Continuing Construction

by Ian Magrath

Earlier this year, I had the opportunity to visit the magnificent but startlingly unusual church in Barcelona, la Sagrada Familia, designed by the Catalonian architect Antoni Gaudi. Based on the style of a Gothic cathedral, the building eschews the classical arches and flying buttresses in favor of an almost surrealistic appearance. Irregular curves and unexpected asymmetries replace the strict proportionality and formal lines that we encounter in most large buildings, whether ancient or modern. In places, the stone seems to have melted and run down the walls like hot wax on a candle, piling up into strange shapes from which human forms representing saints and apostles emerge. The most prominent feature of the building is the soaring spiral towers—there will eventually be 18 of them—inspired, apparently, by Mount Monserrat, a mass of limestone which arises abruptly from a plain some 50 kilometers to the northeast of Barcelona. The mountain has been twisted into strange shapes by earth movements while numerous caves have been sculpted out of the soft rock by that most gentle and patient of artists—water. Gaudi’s towers are pitted with similar, cave-like orifices (see picture above). High up on the steep cliffs of the mountain are the ruins of a Benedictine monastery founded in the 11th century, and its more recent replacement. The latter houses a black wooden image of the Virgin Mary, which, tradition has it, was carved by St Luke. Some would say, however, that the famous “Black Madonnas,” which have been found all over southern Europe, are actually representations of the Egyptian goddess Isis, who was worshiped by a secret sect in Europe for centuries.

Ian Magrath (left) listens to Dr Indraneel Mittra’s ideas on cancer control in developing countries.

In my annual report at INCTR’s Annual Meeting this year, I used la Sagrada Familia as a metaphor for the growth and development of the INCTR. Both are still under construction, both are rather unique edifices which don’t conform to the usual pattern, and both have connections to more distant parts of the world. They are icons of the larger human family, for which the symbolism of mother and child is particularly apt, and in spite of their gravity of purpose, project a certain youthful irreverence. In the case of INCTR, this is essential to the invention and re-invention that must constantly go on if the broad range of problems faced in developing countries is to be addressed and the creative energies of our many collaborators, all too often stifled by lack of resources, are to be released. Unlike la Sagrada Familia, the INCTR was not inspired by a natural rock formation, although its efforts may well be likened to the challenge of climbing to the top of a high mountain: success is dependent upon a team approach, a clear purpose, and a well-planned overall strategy, although the latter needs to be plastic enough to be bent and twisted like Gaudi’s limestone, as the need arises.

Since its creation, INCTR’s growth has been continuous—both with respect to the projects that have been initiated or are in the planning stages, and to the evolution of its network. It has begun by focusing on the cancers of women and children. Last year at this time, I spoke of laying the foundations of INCTR. This year, I’ll discuss the continuing construction.

Cancer in Children
One of the earliest projects, decided upon at the first INCTR Annual Meeting, was to address the problem of retinoblastoma, a tumor of the eye occurring in infants, which is both more prevalent in developing countries and tends to present to treatment centers very late in its course. This leads to the deaths of many children from retinoblastoma—a rare occurrence in more affluent countries. In addition to the development of a questionnaire to identify the causes of late presentation, several members of the Retinoblastoma Strategy Group have initiated national programs designed to bring the importance of early diagnosis to both the doctors who first see the patient, and to the public. Pictures (in the case of Brazil, a brief film) of children with leukocoria, the white appearance of the pupil that occurs shortly after the tumor develops within the eye, are the mainstay of these campaigns (see page 16 ). Protocols for the treatment of advanced disease are presently being designed and we hope that these will be activated in the next year.

A second tumor that occurs in children and adolescents, osteosarcoma, was also selected for study at the first Annual Meeting, in part to explore the issues that would arise in conducting an international clinical trial involving inter- and intra-institutional cooperation. The treatment protocol for advanced osteosarcoma has been completed by the Osteosarcoma Strategy Group and four of the six local ethical review committees that will need to approve the study have already done so.

The basic problem for patients with cancer in developing countries can be summed up as “poor access to cancer care.” This arises because of the limitations in the capacity to deal with the extant cancer burden resulting from the relatively small number of well-trained specialists and ancillary health care personnel, the paucity of well-equipped specialized centers or departments, and limitations in the family’s financial ability to deal with the added burden of a diagnosis of cancer, including the cost of diagnosis, treatment and follow-up, time off work and transportation. To a large degree, capacity and access bear an inverse relationship to each other. Increasing capacity for treatment and prevention would improve access to care.

