A dosimetric analysis of respiration-gated radiotherapy in patients with stage III lung cancer.

BACKGROUND: Respiration-gated radiotherapy can permit the irradiation of smaller target volumes. 4DCT scans performed for routine treatment were retrospectively analyzed to establish the benefits of gating in stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Gross tumor volumes (GTVs) were contoured in all 10 respiratory phases of a 4DCT scan in 15 patients with stage III NSCLC. Treatment planning was performed using different planning target volumes (PTVs), namely: (i) PTVroutine, derived from a single GTV plus 'conventional' margins; (ii) PTVall phases incorporating all 3D mobility captured by the 4DCT; (iii) PTVgating, incorporating residual 3D mobility in 3-4 phases at end-expiration. Mixed effect models were constructed in order to estimate the reductions in risk of lung toxicity for the different PTVs. RESULTS: Individual GTVs ranged from 41.5 - 235.0 cm3. With patient-specific mobility data (PTVall phases), smaller PTVs were derived than when 'standard' conventional margins were used (p < 0.001). The average residual 3D tumor mobility within the gating window was 4.0 +/- 3.5 mm, which was 5.5 mm less than non-gated tumor mobility (p < 0.001). The reductions in mean lung dose were 9.7% and 4.9%, respectively, for PTVall phases versus PTVroutine, and PTVgating versus PTVall phases. The corresponding reductions in V20 were 9.8% and 7.0%, respectively. Dosimetric gains were smaller for primary tumors of the upper lobe versus other locations (p = 0.02). Respiratory gating also reduced the risks of radiation-induced esophagitis. CONCLUSION: Respiration-gated radiotherapy can reduce the risk of pulmonary toxicity but the benefits are particularly evident for tumors of the middle and lower lobes.

Evaluating mobility for radiotherapy planning of lung tumors: a comparison of virtual fluoroscopy and 4DCT.

PURPOSE: Fluoroscopy is widely used for evaluating tumor mobility in radiotherapy planning. Lung tumor mobility was scored using virtual fluoroscopy, and this was compared to mobility derived from contoured tumors in all phases of a respiration-correlated (or 4D) CT scan. METHODS AND MATERIALS: 4DCT datasets were reviewed and 29 patients were identified in whom tumors were visible on anterior-posterior fluoroscopy views. Mobility in all directions was estimated on fluoroscopy movie loops by four clinicians. These results were compared to mobility measured from contoured tumor volumes in all phases of the same 4DCT. Internal target volumes (ITV) were generated for both approaches. RESULTS: In eight patients, fluoroscopy did not allow for tumor mobility to be assessed in at least one direction. No significant inter-clinician variation was observed with respect to fluoroscopic assessment of mobility. Clinicians systematically overestimated mobility in all three directions (p<0.05). The mean ITVs derived using fluoroscopy were 52.2% larger than those derived using 4DCT contours, but the individual ITVs were smaller in three patients. CONCLUSION: Use of virtual fluoroscopy generally overestimates the mobility of visible lung tumors, and results in irradiation of unnecessarily large target volumes. In contrast, use of 4DCT minimizes the risk of normal tissue toxicity.

Time trends in target volumes for stage I non-small-cell lung cancer after stereotactic radiotherapy.

PURPOSE: To identify potential time trends in target volumes and tumor mobility after stereotactic radiotherapy (SRT) for Stage I non-small-cell lung cancer. PATIENTS AND METHODS: Repeat planning computed tomography (CT) scans were performed for 40 tumors during fractionated SRT delivered in either three (n = 21), five (n = 14), or eight fractions (n = 5). The planning CT scans used to define internal target volumes (ITVs) consisted of either six multislice CT scans or a single four-dimensional CT scan. All repeat CT scans were coregistered with the initial (D0) scan to determine volumetric or spatial changes in target volume, and tumor mobility vectors were determined from each scan. RESULTS: A significant decrease in target volumes (ITVs and gross tumor volumes) relative to baseline values was observed starting at the fourth week of SRT (p = 0.015). No trends in tumor mobility were detected during SRT. Significant positional shifts in the ITV, of more than 5 mm, were seen in 26-43% of patients at different times during SRT. CONCLUSION: Significant changes in target volumes can occur during SRT for Stage I non-small-cell lung cancer. A failure to account for such changes e.g., by repeat CT planning or verification using on-board volumetric imaging can lead to inadequate target coverage.

Use of CD-ROM-based tool for analyzing contouring variations in involved-field radiotherapy for Stage III NSCLC.

