J Cancer Res Clin Oncol (1991) 117:290 294
017152169100053M
C/i/icer ~esearch Clinical 9 9 Springer-Verlag1991
Guest editorial* Progress and challenges in the global effort against cancer * * Samuel Broder
Director, National Cancer Institute, Bethesda, Maryland 20892, USA Received 5 January 1991/Accepted 12 January 1991
Summary. The new decade has given birth to a large
number of new concepts in our approach to cancer. The progress in molecular technology that occurred in the 1980's is being transferred in the 1990's to the bedside. The practical clinical application of basic science innovations is aimed at prevention and curative treatment of cancer in all of its forms, and is becoming a central theme of cancer therapeutics. The progress to date reflects a climate that fosters a unity of basic and clinical investigations, for example, where an understanding of tumor genetics or molecular immunoregulation can translate into an innovative clinical approach such as gene transfer therapy. The challenges that we face in this new decade arise in part from progress in certain areas, such as the discovery of natural products that have important antitumor activity but a limited source, or the increasing incidence in AIDS-related lymphomas that has come about from antiretroviral therapy-induced prolongation of survival for AIDS patients. There are critical challenges from a lack of progress in other areas, as well. The challenge of developing curative therapies is surpassed by the need to prevent those cancers before they arise. The challenge of prevention, as exemplified by the link between lung cancer and smoking, is of paramount importance. The ultimate challenge placed before the global oncology community is to ensure that the fruits of modern technology are available to all who need them.
The decade of the 1990s will offer enormous opportunities for scientific advancement, with continued progress at the basic science level and practical clinical application for many basic scientific ideas. To this end, basic science * The "Journal of Cancer Research and Clinical Oncology" publishes in loose succession "Editorials" and "Guest editorials" on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author The Editors ** Presented at the 15th International Cancer Congress in Hamburg, August 17, 1990
and clinical investigation must be united in a bidirectional flow so that basic research observations can inform every aspect of clinical research, and clinical research can direct and enrich the questions to be addressed by basic research. At the same time, there are numerous challenges from diverse areas where there has been a lack of progress, both in the United States and throughout the world. Among the challenges will be the very complex task of maintaining a momentum of scientific development in an era of shrinking resources while, at the same time, ensuring that science and the fruits of modern technology are available to all who need them. The mutual commitment and interaction between basic and clinical research is exemplified by the expanding body of knowledge regarding the molecular basis for cancer. It is known that there are families of genes, so-called oncogenes, whose somatic abnormalities or aberrant expressions are at the root of malignant transformation (Cooper 1982; Shih et al. 1981). On the other hand, there are families of genes, so-called tumor-suppressor genes (Friend et al. 1988; Stanbridge et al. 1981), the function of which appears to be to block oncogenesis and the aberrations of which may be the crucial step in permitting a full and irreversible progression to cancer. These tumor-suppressor genes were first discovered to be abnormal in retinoblastoma, a rare eye tumor that occurs in children (Knudson Jr 1971). The prototype gene is called RB. This R B gene resides on 13q14, a portion of the long arm of chromosome 13 (Cavanee et al. 1983); abnormalities in 13q14 have also been found to occur in malignant cells from common tumors, the most noteworthy being small-cell lung cancer and breast cancer (Harbour et al. 1988; Varley et al. 1989). Another tumor-suppressor gene has been found to be abnormal in colon, breast, and lung cancer cells - the so-called p53 gene (Nigro et al. 1989; Takahashi et al. 1989; Vogelstein et al. 1988). Study of another rare syndrome, the Li-Fraumeni syndrome, has pinpointed an inherited mutation of p53 as the responsible factor for the multiple tumors such as breast cancer, various childhood cancers, brain tumors, bone
291 cancer and leukemia that occur in high frequency in patients with this inherited predisposition to cancer (Malkin et al. 1990). The knowledge that has been generated about these kinds of genes in various kinds of cancer reflects the strong bidirectional interaction between clinical and basic research. Another area of basic knowledge that will gain clinical prominence in the decade of the 1990s is the use of naturally occurring biological substances in multiple forms the so-called biological response modifiers (Dinarello et al. 1987; Groopman et al. 1989; Ruscetti et al. 1981; Sachs 1987; Tomonaga et al. 1986). Through revolutionary technology, multiple growth factors, such as the colony-stimulating factors and the interleukins, have been cloned and expressed, and are being tested for their applicability to the treatment of many types of cancer. Some of these interleukins, for example the lymphokine interleukin-6 (IL-6) (Kishimoto 1989), may actually promote the development of B-cell malignancies such as multiple myeloma and non-Hodgkin's lymphoma. The newly discovered IL-10 closely resembles a viral protein in both structure and function, and inhibits the synthesis of other cytokines with antiviral activity (interferons and IL-2) by helper T cells in the mouse (Moore et al. 1990), thus facilitating viral infection and, through its immunosuppressive effects, perhaps facilitating the development of lymphoid neoplasms. In the future, it may be possible to develop inhibitors to these cancer-promoting interleukins, thereby providing novel therapeutic and possibly preventive approaches for a number of lymphokine-dependent malignancies. One specialized form of such therapy, adoptive cellular therapy, combines IL-2 and lymphocyte-activated killer (LAK) cells. This form of therapy, where IL-2 is used extracorporeally to activate non-specific tumoricidal lymphocytes that may cause significant tumor regression in selected diseases such as widely metastatic melanoma, was pioneered by Rosenberg and his colleagues at the National Cancer Institute (Rosenberg et al. 1987). This modality has been further refined by obtaining immunologically active, tumor-specific cytotoxic T lymphocytes from the patient's tumor (tumor-infiltrating lymphocytes, or TIL) expanding those tumor-directed lymphocytes in vitro, and reinfusing them (Belldegrun et al. 1988; Topalian et al. 1987). The important experimental application of therapies based on adoptive cellular therapy and the appropriate growth factor, in this case IL-2, has led to significant clinical responses for patients with widespread malignant melanoma and renal cell cancers. It has been possible to modify this technique even further by applying genetic-transfer technology for human cells. In the initial cases, the neomycin-resistance gene was inserted into a non-replicating retroviral vector and the vector was then introduced into TIL cells, transducing the TIL to become resistant to neomycin. Neomycin was selected as the "neutral marker" for the purposes of demonstrating the feasibility of using the TIL themselves as a vehicle for inserting a foreign gene into a patient. This landmark clinical trial of gene therapy has been accomplished by Rosenberg and co-workers at the Clinical Center at the National Institutes of Health (Rosenberg et al. 1990).
