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Publications and source records attributed to Ritsuko Komaki.
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PURPOSE: Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown. EXPERIMENTAL DESIGN: The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation. RESULTS: We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells. CONCLUSIONS: These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.
BACKGROUND: Esophageal and esophagogastric junction (EGJ) adenocarcinomas frequently have neuroendocrine (NE) differentiation, but the significance of NE differentiation in patients who have undergone preoperative chemoradiation and resection remains unclear. METHODS: The authors evaluated the presence of NE differentiation in esophageal and EGJ adenocarcinomas by immunohistochemistry for chromogranin A and synaptophysin and evaluated the clinical significance of NE differentiation in 83 patients (10 patients who had a complete tumor response and 73 patients who had residual tumor in resection specimens) who received preoperative chemoradiation. RESULTS: Of 73 patients who had residual tumor after preoperative treatment, 52% showed NE differentiation. The proportion of tumor cells with NE differentiation had increased from 6% +/- 18% in pretreatment biopsy specimens to 47% +/- 42% (P = .00003) in posttreatment resection specimens in 30 patients who had paired pretreatment biopsy and resection specimens available. Disease-free survival (P = .002) and overall survival (P = .006) were significantly better in patients who had a complete tumor response than in patients who had residual tumor. Among patients who had residual tumor after preoperative chemoradiation, disease-free survival (P = .03) and overall survival (P = .045) were significantly better in patients who had residual tumor without NE differentiation than in patients who had residual tumor with NE differentiation. In multivariate analysis, the presence of NE differentiation in residual tumor was a prognostic factor for worse disease-free survival (P = .02) independent of pathologic stage and extent of residual tumor. CONCLUSIONS: The results from this study suggested that tumor cells with NE differentiation were more resistant to neoadjuvant chemoradiation in patients with esophageal and EGJ adenocarcinomas. The presence of NE differentiation in residual tumor was associated with poor survival after preoperative neoadjuvant therapy.
PURPOSE: To investigate factors associated with treatment-related pneumonitis in non-small-cell lung cancer patients treated with concurrent chemoradiotherapy. PATIENTS AND METHODS: We retrospectively analyzed data from 223 patients treated with definitive concurrent chemoradiotherapy. Treatment-related pneumonitis was graded according to Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were performed to identify predictive factors. RESULTS: Median follow-up was 10.5 months (range, 1.4-58 months). The actuarial incidence of Grade > or =3 pneumonitis was 22% at 6 months and 32% at 1 year. By univariate analyses, lung volume, gross tumor volume, mean lung dose, and relative V5 through V65, in increments of 5 Gy, were all found to be significantly associated with treatment-related pneumonitis. The mean lung dose and rV5-rV65 were highly correlated (p < 0.0001). By multivariate analysis, relative V5 was the most significant factor associated with treatment-related pneumonitis; the 1-year actuarial incidences of Grade > or =3 pneumonitis in the group with V5 < or =42% and V5 >42% were 3% and 38%, respectively (p = 0.001). CONCLUSIONS: In this study, a number of clinical and dosimetric factors were found to be significantly associated with treatment-related pneumonitis. However, rV5 was the only significant factor associated with this toxicity. Until it is better understood which dose range is most relevant, multiple clinical and dosimetric factors should be considered in treatment planning for non-small-cell lung cancer patients receiving concurrent chemoradiotherapy.
PURPOSE: Cancer patients undergoing aggressive therapy suffer from multiple nonspecific treatment-related symptoms. The goal of this prospective study was to establish a profile of the development of different symptoms over the time of therapy and to examine symptom-related functional interference in patients with non-small-cell lung cancer (NSCLC) undergoing concurrent chemoradiation therapy (CXRT). PATIENTS AND METHODS: Patients with locally advanced unresectable (stage II-IIIB) NSCLC were recruited for the study (N = 64). The M.D. Anderson Symptom Inventory (MDASI) was used to measure multiple symptoms before and weekly for 12 weeks after the start of CXRT. Mixed-effect growth curve models were used to estimate symptom development during CXRT. RESULTS: Approximately 63% of patients suffered from moderate to severe levels of multiple symptoms by the end of CXRT. Symptom clusters with four development patterns appeared over the time of CXRT. With some variation between patients, all symptoms had a significant impact on the level of interference (all P < .001). Fatigue, distress, and sadness were the single strongest predictors of total symptom interference (each R2 > or = 0.49). Physical symptoms had greater impact on interference with function when they were moderate to severe, whereas affective symptoms had the largest effect on interference when they were mild to moderate. CONCLUSION: Longitudinal analysis identified symptom clusters that have different development patterns in NSCLC patients receiving CXRT, providing a base for more accurate symptom management and suggesting the need for further study to identify potential mechanisms that might lead to better symptom control or prevention.