Acute lymphoblastic leukemia (ALL) has been a longstanding collaborative project among INCTR staff and several Indian centers, initially via the National Cancer Institute, Bethesda, but now, through INCTR’s Leukemia Strategy Group. Analysis of 1,048 patients treated between 1990 and 1997 with the same protocol (MCP841) at three major centers, the Cancer Institute in Chennai, the Tata Memorial Hospital in Mumbai, and the ALL India Institute of Medical Sciences in Delhi, has been largely completed and a manuscript for publication is in preparation. These results demonstrate clear differences in the patient populations being treated at each of these centers as well as differences in outcome. Surprisingly, uniform risk factors that apply to the populations in all three centers cannot be defined, and although risk factors are more similar in Mumbai and Delhi, a careful analysis of the Mumbai data suggests that even in the last three years of the study, the proportions of patients with various clinical characteristics have changed, as have the identifiable risk factors. These data illustrate several very important points. First, it cannot be assumed that risk factors (i.e., patient characteristics associated with prognosis) identified in one patient population will apply to another population, even when the same treatment protocol is used. Thus, application of treatment successful in one part of the world, or even in another institution in the same country, by no means guarantees success in another. The reasons for this include possible differences in the strictness of adherence to the treatment schema and in the ability to support patients through the sometimes life-threatening side effects of treatment, as well as differences in the “biological profile” of what we think of as the same neoplasm. All neoplasms actually consist of families of neoplasms, the members of which differ to a greater or lesser extent from each other, and which may require a somewhat different treatment approach. This is illustrated by the marked differences in the proportion of precursor T and precursor B cell ALLs in each of the three Indian centers. Until recently, the ability to precisely characterize tumors has been limited to morphology—in essence, the study of the size, shape and other physical features of the malignant cells (rather like recognizing one’s neighbor by her facial features), and to the study of the expression of a small, although increasing number of gene products (the proteins responsible for all of the tumors characteristic features, physical and functional). In the last few years, powerful new methods of identifying different family members of the same tumors (and of course, distinguishing one family from another) have been developed. In one such technique, DNA microarray, the pattern of expression of not just a few, but tens of thousands of genes, can be studied simultaneously.

Characterizing Cancer Cells
The examination of the pattern of expression of a large number of genes is a much more precise way of characterizing a cell than simply looking at its size, shape and other architectural features. It is likely that microarray techniques will reveal a great deal more information about tumors, leading to better classification and diagnosis, as well as improved ability to predict the response to therapy. Since the pattern of gene expression also contains within it the modifications caused by the genetic abnormalities responsible for creating the malignant cell in the first place, this kind of technique is also likely to be of value in the development of drugs targeted towards these genetic lesions—i.e., to the development of treatment that is highly specific to the tumor cell. In conjunction with colleagues in India and the King Fahad Children’s Medical Center Research Department as well as the King Faisal Specialist Hospital Research Center in Saudi Arabia, INCTR is developing plans to use molecular profiling techniques, including DNA microarray, to better understand the differences in clinical characteristics and response to therapy that have been identified in Indian patients with ALL treated at different centers, and, of course, between Indian patients and patients in other countries. As time goes by, these same techniques will be applied to other tumors.

The work in India will be extended through two additional projects. The efficacy and toxicity of a new, hopefully improved version of protocol MCP841 will be explored in the same three Indian centers. But as protocol MCP841 has more than doubled the survival rates of ALL, an important step, while studying the pros and cons of the new protocol, will be to introduce MCP841 to other centers in India where results remain poor. This will be done through the development of an Indian cooperative group whereby the major centers will be linked to smaller centers and work closely with them in order to assist implementation of MCP841 and to ensure accurate collection of data pertaining to response and toxicity. Plans for this are already in an advanced stage.

INCTR’s Mission INCTR is dedicated to helping build capacity for cancer treatment and research in countries in which such capacity is presently limited, and thereby to create a foundation on which to build strategies designed to lessen the suffering, limit the lives lost, and promote the highest quality of life for children and adults with cancer in these countries and to increase the quantity and quality of cancer research throughout the world.

To complete its repertoire in the context of childhood cancer, INCTR will work with collaborators in several equatorial African countries to develop an effective treatment protocol for the treatment of Burkitt’s lymphoma. This project will be undertaken alongside the work of other organizations that are members of INCTR’s initiative known as the Global Alliance for the Cure of Childhood Cancer, which met, along with INCTR’s new Strategy Group for Lymphoma and a number of African oncologists and pathologists at the Annual Meeting. Together, it is hoped that these organizations can ensure better access to effective therapy for this potentially curable disease, which accounts for a high fraction of childhood cancer in equatorial Africa.