BACKGROUND: Interclinician variability in defining target volumes is a problem in conformal radiotherapy. A CD-ROM-based contouring tool was used to conduct a dummy run in an international trial of involved-field chemoradiotherapy for Stage III non-small-cell lung cancer. METHODS AND MATERIALS: The CT scan of an eligible patient was installed on an "auto-run" CD-ROM incorporating a contouring program based on ImageJ for Windows, which runs on any personal computer equipped with a CD-ROM drive. This tool was initially piloted at four academic centers and was subsequently mailed, together with all relevant clinical, radiologic, and positron emission tomography findings, to all participating centers in the international trial. Clinicians were instructed to contour separate gross tumor volumes (GTVs) for the tumor and two enlarged nodes and a clinical target volume for the hilus. A reference "consensus" target volume for each target was jointly generated by three other clinicians. RESULTS: The data received from the four academic centers and 16 study participants were suitable for analysis. Data from one center was unsuitable for detailed analysis because the target volumes were contoured at 1.2-cm intervals. GTVs were available for a total of 21 tumors and 19 nodes, and 15 hilar clinical target volumes were available. The mean GTV of the primary tumor was 13.6 cm(3) (SD, 5.2; median, 12.3; range, 8.3-26.9). The variation in the center of the mass relative to the mean center of the mass in the left-right, ventrodorsal, and craniocaudal axes was 1.5, 0.4, and 1.0 mm, respectively. The largest volume variation was observed for the right hilar clinical target volume (mean, 33.7 cm(3); SD, 31.2; median, 20.3; range, 4.8-109.9). Smaller variations were observed for the subcarinal node (mean, GTV, 1.9 cm(3); SD, 1.2; median, 1.7; range, 0.5-5.3), except caudally where the node was difficult to distinguish from the pericardium. The "consensus" volumes for all targets were generally close to the median of the contoured values. CONCLUSION: Most clinicians were able to use this CD-ROM tool to contour target volumes in compliance with the study protocol. The rapid completion of the dummy run indicated the suitability of this approach for quality assurance in multicenter clinical trials. Routine use of similar tools will reduce the risk that new techniques (or study objectives) are misunderstood and/or misapplied in clinical trials.

Use of maximum intensity projections (MIP) for target volume generation in 4DCT scans for lung cancer.

PURPOSE: Single four-dimensional CT (4DCT) scans reliably capture intrafractional tumor mobility for radiotherapy planning, but generating internal target volumes (ITVs) requires the contouring of gross tumor volumes (GTVs) in up to 10 phases of a 4DCT scan, as is routinely performed in our department. We investigated the use of maximum intensity projection (MIP) protocols for rapid generation of ITVs. METHODS AND MATERIALS: 4DCT data from a mobile phantom and from 12 patients with Stage I lung cancer were analyzed. A single clinician contoured GTVs in all respiratory phases of a 4DCT, as well as in three consecutive phases selected for respiratory gating. MIP images were generated from both phantom and patient data, and ITVs were derived from encompassing volumes of the respective GTVs. RESULTS: In the phantom study, the ratio between ITVs generated from all 10 phases and those from MIP scans was 1.04. The corresponding center of mass of both ITVs differed by less than 1 mm. In scans from patients, good agreement was observed between ITVs derived from 10 and 3 (gating) phases and corresponding MIPs, with ratios of 1.07 +/- 0.05 and 0.98 +/- 0.05, respectively. In addition, the center of mass of the respective ITVs differed by only 0.4 and 0.5 mm. CONCLUSION: MIPs are a reliable clinical tool for generating ITVs from 4DCT data sets, thereby permitting rapid assessment of mobility for both gated and nongated 4D radiotherapy in lung cancer.

Benefit of respiration-gated stereotactic radiotherapy for stage I lung cancer: an analysis of 4DCT datasets.

PURPOSE: High local control rates have been reported with stereotactic radiotherapy (SRT) for Stage I non-small-cell lung cancer. Because high-dose fractions are used, reduction in treatment portals will reduce the risk of toxicity to adjacent structures. Respiratory gating can allow reduced field sizes and planning four-dimensional computed tomography scans were retrospectively analyzed to study the benefits for gated SRT and identify patients who derive significant benefit from this approach. METHODS AND MATERIALS: A total of 31 consecutive patients underwent a four-dimensional computed tomography scan, in which three-dimensional computed tomography datasets for 10 phase bins of the respiratory cycle were acquired during free breathing. For a total of 34 tumors, the three planning target volumes (PTVs) were analyzed, namely (1) PTV(10bins), derived from an internal target volume (ITV) that incorporated all observed mobility (ITV(10bins)), with the addition of a 3-mm isotropic setup margin; (2) PTV(gating), derived from an ITV generated from mobility observed in three consecutive phases ("bins") during tidal-expiration, plus addition of a 3-mm isotropic margin; and (3) PTV(10 mm), derived from the addition of a 10-mm isotropic margin to the most central gross tumor volumes in the three bins selected for gating. RESULTS: The PTV(10bins) and PTV(gating) were, on average, 48.2% and 33.3% of the PTV(10 mm), and respective mean volumes of normal tissue (outside the PTV) receiving the prescribed doses were 57.1% and 39.1%, respectively, of that of PTV(10 mm). A significant correlation was seen between the extent of tumor mobility (i.e., a three-dimensional mobility vector of at least 1 cm) and reduction in normal tissue irradiation achieved with gating. The ratio of the intersecting and the encompassing volumes of GTVs at extreme phases of tidal respiration predicted for the benefits of gated respiration. CONCLUSION: The use of "standard population-based" margins for SRT leads to unnecessary normal tissue irradiation. The risk of toxicity is further reduced if respiration-gated radiotherapy is used to treat mobile tumors. These findings suggest that gated SRT will be of clinical relevance in selected patients with mobile tumors.

