Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour

Abstract

Summary.-Radiation survival curves for Lewis lung tumours in the lungs ranging in size from 0-5 to 20 mm3 have been obtained, and a size-dependent variation in hypoxic fraction was found. Cell-survival studies following treatment of various sizes of s.c. tumours indicated that the effects of 60Co y-rays and the chemotherapeutic agents 1,3-bas(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide are all size-dependent. Large pulmonary nodules which had regressed but had not been cured by cyclophosphamide regrew with a radiosensitivity that was characteristic of previously untreated tumours. The results give additional experimental support to the clinical interest in early adjuvant therapy of micrometastases, and sequential combined modality therapy for larger tumours.THE relationship between tumour size and therapeutic sensitivity has been the subject of a number of studies. Experiments from this laboratory have indicated that cells in 0-5-mm3 pulmonarv metastases of the Lewis lung (LL) tumour are considerably more radiosensitive under normal in situ conditions than those in 500-mm3 subcutaneous tumours (Shipley, Stanley and Steel, 1975). At the level of cell survival studied, the presence of a hypoxic fraction could not be detected in 0-5-MM3 pulmonary tumours, whereas the hypoxic fraction in large s.c. tumours was estimated to be 0-36. Fu, Phillips and Wharam (1976), working with the EMT6 tumour system, have also compared the radiosensitivity of large s.c. tumours with that of pulmonary nodules, and have found the smaller tumours to be considerably more radiosensitive and their hvpoxic fraction to be correspondingly lower. DeWys (1972) and Steel and Adams (1975) have found independently, in cell-survival studies with the LL tumour, that small pulmonary nodules are more sensitive to cyclophosphamide than are large s.c. tumours. Twentyman and Bleehen (1976) saw no size-dependent effect when the EMT6 tumour was treated with cyclophosphamide, although their data for the same tumour indicated that sensitivity to BCNU decreased with increasing tumour size.Any effect of tumour size on therapeutic response has important clinical implications for the use both of prophylactic cytotoxic therapy against subclinical disease and of combined modality treatment of larger tumours. The project described in this report was designed to study in greater detail the response of the LL tumour to radiation and drug treatment over a range of sizes, and to investigate the radiosensitivity of regrowing lung nodules which had been treated initially with cyclophosphamide.

TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging

“…This approach is different from clinical practice where fractionated radiotherapy schedules are used. By applying 2 Gy fractions to the tumor, reoxygenation occurs and the HF gradually decreases (22,23). We speculate that the combination of TH-302 with fractionated radiotherapy would also increase the therapeutic effect of the radiotherapy because the HF is reduced by the pretreatment of TH-302, increasing the potential of radiotherapy.…”

The Importance of Spatial Distribution of Stemness and Proliferation State in Determining Tumor Radioresponse

“…In this study we focus on microtumors in the target area of the radiation, with the number of cancer cells being sufficiently low such that hypoxia can be ignored. Tumors smaller than diffusion limited size (≈ 1mm diameter) have been found to be fully oxygenated [42]. Quiescent cells in our model arise due to intratumoral competition for space [22,23], and become reactivated when adjacent space becomes vacant.…”

Early response and local control of stage I non‐small‐cell lung cancer after stereotactic radiotherapy: difference by histology

“…(3,4) In addition, smaller tumors are generally more radiosensitive than larger ones. (5,6) Furthermore, extensive clinical data show that patients with a high hemoglobin level have a better prognosis than those with a low level following definitive radiotherapy of various cancers, (7)(8)(9)(10)(11) indicating that tumors in patients with a high hemoglobin level might be more radiosensitive than tumors in those with a low hemoglobin level. However, these observations mostly come from retrospective analyses of clinical data and have not been properly evaluated in a prospective study.…”