The aim of these studies is to create cells that can produce relevant lymphokines that have activities against tumor cells. One such lymphokine, which has been selected for future studies, is tumor necrosis factor (TNF) (Dinarello et al. 1987; Carswell et al. 1975; Wang et al. 1985). It is already possible to select populations of cell that have been transduced and can produce enormous quantities of TNF and yet retain other aspects of cellular specificity for autologous tumor (Kasid et al. 1990). In the near future, TNF-transduced TIL will be reinfused into patients with the aim that they will home to the tumor sites and, armed with the new endogenous production of TNF, will have an exceedingly potent antitumor effect at the local level. Additional permutations of this technology may include insertion of the genes that encode other lymphokines, such as interleukin-4, which are likely to have an impact on the treatment of cancer, at least at the experimental level (Peschel et al. 1987; Tepper et al. 1989). This type of research activity - the harmonious fusion of basic and clinical investigation - will dominate medical oncology in the 1990s. The new decade will also bring increasing application of computer technology to the structural design of antitumor drugs. For example, perhaps an oligonucleotide could be constructed so that it would fit into a relevant portion of a specific gene and thereby block gene performance and expression (Matsukura et al. 1989). The design of new agents and the rational design of therapies are things that will happen commonly in the decade of the 1990s, and will expand the armamentarium that is already available, as well as providing completely new advances. Some recent advances have also brought with them new challenges. The drug taxol is a natural product currently obtained from the bark of the North American Pacific yew tree (Wall et al. 1976). The net effect of taxol is the stabilization of microtubules in their polymerized form and the prevention of mitotic spindle reorganization (Manfredi et al. 1984; Rowinsky et al. 1990). The drug has shown remarkable antitumor activity in heavily pretreated ovarian cancer, and preliminary studies suggest promising activity in breast cancer (Rowinsky et al. 1990). While taxol can be extracted through a laborious process from its tree-bark source, it is exceedingly difficult to synthesize de novo with current chemical technology. The challenge that this situation raises is to fulfill the need to produce and/or obtain natural products while at the same time respecting the balance of ecosystems and natural resources. Taxol is perhaps the first such drug to present us such a challenge, but certainly not the last. The lack of an infinite supply of certain drugs (and thus the question of ecological balance) will require our attention throughout the coming decade. In the United States, there has been progress against the death rate from various types of cancer, primarily in individuals under the age of 65 (Cancer Statistics Review 1973-1987). Over the last 20 years, the astonishing progress against Hodgkin's disease, for which there has been a 50% reduction in death rate (DeVita et al. 1980), or against testicular cancer, for which there has been a 60%
292 reduction (Loehrer et al. 1988), is well recognized. But there has been progress against several of the more common malignancies, as well, for people under 65. For example, since 1973, the death rate for colon cancer has fallen by approximately 14%. The death rate for ovarian cancer has fallen by 25% and for cervical cancer, by 40%. The death rate for bladder cancer has fallen by more than 30%. These rewarding accomplishments have been achieved through advances in multiple medical technologies, including methods of pl:evention, diagnosi s and treatment using all available modalities - chemotherapy, radiation therapy, and surgery. On the other hand, the death rate has not improved and, for several tumors, has increased in people o v e r the age of 65. This is but one problem area that must be addressed in this new decade. The need to develop successful prevention technologies is critical to achieving overall progress in the resolution of many cancers, and will dominate the direction of both basic and clinical research in the 1990s. Nowhere is this need more clearly demonstrated that for women affected by lung cancer and breast cancer. In the United States, the age-adjusted mortality rates for both diseases in women are similar - about 28 per 100000 for lung cancer, about 28 per 100000 for breast cancer (Cancer Statistics Review 1973-1987). In fact, in 1990, it is estimated that lung cancer will kill 50000 women, while breast cancer will be responsible for the death of 45 000 women in the United States, meaning that lung cancer has now overtaken breast cancer as the leading cause of cancer-related death in American women (Cancer Statistics Review 1973-1987). This astonishing and tragic increase in the death rate due to lung cancer in women can be directly attributes to changes in smoking patterns, from 1973 to 1987, the death rate for women as a result of lung cancer has risen by more than 100% (Cancer Statistics Review 1973-1987). This finding can demoralize the public's commitment to cancer research, and requires an intensive response from the medical oncology community aimed at prevention. The situation with respect to breast cancer demonstrates a different type of problem. The death rate from breast cancer has remained relatively constant during the recent 15-year period (1973 1987), with an approximate ! .5% increase during that time (Cancer Statistics Review 1973-1987). With effective implementation of mammography for early detection, it is estimated that the death rate from breast cancer in women over the age of 50 could be reduced by as much as 30% (Roberts et al. 1990). However, as with lung cancer, the ultimate means of decreasing the death rate rests in prevention. The development of new approaches for chemoprevention or chemosuppression of breast cancer is a high priority for the National Cancer Institute. Another area that defies explanation is the rising incidence of non-Hodgkin's lymphoma (NHL) over the last 20 years in both men and women in the United States and other countries (Cancer Statistics Review 1973 1987). This increase has not been accompanied by an increased incidence of Hodgkin's disease. In the United States, there has been a 50% increase in incidence and a 22% increase in the death rate due to N H L since the early 1970s
