C. Clifton Ling

Iodine‐125 implant and external beam irradiation in patients with localized pancreatic carcinoma. A comparative study to surgical resection

Twelve patients with biopsy‐proven clinically localized ductal pancreatic cancers (less than 7 cm in greatest diameter) judged unsuitable for resection were treated by bypass surgery, an Iodine‐125 implant (20–39 mCi), and postoperative irradiation (4000–4500 rads). The potential problems of significant bleeding, pancreatic fistula, or pancreatitis were not experienced. A local recurrence developed in one patient and two recurred in regional lymph nodes. The projected median survival of the group is 11 months with four of the 12 patients still surviving. For purposes of comparison all patients with pancreatic ductal carcinoma treated by radical resection during a similar time were evaluated. All ten have died with a median survival of six months. Twelve of 22 (55%) of the combined implanted and resected groups have developed distant metastasis. Further pursuit of intraoperative techniques of irradiation in combination with adjuvant multidrug chemotherapy seems indicated in an attempt to prolong patient survival which is now limited by hematogenous metastases. Cancer 45:709‐714, 1980.

Dose-rate effects in external beam radiotherapy redux.

Recent developments in external beam radiotherapy, both in technical advances and in clinical approaches, have prompted renewed discussions on the potential influence of dose-rate on radio-response in certain treatment scenarios. We consider the multiple factors that influence the dose-rate effect, e.g. radical recombination, the kinetics of sublethal damage repair for tumors and normal tissues, the difference in alpha/beta ratio for early and late reacting tissues, and perform a comprehensive literature review. Based on radiobiological considerations and the linear-quadratic (LQ) model we estimate the influence of overall treatment time on radio-response for specific clinical situations. As the influence of dose-rate applies to both the tumor and normal tissues, in oligo-fractionated treatment using large doses per fraction, the influence of delivery prolongation is likely important, with late reacting normal tissues being generally more sensitive to the dose-rate effect than tumors and early reacting tissues. In conventional fractionated treatment using 1.8-2Gy per fraction and treatment times of 2-1 min, the influence of dose-rate is relatively small. Lastly, the dose-rate effect in external beam radiotherapy is governed by the overall beam-on-time, not by the average linac dose-rate, nor by the instantaneous dose-rate within individual linac pulses which could be as high as 3 x 10(6)MU/min.

Oxygen Sensitization of Mammalian Cells under Different Irradiation Conditions

The oxygen dependence of the radiosensitivity of cultured CHO cells was examined in detail with particular attention paid to avoiding possible artifacts due to radiolytic oxygen depletion. Two methods of gas equilibration and irradiation were used. In the first approach, cells were irradiated with 50-kVp X rays in a thin-layer geometry which offered maximum interchange between the cells and the surrounding gas. The second technique employed 280-kVp X irradiation of cells under full-medium conditions with mechanical agitation to minimize the effect of radiochemical oxygen consumption by promoting rapid oxygen replenishment. With these techniques oxygen radiosensitization was clearly resolved at an oxygen concentration of 0.03% in the gas phase. The oxygen K curves measured by these two methods were similar in shape over a wide range of oxygen concentration.

Oxygen Sensitization of CHO Cells at Ultrahigh Dose Rates: Prelude to Oxygen Diffusion Studies

The response of cultured CHO cells to ultrahigh dose rate (approx.10/sup 11/ rad/sec) radiation, as measured by colony-forming ability, was studied under various oxygen concentrations with single electron pulses of 3 nsec duration. A thin-layer technique was designed for these experiments to permit rapid equilibration of the cells with the ambient oxygen-containing gas and to ensure that no segments of the cell population were shielded from the relatively low energy electrons (average energy, approx.450 keV), thus eliminating the possibility of artifacts influencing surviving fraction. Dosimetry was performed using a combination of calorimetric, charge-measuring, and thermoluminescent techniques. At a concentration of 0.44% oxygen, breaking behavior of the survival curve was observed in accord with the radiolytic depletion of intracellular oxygen by the radiation pulse. The sensitivity for doses greater than the breakpoint dose followed an anoxic response, clearly different from that observed when the cells were irradiated at conventional dose rates in the same gas under the identical geometry. The breakpoint dose was found to be approximately linear over the oxygen concentration range 0 to 0.7%. These results are consistent with recent observations of mammalian cell response under high-intensity irradiation conditions and provide a basis for the design of a double-pulsemorexa0» experiment.«xa0less

Interaction of misonidazole and oxygen in the radiosensitization of mammalian cells.