AIM: To evaluate the dosimetry, efficacy and toxicity of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with locally advanced cervical and upper thoracic esophageal cancer. METHODS: A retrospective study was performed on 7 patients who were definitively treated with IMRT and concurrent chemotherapy. Patients who did not receive IMRT radiation and concurrent chemotherapy were not included in this analysis. IMRT plans were evaluated to assess the tumor coverage and normal tissue avoidance. Treatment response was evaluated and toxicities were assessed. RESULTS: Five- to nine-beam IMRT were used to deliver a total dose of 59.4-66 Gy (median: 64.8 Gy) to the primary tumor with 6-MV photons. The minimum dose received by the planning tumor volume (PTV) of the gross tumor volume boost was 91.2%-98.2% of the prescription dose (standard deviation [SD]: 3.7%-5.7%). The minimum dose received by the PTV of the clinical tumor volume was 93.8%-104.8% (SD: 4.3%-11.1%) of the prescribed dose. With a median follow-up of 15 mo (range: 3-21 mo), all 6 evaluable patients achieved complete response. Of them, 2 developed local recurrences and 2 had distant metastases, 3 survived with no evidence of disease. After treatment, 2 patients developed esophageal stricture requiring frequent dilation and 1 patient developed tracheal-esophageal fistula. CONCLUSION: Concurrent IMRT and chemotherapy resulted in an excellent early response in patients with locally advanced cervical and upper thoracic esophageal cancer. However, local and distant recurrence and toxicity remain to be a problem. Innovative approaches are needed to improve the outcome.
PURPOSE: The aim of this study was to investigate the effect of radiation dose distribution in the lung on the risk of postoperative pulmonary complications among esophageal cancer patients. METHODS AND MATERIALS: We analyzed data from 110 patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery at our institution from 1998 to 2003. The endpoint for analysis was postsurgical pneumonia or acute respiratory distress syndrome. Dose-volume histograms (DVHs) and dose-mass histograms (DMHs) for the whole lung were used to fit normal-tissue complication probability (NTCP) models, and the quality of fits were compared using bootstrap analysis. RESULTS: Normal-tissue complication probability modeling identified that the risk of postoperative pulmonary complications was most significantly associated with small absolute volumes of lung spared from doses > or = 5 Gy (VS5), that is, exposed to doses < 5 Gy. However, bootstrap analysis found no significant difference between the quality of this model and fits based on other dosimetric parameters, including mean lung dose, effective dose, and relative volume of lung receiving > or = 5 Gy, probably because of correlations among these factors. The choice of DVH vs. DMH or the use of fractionation correction did not significantly affect the results of the NTCP modeling. The parameter values estimated for the Lyman NTCP model were as follows (with 95% confidence intervals in parentheses): n = 1.85 (0.04, infinity), m = 0.55 (0.22, 1.02), and D50 = 17.5 Gy (9.4 Gy, 102 Gy). CONCLUSIONS: In this cohort of esophageal cancer patients, several dosimetric parameters including mean lung dose, effective dose, and absolute volume of lung receiving < 5 Gy provided similar descriptions of the risk of postoperative pulmonary complications as a function of the radiation dose distribution in the lung.
