Kenneth M. Forster

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

BACKGROUND We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. METHODS In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. FINDINGS Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). INTERPRETATION 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. FUNDING National Cancer Institute and Bristol-Myers Squibb.

Respiratory-driven lung tumor motion is independent of tumor size, tumor location, and pulmonary function

PURPOSE To determine whether superior-inferior lung tumor motion is predictable by tumor size or location, or pulmonary function test results. METHODS AND MATERIALS Superior-inferior tumor motion was measured on orthogonal radiographs taken during simulation of 22 patients with inoperable lung cancer diagnosed by orthogonal radiographs. RESULTS The tumor size averaged 5.5 +/- 3.1 cm (range 1.5-12 cm). Seven of 11 central tumors demonstrated some motion compared with 5 of 11 peripheral tumors. Four of 5 upper lobe tumors moved compared with 8 of 17 tumors that were either middle or lower lobe lesions. The mean fourth rib motion was 7.3 +/- 3.2 mm (range 2-15). The mean FeV(1) was 1.8 +/- 1.2 (range 0.55-5.33. The mean diffusing capacity of the lung for carbon monoxide was 14.0 +/- 6.5 (range 7.8-21.9). The mean total lung capacity was 6.5 +/- 1.2 (range 3.3-8.4). None of these parameters correlated with tumor motion. Although lateral tumor motion could not be consistently determined, 1 tumor moved 10 mm anterior-posteriorly. CONCLUSIONS Lung tumors often move significantly during respiration. Tumor motion is not predictable by tumor size or location, or pulmonary function test results. Therefore, tumor motion must be measured in all patients. Measurement in three dimensions will likely be necessary to maximize the irradiated lung volumes or choose beam arrangements parallel to the major axis of motion.

Promising early local control of malignant pleural mesothelioma following postoperative intensity modulated radiotherapy (IMRT) to the chest

PURPOSEMalignant pleural mesothelioma often recurs locally in spite of aggressive resection by extrapleural pneumonectomy and conventional radiotherapy. This may be due to failure to recognize the extent of clinical target volume (CTV) or suboptimal dose delivery to a target that abuts the heart, esophagus, liver, lung, kidney, and spinal cord. We report how these geometric/dosimetric constraints were overcome by exploiting intensity-modulated radiotherapy in the first cohort patient. MATERIALS AND METHODSTwenty-eight patients who had undergone extrapleural pneumonectomy were treated with intensity-modulated radiotherapy. The CTV included the surgically violated inner chest wall, insertion of diaphragm, pleural reflections, and deep margin of the incision. CTV delineation was facilitated by intraoperative radio-opaque marking. Motion was assessed. CTV doses were 45–50 Gy with boosts taken to 60 Gy. RESULTSDespite the large, irregular CTV (median, 4151 cc; range, 2667–7286 cc), an average of 97% of the CTV was covered to the target dose (range, 92%–100%). Respiratory motion was minimal because of immobility of the prosthetic diaphragm. Normal tissue dose constraints were met. The commonest effects were nausea/vomiting (89%) and dyspnea (80%). Esophagitis was absent (59% of patients) or mild (34% grade 1/2). At median follow-up of 9 months (range, 5–27 months), local control within the contoured target was 100%. One-year survival, disease-specific survival, and disease-free survival are 65%, 91%, and 88%, respectively. CONCLUSIONSIntensity-modulated radiotherapy after extrapleural pneumonectomy is tolerable and seems effective, at least at this early point. As local control improves, systemic metastases become more common, and it may be appropriate to add novel agents to further improve the therapeutic ratio.

Intensity-modulated radiotherapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation

PURPOSE New insight into the extent of the target volume for the postoperative irradiation of malignant pleural mesothelioma as determined during surgery has indicated that standard conformal radiotherapy (IMRT) is not sufficient for curative treatment. We describe a novel technique for implementing intensity-modulated radiotherapy (IMRT) to deliver higher doses to treat the full extent of these complex target volumes. METHODS AND MATERIALS After extrapleural pneumonectomy, 7 patients underwent simulation, treatment planning, and treatment with IMRT to the involved hemithorax and adjacent abdomen. The target volumes encompassed the entire operative bed, including the ipsilateral mediastinum, anterior pleural reflection, and ipsilateral pericardium and the insertion of the diaphragm and crura. These were extensively marked during surgery with radiopaque markers to facilitate target delineation. RESULTS Setup uncertainty and respiratory-dependent motion were found to be small. Coverage of the planning target volume was very good, with the crus of the diaphragm the most difficult volume to irradiate. The radiation doses to normal structures were acceptable. CONCLUSION IMRT for treatment of malignant mesothelioma after extrapleural pneumonectomy results in more potentially curative doses to large, complex target volumes with acceptable doses to normal tissues.

