- Email: [email protected]
Rethinking cancer
efficient solution. Meanwhile, as evidence is accumulating that neutralising antibodies are not adequate protection against HIV infection, recent studies suggest that protection is possible and may be mediated by cellmediated immunity rather than by antibodies. For example, a small population of prostitutes in Nairobi seem to be protected, and remain seronegative and disease-free despite repeated exposure to HIV.4 In addition, a significant number of seronegative individuals have been identified in every known at-risk group who remain HIV seronegative and disease-free but exhibit strong cellmediated immunity to HIV.5 Many of these individuals continue to be exposed, but do not seroconvert. When macaques were exposed to extremely low doses of live SIV and then challenged with an infectious dose of SIV, those that had not been pre-exposed made antibodies, did not show cell-mediated immunity, were polymerase chain reaction (PCR) positive, and developed an AIDSlike condition. By contrast, the animals that were pre-exposed to a very low dose of SIV acquired cellmediated immunity, did not produce antibodies, were PCR negative, and did not develop AIDS.6 Moreover, low-dose immunisation of human beings with the rgpl60 AIDS vaccine can induce cellmediated immunity without antibody formation.’7 These results open the possibility that for vaccination one should use much smaller doses than have previously been considered. In vaccines for which production is a limiting factor, low-dose immunisation might permit increasing 100-fold the number of vaccinees. On the other hand, little is known about the persistence of cell-mediated immunity, and we have to worry also about the best route of immunisation, which probably should not be by injection. There is a growing awareness among AIDS scientists that cell-mediated immunity could be the crucial defence against HIV, and that perhaps something can be done to improve it. What has not been considered until now is the possibility that we may not even have the option of maximising both arms of the immune system simultaneously, owing to cytokine cross-regulation. In these circumstances the cell-mediated arm of immunity is likely to be more protective than the humoral and it might indeed be the only protective component.8 The issue here may be that type 1 (leading to "TH1 ") and type 2 (leading to "TH2") cross-regulatory cytokines will govern the relative strength of these two components of immunity. The vaccines we have discussed until now are all of a prophylactic nature. In the case of a disease like AIDS, there is also urgent need for vaccines of a
efforts
494
to
find
an
therapeutic nature-immunomodulatory vaccines for immunotherapy-and most of the available vaccine candidates should be tested also for possible retardation of disease onset. The three essential issues in the development of a vaccine should now be considered. Is there a need for a vaccine? The answer is clearly yes. What about the safety and toxicity? These obviously have to be established unequivocally. The third issue, which must be recognised, is that all trials should be conducted under the guidance and approval of recognised ethics committees. In the middle of a battle a commander cannot say: "Let us stop for a year until we get better weapons, better ammunition". By analogy, this is no time to slacken our efforts to secure usable vaccines. A cocktail of several vaccine candidates might be the best answer. And we must not forget that the main purpose of a vaccine is to prevent disease and transmission, and not necessarily to prevent infection itself. The Lancet 1 2
3 4
Cadoz M, Strady A, Meignier B, et al. Immunisation with canarypox virus expressing rabies glycoprotein. Lancet 1992; 329: 1429-32. Holley LH, Goudsmit J, Karplus M. Prediction of optimal peptide mixtures to induce broadly neutralising antibodies to human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1991; 88: 6800-04. Cohen J. Jitters jeopardise AIDS vaccine trials. Science 1993; 262: 980-81. Plummer FA, Fowke K, Nagelkerke NJD, et al. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. IX International Conference on AIDS, Berlin, 1993:23
(abstr WS-A07-3). Clerici M,
5
Berzofsky JA, Shearer GM, Tacket CO. Exposure to human immunodeficiency virus (HIV) type 1 indicated by HIV specific T helper cell responses before detection of infection by polymerase chain reaction and serum antibodies. J Infect Dis 1991; 164: 178-82.
6
Benveniste R, Kuller L, Hu S-L, et al. Prior exposure to subinfectious doses of SIV protects macaques from subsequent virus challenge. Bethesda: Gallo Laboratory Meeting, 1993 (abstr). Salk J, Bretscher PA, Salk PL, Clerici M, Shearer GM. A strategy for prophylactic vaccination against HIV. Science 1993; 260: 1270-72. Clerici M, Shearer GM. The aetiology of AIDS: a TH1→TH2 switch? Immunol Today 1993; 14: 107-11.