PURPOSE: This retrospective analysis was performed to assess the outcomes of three-dimensional (3D) conformal radiotherapy and two-dimensional (2D) planning. METHODS AND MATERIALS: Between 1978 and 2003, 200 patients with Stage I non-small-cell lung cancer (NSCLC) were treated with radiotherapy alone at M.D. Anderson Cancer Center. Eighty-five patients were treated with 3D conformal radiotherapy. For the 3D group, median age, radiation dose, and follow-up was 73 (range, 50-92), 66 Gy (range, 45-90.3 Gy), and 19 months (range, 3-77 months), respectively; and for the 2D group, 69 (range, 44-88), 64 Gy (range, 20-74 Gy), 20 months (range, 1-173 months), respectively. Overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) rates were analyzed. RESULTS: There was no statistically significant difference in patient and tumor characteristics between 2D and 3D groups, except the 3D patients were older (p = 0.006). The OS, DSS, and LRC rates were significantly higher in patients who were treated by 3D conformal radiotherapy. Two- and 5-year OS for the 3D group were 68% and 36%, respectively, and 47% and 10% in the 2D group (p = 0.001). DSS at 2 and 5 years for the 3D group were 83% and 68%, respectively, vs. 62% and 29% in the 2D group (p < 0.001). LRC rates at 2 and 5 years for patients in the 3D group were 77% and 70% and 53% and 34% in the 2D group (p < 0.001). On univariate analysis elective, nodal irradiation was associated with decreased OS, DSS, and LRC. On multivariate analysis, 3D conformal radiotherapy was associated with increased OS and DSS. Male sex, age > or =70, weight loss > or =5%, and tumor size > or =4 cm were associated with decreased OS and DSS. CONCLUSIONS: This study demonstrates that 3D conformal radiotherapy improves outcomes in patients with medically inoperable Stage I NSCLC compared with 2D treatment and is an acceptable treatment for this group of patients.
PURPOSE: Prophylactic cranial irradiation (PCI) has been shown to provide survival benefit in patients with limited disease small-cell lung cancer (LD-SCLC) who have achieved complete response. However, PCI may also produce long-term neurotoxicity (NT). The benefits and risks of PCI in LD-SCLC are evaluated. METHODS: We developed a decision-analytic model to compare quality-adjusted life expectancy (QALE) in a cohort of SCLC patients who do or do not receive PCI by varying survival rates and the frequency and severity of PCI-related NT. Sensitivity analyses were applied to examine the robustness of the optimal decision. RESULTS: At current published survival rates (26% 5-year survival rate with PCI and 22% without PCI) and a low NT rate, PCI offered a benefit over no PCI (QALE = 4.31 and 3.70 for mild NT severity; QALE = 4.09 and 3.70 for substantial NT severity, respectively). With a moderate NT rate, PCI was still preferred. If the PCI survival rate increased to 40%, PCI outperformed no PCI with a mild NT severity. However, no PCI was preferred over PCI (QALE = 5.72 v 5.47) with substantial NT severity. Two-way sensitivity analyses showed that PCI was preferred for low NT rates, mild NT severity, and low long-term survival rates. Otherwise, no PCI was preferred. CONCLUSION: The current data suggest PCI offers better QALE than no PCI in LD-SCLC patients who have achieved complete response. As the survival rate for SCLC patients continues to improve, NT rate and NT severity must be controlled to maintain a favorable benefit-risk ratio for recommending PCI.
PURPOSE: To determine the risk factors for acute esophagitis (AE) in non-small-cell lung cancer (NSCLC) patients treated with concurrent chemotherapy (CCT) and three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: Clinical data were retrospectively analyzed for 215 NSCLC patients treated with CCT and 3D-CRT during 2000-2003, 127 of whom also had induction chemotherapy (ICT). Carboplatin and paclitaxel were the most commonly used agents for both ICT and CCT. The median prescription dose of radiotherapy was 63.5 Gy in 35 fractions. AE was graded during each treatment week and 1-month follow-up visits. The factors related to clinical and disease characteristics, CCT and 3D-CRT treatments, and treatment planning were reviewed and analyzed for their association with Grade > or =3 AE using univariate and multivariate logistic tests. RESULTS: The rate of any grade AE was 93.0% and of Grade > or =3 was 20.5%. Univariate analyses showed that none of the clinical factors was significantly associated with Grade > or =3 AE. However, the mean radiation dose to the esophagus, the absolute esophageal volume treated above 15 Gy (aV15) through aV45 Gy, and the relative esophagus volume treated above 10 Gy (rV10) through rV45 Gy were significant risk factors for Grade > or =3 AE. Only rV20 was retained as the single risk factor in multivariate analyses. CONCLUSIONS: The risk of AE in the NSCLC patients treated with CCT and 3D-CRT was primarily determined by dosimetric factors. These factors should be carefully considered during treatment planning to minimize the incidence of AE.
