Effect of Dose Fractionation on the Enhancement by Radiation or Cyclophosphamide of Artificial Pulmonary Metastases

Abstract

Summary.-Thoracic irradiation or cyclophosphamide (CP) treatment of mice before an i.v. injection of tumour cells enhances the number of lung colonies produced by a factor of up to 100+. The effect of fractionation of the X-ray or CP dose on this phenomenon was investigated in several ways.The dose-response curve for the number of lung colonies as a function of the dose of thoracic irradiation was linear, and the degree of enhancement was independent of the number of tumour cells injected. Splitting a dose of 1,000 rad into 2 equal fractions separated by times varying from 1 to 24 h gave the same enhancement as that produced by a single dose of 1000 rad. Similarly, fractionation of 1000 rad into 5 x 200 rad, or 2000 rad into 5 x 400 rad (each interval between fractions being 3 h) had no effect on the radiation enhancement of colony formation.A single dose of 200 mg/kg of CP was compared with 3 doses of 66-7 mg/kg (each dose separated by 12 h) and with a continuous infusion of 200 mg/kg given over 24 h. In this case, fractionation and infusion produced a small reduction in the CP-induced increase, but the factor of colony enhancement compared to control mice remained >100.These data emphasize the potential hazard of prophylactic treatment of pulmonary metastases by X-rays or CP in clinical situations in which control of the primary tumour is not achieved.IT HAS BEEN SHOWN conclusively that irradiation of the lungs of mice and rats increases the number of pulmonary nodules ("artificial metastases") arising from a subsequent i.v. injection of tumour cells (Fidler and Zeidman, 1972;Brown, 1973a; Withers and Milas, 1973;van den Brenk et al., 1973;Peters, 1974;Thompson, 1974). It has also been shown that prophylactic X-irradiation of the lungs of dogs with spontaneous osteosarcomas results in more metastases than in unirradiated lungs, in situations in which the primary tumour is not cured (Owen and Bostock, 1973). All authors are agreed that the enhancement of pulmonary metastases produced by local thoracic irradiation is not due to suppression of any specific immune response against the tumour.Although it has been claimed by several of the above authors that this effect might have clinical relevance in the situation in which prophylactic lung irradiation has been given, this remains speculative. One reason for questioning the clinical relevance of the findings to date is that, with one exception, in each study only large or moderately large single doses of irradiation were given. In the study which is the exception, van den Brenk and Kelley (1974) showed that a fractionated regime of 5 x 350 rad spread over 9 days produced a greater enhancement of lung colonies than a single dose of 1250 rad. However, * Present address: Toledo Radiological Associates Inc., Toledo, Ohio 43606.

A growth-constrained environment drives tumor progression in vivo

“…However, increasing evidence points to a relevant role played by an altered host environment during cancer development at various stages and in different systems (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). For example, primary alterations in the stroma, leading to disruption of the normal epithelial-stromal interactions, have been implicated in the pathogenesis of some epithelial cancers, including bladder (12,13) and mammary cancer (14,15).…”

“…For example, a few decades ago preirradiation of lung was shown to enhance artificial pulmonary metastasis in mice (2,3). More recently, McCullough et al (6) have reported that aging can affect cancer development via modifications induced in the microenvironment outside the tumor.…”

Clinical and volumetric predictors of local control after robotic stereotactic radiosurgery for cerebral metastases: active systemic disease may affect local control in the brain

“…The concept of radiation-induced metastases, and more generally -treatment-induced metastases (TIM), although described in the 50-ties of the XX-th century, was mostly forgotten but regained attention in recent years. [10][11][12] In this specific case it would be rather treatment-induced/facilitated local recurrence associated with exceeding a safe dose for local microenvironment. Of course we cannot provide a proof of sterilization of the irradiated tumor or distinct characteristics of the progressing lesion but we believe our observation is worth further studies.…”

Local Recurrence and Metastasis of Excised Breast Carcinoma in the Rat

“…In others, where the risk of metastases is high, prophylactic chemotherapy may be given (Carter 1976). However, in patients treated by surgery and irradiation, chemotherapy may potentiate the formation of metastases (Finney 1971), as with some animal tumours (Steel & Adams 1977, Brown & Marsa 1978. This suggests that adjuvant chemotherapy requires a detailed knowledge of the biological pattern of tumour spread both in patients and in animal tumour models, particularly if the latter are to be used in developing rational general principles of combined therapy.…”