The radiosensitizing effect of misonidazole in the presence of various oxygen concentrations was studied using cultured Chinese hamster ovary (CHO) cells. Survival curves were measured for cells equilibrated with various combinations of oxygen and misonidazole concentrations and irradiated with 50 kVp x-rays. In cases where the two agents independently yield two moderately different enhancement ratios (ER), the combined ER is simply the higher of the two. Only when the two individual ERs are approximately equal is there some degree of increase in the overall ER. An empirical technique was derived, based on the concept of ER-equivalence and the respective K-curves of the two sensitizers, to predict the combinative effect of the agents in radiosensitization. These experimental and theoretical considerations suggest that oxygen and misonidazole share in the same sensitization mechanism and act on the same target site or sites. Since it is likely that there is a distribution of oxygen tension in a tumor sensitizing tumor cells to varying degrees, knowledge of the additive effects of misonidazole and oxygen in radiosensitization may be valuable in understanding the efficacy of the application of electron affinic drugs to cancer radiotherapy.

Oxygen diffusion into mammalian cells following ultrahigh dose rate irradiation and lifetime estimates of oxygen-sensitive species.

Based on the observation of breaking survival curves for cultured CHO cells irradiated by single pulses of high-intensity radiation, the kinetics of oxygen diffusion into these cells were studied using the double-pulse technique developed previously with bacterial systems. Two high-intensity electron pulses, each of 3 nsec duration, were delivered to a monolayer of CHO cells in equilibrium with a known concentration of oxygen (typically approx.0.44% O/sub 2/). The first pulse was of sufficient dose to deplete the intracellular oxygen radiochemically and preceded a similar second pulse by an accurately known interpulse time, variable from 10/sup -6/ to 60 sec. The relative concentration of oxygen diffusing to critical sites in the cell during the interpulse time was inferred by comparing the cellular response to the time-delayed second pulse with that to single pulses under various known oxygen concentrations. The oxygen diffusion curve obtained experimentally can be described by the solution of a one-dimensional diffusion equation using the oxygen diffusion coefficient in water of 2 x 10/sup -5/ cm/sup 2/ sec/sup -1/ and an average depth of the critical sites of 4 ..mu..m corresponding approximately to a cell radius. The oxygen diffusion curve indicates that a significant amount of O/sub 2/ diffusedmorexa0» to these sites by approx.3 x 10/sup -3/ sec. This can be interpreted as an upper limit to the average lifetime of the radiation-induced oxygen-dependent damage since otherwise breaking survival curves would not have been observed.«xa0less

Preoperative Irradiation, Lymphadenectomy and 125Iodine Implant for Patients with Localized Prostatic Carcinoma: a Correlation of Implant Dosimetry with Clinical Results

The 30 patients with clinically and surgically localized prostatic carcinoma who were selected for treatment by a short course of preoperative irradiation (1,050 rad), pelvic lymphadenectomy and 125iodine implant have been followed for 1 to 4 years. Perioperative morbidity (10 per cent), postimplant impotence (11 per cent), lymphedema (17 per cent), tumor recurrence (4 per cent) and distant metastasis (4 per cent) have been minimal to date. However, urinary irritative symptoms, which usually subsided in 6 to 9 months, occurred in half of the patients and correlated with implant volume. Total dose and total dose per unit of implanted activity were calculated. Of the various implant parameters evaluated implant dose homogeneity has corrrelated with the rate of tumor regression.