PURPOSE: To compare dose-volume histograms (DVH) in patients with non-small-cell lung cancer (NSCLC) treated by photon or proton radiotherapy. METHODS AND MATERIALS: Dose-volume histograms were compared between photon, including three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and proton plans at doses of 66 Gy, 87.5 Gy in Stage I (n=10) and 60-63 Gy, and 74 Gy in Stage III (n=15). RESULTS: For Stage I, the mean total lung V5, V10, and V20 were 31.8%, 24.6%, and 15.8%, respectively, for photon 3D-CRT with 66 Gy, whereas they were 13.4%, 12.3%, and 10.9%, respectively, with proton with dose escalation to 87.5 cobalt Gray equivalents (CGE) (p=0.002). For Stage III, the mean total lung V5, V10, and V20 were 54.1%, 46.9%, and 34.8%, respectively, for photon 3D-CRT with 63 Gy, whereas they were 39.7%, 36.6%, and 31.6%, respectively, for proton with dose escalation to 74 CGE (p=0.002). In all cases, the doses to lung, spinal cord, heart, esophagus, and integral dose were lower with proton therapy even compared with IMRT. CONCLUSIONS: Proton treatment appears to reduce dose to normal tissues significantly, even with dose escalation, compared with standard-dose photon therapy, either 3D-CRT or IMRT.
BACKGROUND: Solitary brain metastases occur in about 50% of patients with brain metastases from nonsmall cell lung cancer (NSCLC). The standard of care is surgical resection of solitary brain metastases, or stereotactic radiosurgery (SRS) plus whole brain radiation therapy (WBRT). However, the optimal treatment for the primary site of newly diagnosed NSCLC with a solitary brain metastasis is not well defined. The goal was to distinguish which patients might benefit from aggressive treatment of their lung primary in patients whose solitary brain metastasis was treated with surgery or SRS. METHODS: The cases of 84 newly diagnosed NSCLC patients presenting with a solitary brain metastasis and treated from December 1993 through June 2004 were retrospectively reviewed at The University of Texas M. D. Anderson Cancer Center. All patients had undergone either craniotomy (n = 53) or SRS (n = 31) for management of the solitary brain metastasis. Forty-four patients received treatment of their primary lung cancer using thoracic radiation therapy (median dose 45 Gy; n = 8), chemotherapy (n = 23), or both (n = 13). RESULTS: The median Karnofsky performance status score was 80 (range, 60-100). Excluding the presence of the brain metastasis, 12 patients had AJCC Stage I primary cancer, 27 had Stage II disease, and 45 had Stage III disease. The median follow-up was 9.7 months (range, 1-86 months). The 1-, 2-, 3-, and 5-year overall survival rates from time of lung cancer diagnosis were 49.8%, 16.3%, 12.7%, and 7.6%, respectively. The median survival times for patients by thoracic stage (I, II, and III) were 25.6, 9.5, and 9.9 months, respectively (P = .006). CONCLUSIONS: By applying American Joint Committee on Cancer staging to only the primary site, the thoracic Stage I patients in our study with solitary brain metastases had a more favorable outcome than would be expected and was comparable to Stage I NSCLC without brain metastases. Aggressive treatment to the lung may be justified for newly diagnosed thoracic Stage I NSCLC patients with a solitary brain metastasis, but not for locally advanced NSCLC patients with a solitary brain metastasis.
PURPOSE: To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). METHODS AND MATERIALS: Adenoviral vector Ad/TRAIL-F/RGD with a tumor-specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed by Western blot, fluorescent activated cell sorting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate labeling (TUNEL) assay. A human esophageal adenocarcinoma mouse model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy. RESULTS: The combination of Ad/TRAIL-F/RGD and radiotherapy increased the cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 deoxyribonucleic acid accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, caspase-8, and caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase in vitro and TUNEL assay in vivo. Combined Ad/TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in the esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p < 0.05). CONCLUSIONS: The combination of tumor-specific TRAIL gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival.