(Cancer Statistics Review 1973 1987). In fact, there are approximately 36000 cases of N H L per year in the United States alone, so that this disease can no longer be considered minor or rare (Cancer Statistics Review 1973 1987). These statistics demonstrate the need to understand the pathogenesis of N H L , identifying environmental causes and defining the relationship between the immune system and oncogenic viruses and lymphoma development (Cremer et al. 1990; Filopovich et al. 1987; Kersey et al. 1973). There are effective treatments that can lead to cure in some patients with selected types of N H L , but the challenge to be faced spands the entire range of early diagnosis, curative treatment, and ultimately prevention for these types of lymphoma. In addition, there is the emerging problem that will be felt on a global scale, and that is the problem of N H L associated with AIDS (Knowles et al. 1988; Pluda et al. 1990; Ziegler et al. 1984). The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute has been able to track the unexpected increase in incidence of specific types of NHL. Beginning in 1983, a sharp rise in the numbers of N H L has been detected exclusively for men aged 20-49. This is related to AIDS (Cancer Statistics Review 1973-1987; Biggar et al. 1987). The increase has been seen for specific N H L types - immunoblastic sarcomas and small non-cleaved lymphomas, which most commonly have the cytogenetic pattern characteristic of Burkitt's lymphoma (Knowles et al. 1988; Ziegler et al. 1984). These aggressive lymphomas are likely to increase in every country where AIDS is prevalent, and demand attention at all levels of basic and clinical investigation and practice. There are now a number of possibilities in the domain of treating infection with the AIDS-causing retrovirus, HIV. While there is not yet a cure, there are a number of therapies, the dideoxynucleoside AZT being the first of several anti-retroviral agents that are capable of suppressing viral replication and consequently prolonging survival for AIDS patients (Broder et al. 1990). It is this prolongation of survival, however, that may drive the increasing incidence of N H L in the AIDS patients population (Pluda et al. 1990). N H L is likely to be a particular problem for patients with CD4-positive lymphocyte counts less than 50/mm 3. The relationship between immunodeficiency and lymphoma development, first demonstrated more than 25 years ago for the genetically determined immunocompromised states, is likely being mirrored in AIDS. For example, Wiskott-Aldrich syndrome is a sex-linked disorder that is associated with a profound defect in both platelet function and in T-cell-based immunity (Cotelingam et al. 1985). These immunocompromised children are exquisitely susceptible to opportunistic infections such as disseminated herpes virus infections. As blood product support and anti-herpes virus treatments became available, the survival of children with Wiskott-Aldrich syndrome lengthened and, as a consequence, aggressive B-cell lymphomas emerged in this population. These lymphomas have been associated with other genetically determined and acquired immunodeficiency states, such as ataxia telangiectasia (Waldmann et al. 1983) and organ
293 transplantation, particularly cardiac and renal, with exogenous immunosuppression (Penn 1978). The same phenomenon is emerging in A I D S where anti-retroviral and other therapies are prolonging survival in the immunoincompetent state, thereby allowing B-cell N H L to occur (Pluda et al.). The prevention of l y m p h o m a development m a y hinge on the development of an ability to restore immune function to a critical protective level. The projections made by Gail and his co-workers for the occurrence of N H L in the United States, showing significant potential increases in N H L incidence over the next 2-5 years (Gall et al. 1991), are relevant to all countries where A I D S occurs and is being treated aggressively with antiviral and antimicrobial therapies. The increased rate of these high-grade lymphomas could present a major burden to the medical care delivery system as a whole. In this light, the need to develop therapeutic and preventive strategies is critical. As we enter the decade of the 1990s, there are still m a n y challenges to be addressed. While there are some cancers and some groups of people for w h o m the progress against disease is obvious, there are more cancers occurring in the older population, in minorities, and a m o n g the impoverished - the underserved - who do not have access to the advancing technologies that will change the impact of cancer on both the length and the quality of life. The cost of medical care is another cause for concern, especially when the ability to implement live-prolonging technologies is prevented by that cost. The medical oncology community needs to focus its efforts on the development of practical programs that will effectively treat and prevent the death and suffering that is caused by cancers, in particular by the c o m m o n tumors. Such programs must be applied broadly to all who need them. As shown by Muir and colleagues from the World Health Organization (Muir et al. 1988), lung cancer remains a dominant cancer in men on a worldwide scale it is number one in most of the United States and throughout western and eastern Europe. In women, breast cancer dominates on a worldwide scale, followed by cervical cancer. In cervical cancer, the institution of early detection programs where there are few or none presently, such as in China or western Africa, will have an impact on the incidence of and survival