The single-isocentre treatment of head and neck cancer: time gain using MLC and automatic set-up.

PURPOSE: In this manuscript, we studied the difference in the treatment time required to execute a single-isocentre three-field irradiation of the head and neck, using either tray-mounted cerrobend blocks or a multileaf collimator (MLC) for field shaping and automatic set-up. MATERIALS AND METHODS: A total of twenty consecutive, unselected patients (16 males, four females), were eligible for this study because the dose they were to received was 44 Gy (2 Gy/fraction) to the head, neck and supraclavicular regions. Patients were randomly allocated to one of two treatment groups. The first group (n = 11) was treated on a Philips SL-75 linear accelerator (SL-75), using 5 MV photons and tray-mounted cerrobend blocks. The second group (n = 9) was treated on a Philips SL-25 linear accelerator (SL-25-MLC), using 6 MV photons and a MLC. Patients of the second group were treated using the automatic set-up facility of the SL-25-MLC, without entering the treatment room between consecutive fields. RESULTS: Overall treatment time was significantly shorter on the SL-25-MLC than on the SL-75 (P < 0.0001). The difference in total treatment-execution time was in the range of 157 s per treatment session. The largest difference was observed in the set-up time. There was an average of a 125 s time gain per treatment day (P < 0.0001) in favour of the SL-25-MLC. CONCLUSIONS: Compared to tray-mounted cerrobend blocks, a MLC and automatic set-up results in a significant time advantage when a single isocentre technique is used to treat head and neck cancer.

Inhomogeneous target-dose distributions: a dimension more for optimization?

PURPOSE: To evaluate if the use of inhomogeneous target-dose distributions, obtained by 3D conformal radiotherapy plans with or without beam intensity modulation, offers the possibility to decrease indices of toxicity to normal tissues and/or increase indices of tumor control stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Ten patients with stage III NSCLC were planned using a conventional 3D technique and a technique involving noncoplanar beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic tumor volume. Virtual simulation defined the beam shapes and incidences as well as the wedge orientations (3D) and segment outlines (BIM). Weights of wedged beams, unwedged beams, and segments were determined by optimization using an objective function with a biological and a physical component. The biological component included tumor control probability (TCP) for PTV1 (TCP1), PTV2 (TCP2), and normal tissue complication probability (NTCP) for lung, spinal cord, and heart. The physical component included the maximum and minimum dose as well as the standard deviation of the dose at PTV1. The most inhomogeneous target-dose distributions were obtained by using only the biological component of the objective function (biological optimization). By enabling the physical component in addition to the biological component, PTV1 inhomogeneity was reduced (biophysical optimization). As indices for toxicity to normal tissues, NTCP-values as well as maximum doses or dose levels to relevant fractions of the organ's volume were used. As indices for tumor control, TCP-values as well as minimum doses to the PTVs were used. RESULTS: When optimization was performed with the biophysical as compared to the biological objective function, the PTV1 inhomogeneity decreased from 13 (8-23)% to 4 (2-9)% for the 3D-(p = 0.00009) and from 44 (33-56)% to 20 (9-34)% for the BIM plans (p < 0. 00001). Minimum PTV1 doses (expressed as the lowest voxel-dose) were similar for both objective functions. The mean and maximum target doses were significantly higher with biological optimization for 3D as well as for BIM (all p values < 0.001). Tumor control probability (estimated by TCP1 x TCP2) was 4.7% (3D) and 6.2% (BIM) higher for biological optimization (p = 0.01 and p = 0.00002 respectively). NTCP(lung) as well as the percentage of lung volume exceeding 20 Gy was higher with the use of the biophysical objective function. NTCP(heart) was also higher with the use of the biophysical objective function. The percentage of heart volume exceeding 40 Gy tended to be higher but the difference was not significant. For spinal cord, the maximum dose as well as NTCP(cord) were similar for 3D plans (D(max): p = 0.04; NTCP: p = 0.2) but were significantly lower for BIM (D(max): p = 0.002; NTCP: p = 0.008) if the biophysical objective function was used. CONCLUSIONS: When using conventional 3D techniques, inhomogeneous dose distributions offer the potential to further increase the probability of uncomplicated local control. When using techniques as BIM that would lead to large escalation of the median and maximum target doses, it seems indicated to limit target-dose inhomogeneity to avoid dose levels that are so high that the safety becomes questionable.