Patient-specific point dose measurement for IMRT monitor unit verification

PURPOSE To review intensity-modulated radiation therapy (IMRT) monitor unit verification in a phantom for 751 clinical cases. METHODS AND MATERIALS A custom water-filled phantom was used to measure the integral dose with an ion chamber for patient-specific quality assurance. The Corvus IMRT planning system was used for all cases reviewed. The 751 clinical cases were classified into 9 treatment sites: central nervous system (27 cases), gastrointestinal (24 cases), genitourinary (447 cases), gynecologic (18 cases), head and neck (200 cases), hematology (12 cases), pediatric (3 cases), sarcoma (8 cases), and thoracic (12 cases). Between December 1998 and January 2002, 1591 measurements were made for these 751 IMRT quality assurance plans. RESULTS The mean difference (MD) in percent between the measurements and the calculations was +0.37% (with the measurement being slightly higher). The standard deviation (SD) was 1.7%, and the range of error was from -4.5% to 9.5%. The MD and SD were +0.49% and 1.4% for MIMiC treatments delivered in 2-cm mode (261 cases) and -0.33% and 2.7% for those delivered in 1-cm mode (36 cases). Most treatments (420) were delivered using the step-and-shoot multileaf collimator with a 6-MV photon beam; the MD and SD were +0.31% and 1.8%, respectively. Among the 9 treatment sites, the prostate IMRT (in genitourinary site) was most consistent with the smallest SD (1.5%). There were 23 cases (3.1% of all cases) in which the measurement difference was greater than 3.5%; of those, 6 cases used the MIMiC in 1-cm mode, and 14 of the cases were from the head-and-neck treatment site. CONCLUSION IMRT monitor unit calculations from the Corvus planning system agreed within 3.5% with the point-dose ion chamber measurement in 97% of 751 cases representing 9 different treatment sites. A good consistency was observed across sites.

The relationship between local dose and loss of function for irradiated lung.

PURPOSE To determine the relationship between the local radiation dose and the decrease in lung function associated with thoracic irradiation. PATIENTS AND METHODS Twenty-six patients treated with thoracic irradiation for lung cancer, for whom three-dimensional CT-based dosimetry was used in treatment planning, were evaluated with before and after treatment pulmonary function tests. Six patients were treated with radiotherapy alone (2.15 Gy daily fractions), and 20 patients with concurrent chemotherapy (cisplatin, etoposide) with hyperfractionated (HF) radiation therapy (1.2 Gy in twice-daily fractions). Eleven patients treated with concurrent HF chemoradiation also received the radioprotector amifostine. The normalized decrease in the diffusing capacity for carbon monoxide (DL(CO)) was used as an objective measure of the change in lung function. The dose-volume histogram (DVH) data were used to estimate the local dose-response relationship for loss of DL(CO). In each subvolume of lung, the loss in normalized DL(CO) was assumed to be a sigmoid function of dose, ranging from no loss at low doses to total loss at high doses. The whole-lung decrease in DL(CO) was modeled as the sum of the local declines in DL(CO) over all subvolumes. Nonlinear regression analysis was used to estimate the parameters of the local dose-response function. RESULTS The data are most consistent with a pronounced decrease in DL(CO) when the local dose (for radiotherapy alone or HF concurrent chemoradiation) exceeds 13 Gy (95% CI, 11-15 Gy). In patients who received amifostine in addition to HF radiotherapy with concurrent chemotherapy, this stepwise loss of DL(CO) occurred above 36 Gy (95% CI, 25-48 Gy). Grade 2 or higher pulmonary symptoms were associated with a DL(CO) loss of >30% (p = 0.003). CONCLUSIONS The decrease in pulmonary diffusion capacity correlates with the local dose to irradiated lung. Amifostine significantly reduces the loss in DL(CO). A local dose-loss relationship for normalized DL(CO) can be extracted from DVH data. This relationship allows an estimate of the loss of function associated with a radiation treatment plan. Different plans can thus be compared without resort to an empiric DVH reduction algorithm. The very low (13 Gy) threshold for deterioration of DL(CO) suggests that it is better to treat a little normal lung to a high dose than to treat a lot to a low dose.

Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head

AbstractPurpose: We hypothesized that dynamic intensity-modulated radiotherapy (IMRT) would protect normal tissues enough to allow the escalation of either the gemcitabine or radiotherapy dose in unresectable pancreatic cancer patients. Methods and Materials: The trial was designed to build on a previous phase I trial that determined the maximum tolerated dose (MTD) of gemcitabine (350 mg/m2) with concurrent radiotherapy (30 Gy/10 fractions). Only patients with unresectable disease based on established criteria were eligible. The plan was to alternate escalating the radiation dose by 3 Gy and the gemcitabine dose by 50 mg/m2. The starting dose of gemcitabine was 350 mg/m2 and 33 Gy/11 fractions of IMRT to the regional lymphatics and primary disease. The NCl Common Toxicity Criteria were used for dose-limiting toxicity (DLT). Results: All three patients in the first cohort treated suffered DLT. Therefore, a second cohort of patients received a lower gemcitabine dose (250 mg/m2). Both patients treated at this dose level experienced DLT. The DLTs were all due to myelosuppression and upper gastrointestinal toxicity. All patients required a gemcitabine dose reduction. Also, four patients required hospital admission for supportive care, while the fifth died of an unrelated cause shortly after completing therapy. The trial was then closed due to excessive toxicity. Conclusion: Hypofractionated dynamic IMRT to the primary site and regional lymphatics did not permit escalation of either the radiation or gemcitabine dose. Dynamic IMRT requires further investigation before it can be applied to toxic combinations of chemotherapy and radiation in the upper abdomen.