7 8
COMMENTARY
Rethinking cancer oncologist colleague lately returned from an autopsy conference at my hospital and proudly announced that his patient, who had had widespread cancer, had died "cancer-free". The patient had succumbed instead to chemotherapy-induced lung disease. It is precisely this sort of thinking and practice, where our zeal to eliminate the cancer sometimes eliminates the patient as well, that Schipper and colleagues take issue with in a comprehensive critique of the cytotoxic model for cancer treatment.’.2 An
discouraging statistics of cancer epidemiology provide the background for their discussion. After a 25year "war on cancer", with a growing armamentarium of effective anticancer drugs, ever more radical treatment strategies, and spectacular advances in our understanding of the molecular mechanisms of oncogenesis, mortality rates from cancer in the USA are rising. Common The
such as cancer of the breast and prostate show in incidence.’ Clinical oncologists cure increases striking an occasional patient with a haematological malignant condition or a germ-cell tumour but spend most of their time practising palliation. Two rival explanations have been advanced for this unhappy state of affairs. Optimists see enhanced cure rates just around the corner, as wider dissemination of the promising results from clinical trials leads to earlier use of chemotherapeutic agents in higher doses and in combination with aggressive surgery and radiotherapy.’4 Rational anticancer drug development promises us new and better agents designed to circumvent multidrug resistance. Biological therapies such as alpha-interferon or interleukin have yet to be widely prescribed and are certain, so the argument goes, to produce striking benefits when we understand better how to use them.5 Pessimists (realists perhaps) see us engaged in a war that we cannot win. They view clinical cancer as an intractable biological entity and, while endorsing accurate diagnosis and the best possible therapy, they advocate a shift in research priorities from treatment to prevention.6 Schipper et al offer a third approach. They concede that the existing model for cancer treatment is delivering less than had been promised, but they nonetheless maintain the hope that the cancer problem can be solved. They support continued intensive efforts to improve cancer therapy but propose a paradigm shift in our approach to focus on controlling cancer cells rather than killing them. Their argument can be summarised as follows. The conventional cancer treatment model requires that every last cancer cell must be killed or removed, a strategy that demands intensive attacks on the cancer (and on the patient). Schipper et al believe that this model is based on a false analogy between oncology and microbiology. Cancer cells, they explain, far from being foreign invaders are an intimate part of ourselves"essentially normal cells in which proportionately small changes in the genes lead to large changes in behavior". In view of recent discoveries in cancer biology that have revealed frequent evidence for tumour heterogeneity,’7 they are sceptical about our ability ever to eradicate cancer from individuals in the vast majority of currently incurable cases. Regulation and control of established cancer offers us the best hope for improvement in the length and quality of life of the cancer patient. In practice, this means that we need to seek agents designed to "re-establish intercellular communications". Schipper and colleagues support this argument less with experimental observation than with explicit reference to social science theory-"the restoration of order begins with the establishment of communications mechanisms". The current goal of clinical remission-anatomical evidence of disappearance of a cancer-will be "replaced by measures of tumor re-regulation and clinical functional performance as predictors of therapeutic response". Their new model enjoins us to restore bodily function while tumours
enabling patients to live with their cancer. Although conventional treatment methods will continue to play a part, mainly as "debulkers", high-dose therapies they believe will be replaced by a regulatory strategy encompassing immunological or metabolic treatments such as biological response modifiers." They acknowledge that this scheme is almost entirely hypothetical but hope that by adopting new screening methods we may "identify substances able to block, bypass or re-regulate aberrant pathways" and "find a host of useful agents old and new". Is this proposal plausible? Could an altered mindset break the stalemate in cancer therapy? The suggestion that we focus on the patient’s ability to function rather than simply monitor anatomical tumour response is a welcome but not particularly original suggestion. More challenging is Schipper’s assertion that an established cancer can be "tamed" without being destroyed. Schipper et al provide few examples from human or animal experience to support their claims. Nevertheless, the recent discovery that all-trans retinoic acid can induce remission in a high percentage of patients with acute promyelocytic leukaemia by inducing the leukaemic cells to differentiate shows that alternative approaches are feasible.8 Yet even in this rare disorder, the remissions are transient and must be consolidated with conventional cytotoxic treatment. Moreover, it is unclear whether these results can be generalised to the more common epithelial tumours. At a more fundamental level, work by Leder’s group at Harvard with transgenic mice has offered a glimpse into the possibilities for altering cellular developmental pathways to reduce the risk of neoplasia,9 and may eventually come to have bedside relevance. Schipper and colleagues have made a strong case that cytotoxic chemotherapy holds inherent limitations, but can show scant evidence at this point that their proposed regulatory model would prove more successful. The cytotoxic model, whatever its shortcomings from a public health standpoint, has at least produced cures in a substantial number of individuals with uncommon cancers and has provided useful symptom relief and prolongation of life in others. We can only await further
developments
in
cancer
put these
therapeutics clinical applicability. to
Alan B Astrow Department of Medicine,
biology and experimental thoughts to the test of
new
St Vincent’s
Hospital and Medical Center of
New York, NY, USA 1
2 3 4
5
Schipper H, Goh CR, Wang TL. Rethinking cancer: should rather than kill? Part 1. Can J Oncol 1993; 3: 207-16. Schipper H, Goh CR, Wang TL. Rethinking cancer: should rather than kill? Part 2. Can J Oncol 1993; 3: 220-24.
we
control
we
control
Anon. Cancer statistics reflect overall rise in incidence and mortality since 1973. NIH Observer 1993; 4: 1. DeVita VT. Principles of chemotherapy in cancer: principles and practice of oncology. Philadelphia: Lippincott, 1993; 289-90.