Our goal was to develop a method for generating high-resolution three-dimensional pulmonary compliance images in rodents from computed tomography (CT) images acquired at a series of constant pressures in ventilated animals. One rat and one mouse were used to demonstrate this technique. A pre-clinical GE flat panel CT scanner (maximum 31 line-pairs cm(-1) resolution) was utilized for image acquisition. The thorax of each animal was imaged with breath-holds at 2, 6, 10, 14 and 18 cm H2O pressure in triplicate. A deformable image registration algorithm was applied to each pair of CT images to map corresponding tissue elements. Pulmonary compliance was calculated on a voxel by voxel basis using adjacent pairs of CT images. Triplicate imaging was used to estimate the measurement error of this technique. The 3D pulmonary compliance images revealed regional heterogeneity of compliance. The maximum total lung compliance measured 0.080 (+/-0.007) ml air per cm H2O per ml of lung and 0.039 (+/-0.004) ml air per cm H2O per ml of lung for the rat and mouse, respectively. In this study, we have demonstrated a unique method of quantifying regional lung compliance from 4 to 16 cm H2O pressure with sub-millimetre spatial resolution in rodents.
BACKGROUND: The current study tested the hypothesis that the clinical outcome of patients with localized esophageal carcinoma after preoperative chemoradiotherapy (CTRT) depends on histology. METHODS: The authors stratified patients by adenocarcinoma (ACA) or squamous cell carcinoma (SCC) and compared the overall survival (OS) and patterns of failure among patients achieving pathologic complete response (pathCR) and or=0.05). In the ACA group, a greater portion of <pathCR patients (32%) than pathCR patients (16%) had distant metastases (P=0.02) and the distant metastases-free survival of pathCR patients was longer than that of <pathCR patients (P=0.0012). In the SCC group, the proportion or time to distant-metastases did not differ significantly. Pretreatment clinical stage did not correlate with pathologic response for either histology. CONCLUSIONS: The results of the current study suggest that the clinical biology of SCC and ACA is different after CTRT. An investigation of molecular and patient genetics is needed to improve therapy.
A novel method for dynamic ventilation imaging of the full respiratory cycle from four-dimensional computed tomography (4D CT) acquired without added contrast is presented. Three cases with 4D CT images obtained with respiratory gated acquisition for radiotherapy treatment planning were selected. Each of the 4D CT data sets was acquired during resting tidal breathing. A deformable image registration algorithm mapped each (voxel) corresponding tissue element across the 4D CT data set. From local average CT values, the change in fraction of air per voxel (i.e. local ventilation) was calculated. A 4D ventilation image set was calculated using pairs formed with the maximum expiration image volume, first the exhalation then the inhalation phases representing a complete breath cycle. A preliminary validation using manually determined lung volumes was performed. The calculated total ventilation was compared to the change in contoured lung volumes between the CT pairs (measured volume). A linear regression resulted in a slope of 1.01 and a correlation coefficient of 0.984 for the ventilation images. The spatial distribution of ventilation was found to be case specific and a 30% difference in mass-specific ventilation between the lower and upper lung halves was found. These images may be useful in radiotherapy planning.
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BACKGROUND: The purpose of the current study was to test the hypothesis that a lower clinical TNM stage is associated with a higher rate of pathologic complete response (pathCR) in patients with esophageal carcinoma receiving preoperative chemoradiotherapy and to determine whether outcome after pathCR is related to clinical stage or treatment. METHODS: Clinical parameters and surgical specimens of patients with esophageal carcinoma undergoing preoperative chemoradiotherapy were analyzed to identify predictors of pathCR. In patients with pathCR, predictors of overall survival (OS), disease-free survival (DFS), and distant recurrence were studied. RESULTS: Sixty-nine (29%) of 235 patients achieved pathCR. In patients with American Joint Committee on Cancer (AJCC) Stage II carcinoma, the proportion achieving pathCR was significantly larger than that achieving <pathCR (65% vs. 35%; P = 0.03). The proportion of patients who received induction chemotherapy was higher in the pathCR group than in the <pathCR group (54% vs. 46%; P = 0.05). However, neither TNM classification, primary tumor location, histologic type, gender, therapy sequence, or radiation dose (45 grays [Gy] vs. 50.4 Gy) were found to have any influence on OS or DFS. The median OS from pathCR was significantly longer than that from <pathCR (133 mos vs. 34 mos; P = 0.002). Similarly, DFS was longer in the pathCR group than in the <pathCR (P = 0.001). CONCLUSIONS: Patients with clinical AJCC Stage II esophageal carcinoma are more likely to achieve a pathCR after preoperative chemoradiotherapy than are those with Stage III carcinoma. Chemoradiotherapy as primary therapy for patients with Stage I esophageal carcinoma warrants investigation as a means to preserve their esophagus.