-kind to support costs of some of the more expensive drugs used in the treatment protocol - asparaginase and cytarabine.

As with all studies, INCTR ensures that the data collected is of the highest quality. INCTR, in partnership with Capital Technology Information Services, Inc. (CTIS), has developed a web-based data entry system for use by the participating institutions so that the study can be monitored closely. Measures of submitted data quality are in place and a data monitor, employed through the INCTR India Office, as well as staff members of INCTR's Clinical Trials Office, will be conducting site visits of each of the participating institutions throughout the duration of the study.

Another important goal of the group is to assist additional institutions throughout India to effectively use the treatment protocol for ALL, MCP841, previously used by the major institutions. With the guidance and supervision of the investigators at major centers, it is anticipated that more centers in India will be trained in the conduct of clinical research and improved data management in the context of this earlier protocol which is now widely accepted as standard treatment for ALL in India. We hope that the support of additional institutions in using MCP841 will lead to the development of a formal cooperative group within India.

A manuscript detailing the results of an analysis of 1,048 patients treated on protocol MCP841 between 1993 and 1997, in which survival rates were markedly improved, and over time, serious toxic complications reduced, has recently been accepted for publication in the European Journal of Cancer.

Ongoing INCTR Clinical Trials INCTR 01-01. PHASE II STUDY OF PREVIOUSLY UNTREATED METASTATIC OSTEOSARCOMA WITH A COMBINATION OF CHEMOTHERAPY (CISPLATIN, DOXORUBICIN, IFOSFAMIDE) AND SURGERY. Active patient accrual. Patients accrued by two of six participating Institutions. TOTAL ACCRUED: 7. INCTR 01-02. STUDY OF ADULT AND PEDIATRIC LYMPHOMA LOSS TO FOLLOW-UP. SINGLE INSTITUTIONAL STUDY. Closed to new subject enrollment. Enrolled subject follow-up only. TOTAL ACCRUED: 196. INCTR 01-03. UNDERSTANDING PROBLEMS FACED BY PARENTS OF CHILDREN WITH RETINOBLASTOMA PRIOR TO TREATMENT. Multi-institutional questionnaire study. New subject enrollment continues. Parents enrolled by 10 of 15 participating institutions. TOTAL ACCRUED: 309. INCTR 02-04. THE TREATMENT AND CHARACTERIZATION OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS. Multi-institutional study involving four centers in India. New subject enrollment is ongoing. TOTAL ACCRUED: >80. INCTR 03-06. THE TREATMENT AND CHARACTERIZATION OF BURKITT’S LYMPHOMA IN AFRICA. Multi-institutional study involving five centers in four countries in Africa. New subject enrollment is ongoing. TOTAL ACCRUED: 27. INCTR 03-08. A RETROSPECTIVE SURVEY OF PRESENTATION FEATURES OF BREAST CANCER AND RISK FACTORS FOR TREATMENT OUTCOME. Data collection in process in two of four centers. Two other centers will begin in 2005. TOTAL ACCRUED: >1,000.

A Model Program In Nepal When resources are particularly limited, palliative care must be a high priority because the majority of patients will have very advanced cancer. Unfortunately, this tends to support the erroneous notion that there is little that can be done about cancer. Thus, it is critically important to ensure that the message that cancer can be prevented is emphasized, and to develop programs directed at curing curable cancers at the earliest opportunity. INCTR has worked closely with several institutions and organizations in Nepal, one of the world’s poorest countries, in helping to improve cancer control in a stepwise fashion. Palliative care has been considerably enhanced, with new programs in three institutions, and the initiation of a home-care program (see Palliative Care, page 23). Cancer prevention efforts have also been significantly boosted in the Kathmandu valley through public education (primarily of schoolchildren), which has been undertaken by INCTR Nepal (also known as the Nepalese Network for Cancer Treatment and Research) and screening for pre-malignant lesions (cervical intraepithelial neoplasia) which can often lead to invasive cervical cancer - the most frequent cancer in women with low socioeconomic status. Cancer of the uterine cervix is deadly if left untreated but easily curable if detected early. In collaboration with the International Agency for Research in Cancer (IARC), INCTR has initiated direct visualization cervical cancer screening programs that have reached thousands of rural Nepalese women. Women line up for cervical cancer screening at the Scheer Memorial Hospital in Banepa, Nepal INCTR staff and professional volunteers recently met with Nepalese organizations, including the Nepalese Cancer Relief Society, the staff of the Maternity Hospital in Kathmandu and the teams already undertaking screening at Scheer Memorial Hospital and Bhaktapur Cancer Center to discuss how to extend cervical cancer screening to other parts of the country, and how to introduce additional simple measures aimed at preventing other diseases in women who attend for cervical cancer screening. The next step in improving cancer control was taken in meetings with staff of the Kanti Children’s Hospital, which is already participating in the palliative care program. It was decided to develop a formal training program in pediatric oncology in order to ensure that children with potentially curable cancer (79-80% of childhood cancer in affluent countries) are given the opportunity of cure. Meetings were also held with members of the Nepalese government to discuss issues such as opioid availability and the implementation of broader national cancer control strategies. Registered Nurse Virginia le Baron, an INCTR Visiting Expert, discusses the role of the Palliative Care Nurse at Kanti Children’s Hospital.