Off-line verification of the day-to-day three-dimensional table position variation for radiation treatments of the head and neck region using an immobilization mask.

Variation in the table height position for 175 treatments of 167 patients was calculated as a measure for day-to-day set-up precision in 2063 treatment sessions and resulted in a median standard deviation of 1 mm. The median standard deviations of table longitudinal and lateral position were 3 and 5 mm, respectively.

3D conformal intensity-modulated radiotherapy planning: interactive optimization by constrained matrix inversion.

BACKGROUND AND PURPOSE: This paper presents a method for interactive optimization of 3D conformal intensity-modulated radiotherapy plans employing a quadratic objective that also contains dose limitations in the organs at risk. This objective function is minimized by constrained matrix inversion (CMI) that follows the same approach as the gradient technique using matrix notation. MATERIALS AND METHODS: Sherouse's GRATIS radiotherapy design system is used to determine the outlines of the target volume and the organs at risk and to input beam segments which are given by the beam segmentation technique. This technique defines the beam incidences and the beam segmentation. The weights of the segments are then calculated using a quadratic objective function and CMI. The objective function to be minimized consists of two components based on the planning target volume (PTV) and the organ at risk (OAR) with an importance factor w associated with the OAR. RESULTS: Optimization is tested for concave targets in the head and neck region wrapping around the spinal cord. For a predefined w-value, segment weights are optimized within a few seconds on a DEC Alpha 3000. In practice, 5-10 w-values have to be tested, making optimization a less than 5 min procedure. This optimization procedure predicts the possibility of target dose escalation for a tumour in the lower neck to 120-150 Gy without exceeding the spinal cord tolerance, whereas human planners could not increase the dose above 65-80 Gy. CONCLUSIONS: Treatment plans optimized using a quadratic objective function and the CMI algorithm are superior to those which are generated by human planners. The optimization algorithm is very fast and allows interactive use. Quadratic optimization by CMI is routinely used by clinicians at the Division of Radiotherapy, U.Z.-Gent.

Execution of a single-isocenter three-field technique, using a multileaf collimator or tray-mounted cerrobend blocks: effect on treatment time.

PURPOSE: In this article, we studied the total treatment time of a single-isocenter three-field irradiation of breast and axilla, using either tray-mounted cerrobend blocks, or a multileaf collimator (MLC) for field shaping. METHODS AND MATERIALS: A total of 20 female, unselected patients were given 50 Gy (2 Gy/fraction) on breast and 46 Gy on axilla and supraclavicular region (2 Gy/fraction). Patients were randomized between two different treatment groups. The first group (n = 10) was treated on a Philips SL-75 linear accelerator (SL-75), using 5 MV photons with tray-mounted cerrobend blocks. The second group (n = 10) was treated on a Philips SL-25 linear accelerator, using 6 MV photons and a MLC (SL-25-MLC). RESULTS: Although the beam-on time on the SL-25-MLC was significantly higher (p < 0.0001) compared to the SL-75, overall treatment time was significantly shorter using a MLC instead of tray-mounted cerrobend blocks (p < 0.0001). The difference in total treatment time was in the range of 100 s per patient per day. The main difference between the two accelerators was observed when setup of the second and third field was done using the automatic setup facility of the SL-25-MLC (avoids entering the treatment room). A mean time gain of 124 s per treatment session was observed using automatic setup. Considering the yearly number of patients receiving this treatment, a total time gain equivalent to 16.15 8-h workdays was calculated. CONCLUSIONS: Compared to a technique using tray-mounted cerrobend blocks in the single-isocenter three-field irradiation of a breast and axilla, a MLC combined with automatic field setup provides a significant time advantage, by reducing the number of manipulations inside the treatment room.

Low-level doxorubicin resistance in P-glycoprotein-negative human pancreatic tumour PSN1/ADR cells implicates a brefeldin A-sensitive mechanism of drug extrusion.