Cancer in Women
In the context of cancer in women, INCTR’s efforts have just begun. A collaboration has been forged with Dr Sankarnarayanan of the International Agency against Cancer (IARC). IARC has been studying the optimal method for preventing cancer of the uterine cervix in a number of countries in Africa and Asia. This disease is a major problem in a high proportion of developing countries, and more important than breast cancer as a cause of death in middle-aged women (aged 39-59 years) in poor populations. Visual inspection of the cervix after painting it with either acetic acid (vinegar) or Lugol’s iodine has proved to be a sensitive, but inexpensive method of detecting abnormal cells on the surface of the uterine cervix which have a high chance of evolving into cancer. These techniques have the major advantage over the more well-known “Pap smear” that trained cytologists are not required to make the diagnosis, and results are obtained within minutes. This avoids the need for most women to return—treatment can even be given immediately when the pre-malignant lesions are small enough, e.g., by freezing the cervix (cryotherapy). Three centers have been established in Nepal, where health personnel have already undergone training in the visual inspection techniques, and screening of women in the appropriate target populations in the regions is about to begin. A second site, in the Ocean Road Cancer Center in Tanzania, has been selected as another potential partner in this first phase of a cervical cancer screening program. Through INCTR’s newly established Cervical Cancer Strategy Group, which includes members from a number of Asian, African and Latin American countries, and in conjunction with IARC, this program will be developed further. The Strategy Group will also decide whether to undertake a therapeutic program in locally advanced cervical cancer. INCTR (USA) will take a leading role in coordinating programs in Latin America, and Drs Robert Hilgers and Ted Trimble of the International Gynecological Cancer Society, who attended the first meeting of the group, have offered their assistance in the development of future projects.

Breast cancer was a selected theme at INCTR’s 2002 Annual Meeting, and a number of topics were identified as future activities of the also newly established Breast Cancer Strategy Group. This is now the most common cancer in the world in women, and must clearly be on INCTR’s agenda. Potential projects include characterizing risk factors for the development of breast cancer in women in developing countries, identifying the causes of late presentation, establishing programs of early detection, and the development of appropriate treatment protocols for locally advanced disease. Decisions will be made this year in concert with Strategy Group members regarding areas most feasible for the establishment of INCTR-coordinated collaborative studies.

Information Needed for Effective Cancer Control
In addition to its disease-specific endeavors, INCTR has begun to move forward in the area of collecting information relevant to cancer control, particularly with respect to cancer registration. It is working to establish a new cancer registry in Lahore, Pakistan, which will be located at the Shaukat Khanum Memorial Cancer Center and Research Center, this edition’s featured “Partner.” This project will be developed in collaboration with Dr Max Parkin’s department of Descriptive Epidemiology at the IARC, which has a vast experience in the area of cancer registration in developing countries. INCTR is also hoping to develop, again in collaboration with IARC, improved cancer registration in children (in which the primary “site” orientation of most cancer registries is not very effective), and to identify available resources for cancer control in selected regions or countries. Combined information of this kind should make the development and institution of cancer control programs more rational and effective.

Educational Programs
Education, of course, is an element in everything INCTR undertakes—and is the central pillar of its strategy to build capacity for cancer research and treatment in developing countries. In addition to the learning experiences of participating in INCTR strategy groups and collaborative projects, INCTR is developing a discipline-related educational program. Last year, the first meeting of the Education Committee, chaired by Professor Ama Rohatiner, took place, and a decision was made to form subcommittees for the development of educational tools and programs in various areas relevant to cancer control. The sub-committee for data management met at the Annual Meeting, and a second group decided to form a new sub-committee for palliative care, the latter to meet again later this year. Discussion has also been held with respect to developing a sub-committee for cancer nursing, and a number of persons active in this area in developing countries have expressed a strong interest in participating in expanding educational and training programs for cancer nurses. INCTR has also agreed to help develop a module for cancer education for medical students which will be used at the recently established University of Kathmandu Medical School. This is a particularly important area of endeavor, since a significant factor in late diagnosis or inappropriate referral of patients with cancer results from lack of knowledge on the part of the physician who first sees the patient. Ensuring that all young physicians have at least a basic knowledge of cancer, including predisposing factors—particularly tobacco use—and are also familiar with available resources within their country for cancer treatment, would eventually help to decrease the time it takes for patients in developing countries to reach a center able to deliver effective care. This represents one of the components of INCTR’s long-term strategic approach to capacity building.

Continuing education is another area of considerable importance. Dedication to the care of patients with cancer infers a commitment to life-long learning. There is still a paucity of clinical research in the world—even in resource-rich countries only a few percent of all patients with cancer but most children less than 14 years are entered into clinical research studies. The relatively greater amount of research that has been done in childhood cancer is doubtless a factor in the rapid progress made in recent decades—the five-year survival rate, which is close to the anticipated cure rate, is now more than 77% for childhood cancers in the USA, for example. Clearly, it is essential that more cancer specialists are trained in the conduct of clinical trials. This entails an understanding of the disease or diseases being studied, a knowledge of scientific methodology and also of the ethical and regulatory issues that apply nationally and internationally. INCTR has therefore begun, with the support of Eli Lilly, to conduct workshops on clinical trials methodology. The first of these was held in Beijing in conjunction with the Chinese Society of Clinical Oncology and was very successful. Other workshops of this kind are in the planning phases, and it is anticipated that training workshops in a variety of disciplines, as well as in specific areas of oncology, will become an important element in INCTR’s educational program in the future.