Lymphoma

Investigators from the Lymphoma Strategy Group have agreed to collaborate in the treatment of newly diagnosed adult patients with diffuse large B cell lymphoma. A standard anthracycline-containing chemotherapy regimen given with anti-CD20 (Rituximab) will be used, and results in patients from different ethnic backgrounds and different geographical areas will be compared with respect to both treatment outcome and molecular characteristics of the tumor cells. Investigators from institutions in Brazil, Egypt, Saudi Arabia, Pakistan and India have agreed to participate in this study. An investigator-initiated proposal is in development and will be formally submitted to Roche International. Roche has already agreed to donate Rituximab (anti-CD20) for this study.

Osteosarcoma

The Osteosarcoma Strategy Group is comprised of investigators from Brazil, Colombia, Mexico, Saudi Arabia, Pakistan, China and the Philippines. The group is conducting a protocol for the treatment of previously untreated patients with metastatic osteosarcoma. The treatment consists of a combination of chemotherapy - cisplatin, doxorubicin and ifosfamide - and surgery, with preservation of limbs whenever possible. Although patient entry has been low, the protocol has been shown to be feasible and affordable, and the group will consider developing a similar protocol in which all patients with osteosarcoma will be included.

Planned Studies for 2005 and 2006 THE TREATMENT AND CHARACTERIZATION OF ACUTE LYMPHOBLASTIC LEUKEMIA USING A STANDARD TREATMENT PROTOCOL. Approval by INCTR ERC with stipulations. Re-submission planned for July 2005 following revisions by Indian Principal Investigators. PLANNED ACCRUAL: 1,000. RANDOMIZED TRIAL COMPARING THREE REGIMENS FOR THE TREATMENT OF LOCALLY ADVANCED BREAST CANCER. Multi-institutional study planned with four centers in four countries. Finalization of protocol document planned for 2005. Activation anticipated for late 2005 or early 2006. PLANNED ACCRUAL: 1,500. PHASE II STUDY OF LIPOSOMAL ARA-C IN AFRICAN BURKITT LYMPHOMA PATIENTS WITH RECURRENT CENTRAL NERVOUS SYSTEM DISEASE. Multi-institutional study planned in five centers in four African countries. Protocol document in preparation. Anticipated activation date — late 2005. PLANNED ACCRUAL: 40. PHASE II STUDY OF FLUOXETINE IN AFRICAN BURKITT LYMPHOMA PATIENTS. Multi-institutional study planned in five centersin four African countries. Protocol document in preparation. Anticipated activation date — late 2005. PLANNED ACCRUAL: 20. THE TREATMENT OF NEWLY DIAGNOSED PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA USING AN ANTHRACYCLINE - BASED CHEMOTHERAPY REGIMEN WITH ANTI-CD20. Multi-institutional study planned in eight centers in five countries. PLANNED ACCRUAL: 250. THE TREATMENT OF EXTRA-OCULAR RETINOBLASTOMA. Multi-institutional study planned in centers located in Latin America and Asia. PLANNED ACCRUAL: 60.

Retinoblastoma

Retinoblastoma is a disease that is curable in over 90% of children in industrialized nations and many children can be treated with preservation of the eye - largely because the disease is nearly always detected when confined to the eye and thus very limited. Unfortunately, in developing countries, where the disease appears to have a higher incidence rate, children with retinoblastoma usually present with much more advanced disease, and a high proportion of children lose an eye, and occasionally both eyes. Some children even present with metastatic disease, such that there is a significantly higher mortality rate than in affluent countries. The major objective of the Retinoblastoma Strategy Group, comprised of investigators from one or more centers in Brazil, Bolivia, Mexico, Nigeria, Tanzania, Zimbabwe, Turkey, India, Pakistan, Vietnam and the Philippines, is to develop a multi-national program for the control of retinoblastoma in which a two-pronged approach will be used - 1) public and professional education to increase the likelihood of early detection and 2) the development of treatment for patients with advanced disease. Because of the rarity of retinoblastoma, and particularly of advanced retinoblastoma in affluent countries, the lead in the development of effective treatment of advanced disease will need to come from developing countries. In early 2001, the group decided to conduct a survey in an attempt to identify problems faced by parents prior to their child's diagnosis and to identify other factors that may have contributed to delays in diagnosis and treatment. The survey is designed to obtain information through an interview with parents and to retrieve clinical data relating to the child's illness.