The human pancreatic tumour cell line PSN1/ADR, stepwise selected in 17-510 nM doxorubicin, displayed a multidrug resistance not conferred by P-glycoprotein (P-gp). Resistance to 17-51 nM doxorubicin was accompanied by overexpression of the vesicular marker lung resistance-related protein (LRP). Further selection in 170 nM doxorubicin led to the activation of multidrug resistance-associated protein (MRP) and to the development of drug accumulation/retention defects sensitive to verapamil. In addition, these defects were reversible by the vesicular traffic inhibitors brefeldin A, fluoroaluminate and nocodazole. In contrast, in human ovarian H134AD cells that are resistant to 1700 nM doxorubicin and used as P-gp-positive controls, the drug efflux was inhibited only by verapamil. The tyrosine kinase inhibitor genistein was a potent blocker of doxorubicin efflux in the PSN1/ADR cells but showed no activity in the H134 AD cells. The doxorubicin cytotoxicity in the PSN1/ADR cells was enhanced both by verapamil and brefeldin A, whereas in the parental PSN1 cells they demonstrated the opposite effects, being respectively sensitising and protecting. The P-gp-negative PSN1/ADR cells adapted to 510 nM doxorubicin retained brefeldin A-sensitive doxorubicin accumulation defects while MRP declined. The persistence of brefeldin A-responsive phenotype on the background of variable MRP expression suggests this agent as a useful functional probe for non-P-gp-mediated resistance to plasma-achievable doxorubicin concentrations.

Low-dose total body irradiation in non-Hodgkin lymphoma: short- and long-term toxicity and prognostic factor.

The toxicity of low-dose total body irradiation (LTBI), the prognostic factors related to survival and relapse-free survival, and the efficacy of treatment given for relapse after LTBI were analyzed in 68 patients with non-Hodgkin lymphoma (NHL) treated at the Rotterdamsch Radiotherapeutisch Instituut. All patients received LTBI between 1973 and 1979. The patient material was heterogeneous with respect to malignancy grade, stage, age, and therapy given before or after LTBI; the unifying principle was that all patients received LTBI and had symptomatic NHL. Analysis of prognostic variables with Cox's model revealed grade (p less than 0.001) and age (p = 0.004) as predictors for survival and grade (p less than 0.001) and dose of LTBI (p = 0.056) as predictors for relapse-free survival after LTBI. No subjective toxicity was observed during or after LTBI treatment. Hematologic toxicity was dose-limiting and was increased if patients had received cytotoxic treatment before LTBI. LTBI-related hematologic toxicity was lower in patients with low-grade NHL than in those with intermediate or high-grade NHL, was limited in time, and recovered in all patients. Patients relapsing after LTBI received a variety of therapies. Response rates were high, but of short duration, especially in intermediate or high-grade NHL. Duration of response was progressively shorter after multiple relapses.

Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastasis in limited squamous cell lung cancer? A randomized study.

In order to study the usefulness of treatment with vinblastine (VLB) in the prevention of cancer metastasis in squamous cell lung cancer, 50 patients with locoregional disease were randomized to receive either locoregional RT alone (group A) or a weekly intravenous bolus injection of VLB (6 mg/m2) concurrently with and after locoregional radiotherapy (RT) (55 Gy in 6 weeks) until the appearance of metastases (group B). Neither the incidence of death with metastases, metastasis-free survival (MFS) nor overall survival (S) were significantly affected by treatment with the drug. However, due to the limited number of patients in each group, the power of the statistical test was such to allow only the detection of differences in MFS and S to or more than 80 per cent at the P = 0.05 level. Local tumor response was significantly superior in group B (P less than 0.05). Acute toxicity (dysphagia, myelosuppression) during RT was significantly worse in group B. During long-term therapy with VLB, mild polyneuropathy developed in the majority of patients in group B. Furthermore, seven patients discontinued treatment with VLB during maintenance due to compliance (4) and excessive neurotoxicity (3). This treatment schedule with VLB is not recommended for patients with locoregional squamous cell lung cancer as significant toxicity is present during and after RT and significant increase in MFS and S is lacking. Because of an apparent increase in local response, the combination of VLB and RT merits further investigation in those tumors where local tumor control is crucial.

An image analysis system for the quantification of invasion in vitro.

We have tested the value of a computer-assisted image analysis program for the quantitative study of invasion in vitro using experiments that were previously described semi-quantitatively. Mouse fibrosarcoma cell (MO4) aggregates were confronted with precultured fragments of embryonic chick heart in organ culture. Confronting pairs were fixed after 1, 2, 3 and 4 days, and processed for paraffin sectioning and immunostaining with an antiserum against chick heart. The image analysis system allowed separate quantification of two aspects of invasion, namely, occupation of the heart tissue by MO4 cells and degeneration of the invaded heart tissue. Complex combination of occupation and invasion added a qualitative aspect of invasion that has not been described previously and that revealed qualitative differences in invasion under various circumstances.