The Cancer Journal - Volume 11, Number 5 (September-October 1998)
If paraneoplastic syndromes facilitate tumor growth !
The recent experience with biphosphonates and their application in cancer therapy seems to be a case of serendipity. On the other hand, it might be the first in a series of similar discoveries, which are not due to chance but to the systematic investigation of a hypothesis which could hold for all progressive cancers?
Biphosphonates were first used in cases of breast cancer with osteolytic metastases, in order to reduce osteolysis and hypercalcaemia; however, they were found to have anti-tumoral activity and to reduce the incidence of visceral metastases (1) (2). This suggests that osteolytic metastases are not simply the result of the growth of disseminated tumour cells but also represent an expansion of the tumour tissue.
We would like to propose the hypothesis, detailed below, that two-directional relationships can exist between the tumour tissue and all kinds of paraneoplastic lesions (3). Several consequences of this hypothesis could be tested experimentally.
a - the growth of tumour tissue causes paraneoplastic syndromes: this is the classical concept;
b - the paraneoplastic syndrome can similarly favour the growth of the tumour. This could be the interpretation of the action of biphosphonates in breast cancer (2);
c - the development of the tumour tissue does not necessarily precede that of the paraneoplastic syndrome;
d - drugs which can act on the paraneoplastic syndromes and reduce the symptoms associated with them could have anti-tumoral effects by interfering with growth factors involved in tumour cell proliferation. This effect could be direct, or via an action on angiogenesis, or on the immune response, or via a trophic action on the tumour stroma (4).
This hypothesis suggests the following lines of research:
1- determining whether other biphosphonates which are active against osteolytic bone metastases are also active on visceral metastases, and on the progession of primary tumours of the breast or elsewhere;
2- determining whether drugs which are active in paraneoplastic syndromes are able to arrest the proliferation of tumour tissue, as for clodronate.
3 - testing the anti-tumoral activity of associations of drugs in the above two categoreies;
4 - studying the possible prevention of breast cancer in women treated with biphosphonates for post-menopausal osteoporesis and of prostate cancer in men treated for osteoporesis with the same drugs;
5 - extending this approach to all the causes of cancer co-morbidity and to the wide range of drugs which cancer patients receive during the course of their disease.
If suitable methods of data processing are used to take into account the heterogeneity of the patient populations, it should be possible to detect associations of some of the drugs prescribed for diverses reasons which have unexpected and unexplained effects on the course of the disease, either to restrain or to exacerbate it.
The use of biphosphonates in the treatment of malignant hypercalcaemia and in osteolytic metastases from a variety of cancers dates back to the end of the 1970s. The elucidation of their mode of action is far from complete. It may never be? This is not an important issue. The work of Diet et al.<ital> (1) brings a new insight into the biology of breast cancer which could be of great significance. These authors analysed hitherto unexploited data from several series of patients. With a little imagination and the application of appropriate methods, it should be possible to discover important information hidden in the mass of clinical, biological, radiological and therapeutic results. Unexpected changes in the course of cancers have often been observed. By unexpected, we mean statistically rare events, situated at the extremities of the curves, and probably capable of yielding up more information than the frequent, predictable outcomes. This includes cases which evolved, favourably or unfavourably, significantly faster or slower than average.
All of these rare events, whether or not they were associated with a clinical evolution, should provide a large number of cases. We suggest that clinical researchers should now be sifting through this enormous amount of data which has accumulated in their records, as tenaciously as miners searching for nuggets during the gold rush.
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1. Diel IJ, Solomayer E-F, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N. Engl J Med 339, 357-363, 1998.
2. Mundy GR, Yoneda T Biphosphonates as anticancer drugs. N. Engl J Med 339, 398-400, 1998.
3. Salomon J-C Cancer, Tumors and Paraneoplastic Syndromes. in "New Frontiers in Cancer Causation" O.H. Iversen edit. Taylor and Francis, Washington 1993, pp. 73-80.
4. Hii S-I., Niclo DL, Gotley DC et al. Captopril inhibits tumor growth in a xenograft model of human renal cell carcinoma, Brit. J. Cancer 77, 880-883, 1998.