Posters like this one teach parents in Mexico to recognize the early signs of retinoblastoma.

A preliminary analysis of the first 289 surveys has been performed. Many statistically significant findings were observed. Children with higher stages of disease tended to be older than children with less advanced disease. Longer intervals between the time when the first sign was noticed to the date of diagnosis were also associated with higher stages of disease. Both findings suggest that the vast majority of tumors arise early in life and grow progressively in the first few years. The father's educational level was inversely associated with the duration of symptomatic disease - the duration was significantly longer in fathers who were either illiterate or who had primary school education only. The children of fathers with lower education levels in general also tended to have children with higher stages of disease. These preliminary findings suggest that public awareness campaigns to teach the early signs of retinoblastoma are essential, but it will also be necessary to target fathers, who have the primary decision-making role in families in developing countries, and to emphasize that lives and eyes can be saved by early detection.

Activities related to increasing public and professional awareness have been initiated in many countries represented in the Retinoblastoma Strategy Group. Materials for both health care professionals and the public have been developed. A public service announcement (a brief video) produced in Brazil has been translated into many languages for use in other countries. This announcement is on the INCTR web site (from where it can be downloaded) and also on that of a Brazilian non-profit organization, Tucca (http://www.tucca.org.br). Several countries, including Mexico, Turkey and the Philippines, have formed, or are in the process of forming, cooperative groups of health care professionals interested in the care of children with this disease in order to improve early detection and standardize treatment approaches.

The Retinoblastoma Strategy Group plans to finalize the design of a treatment protocol for children with very advanced disease in 2005.

The Multiple Benefits of Clinical Trials Cancer control must, to have any chance of success, be based on evidence derived from clinical research with human subjects. Practice guidelines can be valuable if based on relevant evidence, and when the necessary resources are available to employ them, including appropriate knowledge, skills and discipline. Unfortunately, all are in short supply in developing countries. Thus, guidelines devised in more affluent countries may prove to be either not feasible, or inappropriate for particular populations in developing countries. This creates an urgent need for regionally-relevant research, including surveys (directed towards investigating the reasons for late presentation or poor follow-up, or current practice), and prevention and treatment trials in collaboration with experienced clinical researchers – if necessary, from outside organizations or institutions. Such trials, in their simplest form, consist of the disciplined application of appropriate treatment (or prevention) guidelines coupled to outcome measures, but may also involve epidemiological or translational research elements. Treatment studies, especially in the setting of developing countries, generally lead to improvements in patient diagnosis, management and outcome, and provide a focus for hands-on training of a broad range of health professionals, not only in research - which is essential for the improved definition and solution of local problems - but also in good medical practice. The Implementation Meeting of the new protocol of the Leukemia Study Group of India took place in July 2004 by video teleconference connecting Brussels, Mumbai and Delhi. Moreover, clinical research results in the creation of a more scientifically-minded medical culture and hence more rational medical and public health decisions. Where such trials involve multiple centers, they also lead to greater accessibility to the limited local expertise (as well as international expertise), improved educational and professional opportunities for a broad range of personnel, and the creation of valuable scientific resources, such as tissue banks. The desire for an enhanced professional reputation and the quality assurance built into data collection methods create added incentives for improving the quality of care, while the information collected in the course of a series of clinical studies provides a growing foundation of evidence relevant to national or regional problems, on which ever more efficient cancer control strategies can be built. Information technology (IT) can enhance all aspects of communication, including consultations, education (e.g., through multi-disciplinary telemedicine conferences and a variety of e-learning tools), knowledge assessment and recordkeeping. A critical element of high-quality clinical trials management, IT is inexpensive compared to imaging or radiotherapy equipment, and in addition to increased efficiency and reduced costs (from savings on staff time and travel) provides rapid access to a wide range of information. It can also greatly enhance the efficiency of eligibility assessment, patient tracking and follow-up, improve treatment documentation and reduce errors, e.g., through the use of bar codes and automatic label generation. Information “on-the-move” can be provided by hand-held “PDA’s” connected to the local Intranet or Internet.