Medical oncology in the 1990s

901

VIEWPOINT Medical

oncology in the 1990s

The time has come to cut back on the clinical investigation of new chemotherapeutic regimens for cancer and to cast a critical eye on the way chemotherapeutic treatment is now being administered. A brief survey of the history of cancer chemotherapy may help us to make sound decisions for the future. Between the late 1940s and the mid 1960s several active drugs were discovered, but, except in the case of childhood acute leukaemia, they had little impact on the treatment of neoplastic disease. Then came great progress. Curative drug combinations were found for Hodgkin’s disease and nonHodgkin lymphomas, for metastatic germ cell tumours and choriocarcinoma, and for tumours of children such as Wilms’ and embryonal rhabdomyosarcoma. Long remissions were obtained in a high proportion of patients with metastatic breast, ovarian, and small-cell bronchogenic carcinoma, and most patients with myeloma or myeloblastic leukaemia showed a response to treatment. In various carcinomas and sarcomas adjuvant chemotherapy seemed to offer a chance of increasing the cure rates, and large scale controlled studies were initiated. These achievements were won against considerable opposition. Because of the limited scientific basis for chemotherapy and its obvious toxicity, the medical community had strong reservations about the method and its practitioners. Many of the innovators displayed great courage and energy in the face of their colleagues’ doubts, and this may account for the sanguine character and missionary zeal of so many medical oncologists today. In the late 1970s there were good reasons to expect that the curable neoplasms would soon include metastatic breast and small-cell lung carcinomas, and that chemotherapy would prove useful in tumours of head and neck and gastrointestinal tract and in non-small-cell tumours of lung. In 1986 two sharply contrasting evaluations of our progress were published How do matters stand today? The efficacy of adjuvant therapy for certain groups of breast cancer patients and for osteogenic sarcoma has been demonstrated, and we know that some locally advanced colon carcinoma patients benefit from adjuvant treatment. Increases in the remission rates of metastatic transitional cell tumours and colon carcinoma have been reported, but survival advantages have not been shown. Platinum-based drugs have improved results in advanced ovarian carcinoma. Hepatic artery infusion chemotherapy improves the remission rate of colonic hepatic metastases, and systemic infusion increases the radiocurability of locally advanced anal and rectal carcinomas. Bone marrow

transplantation cures some leukaemias and lymphomas. But this is all. No disseminated neoplasm incurable in 1975 is curable today. Various dose-intensive and alternating non-crossresistant regimens have been studied. Biochemically sophisticated techniques, such as methotrexate therapy with citrovorum rescue, have permitted almost unlimited dose

as has autologous bone marrow transplantation in the treatment of certain carcinomas. Innovations in dose scheduling, such as split-course or short and long term continuous infusions, have alleviated the toxic side-effects of several chemotherapeutic agents. But the rate and duration of remissions obtained for the more responsive tumours, such as small-cell lung cancer or stage IV breast cancer, have not improved, and cures are rare. Metastatic melanoma and sarcoma remain neglibly responsive. The apparent chemosensitivity of head and neck tumours is not reflected in survival benefits. The role of third-generation chemotherapy regimens in non-Hodgkin lymphomas remains uncertain. The last important new drug was etoposide, approved in the early 1980s, and it is not clear that the addition of estramustine, ifosamide, and mitoxantrone to the formulary has added much to cancer treatment today. The past decade has produced very interesting data on the mechanism of neoplastic cell resistance to cytotoxic drugs. Although clinical studies to determine the effects of blocking of these mechanisms have not yet improved response rates, they should be pursued. But the many failures of chemotherapy are more likely to be due to the intrinsic lack of sensitivity of most human tumours to all classes of cytotoxic drugs than to specific resistance mechanisms. Despite these disappointments, there has been no let-up in effort devoted to trials of clinical chemotherapy; and in many of them the lack of benefit could have been predicted at the outset (a glance at any issue of Cancer or the Journal of Clinical Oncology illustrates the point). Yet at meetings of specific disease committees of cooperative groups there is a make-work atmosphere, with chairmen appealing to the audience to propose ideas for new regimens or drugs to study. These groups’ raison ditre was not to invent questions, but to answer those arising from promising small (phase-II) therapeutic trials. The phase II trials continue to appear, but, since virtually none are promising, the cooperative groups have become aimless. As to clinical practice, many medical oncologists recommend chemotherapy for virtually any tumour, with a hopefulness undiscouraged by almost invariable failure. The skills of many professionals are squandered upon these

escalation,

costly treatments. The oncology community should respond to the data of the past decade by scaling back the whole chemotherapeutic enterprise. Chemotherapy should be prescribed only when there is

a

reasonable prospect either of cure

or

of benefit in

quantity and quality of life. Our oncology trainees should be taught that chemotherapy is not part of the management of every cancer patient; for many or most patients medical intervention should be confined to symptom management and enrolment in a hospice programme. On the clinical research side, studies should be confined to agents with novel mechanisms of action, and to refinement of regimens already known to be effective. The principle that every cancer patient should, if possible, be entered on a therapeutic protocol, is obsolete. We must learn to accept the limited role of conventional cytotoxic therapies in the

oncological scheme of things. Is there any gleam of light in this gloomy picture? One group of agents that deserve further investigation are the biological response modifiers. As with chemotherapy in its ADDRESS Division of Hematology-Oncology, Department of Medicine, Health Sciences Center at Brooklyn, State University of New York—Box 55, 450 Clarkson Avenue, Brooklyn, New York 11203, USA (A. S Braverman, MD)