fi'om this disease (Muir et al. 1988; Eddy 1990). In liver cancer, also prominent in western Africa, the availability of new vaccine technologies directed against specific types of hepatitis virus m a y help to prevent that disease (Muir et al. 1988; W H O 1983). In the case of stomach cancer, a disease that is prominent in J a p a n and China, the restriction of salt and the appropriate use of fruits and vegetables and micronutrients such as vitamin C will likely have an impact against that tumor (Muir et al. 1988; Block 1991). But, again focusing on lung cancer, there is b o t h good news and bad news. In some countries such as Finland and the United Kingdom, especially in the birth cohort that is now aged 5 ~ 5 4 , there has been a reduction in lung cancer mortality. This success relates to the development of effective public health measures that induced a cessation or reduction of smoking (Muir et al. 1988; Devesa et
al. 1989). In the United States there are mixed results, with an early downward trend in relatively young white men as a result of a successful p r o g r a m to induce smoking cessation in that part of the population. The efforts in women and in some minorities are just starting to gain ground (Devesa et al. 1989). On the other hand, lung cancer in Poland is in an upward spiral, assuredly due to smoking. We can expect Poland to typify the experience of every country that fails to come to grips with smoking as a public health problem. Smoking, both directly and indirectly by passive inhalation, causes not only lung cancer, but also head and neck cancers and cancer at several other sites. Smoking, in both direct and indirect ways probably contributes to approximately one-third of all cancers in the United States, with similar statistics likely in other countries, as well (Cancer Statistics Review 1973 1987; Muir et al. 1988; Devesa et al. 1989). Smoking to a growing extent is a risk behavior of the p o o r and underserved. If the oncology community is unable to mobilize a reduction in lung cancer and related diseases caused by smoking, where the etiology is well-defined and where the necessary preventive measures are straightforward and do not involve sophisticated technology, then what is the prognosis for prevention in other cancers when the causative principles are less obvious and the technologies are more complex? The challenge of this new decade will continue to be the eradication of pain and suffering from cancers, the cure of these diseases once they start, and ultimately their prevention. Basic science provides the foundation upon which the advances in clinical medicine are built. The great irony is that the oncology community stands on the threshhold of using sophisticated science to end the devastation of cancer, yet there is an underserved population the poor, the elderly, minorities, the under-educated who are unable to reap the benefits of the technological advances that have revolutionized medicine. The goals for the global oncology community in the 1990s require continued basic science to provide the tools for maintaining health, and a unified effort to bring those advances from the laboratory to the bedside in a way that reaches all who are in need.
Acknowledgement. The contributions of Drs. Judith Karp and Ed Sondik in the preparation of this manuscript are gratefully acknowledged. References Belldegrun A, Muul LM, Rosenberg SA (1988) Interleukin-2 expanded tumor infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer Res 48:206-214 Biggar RJ, Horm J, Goedert JJ, Melbye M (1987) Cancer in a group at risk of acquired immunodeficiency syndrome (AIDS) thorugh 1984. Am J Epidemiol 126:578-586 Block G (1991) Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr 53 (in press) Broder S, Mitsuya H, Yarchoan R, Pavlakis GN (1990) Antiretroviral therapy in AIDS. Ann Intern Med 113:604-618 Cancer Statistics Review 1973-1987. National Cancer Institute, Division Cancer Prevention and Control. NIH publication no. 902789
294 Carswell EA, Old L J, Kassel RL, et al. (1975) An endotoxin induced serum factor causes necrosis of tumors. Proc Natl Acad Sci USA 72:3666-3670 Cavanee WK, Dryja TP, Phillips RA, et al. (1983) Expression of recessive alleles by chromosomal mechanisms in retino-blastoma. Nature 305:779 784 Cooper G M (1982) Cellular transforming genes. Science 218:801 8O6 Cotelingam JD; Witebsky FG, Hsu SM, et al. (1985) Malignant lymphoma in patients with the Wiscott-Aldrich syndrome. Cancer Invest 3:515-522 Cremer KJ, Spring SB, Gruber J (1990) Role of human immunodeficiency virus type I and other viruses in malignancies associated with acquired immunodeficiency syndrome. J Natl Cancer Inst 82:1016 1024 Devesa SS, Blot WJ, Fraumeni JF Jr (1989) Declining lung cancer rate among young men and women in the United States: a cohort analysis. J Natl Cancer Inst 81:1568 1571 DeVita VT Jr, Simon RM, Hubbard SM, et al. (1980) Curability of advanced Hodgkin's disease with chemotherapy. Long term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 92:587-595 Dinarello CA, Mier JW (1987) Lymphokines. N Engl J Med 317:940-945 Eddy DM (1990) Screening for cervical cancer. Ann Intern Med 113:214-226 Filopovich AH, Heinitz K J, Robison LL, et al. (1987) The immunodeficiency cancer registry: a research resource. Am J Pediatr Hematol Oncol 9:183-184 Friend SH, Dryja TP, Weinberg RA (1988) Oncogenes and tumorsuppressing genes. N Engl J Med 318:618-622 Gail MH, Pluda JM, Rabkin CS, et al. (1991) Projections of the incidene of AIDS-related non-Hodgkin's tymphoma. J Natl Cancer inst (in press) Groopman JE; Molina JM; Scaddin DT (1989) Hematopoietic growth factors. Biology and clinical applications. N Engl J Med 321:1449-1459 Harbour JW, Lai OH, Whang-Peng J, et al. (1988) Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 241:353-357 Kasid A, Morecki S, Aebersold P, et al. (1990) Human gene transfer: characterization of human tumor-infiltrating lymphocytes as vehicles for retroviral-mediated gene transfer in men. Proc Natl Acad Sci USA 87:473-477 Kersey JH, Spector BD, Good RA (1973) Primary immunodeficiency