Repair of sublethal damage in mammalian cells irradiated at ultrahigh dose rates.

The lethal response of asynchronous Chinese hamster ovary (CHO) cells exposed to single and split doses of radiation at conventional or ultrahigh dose rates has been examined to determine whether repair of sublethal damage occurs in cells irradiated at ultrahigh dose rates. The high-intensity irradiations were performed with electrons delivered in single 3-nsec pulses from a 600-kV field emission source under medium-removed, thin-layer conditions. Conventional dose-rate experiments were done under identical thin-layer conditions with 50-kVp x rays, or under full-medium conditions with 280-kVp x rays. Oxygenated cells were irradiated and maintained at 22 to 24/sup 0/C between exposures. Survival did not increase as the time between two doses of pulsed electrons increased from 0 to 4 min, indicating no evidence of fast repair. However, increased survival was observed when 30 to 90 min was allowed to elapse between the split doses. The half-time for maximum repair was approx. = 30 min irrespective of the exposure conditions and radiation modality used. Observed repair ratios increased from approx. = 2 to 4 as the single-dose surviving fraction decreased from 10/sup -2/ to 5 x 10/sup -4/. Over this survival range the repair ratios, measured at the same value of surviving fraction, weremorexa0» independent of dose rate. The observed repair ratios imply that the shoulder regions of the nonfractionated x-ray and pulsed-electron survival curves were not completely restored between the split doses. However, the fraction of the shoulder restored between split doses of radiation was dose-rate-independent. It is concluded that sublethal damage can be repaired in oxygenated CHO cells irradiated at dose rates of the order of 10/sup 11/ rad/sec.«xa0less

Combined Effects of Misonidazole Radiosensitization and Hypoxic Cell Toxicity in Mammalian Cells

It has been established that the hypoxic cell radiosensitizer misonidazole (Ro-07-0582) is also a toxic agent to hyposic cells in the absence of radiation. In this study, the combined effects of radiation sensitization and toxicity were examined in hypoxic CHO cells. Complete radiation survival curves were measured for cells in the presence of 15 mM misonidazole prior to or following incubation with the drug for various times in hypoxia at 37/sup 0/C. The latter case is the condition for the preincubation effect observed previously for misonidazole. The cells were irradiated as a monolayer in stoppered glass flasks with 280-kVp x rays; survival was assayed by colony formation. The survival data obtained in these experiments were analyzed by comparing the experimentally observed survival curves with those theoretically predicted based on the concepts of independent and additive interaction of the two effects of hypoxic cell toxicity and radiation sensitization. For incubation times of 1 to 3 hr, for which the cytotoxic effect is moderate, the combined response appears to be of an additive rather than an independent nature. The data in fact suggest a somewhat greater than additive response, and also a slight change in the slope as well as the shouldermorexa0» of the survival curve, when compared with the predicted curves. The results are discussed with regard to both in vitro and in vivo studies.«xa0less

Prolonged "Ultra" Low-Dose-Rate Irradiation: Effects on Chinese Hamster Cell Population Growth, Survival, and Radiation Sensitivity

The apparent clinical efficacy of125 I implants of solid tumors and32 P as an intraperitoneal adjuvant in patients with early ovarian carcinoma has raised clinical interest in the radiobiology of continuous radiation at dose rates in the range of 10 rad/hr. Cell population growth, survival, and radiation survival curve characteristics were examined for two Chinese hamster lines, CHO and V-79. Nonconfluent monolayers of these cells were passed serially and maintained at 37°C in226 Ra fields with dose rates of 9.5 or 12.5 rad/hr. Cell population growth continued with an increased doubling time (T2) for long (4-12 weeks) intervals during which the surviving fraction (S.F.) initially decreased to the range 0.10-0.05 for prolonged periods (23-103 days) until an abrupt drop to less than 0.00001 occurred. During the prolonged stable period (re T2 and S.F.) no change in sensitivity to acute doses of X irradiation was observed in the asynchronous populations surviving the continuous radiations at 9.5 or 12.5 rad/hr.