Chabner BA. The oncologic end game. J Clin Oncol 1986; 4: 625-38.
6
Bailar JC, Smith EL. Progress against cancer? N Engl J Med 1986;
314:
1226-32. 7
8 9
Schnipper LE. Clinical implications of tumor-cell heterogeneity. N Engl J Med 1986; 314: 1423-31. Warrell RP Jr, The HD, Wang Z, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-88. Leder P. Development, biologic response modification, and tumorigenesis. Presidential symposium. American Society of Hematology, 35th annual meeting, December, 1993.
495
efforts
494
to
find
an
therapeutic nature-immunomodulatory vaccines for immunotherapy-and most of the available vaccine candidates should be tested also for possible retardation of disease onset. The three essential issues in the development of a vaccine should now be considered. Is there a need for a vaccine? The answer is clearly yes. What about the safety and toxicity? These obviously have to be established unequivocally. The third issue, which must be recognised, is that all trials should be conducted under the guidance and approval of recognised ethics committees. In the middle of a battle a commander cannot say: "Let us stop for a year until we get better weapons, better ammunition". By analogy, this is no time to slacken our efforts to secure usable vaccines. A cocktail of several vaccine candidates might be the best answer. And we must not forget that the main purpose of a vaccine is to prevent disease and transmission, and not necessarily to prevent infection itself. The Lancet 1 2
3 4
Cadoz M, Strady A, Meignier B, et al. Immunisation with canarypox virus expressing rabies glycoprotein. Lancet 1992; 329: 1429-32. Holley LH, Goudsmit J, Karplus M. Prediction of optimal peptide mixtures to induce broadly neutralising antibodies to human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1991; 88: 6800-04. Cohen J. Jitters jeopardise AIDS vaccine trials. Science 1993; 262: 980-81. Plummer FA, Fowke K, Nagelkerke NJD, et al. Evidence of resistance to HIV among continuously exposed prostitutes in Nairobi, Kenya. IX International Conference on AIDS, Berlin, 1993:23
(abstr WS-A07-3). Clerici M,
5
Berzofsky JA, Shearer GM, Tacket CO. Exposure to human immunodeficiency virus (HIV) type 1 indicated by HIV specific T helper cell responses before detection of infection by polymerase chain reaction and serum antibodies. J Infect Dis 1991; 164: 178-82.
6
Benveniste R, Kuller L, Hu S-L, et al. Prior exposure to subinfectious doses of SIV protects macaques from subsequent virus challenge. Bethesda: Gallo Laboratory Meeting, 1993 (abstr). Salk J, Bretscher PA, Salk PL, Clerici M, Shearer GM. A strategy for prophylactic vaccination against HIV. Science 1993; 260: 1270-72. Clerici M, Shearer GM. The aetiology of AIDS: a TH1→TH2 switch? Immunol Today 1993; 14: 107-11.
7 8
COMMENTARY
Rethinking cancer oncologist colleague lately returned from an autopsy conference at my hospital and proudly announced that his patient, who had had widespread cancer, had died "cancer-free". The patient had succumbed instead to chemotherapy-induced lung disease. It is precisely this sort of thinking and practice, where our zeal to eliminate the cancer sometimes eliminates the patient as well, that Schipper and colleagues take issue with in a comprehensive critique of the cytotoxic model for cancer treatment.’.2 An
discouraging statistics of cancer epidemiology provide the background for their discussion. After a 25year "war on cancer", with a growing armamentarium of effective anticancer drugs, ever more radical treatment strategies, and spectacular advances in our understanding of the molecular mechanisms of oncogenesis, mortality rates from cancer in the USA are rising. Common The
such as cancer of the breast and prostate show in incidence.’ Clinical oncologists cure increases striking an occasional patient with a haematological malignant condition or a germ-cell tumour but spend most of their time practising palliation. Two rival explanations have been advanced for this unhappy state of affairs. Optimists see enhanced cure rates just around the corner, as wider dissemination of the promising results from clinical trials leads to earlier use of chemotherapeutic agents in higher doses and in combination with aggressive surgery and radiotherapy.’4 Rational anticancer drug development promises us new and better agents designed to circumvent multidrug resistance. Biological therapies such as alpha-interferon or interleukin have yet to be widely prescribed and are certain, so the argument goes, to produce striking benefits when we understand better how to use them.5 Pessimists (realists perhaps) see us engaged in a war that we cannot win. They view clinical cancer as an intractable biological entity and, while endorsing accurate diagnosis and the best possible therapy, they advocate a shift in research priorities from treatment to prevention.6 Schipper et al offer a third approach. They concede that the existing model for cancer treatment is delivering less than had been promised, but they nonetheless maintain the hope that the cancer problem can be solved. They support continued intensive