diseases and cancer: the immunodeficiency-cancer registry. Int J Cancer 12:333 347 Kishimoto T (1989) The biology ofinterleukin-6. Blood 74:1 10 Knowles DM, Chamulak GA, Subar M, et al. (1988) Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 108:744-753 Kundson A G Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823 Loehrer PJ, Williams SD, Einhorn LH (1988) Testicular cancer: the quest continues. J Natl Cancer Inst 80:1373 1382 Malkin D, Li FP, Strong LC, et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233-1238 Manfredi JJ, Horwitz SB (1984) Taxol: an antimitotic agent with a new mechanism of action. Pharmacol Ther 25:83 125 Matsukura M, Zon G, Shinozuka K, et al. (1989) Regulation of viral expression of HIV (human immunodeficiency virus) in vitro by an antisense phosphorothioate oligodeoxynucleotide agains rev (art/trs) in chronically infected cells. Proc Natl Acad Sci USA 86:42444248 Moore KW, Vieira P, Fiorentino DF, et al. (1990) Homology ofcytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BSRFI. Science 248:1230-1234 Muir CS, Waterhouse J, Mack T, Powell J, Whelan S (1988) Cancer incidence in five continents. IARC Scientif. PuN. No. 88, Lyon
Nigro JM, Baker S J, Preisinger AC, et al. (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342:705 708 Penn I (1978) Tumors arising in organ transplant recipients. Adv Cancer Res 28:31-61 Peschel C, Paul WE, Ohara J, Green I (1987) Effects of B cell stimulatory factor-l/interleukin-4 on hematopoietic progenitor cells. Blood 70:254-263 Pluda JM, Yarchoan R, Jaffe ES, et al. (1985) Development ofnonHodgkin lymphoma in a cohort of patients with severe immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 113:276-282 Roberts MM; Alexander FE, Anderson T J, et al. (1990) Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 335:241 246 Rosenberg SA, Lotze MT, Muul LM, et al. (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-905 Rosenberg SA, Aebersold P, Cornetta K, et al. (1990) Gene transfer into humans. Immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323:570-578 Rowinsky EK, Cazenave LA, Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natt Cancer Inst 82:1247 1258 Ruscetti FW, Gallo RC (1981) Human T-lymphocyte growth factor: regulation of growth and function of T lymphocytes. Blood 57:379 394 Sachs L (1987) The molecular control of blood cell development. Science 238:1374-1379 Shih C, Padhy LC, Murray M, Weinberg RA (1981) Transforming genes of carcinomas and neuroblastomas introduced into mous fibroblasts. Nature 290:261-264 Stanbridge EJ, Flandermeyer RR, Daniels DW, Nelson-Rees WA (1981) Specific chromosome loss associated with the expression of tumorigenicity in human cell hybrids. Somatic Cell Genet 7:699 712 Takahashi T, Nau WM, Chiba I, et al. (1989) p53: a frequent target for genetic abnormalities in lung cancer. Science 246:491-494 Tepper RI, Pattengale PK, Leber P (1989) Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 57:503-512 Tomonaga M, Golde DW, Gasson JC (1986) Biosynthetic (recombinant) human granulocyte-macrophage colony stimulating factor: effect on normal bone marrow and leukemia cell lines. Blood 67:31-36 Topalian SL, Muul LM, Solomon D, Rosenberg SA (1987) Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. J Immunol Methods 102:127 141 Varley JM, Armour J, Swallow JE, et al. (1989) The retinoblastoma gene is frequently altered leading to loss of expression in primary breast cancer. Oncogene 4:725 729 Vogelstein B, Fearon ER, Hamilton SR, et al. (1988) Genetic alterations during colorectal tumor development. N Engl J Med 319:525-532 Waldmann TA, Misiti J, Nelson DL, Kraemer KH (1983) Ataxiateleangiesctasia: a multisystem hereditary disease with immunodeficiency, impaired organ maturation, X-ray hypersensitivity, and a high incidence of neoplasia. Ann Intern Med 99:367 379 Wall ME, Wani MC, Taylor H (1976) Isolation and chemical characterization of antitumor agents from plants. Cancer Treat Rep 60:1011-1030 Wang AM, Creasey AA, Ladner MB, et al. (1985) Molecular cloning of the complementary D N A for human tumor necrosis factor. Science 228:149-154 World Healt Organization (1983) Prevention of liver cancer. WHO Tech Rep Series 691, Geneva Ziegler JL, Beckstead JA, Volberding PA, et al. (1984) Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311:565 570
017152169100053M
C/i/icer ~esearch Clinical 9 9 Springer-Verlag1991
Guest editorial* Progress and challenges in the global effort against cancer * * Samuel Broder
Director, National Cancer Institute, Bethesda, Maryland 20892, USA Received 5 January 1991/Accepted 12 January 1991
Summary. The new decade has given birth to a large
number of new concepts in our approach to cancer. The progress in molecular technology that occurred in the 1980's is being transferred in the 1990's to the bedside. The practical clinical application of basic science innovations is aimed at prevention and curative treatment of cancer in all of its forms, and is becoming a central theme of cancer therapeutics. The progress to date reflects a climate that fosters a unity of basic and clinical investigations, for example, where an understanding of tumor genetics or molecular immunoregulation can translate into an innovative clinical approach such as gene transfer therapy. The challenges that we face in this new decade arise in part from progress in certain areas, such as the discovery of natural products that have important antitumor activity but a limited source, or the increasing incidence in AIDS-related lymphomas that has come about from antiretroviral therapy-induced prolongation of survival for AIDS patients. There are critical challenges from a lack of progress in other areas, as well. The challenge of developing curative therapies is surpassed by the need to prevent those cancers before they arise. The challenge of prevention, as exemplified by the link between lung cancer and smoking, is of paramount importance. The ultimate challenge placed before the global oncology community is to ensure that the fruits of modern technology are available to all who need them.