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early days, their efficacy is limited and their toxicity substantial, but we may eventually learn how to use them effectively. Interferon has shown activity in chronic myelogenous and hairy cell leukaemia, and in hypernephroma. False hopes, however, have been raised in many desperate patients; and these agents are being used in the same way as chemotherapy, as pretexts for futile investigative and ad-hoc therapeutic exercises, in many medical oncology units. Another hopeful area is the induction of differentiation in certain acute leukaemias, and perhaps squamous cell tumours. In the 1970s I began my oncology lectures by pointing out that we knew less about the pathogenesis of cancer then than

did about that of tuberculosis in 1890. Thanks to progress in the molecular biology of neoplastic disease this is no longer true, and basic research on oncogenes and oncogenesis has finally provided medical oncology with a solid pathophysiological foundation. Such basic investigation is a far better object for the public resources allocated to the "war against cancer" than the increasingly sterile pursuit of cytotoxic drug combinations. we

REFERENCES 1.

Bailara JC, Smith EM. Progress against cancer? N Engl J Med 1986; 314:

1226-32. 2. Chabner BA. The oncologic end

game. J Clin Oncol 1986; 4: 625-38.

IttKSHEL1 Ovarian

Endocrinology

Edited by S. G. Hillier. Oxford: Blackwell Scientific. 1990. Pp 356. 69.50. ISBN 0-632027320.

Of the endocrine glands, each of us owes more to the ovary than to any other. It provided half our genetic material and the hormonal environment that led to ovulation, successful mating, and early pregnancy. Recent scientific advances in molecular biology and the novel concepts of local paracrine control by cytokines and growth factors have greatly advanced our understanding of ovarian endocrinology. Nevertheless, despite the apparently spectacular impact of some modem reproductive technologies, such as in-vitro fertilisation and gamete intrafallopian transfer, on the treatment of infertile couples, the application of science to the clinic has not always been rigorous-especially when it comes to clear definition of diagnostic categories and objective assessment of

therapeutic success. This dichotomy is amply illustrated in this multi-author book. The first seven chapters give excellent accounts of the physiology, biochemistry, and molecular biology of the ovary; all are well structured, comprehensive, and up-todate. However, the standard drops strikingly when clinical aspects

are

discussed. 58 pages devoted

to

so-called luteal

dysfunction contain no convincing evidence for a clear link with infertility nor for the existence of supposed entities such as "luteinized unruptured follicles" or "mild hyperprolactinaemia". Half this space is given to a rather thin and anecdotal contribution on the far more important topic of hormonal manipulation of follicular function. Hillier’s book can be strongly recommended for its excellent reviews of the science underlying recent exciting developments in our knowledge of ovarian endocrinology, but those who are more interested in their clinical applications will be disappointed. Division of Endocrmology, National Institute for Biological Standards and Control, Potters Bar EN6 3QG, UK

Handedness and

S. L.

JEFFCOATE

Developmental Disorder

D. V. M. Bishop. Oxford: Blackwell Scientific. 1990. 21.00. ISBN 0-632028424.

People are peculiarly asymmetrical. independent levels of lateralisation can

Pp 208.

At least four be identified:

molecular, in that all our sugars are dextro and our aminoacids laevo; visceral, as only 1 in 20 000 people do not have their heart on the left side; neural, so that 90% of the

population use the left hemisphere for writing and for speaking; and symbolic, with synonyms for left used pejoratively in many societies, in terms such as sinister and gauche. Dorothy Bishop’s excellent and scholarly monograph is concerned principally with left-handedness, which has been related to conditions as varied as epilepsy, mental retardation, autism, dyslexia, and stuttering. Her critical account indicates that the evidence for many such associations is dubious-maintained not by hard scientific data but by symbolism, which deems that ifleft-handedness is construed as bad, wrong, or awkward, then it must necessarily be associated with disease and depravity. The poverty of much theorising is seen, as Bishop points out, when different authors can state that dyslexia is associated with mixed handedness, strong left-handedness, strong right-handedness, and lack of strong right-handedness. She ends her book with a detailed review of Geschwind, Behan, and Galaburda’s much publicised, much cited theory which associates left-handedness, dyslexia, and mathematical ability with autoimmune diseases such as myasthenia gravis, asthma, and ulcerative colitis. Testosterone is the putative common agency, suggested to impair or to retard development of both the immune system and the left cerebral hemisphere. Bishop fmds few firm foundations to support this elaborate theoretical superstructure: the enduring appeal of the hypothesis seems best explained by linkage of the ancient symbolic dichotomy of right versus left with two others, male against female and health vs

disease. Symbolism again, not neurology. Left-handedness and right-handedness, the only major behavioural polymorphism, is an intriguing phenomenon and a challenge for neurobiologists. Bishop provides an accurate and intelligent account of the problems of measurement and definition, and of the genetics and development of handedness. In striking contrast to much published work on this topic, too often accompanied by woolly, half-worked ideas, her monograph clearly and fairly outlines these difficult concepts. Academic Department of Psychiatry, St Mary’s Hospital Medical School, London W2 1 NY, UK

CHRIS MCMANUS