Mark Skwarchuk

Does prone positioning reduce small bowel dose in pelvic radiation with intensity-modulated radiotherapy for gynecologic cancer?

PURPOSE Intensity-modulated radiotherapy (IMRT) has been shown to reduce the radiation dose to small bowel in pelvic RT in gynecology patients. Prone positioning has also been used to decrease small bowel dose by displacement of small bowel from the RT field in these patients. The purpose of this study was to determine whether the combination of both IMRT and prone positioning on a belly board can reduce small bowel dose further in gynecologic cancer patients undergoing pelvic RT. METHODS AND MATERIALS IMRT plans for pelvic RT were computed in 16 patients with gynecologic cancer who had undergone planning CT scans in both the supine and the prone positions on a belly board. For the gross tumor volume, the uterus, cervix, and tumor (or postoperative region) were traced. The clinical target volume was defined as the vessels and lymph nodes from the obturator level to the aortic bifurcation, presacral region, and upper 4 cm of the vagina, in addition to gross tumor volume. The planning target volume was defined as a 2-cm margin in addition to the gross tumor volume and upper 4 cm of the vagina, and 1.5 cm for lymph nodes and vessels. Normal tissue regions of interest included small bowel, large bowel, and bladder. IMRT plans using (1) the limited arc technique (180 degrees arc length) and (2) the extended arc technique (340 degrees arc length) were computed. Dose-volume histograms for normal tissue structures and target were compared between the supine and prone IMRT plans using the paired t test. RESULTS Prone positioning on a belly board decreased the small bowel dose in gynecologic pelvic IMRT, and the magnitude of improvement depended on the specific IMRT technique used. With the limited arc technique, prone positioning significantly decreased the irradiated small bowel volume at the 25-50-Gy dose levels compared with supine positioning. Small bowel volumes receiving > or =45 Gy decreased from 19% to 12.5% (p = 0.005) with prone positioning. With the extended arc technique, the decrease in irradiated small bowel volume was less marked, but remained detectable in the 35-45-Gy dose levels. Small bowel volumes receiving > or =45 Gy decreased from 13.6% to 10.1% (p = 0.03) with prone positioning. The effect of prone positioning on large bowel and bladder was variable. Large bowel volumes receiving > or =45 Gy increased with prone positioning from 16.5% to 20.6% (p = 0.02) in the limited arc technique and was unaffected in the extended arc technique. CONCLUSION These preliminary data suggest that prone positioning on a belly board can reduce the small bowel dose further in gynecology patients treated with pelvic RT, and that the dose reduction depends on the IMRT technique used.

In vivo determination of extra-target doses received from serial tomotherapy

BACKGROUND AND PURPOSE The purpose of this study was to perform in-vivo measurements of extracranial doses received by patients undergoing serial tomotherapy of the head and neck. MATERIAL AND METHODS Intensity modulated radiotherapy treatment (IMRT) plans were designed for nine patients using the CORVUS treatment planning system (NOMOS Corp.). These plans were delivered using a tertiary collimator dedicated for serial tomotherapy attached to a 10-MV linear accelerator. For each patient, one optically stimulated luminescence dosimeter (OSLD) was placed on the sternum and one on the lower abdomen. The OSLDs were then processed, thereby estimating the in vivo absorbed doses to the sternum and gonads as a function of distance from the treatment site. RESULTS The OSLDs were shown to measure known doses to within 5%, thereby validating their accuracy for this dose and energy range. In the patient studies, the dose received by the OSLDs varied in direct proportion to the number of monitor units delivered and inversely with the distance from the target volume; the patient dose at a distance of 15 cm from the target is approximately 0.4% of the total monitor units delivered, and drops to below 0.1% of the total MUs at approximately 40 cm from the center of the target. The average sternal dose was 1353 mSv and the average abdominal dose was 327 mSv for an average prescribed dose of 60.1 Gy. This can be attributed, at least partially, to the inefficient treatment delivery that on average required 9.9 MU/0.01 Gy. CONCLUSIONS While IMRT reduces the normal tissue volume in the high-dose region, it also increases the overall monitor units delivered, and hence the whole-body dose, when compared with conventional treatment delivery. As has been noted in existing literature, these increases in whole-body dose from radiotherapy delivery may increase the likelihood of a radiation-induced secondary malignancy. Therefore, it is important to assess the risk of secondary malignancies from IMRT delivery, and compare this relative risk against the potential benefits of decreased normal tissue complication probabilities.