The decade of the 1990s will offer enormous opportunities for scientific advancement, with continued progress at the basic science level and practical clinical application for many basic scientific ideas. To this end, basic science * The "Journal of Cancer Research and Clinical Oncology" publishes in loose succession "Editorials" and "Guest editorials" on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author The Editors ** Presented at the 15th International Cancer Congress in Hamburg, August 17, 1990
and clinical investigation must be united in a bidirectional flow so that basic research observations can inform every aspect of clinical research, and clinical research can direct and enrich the questions to be addressed by basic research. At the same time, there are numerous challenges from diverse areas where there has been a lack of progress, both in the United States and throughout the world. Among the challenges will be the very complex task of maintaining a momentum of scientific development in an era of shrinking resources while, at the same time, ensuring that science and the fruits of modern technology are available to all who need them. The mutual commitment and interaction between basic and clinical research is exemplified by the expanding body of knowledge regarding the molecular basis for cancer. It is known that there are families of genes, so-called oncogenes, whose somatic abnormalities or aberrant expressions are at the root of malignant transformation (Cooper 1982; Shih et al. 1981). On the other hand, there are families of genes, so-called tumor-suppressor genes (Friend et al. 1988; Stanbridge et al. 1981), the function of which appears to be to block oncogenesis and the aberrations of which may be the crucial step in permitting a full and irreversible progression to cancer. These tumor-suppressor genes were first discovered to be abnormal in retinoblastoma, a rare eye tumor that occurs in children (Knudson Jr 1971). The prototype gene is called RB. This R B gene resides on 13q14, a portion of the long arm of chromosome 13 (Cavanee et al. 1983); abnormalities in 13q14 have also been found to occur in malignant cells from common tumors, the most noteworthy being small-cell lung cancer and breast cancer (Harbour et al. 1988; Varley et al. 1989). Another tumor-suppressor gene has been found to be abnormal in colon, breast, and lung cancer cells - the so-called p53 gene (Nigro et al. 1989; Takahashi et al. 1989; Vogelstein et al. 1988). Study of another rare syndrome, the Li-Fraumeni syndrome, has pinpointed an inherited mutation of p53 as the responsible factor for the multiple tumors such as breast cancer, various childhood cancers, brain tumors, bone
291 cancer and leukemia that occur in high frequency in patients with this inherited predisposition to cancer (Malkin et al. 1990). The knowledge that has been generated about these kinds of genes in various kinds of cancer reflects the strong bidirectional interaction between clinical and basic research. Another area of basic knowledge that will gain clinical prominence in the decade of the 1990s is the use of naturally occurring biological substances in multiple forms the so-called biological response modifiers (Dinarello et al. 1987; Groopman et al. 1989; Ruscetti et al. 1981; Sachs 1987; Tomonaga et al. 1986). Through revolutionary technology, multiple growth factors, such as the colony-stimulating factors and the interleukins, have been cloned and expressed, and are being tested for their applicability to the treatment of many types of cancer. Some of these interleukins, for example the lymphokine interleukin-6 (IL-6) (Kishimoto 1989), may actually promote the development of B-cell malignancies such as multiple myeloma and non-Hodgkin's lymphoma. The newly discovered IL-10 closely resembles a viral protein in both structure and function, and inhibits the synthesis of other cytokines with antiviral activity (interferons and IL-2) by helper T cells in the mouse (Moore et al. 1990), thus facilitating viral infection and, through its immunosuppressive effects, perhaps facilitating the development of lymphoid neoplasms. In the future, it may be possible to develop inhibitors to these cancer-promoting interleukins, thereby providing novel therapeutic and possibly preventive approaches for a number of lymphokine-dependent malignancies. One specialized form of such therapy, adoptive cellular therapy, combines IL-2 and lymphocyte-activated killer (LAK) cells. This form of therapy, where IL-2 is used extracorporeally to activate non-specific tumoricidal lymphocytes that may cause significant tumor regression in selected diseases such as widely metastatic melanoma, was pioneered by Rosenberg and his colleagues at the National Cancer Institute (Rosenberg et al. 1987). This modality has been further refined by obtaining immunologically active, tumor-specific cytotoxic T lymphocytes from the patient's tumor (tumor-infiltrating lymphocytes, or TIL) expanding those tumor-directed lymphocytes in vitro, and reinfusing them (Belldegrun et al. 1988; Topalian et al. 1987). The important experimental application of therapies based on adoptive cellular therapy and the appropriate growth factor, in this case IL-2, has led to significant clinical responses for patients with widespread malignant melanoma and renal cell cancers. It has been possible to modify this technique even further by applying genetic-transfer technology for human cells. In the initial cases, the neomycin-resistance gene was inserted into a non-replicating retroviral vector and the vector was then introduced into TIL cells, transducing the TIL to become resistant to neomycin. Neomycin was selected as the "neutral marker" for the purposes of demonstrating the feasibility of using the TIL themselves as a vehicle for inserting a foreign gene into a patient. This landmark clinical trial of gene therapy has been accomplished by Rosenberg and co-workers at the Clinical Center at the National Institutes of Health (Rosenberg et al. 1990).