Four-dimensional CT scans for treatment planning in stereotactic radiotherapy for stage I lung cancer.

PURPOSE: Hypofractionated stereotactic radiotherapy (SRT) for Stage I non-small-cell lung cancer requires that meticulous attention be paid toward ensuring optimal target definition. Two computed tomography (CT) scan techniques for defining internal target volumes (ITV) were evaluated. METHODS AND MATERIALS: Ten consecutive patients treated with SRT underwent six "standard" rapid multislice CT scans to generate an ITV(6 CT) and one four-dimensional CT (4DCT) scan that generated volumetric datasets for 10 phases of the respiratory cycle, all of which were used to generate an ITV(4DCT). Geometric and dosimetric analyses were performed for (1) PTV(4DCT), derived from the ITV(4DCT) with the addition of a 3-mm margin; (2) PTV(6 CT), derived from the ITV(6 CT) with the addition of a 3-mm margin; and (3) 6 PTV(10 mm), derived from each separate GTV(6 CT), to which a three-dimensional margin of 10 mm was added. RESULTS: The ITV(4DCT) was not significantly different from the ITV(6 CT) in 8 patients, but was considerably larger in 2 patients whose tumors exhibited the greatest mobility. On average, the ITV(6 CT) missed on average 22% of the volume encompassing both ITVs, in contrast to a corresponding mean value of only 8.3% for ITV(4DCT). Plans based on PTV(4DCT) resulted in coverage of the PTV(6 CT) by the 80% isodose in all patients. However, plans based on use of PTV(6 CT) led to a mean PTV(4DCT) coverage of only 92.5%, with a minimum of 77.7% and 77.5% for the two most mobile tumors. PTVs derived from a single multislice CT expanded with a margin of 10 mm were on average twice the size of PTVs derived using the other methods, but still led to an underdosing in the two most mobile tumors. CONCLUSIONS: Individualized ITVs can improve target definition for SRT of Stage I non-small-cell lung cancer, and use of only a single CT scan with a 10-mm margin is inappropriate. A single 4D scan generates comparable or larger ITVs than are generated using six unmonitored rapid CT scans, a finding related to the ability to account for all respiration-correlated mobility.

Randomized phase I clinical and pharmacologic study of weekly versus twice-weekly dose-intensive cisplatin and gemcitabine in patients with advanced non-small cell lung cancer.

PURPOSE: To establish the maximum dose intensity of cisplatin plus gemcitabine on a weekly or two-weekly schedule in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC stage IIIB or IV were randomized to receive weekly or two-weekly courses of gemcitabine on day 1 and cisplatin on day 2. An interpatient dose escalation scheme was used, and pharmacokinetics were determined for both agents in plasma and WBCs. RESULTS: Seventy-three patients were included, 32 on the weekly schedule and 41 on the two-weekly schedule. Fifty patients received all planned courses. Dose-limiting toxicities were leukocytopenia, neutropenia, and trombocytopenia on the weekly schedule and ototoxicity on the two-weekly schedule. Most common nonhematological toxicities consisted of nausea, vomiting, and fatigue. The highest dose intensity of cisplatin could be achieved on the two-weekly schedule, and therefore, further development of the weekly schedule was abandoned. The maximum tolerated dose was established at 1500 mg/m(2) gemcitabine in combination with cisplatin 90 mg/m(2). More than half (53%) of patients achieved an objective response on the two-weekly schedule, versus 23% in the weekly treatment arm. The pharmacokinetic studies revealed a significant interaction: gemcitabine reduced both GG and AG platinum-DNA intrastrand adducts in WBCs. CONCLUSION: The combination of gemcitabine (1500 mg/m(2)) with cisplatin at a dose intensity of 50 mg/m(2)/week is feasible on a two-weekly administration scheme in NSCLC patients.