INTENSITY-MODULATED RADIATION THERAPY IN THE TREATMENT OF CHILDREN

Intensity-modulated radiation therapy (IMRT) is a relatively new method of conformal radiotherapy delivery that is rapidly being incorporated in clinical practice. Of all patients treated with conformal techniques, children are the most likely to benefit as normal, developing structures can be minimized in the radiation field. The advantages of IMRT, including increased conformality and possible dose escalation, are discussed in this review. Possible disadvantages of IMRT in children are also discussed, such as lack of dose homogeneity in the target volume, increased dose to nontarget tissues, reliability of treatment setup, increased anesthesia time in younger children, and prolonged treatment planning. The issue of increased risk of second malignancy in this very young population is important, as many of these children will be long-term survivors with current multimodality therapy.

Substructure in the radiation survival response at low dose in cells of human tumor cell lines.

In earlier studies using asynchronously growing Chinese hamster cells, we observed substructure in the survival response at low doses. The substructure appeared to result from subpopulations of cells having different, cell cycle phase-dependent radiosensitivity. We have now applied the same flow cytometry and cell sorting technique to accurately measure the responses of cells of eight different asynchronously growing human tumor cell lines, representing a wide range in radiosensitivity. When the data were fitted with a linear-quadratic (LQ) function, most of these lines showed substructure similar to that observed in Chinese hamster cells, with the result that values of alpha and beta were dependent on the dose range used for fitting. Values of alpha describing the low-dose response were typically smaller (by as much as 2.2 times) than the alpha describing the high-dose response, while values of beta were larger at low doses. Values of alpha/beta from our measurements are in reasonable agreement with other values published recently if we fit the data for the high-dose range (excluding, for example, 0-4 Gy), which corresponds to a conventional survival response measurement. However, the values of alpha/beta describing the low-dose range were, on average, 2.8-fold smaller. The results show that the usual laboratory measurement of cell survival over 2 or 3 logs of cell killing, if fitted with a single LQ function, will yield alpha and beta values which may give a rather poor description of cell inactivation at low dose in asynchronous cells, no matter how carefully those measurements are done, unless the low-dose range is fitted separately. The contribution of killing represented by the beta coefficient at low doses was found to be surprisingly large, accounting for 40-70% of cell inactivation at 2 Gy in these cell lines. A two-population LQ model provides excellent fits to the data for most of the cell lines though, as one might expect with a five-parameter model, the best-fitting value of the various parameters is far from unique, and the values are probably not reliable indicators of the size and radiosensitivity of the different cell subpopulations. At very low dose, below 0.5-1 Gy, another order of substructure is observed: the hypersensitive response; this is described in the accompanying paper (Wouters et al., Radiat. Res. 146, 399-413, 1996).

The survival of asynchronous V79 cells at low radiation doses : modeling the response of mixed cell populations

We have observed that when a single linear-quadratic (LQ) function is used to fit the radiation survival response of an asynchronously dividing population of V79 cells, a consistent misfit occurs at low doses. The data can be better described by fitting the low-dose and high-dose ranges separately, and there is evidence of a two-component response. The most obvious explanation is that we may simply be seeing the response of subpopulations of cells of different radiosensitivity: sensitive G1-, G2- and M-phase cells and resistant S-phase cells. The cell sorting assay for cell survival which we have used in these studies may thus be providing sufficient accuracy to resolve these subpopulations, not previously seen in conventional survival measurements. An alternative explanation is that the linear-quadratic function may be inappropriate for accurate description of the radiation survival response at low dose, at least for these cells. To test this hypothesis we have used three other models to fit the data: the single-hit plus multi-target (SHMT) model and the two-parameter repair-misrepair (RMR) model both yielded inferior fits to the asynchronous survival data; the three-parameter RMR model provided an improved fit to the data. The best fit, however, was obtained using a two-population LQ model, which suggested approximately equal numbers of sensitive and resistant cells. When the survival response of tightly synchronized G1/S-phase cells was measured using the cell sorting assay, no substructure was observed. This offers strong support to the hypothesis that the substructure observed in the asynchronous survival response is due to subpopulations of cells of different, cycle-dependent radiosensitivity.

