BLOOD FLO\ol, OXYGEN CONSUHPTION AND TISSUE OXYGENATION OF HUNAN TUHORS
P. Vaupel, F. Kallinowski, P. Okunieff Dept. Radiation Nedi.cine, 1'lassachusetts General Hospital Cancer Center, Harvard i'ledical School Boston, HA 02114, USA
INTRODUCTION
A great number of malignancies are relatively resistant to radiotherapy, chemotherapy and other non-surgical treatment modal i ties. A variety of factors are involved in the lack of responsiveness of these neoplasms including an intrinsic, genetically determined resistance and physiological, extrinsic (epigenetic, environmental) factors primarily created by inadequate and heterogeneous vascular networks l - 3 • Thus, properties such as tumor blood flow and tissue oxygen supply. factors Ivhich usually go hand in hand, can markedly influence the therapeutic respons~ Data on these parameters are mostly derived from rodent tumors. llowever, fast-growing rodent tumors might not adequately represent the multitude of neoplastic growths encountered in patients. Unfortunately, data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements. This should be kept in mind when comparing available results from the literature. In order to create a factual basis for further research, the currently available information on tumor blood flow, 02 supply, and tissue oxygen distribution is compiled in this article. This synopsis attempts to identify areas in which future research might be most beneficial (e.g., for designing specifically tailored treatment protocols for individual subjects, for assessing early tumor response to treatment and/or for examining potentially useful tools for prediction of long-term tumor response). BLOOD FLOH OF HUMAN TUNORS
Hhereas blood flow rates of most rodent tumors decrease with increasing tumor size, a similar relationship has not been found to be valid for all human tumors 4 - 9 . \~hether the latter indicates a lack of sufficient data or a fundamental deviation from animal tumors is unclear at this time. Considering the pathogenetic mechanisms directly
Oxygen Transport to Tissue XII, Edited by J. Piiper et a/. Plenum Press, New York, 1990
895
responsible for the weight-adjusted flow decline that occurs with tumor growth, (i) a progressive rarefaction of the vascular bed, i.e., a decrease in the number of patent vessels per gram tumor, (ii) severe structural and functional abnormalities of the tumor microcirculation, and (iii) the development of necrosis have to be taken into account. These disturbances of tumor microcirculation are apparent even at early growth stages and, at least in iso- or xenografted rodent tumor models, become more pronounced with tumor growth. There are some indications that considerable spatial and temporal heterogeneity of the microcirculation exists amongst individual vessels and different microareas within one tumor, in the same tumor line at different sizes or at different growth sites, between different tumor lines with the same grading and staging as well as between tumors of different histologies. Global tumor perfusion (blood flow) has been measured in patients using various techniques. To date, none of the approaches employed to measure tumor perfusion provide the information needed on the events occurring at the microscopic level. Furthermore they cannot give detailed data on arterio-venous shunt perfusion. For comparison the blood supply to normal organs, and of tumors is gi ven in Fig. 1 using specific perfusion rate units (ml·g-l.min- 1 ). Flow values through normal organs are averages from which there may be departures in individual cases. Moreover, the specific perfusion may vary considerably in different parts of an organ (e.g., renal cortex vs. medulla, subendocardial vs. subepicardial regions of the myocardium,
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P. Vaupel, F. Kallinowski, P. Okunieff Dept. Radiation Nedi.cine, 1'lassachusetts General Hospital Cancer Center, Harvard i'ledical School Boston, HA 02114, USA
INTRODUCTION
A great number of malignancies are relatively resistant to radiotherapy, chemotherapy and other non-surgical treatment modal i ties. A variety of factors are involved in the lack of responsiveness of these neoplasms including an intrinsic, genetically determined resistance and physiological, extrinsic (epigenetic, environmental) factors primarily created by inadequate and heterogeneous vascular networks l - 3 • Thus, properties such as tumor blood flow and tissue oxygen supply. factors Ivhich usually go hand in hand, can markedly influence the therapeutic respons~ Data on these parameters are mostly derived from rodent tumors. llowever, fast-growing rodent tumors might not adequately represent the multitude of neoplastic growths encountered in patients. Unfortunately, data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements. This should be kept in mind when comparing available results from the literature. In order to create a factual basis for further research, the currently available information on tumor blood flow, 02 supply, and tissue oxygen distribution is compiled in this article. This synopsis attempts to identify areas in which future research might be most beneficial (e.g., for designing specifically tailored treatment protocols for individual subjects, for assessing early tumor response to treatment and/or for examining potentially useful tools for prediction of long-term tumor response). BLOOD FLOH OF HUMAN TUNORS
Hhereas blood flow rates of most rodent tumors decrease with increasing tumor size, a similar relationship has not been found to be valid for all human tumors 4 - 9 . \~hether the latter indicates a lack of sufficient data or a fundamental deviation from animal tumors is unclear at this time. Considering the pathogenetic mechanisms directly
Oxygen Transport to Tissue XII, Edited by J. Piiper et a/. Plenum Press, New York, 1990
895
responsible for the weight-adjusted flow decline that occurs with tumor growth, (i) a progressive rarefaction of the vascular bed, i.e., a decrease in the number of patent vessels per gram tumor, (ii) severe structural and functional abnormalities of the tumor microcirculation, and (iii) the development of necrosis have to be taken into account. These disturbances of tumor microcirculation are apparent even at early growth stages and, at least in iso- or xenografted rodent tumor models, become more pronounced with tumor growth. There are some indications that considerable spatial and temporal heterogeneity of the microcirculation exists amongst individual vessels and different microareas within one tumor, in the same tumor line at different sizes or at different growth sites, between different tumor lines with the same grading and staging as well as between tumors of different histologies. Global tumor perfusion (blood flow) has been measured in patients using various techniques. To date, none of the approaches employed to measure tumor perfusion provide the information needed on the events occurring at the microscopic level. Furthermore they cannot give detailed data on arterio-venous shunt perfusion. For comparison the blood supply to normal organs, and of tumors is gi ven in Fig. 1 using specific perfusion rate units (ml·g-l.min- 1 ). Flow values through normal organs are averages from which there may be departures in individual cases. Moreover, the specific perfusion may vary considerably in different parts of an organ (e.g., renal cortex vs. medulla, subendocardial vs. subepicardial regions of the myocardium,
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I:),
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10.0 8.0 6.0
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1.0 0.80 0.60 0.40
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