Evaluation of a biplanar diode array dosimeter for quality assurance of step-and-shoot IMRT.

In this paper, we describe and characterize a novel biplanar diode array, and demonstrate its applicability to dosimetric QA of step‐and‐shoot IMRT. It is the first commercially available device of its kind specifically designed for performing measurements at varying gantry angles. The detector consists of a cylindrical PMMA phantom with two orthogonal detector boards. There are a total of 1069 p‐type 1 mm wide diode detectors covering the measurement area of 20×20cm2 in each of the measurement planes. The orthogonal detector arrays ensure that the dose modulation information is not lost regardless of the beam incidence angle. For absolute calibration, the dose to the reference detector is calculated at the appropriate SSD and radiological depth by the treatment planning system and is scaled by the measured accelerator output. The directly measured rotational response on the central axis shows the maximum variation of approximately ± 3% in the narrow ±1º angular intervals centered on the detector boards. This variation is reduced to less than ± 2% outside of the four similarly centered ± 5% angular intervals. For all detectors, the difference between the measured and the calculated dose for a plan with 12 equally spaced beams is −0.2±0.9%. Of eleven IMRT plans, ten passed the γ (3%,3 mm) criterion at or above 95%, while one passed at 92%. The biplanar diode array is a useful tool for IMRT QA, allowing for essentially instantaneous online analysis of absolute dose errors in 3D. PACS number: 87.55Qr

Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody.

Epidermal growth factor receptor (EGFR) plays an important role in cell division and cancer progression, as well as angiogenesis and metastasis. Since many tumor cells exhibit the EGFR on their surface, functional imaging of EGFR provides not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-EGFR therapy could be assessed effectively. C225 is a chimeric monoclonal antibody that targets the human extracellular EGFR and inhibits the growth of EGFR-expressing tumor cells. Also, it has been demonstrated that C225, in combination with chemotherapeutic drugs or radiotherapy, is effective in eradicating well-established tumors in nude mice. We have developed 99mTc-labeled C225 using ethylenedicysteine (EC) as a chelator. This study aimed at measuring uptake of 99mTc–EC–C225 in EGFR+ tumor-bearing animal models and preliminary feasibility of imaging patients with head and neck carcinomas. In vitro Western blot analysis and cytotoxicity assays were used to examine the integrity of EC–C225. Tissue distribution studies of 99mTc–EC–C225 were evaluated in tumor-bearing rodents at 0.5–4 h. In vivo biodistribution of 99mTc–EC–C225 in tumor-bearing rodents showed increased tumor-to-tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using 99mTc–EC–C225 to assess EGFR expression. SPECT images confirmed that the tumors could be visualized with 99mTc–EC–C225 from 0.5 to 4 h in tumor bearing rodents. We conclude that 99mTc–EC–C225 may be useful to assess tumor EGFR expression. This may be useful in the future for selecting patients for treatment with C225.

Dosimetric benefits of respiratory gating: a preliminary study

In this study, we compared the amount of lung tissue irradiated when respiratory gating was imposed during expiration with the amount of lung tissue irradiated when gating was imposed during inspiration. Our hypothesis was that the amount of lung tissue spared increased as inspiration increased. Computed tomography (CT) image data sets were acquired for 10 patients diagnosed with primary bronchogenic carcinoma. Data sets were acquired during free breathing, during breath‐holds at 0% tidal volume and 100% tidal volume, and, when possible, at deep inspiration corresponding to approximately 60% vital capacity. Two treatment plans were developed on the basis of each of the gated data sets: one in which the treatment portals were those of the free‐breathing plan, and the other in which the treatment portals were based on the gated planning target volumes. Dose‐mass histograms of the lungs calculated at 0% tidal volume were compared to those calculated at deep inspiration and at 100% tidal volume. Data extracted from the dose‐mass histograms were used to determine the most dosimetrically beneficial point to gate, the reduction in the amount of irradiated lung tissue that resulted from gating, and any disease characteristics that might predict a greater need for gating. The data showed a reduction in the mass of normal tissue irradiated when treatment portals based on the gated planning target volume were used. More normal lung tissue was spared at deep inspiration than at the other two gating points for all patients, but normal lung tissue was spared at every point in the respiratory cycle. No significant differences in the amount of irradiated tissue by disease characteristic were identified. Respiratory gating of thoracic radiation treatments can often improve the quality of the treatment plan, but it may not be possible to determine which patients may benefit from gating prior to performing the actual treatment planning. PACS numbers 87.53 –j; 87.53.Tf