The effect of hypoxia and low pH on the cytotoxicity of chlorambucil

Studies with mouse tumors have shown that the effectiveness of certain chemotherapeutic agents can be enhanced if they are used in appropriate combination with an anti-hypertensive drug such as hydralazine. This results in reduced tumor blood flow with, among other things, a consequent decrease in oxygenation and increase in acidity in the tumor tissue. The purpose of the present work was to determine to what extent hypoxia and low pH are involved in the mechanism of this effect for chlorambucil. V79-WNRE cells were exposed to various drug concentrations under aerobic or hypoxic conditions, pH 6.4 or 7.4. Measurements of cell survival following 1 hr exposure at 37 degrees C showed that pH 6.4 produced a large potentiation of cell killing by chlorambucil (ER = 4 approx.); hypoxia, on the other hand, had little effect. The potentiation was shown to be greatest for pH values below 7.0. HPLC measurements of drug uptake were made since it was anticipated that chlorambucil, a weak acid, might tend to accumulate in cells under conditions of low extracellular pH. It was found that at an extracellular pH of 6.4 the ratio of the intracellular (Ci) and extracellular (Ce) drug concentrations was increased 4.5 and 3.6 fold for aerobic and hypoxic conditions, respectively. This probably explains most, if not all, of the cell killing potentiation observed at low pH.

Principal component, Varimax rotation and cost analysis of volume effects in rectal bleeding in patients treated with 3D-CRT for prostate cancer

We investigate the utility of principal component analysis as a tool for obtaining dose-volume combinations related to rectal bleeding after radiotherapy for prostate cancer. A direct implementation of principal component analysis reduces the number of degrees of freedom from the patients dose-volume histograms that are associated with bleeding. However, when low-variance principal components are strongly correlated to outcome, their interpretation is problematic. A Varimax rotation is employed to aid in interpretability of the low-variance principal components. This procedure brings us closer to finding unique dose-volume combinations related to outcome but reintroduces correlation, requiring analysis of the overlap of information contained in such modes. Finally, we present examples of cost-benefit analyses for candidate dose-volume constraints for use in treatment planning.

THE EFFECT OF LOW PH AND HYPOXIA ON THE CYTOTOXIC EFFECTS OF SR4233 AND MITOMYCIN C IN VITRO

PURPOSE We examined the effect of acidic pH and hypoxia on the cytotoxicity of SR4233 and mitomycin C in vitro. METHODS AND MATERIALS The importance of tumor microenvironment to the response of solid tumors to cytotoxic treatment is well established. The bioreductive drug SR4233 has a very substantial selective toxicity for hypoxic cells. We have used both Chinese hamster and human tumor cells to investigate the influence of low pH and hypoxia on the response of cultured cells to treatment with SR4233 or mitomycin C. RESULTS We found that low pH (6.6) had little effect on the hypoxic toxicity of SR4233; under aerobic conditions, however, low pH substantially increased the cytotoxic effects of 1 h exposure to SR4233, with drug dose enhancement ratios (ER) of 3.9 and 2.5 in V79 and HT-29 cells, respectively. In similar studies with mitomycin C, hypoxia had little effect on the cytotoxicity of mitomycin C in V79 cells, though a low pH of 6.6 enhanced the cytotoxicity under both aerobic and hypoxic conditions (ER approximately 2). In HT-29 cells, neither low pH nor hypoxia had any significant effect on mitomycin C toxicity. CONCLUSION Low pH, like hypoxia, is a common feature of solid tumors and can be an important determinant of the cytotoxic effect of bioreductive drugs such as SR4233 and mitomycin C.