efforts to improve cancer therapy but propose a paradigm shift in our approach to focus on controlling cancer cells rather than killing them. Their argument can be summarised as follows. The conventional cancer treatment model requires that every last cancer cell must be killed or removed, a strategy that demands intensive attacks on the cancer (and on the patient). Schipper et al believe that this model is based on a false analogy between oncology and microbiology. Cancer cells, they explain, far from being foreign invaders are an intimate part of ourselves"essentially normal cells in which proportionately small changes in the genes lead to large changes in behavior". In view of recent discoveries in cancer biology that have revealed frequent evidence for tumour heterogeneity,’7 they are sceptical about our ability ever to eradicate cancer from individuals in the vast majority of currently incurable cases. Regulation and control of established cancer offers us the best hope for improvement in the length and quality of life of the cancer patient. In practice, this means that we need to seek agents designed to "re-establish intercellular communications". Schipper and colleagues support this argument less with experimental observation than with explicit reference to social science theory-"the restoration of order begins with the establishment of communications mechanisms". The current goal of clinical remission-anatomical evidence of disappearance of a cancer-will be "replaced by measures of tumor re-regulation and clinical functional performance as predictors of therapeutic response". Their new model enjoins us to restore bodily function while tumours
enabling patients to live with their cancer. Although conventional treatment methods will continue to play a part, mainly as "debulkers", high-dose therapies they believe will be replaced by a regulatory strategy encompassing immunological or metabolic treatments such as biological response modifiers." They acknowledge that this scheme is almost entirely hypothetical but hope that by adopting new screening methods we may "identify substances able to block, bypass or re-regulate aberrant pathways" and "find a host of useful agents old and new". Is this proposal plausible? Could an altered mindset break the stalemate in cancer therapy? The suggestion that we focus on the patient’s ability to function rather than simply monitor anatomical tumour response is a welcome but not particularly original suggestion. More challenging is Schipper’s assertion that an established cancer can be "tamed" without being destroyed. Schipper et al provide few examples from human or animal experience to support their claims. Nevertheless, the recent discovery that all-trans retinoic acid can induce remission in a high percentage of patients with acute promyelocytic leukaemia by inducing the leukaemic cells to differentiate shows that alternative approaches are feasible.8 Yet even in this rare disorder, the remissions are transient and must be consolidated with conventional cytotoxic treatment. Moreover, it is unclear whether these results can be generalised to the more common epithelial tumours. At a more fundamental level, work by Leder’s group at Harvard with transgenic mice has offered a glimpse into the possibilities for altering cellular developmental pathways to reduce the risk of neoplasia,9 and may eventually come to have bedside relevance. Schipper and colleagues have made a strong case that cytotoxic chemotherapy holds inherent limitations, but can show scant evidence at this point that their proposed regulatory model would prove more successful. The cytotoxic model, whatever its shortcomings from a public health standpoint, has at least produced cures in a substantial number of individuals with uncommon cancers and has provided useful symptom relief and prolongation of life in others. We can only await further
developments
in
cancer
put these
therapeutics clinical applicability. to
Alan B Astrow Department of Medicine,
biology and experimental thoughts to the test of
new
St Vincent’s
Hospital and Medical Center of
New York, NY, USA 1
2 3 4
5
Schipper H, Goh CR, Wang TL. Rethinking cancer: should rather than kill? Part 1. Can J Oncol 1993; 3: 207-16. Schipper H, Goh CR, Wang TL. Rethinking cancer: should rather than kill? Part 2. Can J Oncol 1993; 3: 220-24.
we
control
we
control
Anon. Cancer statistics reflect overall rise in incidence and mortality since 1973. NIH Observer 1993; 4: 1. DeVita VT. Principles of chemotherapy in cancer: principles and practice of oncology. Philadelphia: Lippincott, 1993; 289-90.
Chabner BA. The oncologic end game. J Clin Oncol 1986; 4: 625-38.
6
Bailar JC, Smith EL. Progress against cancer? N Engl J Med 1986;
314:
1226-32. 7
8 9
Schnipper LE. Clinical implications of tumor-cell heterogeneity. N Engl J Med 1986; 314: 1423-31. Warrell RP Jr, The HD, Wang Z, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329: 177-88. Leder P. Development, biologic response modification, and tumorigenesis. Presidential symposium. American Society of Hematology, 35th annual meeting, December, 1993.
495