The aim of these studies is to create cells that can produce relevant lymphokines that have activities against tumor cells. One such lymphokine, which has been selected for future studies, is tumor necrosis factor (TNF) (Dinarello et al. 1987; Carswell et al. 1975; Wang et al. 1985). It is already possible to select populations of cell that have been transduced and can produce enormous quantities of TNF and yet retain other aspects of cellular specificity for autologous tumor (Kasid et al. 1990). In the near future, TNF-transduced TIL will be reinfused into patients with the aim that they will home to the tumor sites and, armed with the new endogenous production of TNF, will have an exceedingly potent antitumor effect at the local level. Additional permutations of this technology may include insertion of the genes that encode other lymphokines, such as interleukin-4, which are likely to have an impact on the treatment of cancer, at least at the experimental level (Peschel et al. 1987; Tepper et al. 1989). This type of research activity - the harmonious fusion of basic and clinical investigation - will dominate medical oncology in the 1990s. The new decade will also bring increasing application of computer technology to the structural design of antitumor drugs. For example, perhaps an oligonucleotide could be constructed so that it would fit into a relevant portion of a specific gene and thereby block gene performance and expression (Matsukura et al. 1989). The design of new agents and the rational design of therapies are things that will happen commonly in the decade of the 1990s, and will expand the armamentarium that is already available, as well as providing completely new advances. Some recent advances have also brought with them new challenges. The drug taxol is a natural product currently obtained from the bark of the North American Pacific yew tree (Wall et al. 1976). The net effect of taxol is the stabilization of microtubules in their polymerized form and the prevention of mitotic spindle reorganization (Manfredi et al. 1984; Rowinsky et al. 1990). The drug has shown remarkable antitumor activity in heavily pretreated ovarian cancer, and preliminary studies suggest promising activity in breast cancer (Rowinsky et al. 1990). While taxol can be extracted through a laborious process from its tree-bark source, it is exceedingly difficult to synthesize de novo with current chemical technology. The challenge that this situation raises is to fulfill the need to produce and/or obtain natural products while at the same time respecting the balance of ecosystems and natural resources. Taxol is perhaps the first such drug to present us such a challenge, but certainly not the last. The lack of an infinite supply of certain drugs (and thus the question of ecological balance) will require our attention throughout the coming decade. In the United States, there has been progress against the death rate from various types of cancer, primarily in individuals under the age of 65 (Cancer Statistics Review 1973-1987). Over the last 20 years, the astonishing progress against Hodgkin's disease, for which there has been a 50% reduction in death rate (DeVita et al. 1980), or against testicular cancer, for which there has been a 60%
292 reduction (Loehrer et al. 1988), is well recognized. But there has been progress against several of the more common malignancies, as well, for people under 65. For example, since 1973, the death rate for colon cancer has fallen by approximately 14%. The death rate for ovarian cancer has fallen by 25% and for cervical cancer, by 40%. The death rate for bladder cancer has fallen by more than 30%. These rewarding accomplishments have been achieved through advances in multiple medical technologies, including methods of pl:evention, diagnosi s and treatment using all available modalities - chemotherapy, radiation therapy, and surgery. On the other hand, the death rate has not improved and, for several tumors, has increased in people o v e r the age of 65. This is but one problem area that must be addressed in this new decade. The need to develop successful prevention technologies is critical to achieving overall progress in the resolution of many cancers, and will dominate the direction of both basic and clinical research in the 1990s. Nowhere is this need more clearly demonstrated that for women affected by lung cancer and breast cancer. In the United States, the age-adjusted mortality rates for both diseases in women are similar - about 28 per 100000 for lung cancer, about 28 per 100000 for breast cancer (Cancer Statistics Review 1973-1987). In fact, in 1990, it is estimated that lung cancer will kill 50000 women, while breast cancer will be responsible for the death of 45 000 women in the United States, meaning that lung cancer has now overtaken breast cancer as the leading cause of cancer-related death in American women (Cancer Statistics Review 1973-1987). This astonishing and tragic increase in the death rate due to lung cancer in women can be directly attributes to changes in smoking patterns, from 1973 to 1987, the death rate for women as a result of lung cancer has risen by more than 100% (Cancer Statistics Review 1973-1987). This finding can demoralize the public's commitment to cancer research, and requires an intensive response from the medical oncology community aimed at prevention. The situation with respect to breast cancer demonstrates a different type of problem. The death rate from breast cancer has remained relatively constant during the recent 15-year period (1973 1987), with an approximate ! .5% increase during that time (Cancer Statistics Review 1973-1987). With effective implementation of mammography for early detection, it is estimated that the death rate from breast cancer in women over the age of 50 could be reduced by as much as 30% (Roberts et al. 1990). However, as with lung cancer, the ultimate means of decreasing the death rate rests in prevention. The development of new approaches for chemoprevention or chemosuppression of breast cancer is a high priority for the National Cancer Institute. Another area that defies explanation is the rising incidence of non-Hodgkin's lymphoma (NHL) over the last 20 years in both men and women in the United States and other countries (Cancer Statistics Review 1973 1987). This increase has not been accompanied by an increased incidence of Hodgkin's disease. In the United States, there has been a 50% increase in incidence and a 22% increase in the death rate due to N H L since the early 1970s
(Cancer Statistics Review 1973 1987). In fact, there are approximately 36000 cases of N H L per year in the United States alone, so that this disease can no longer be considered minor or rare (Cancer Statistics Review 1973 1987). These statistics demonstrate the need to understand the pathogenesis of N H L , identifying environmental causes and defining the relationship between the immune system and oncogenic viruses and lymphoma development (Cremer et al. 1990; Filopovich et al. 1987; Kersey et al. 1973). There are effective treatments that can lead to cure in some patients with selected types of N H L , but the challenge to be faced spands the entire range of early diagnosis, curative treatment, and ultimately prevention for these types of lymphoma. In addition, there is the emerging problem that will be felt on a global scale, and that is the problem of N H L associated with AIDS (Knowles et al. 1988; Pluda et al. 1990; Ziegler et al. 1984). The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute has been able to track the unexpected increase in incidence of specific types of NHL. Beginning in 1983, a sharp rise in the numbers of N H L has been detected exclusively