This year, INCTR’s Visiting/Exchange Expert program was also launched. This program has two components. In the first, a specialist from one country visits an institution in a developing country for a mutually beneficial exchange of experiences and views with multiple staff members and trainees. Such visits may include ward rounds, viewing of pathology slides or diagnostic images, and delivery of seminars and/or more formal lectures. In the second, a specialist trainee from an affluent nation spends an elective period in a developing country. This will greatly expand the experience of the trainee, and hopefully engender a lifelong interest in cancer in developing countries. By maintaining contact with Visiting Fellows, INCTR hopes to gradually increase the pool of specialist talent that it can call upon—a second component of its longer term strategy.

In the course of the next year, INCTR plans to expand its website by making available slide presentations on a variety of topics, including global cancer issues, research methods (e.g., clinical trials management) and disease-specific presentations.

Network Infrastructure
Finally, the INCTR itself has continued to envolve. A new branch has been opened in France (Alliance Mondiale Contre le Cancer, AMCC, described on page 17) and an office will open in the UK later this year. As the year progresses, these should have a significant impact on INCTR’s resources for program development. It is anticipated that AMCC will focus particularly on women’s and children’s cancers in Africa, and the London Office on education. Offices have also been established in Nepal and India, and additional offices in Egypt and Brazil should be functional before the end of the year. It is anticipated that the offices/branches in developing countries will assist with local coordination of projects, with quality control (e.g., through the employment of data monitors who will visit collaborating units and assess operating procedures and the accuracy of data) and with training and education. These offices will also assist in the identification of resources within the country, and in the establishment of additional collaborative links. As time goes by they should contribute to the cancer control infrastructure of the country in which they are located, thus directly assisting in the building of capacity—yet another component of the longer-term strategy.

INCTR’s Clinical Trials Office has gone from strength to strength and is already capable of managing clinical trials in line with the stringent requirements of Good Clinical Practice. Along with the Education Program, it will provide one of the bastions of INCTR’s own infrastructure. While the Laboratory Program in Brussels remains rudimentary, this is more than compensated for by the close collaboration with our colleagues in Riyadh.

Finally, INCTR is developing excellent relationships with the corporate and academic worlds, in part through its Associate Membership program. It now has 63 Institutional and Corporate Associate Members (new members are listed in the panel at left). In the future, cooperative groups and professional societies will be able to become Associate Members—as INCTR’s own resources expand, it plans to work more closely with such organizations in developing countries. INCTR’s Corporate Liaison Committee meets regularly, and the newly established Special Panel of the Advisory Board, comprised of distinguished oncologists and pathologists from developing countries, will provide valuable advice in the coming years.

Antoni Gaudi put all of the creative energies of the latter part of his life into his sacred and symbolic building. Its construction was begun in 1884 and is likely to continue until at least 2020, such that it already spans three centuries. INCTR, in comparison, is still in its infancy, but it is making rapid progress and shows every sign that it will continue to grow and develop long after la Sagrada Familia is completed.

New Associate Members

Tang-Ji Hospital of Tong-Ji University, Shanghai, China
Hospital Universitario Del Valle, Cali, Colombia
Instituto De Enfermedades Neoplàsicas, Lima, Peru
Kenya Medical Research Institute, Kenya 001, Kenya
OAUTHC - Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria
PGIMER - Postgraduate Institute of Medical Education and Research, Chandigarh, India
Tygerberg Hospital and University of Stellenbosch, Tygerberg, Germany
Rizk Hospital, Beirut, Lebanon
Kothari Medical Centre, Calcutta, India
Government Cancer Hospital, Indore, India
DETEA - Institute for Experimental Medicine, Istanbul, Turkey
Vasanthal Memorial Trust, Coimbatore, India
Union Hospital of Tongij Medical College, Wuhan, China
B.P. Koirala Memorial Cancer Hospital, Bharatpur, Nepal
DCHRC - Dharamshila Cancer Hospital and Research Center, New Delhi, India
Funcancer - Hospital Universitario, Cali, Colombia
University Hospital of Antwerp, Antwerp, Belgium
Sulakshan Kirti Health Center, Kathmandu, Nepal
Third Hospital Affiliate, Guong Zhou , China
International Society of Gynecological Cancer, Louisville, Kentucky, USA