for men aged 20-49. This is related to AIDS (Cancer Statistics Review 1973-1987; Biggar et al. 1987). The increase has been seen for specific N H L types - immunoblastic sarcomas and small non-cleaved lymphomas, which most commonly have the cytogenetic pattern characteristic of Burkitt's lymphoma (Knowles et al. 1988; Ziegler et al. 1984). These aggressive lymphomas are likely to increase in every country where AIDS is prevalent, and demand attention at all levels of basic and clinical investigation and practice. There are now a number of possibilities in the domain of treating infection with the AIDS-causing retrovirus, HIV. While there is not yet a cure, there are a number of therapies, the dideoxynucleoside AZT being the first of several anti-retroviral agents that are capable of suppressing viral replication and consequently prolonging survival for AIDS patients (Broder et al. 1990). It is this prolongation of survival, however, that may drive the increasing incidence of N H L in the AIDS patients population (Pluda et al. 1990). N H L is likely to be a particular problem for patients with CD4-positive lymphocyte counts less than 50/mm 3. The relationship between immunodeficiency and lymphoma development, first demonstrated more than 25 years ago for the genetically determined immunocompromised states, is likely being mirrored in AIDS. For example, Wiskott-Aldrich syndrome is a sex-linked disorder that is associated with a profound defect in both platelet function and in T-cell-based immunity (Cotelingam et al. 1985). These immunocompromised children are exquisitely susceptible to opportunistic infections such as disseminated herpes virus infections. As blood product support and anti-herpes virus treatments became available, the survival of children with Wiskott-Aldrich syndrome lengthened and, as a consequence, aggressive B-cell lymphomas emerged in this population. These lymphomas have been associated with other genetically determined and acquired immunodeficiency states, such as ataxia telangiectasia (Waldmann et al. 1983) and organ
293 transplantation, particularly cardiac and renal, with exogenous immunosuppression (Penn 1978). The same phenomenon is emerging in A I D S where anti-retroviral and other therapies are prolonging survival in the immunoincompetent state, thereby allowing B-cell N H L to occur (Pluda et al.). The prevention of l y m p h o m a development m a y hinge on the development of an ability to restore immune function to a critical protective level. The projections made by Gail and his co-workers for the occurrence of N H L in the United States, showing significant potential increases in N H L incidence over the next 2-5 years (Gall et al. 1991), are relevant to all countries where A I D S occurs and is being treated aggressively with antiviral and antimicrobial therapies. The increased rate of these high-grade lymphomas could present a major burden to the medical care delivery system as a whole. In this light, the need to develop therapeutic and preventive strategies is critical. As we enter the decade of the 1990s, there are still m a n y challenges to be addressed. While there are some cancers and some groups of people for w h o m the progress against disease is obvious, there are more cancers occurring in the older population, in minorities, and a m o n g the impoverished - the underserved - who do not have access to the advancing technologies that will change the impact of cancer on both the length and the quality of life. The cost of medical care is another cause for concern, especially when the ability to implement live-prolonging technologies is prevented by that cost. The medical oncology community needs to focus its efforts on the development of practical programs that will effectively treat and prevent the death and suffering that is caused by cancers, in particular by the c o m m o n tumors. Such programs must be applied broadly to all who need them. As shown by Muir and colleagues from the World Health Organization (Muir et al. 1988), lung cancer remains a dominant cancer in men on a worldwide scale it is number one in most of the United States and throughout western and eastern Europe. In women, breast cancer dominates on a worldwide scale, followed by cervical cancer. In cervical cancer, the institution of early detection programs where there are few or none presently, such as in China or western Africa, will have an impact on the incidence of and survival fi'om this disease (Muir et al. 1988; Eddy 1990). In liver cancer, also prominent in western Africa, the availability of new vaccine technologies directed against specific types of hepatitis virus m a y help to prevent that disease (Muir et al. 1988; W H O 1983). In the case of stomach cancer, a disease that is prominent in J a p a n and China, the restriction of salt and the appropriate use of fruits and vegetables and micronutrients such as vitamin C will likely have an impact against that tumor (Muir et al. 1988; Block 1991). But, again focusing on lung cancer, there is b o t h good news and bad news. In some countries such as Finland and the United Kingdom, especially in the birth cohort that is now aged 5 ~ 5 4 , there has been a reduction in lung cancer mortality. This success relates to the development of effective public health measures that induced a cessation or reduction of smoking (Muir et al. 1988; Devesa et
al. 1989). In the United States there are mixed results, with an early downward trend in relatively young white men as a result of a successful p r o g r a m to induce smoking cessation in that part of the population. The efforts in women and in some minorities are just starting to gain ground (Devesa et al. 1989). On the other hand, lung cancer in Poland is in an upward spiral, assuredly due to smoking. We can expect Poland to typify the experience of every country that fails to come to grips with smoking as a public health problem. Smoking, both directly and indirectly by passive inhalation, causes not only lung cancer, but also head and neck cancers and cancer at several other sites. Smoking, in both direct and indirect ways probably contributes to approximately one-third of all cancers in the United States, with similar statistics likely in other countries, as well (Cancer Statistics Review 1973 1987; Muir et al. 1988; Devesa et al. 1989). Smoking to a growing extent is a risk behavior of the p o o r and underserved. If the oncology community is unable to mobilize a reduction in lung cancer and related diseases caused by smoking, where the etiology is well-defined and where the necessary preventive measures are straightforward and do not involve sophisticated technology, then what is the prognosis for prevention in other cancers when the causative principles are less obvious and the technologies are more complex? The challenge of this new decade will continue to be the eradication of pain and suffering from cancers, the cure of these diseases once they start, and ultimately their prevention. Basic science provides the foundation upon which the advances in clinical medicine are built. The great irony is that the oncology community stands on the threshhold of using sophisticated science to end the devastation of cancer, yet there is an underserved population the poor, the elderly, minorities, the under-educated who are unable to reap the benefits of the technological advances that have revolutionized medicine. The goals for the global oncology community in the 1990s require continued basic science to provide the tools for maintaining health, and a unified effort to bring those advances from the laboratory to the bedside in a way that reaches all who are in need.
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