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Browsing by Author "Kong, Feng-Ming"
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Item Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer(American Medical Association, 2017-10-01) Kong, Feng-Ming; Ten Haken, Randall K.; Schipper, Matthew; Frey, Kirk A.; Hayman, James; Gross, Milton; Ramnath, Nithya; Hassan, Khaled A.; Matuszak, Martha; Ritter, Timothy; Bi, Nan; Wang, Weili; Orringer, Mark; Cease, Kemp B.; Lawrence, Theodore S.; Kalemkerian, Gregory P.; Radiation Oncology, School of MedicineIMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01190527Item Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy(Elsevier, 2018) Shiue, Kevin; Cerra-Franco, Alberto; Shapiro, Ronald; Estabrook, Neil; Mannina, Edward M.; Deig, Christopher R.; Althouse, Sandra; Liu, Sheng; Wan, Jun; Zang, Yong; Agrawal, Namita; Ioannides, Pericles; Liu, Yongmei; Zhang, Chen; DesRosiers, Colleen; Bartlett, Greg; Ewing, Marvene; Langer, Mark P.; Watson, Gordon; Zellars, Richard; Kong, Feng-Ming; Lautenschlaeger, Tim; Radiation Oncology, School of MedicineIntroduction It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. Results At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.Item Long-term outcomes of replanning during intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: An updated and expanded retrospective analysis(Elsevier, 2022-05) Zhou, Xiate; Wang, Wei; Zhou , Chao; Zhu , Jian; Ding , Weijun; Chen, Meng; Chen, Kuifei; Shi, Yangyang; Chen , Xiaofeng; Kong, Feng-Ming; Yang , Haihua; Radiation Oncology, School of MedicineBackground and purpose Recent studies show that adaptive replanning for patients with nasopharyngeal carcinoma (NPC) during intensity-modulated radiation therapy (IMRT) improve the short-term local–regional recurrence-free survival (LRFS), and quality of life (QoL). We aimed to assess the long-term survival outcomes and QoL in patients with non-metastatic NPC who received IMRT with replanning compared to those who received IMRT without replanning. Methods and materials We conducted an updated and expanded retrospective analysis from an existing prospective cohort for non-metastatic NPC patients undergoing IMRT in our institution. Non-metastatic NPC patients receiving IMRT from June 2007 to December 2015 were consecutively enrolled based on electronic medical record. Patients who were still alive were eligible for the QoL study. The survival outcomes and QoL were compared between patients with and without replanning. Results Among 290 patients, 147 (50.7%) received IMRT without replanning and 143 (49.3%) received IMRT with replanning. Replanning group had a higher 8-year LRFS rate (87.4% vs. 75.6%, P = 0.025). However, 8-year overall survival rate was not statistically significant. Patients with replanning compared to those who without replanning had significant improvements in social functioning (P = 0.016), insomnia (P = 0.048), dry mouth (P = 0.004), and sticky saliva (P = 0.005). Additionally, the score of the role functioning was marginally higher in patients treated with IMRT replanning (P = 0.063). Conclusion This extended follow-up study demonstrates the long-term security and validity for adaptive radiotherapy in IMRT for non-metastatic NPC patients. We highly recommend that adaptive replanning should be routinely implemented for non-metastatic NPC patients.Item A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer(Elsevier, 2018-03) Wang, Shulian; Campbell, Jeff; Stenmark, Matthew H.; Stanton, Paul; Zhao, Jing; Matuszak, Martha M.; Ten Haken, Randall K.; Kong, Feng-Ming; Radiation Oncology, School of MedicineBackground and purpose To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. Materials and methods A total of 129 patients with stage I-III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. Results Forty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE (p <0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019). Conclusions Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted.Item A Multi-Objective Bayesian Networks Approach for Joint Prediction of Tumor Local Control and Radiation Pneumonitis in Non-Small-Cell Lung Cancer (NSCLC) for Response-Adapted Radiotherapy(Wiley, 2018) Luo, Yi; McShan, Daniel L.; Matuszak, Martha M.; Ray, Dipankar; Lawrence, Thodore S.; Jolly, Shruti; Kong, Feng-Ming; Ten Haken, Randall K.; El Naqa, Issam; Radiation Oncology, School of MedicinePurpose Individualization of therapeutic outcomes in NSCLC radiotherapy is likely to be compromised by the lack of proper balance of biophysical factors affecting both tumor local control (LC) and side effects such as radiation pneumonitis (RP), which are likely to be intertwined. Here, we compare the performance of separate and joint outcomes predictions for response‐adapted personalized treatment planning. Methods A total of 118 NSCLC patients treated on prospective protocols with 32 cases of local progression and 20 cases of RP grade 2 or higher (RP2) were studied. Sixty‐eight patients with 297 features before and during radiotherapy were used for discovery and 50 patients were reserved for independent testing. A multiobjective Bayesian network (MO‐BN) approach was developed to identify important features for joint LC/RP2 prediction using extended Markov blankets as inputs to develop a BN predictive structure. Cross‐validation (CV) was used to guide the MO‐BN structure learning. Area under the free‐response receiver operating characteristic (AU‐FROC) curve was used to evaluate joint prediction performance. Results Important features including single nucleotide polymorphisms (SNPs), micro RNAs, pretreatment cytokines, pretreatment PET radiomics together with lung and tumor gEUDs were selected and their biophysical inter‐relationships with radiation outcomes (LC and RP2) were identified in a pretreatment MO‐BN. The joint LC/RP2 prediction yielded an AU‐FROC of 0.80 (95% CI: 0.70–0.86) upon internal CV. This improved to 0.85 (0.75–0.91) with additional two SNPs, changes in one cytokine and two radiomics PET image features through the course of radiotherapy in a during‐treatment MO‐BN. This MO‐BN model outperformed combined single‐objective Bayesian networks (SO‐BNs) during‐treatment [0.78 (0.67–0.84)]. AU‐FROC values in the evaluation of the MO‐BN and individual SO‐BNs on the testing dataset were 0.77 and 0.68 for pretreatment, and 0.79 and 0.71 for during‐treatment, respectively. Conclusions MO‐BNs can reveal possible biophysical cross‐talks between competing radiotherapy clinical endpoints. The prediction is improved by providing additional during‐treatment information. The developed MO‐BNs can be an important component of decision support systems for personalized response‐adapted radiotherapy.Item Predictors of Nodal and Metastatic Failure in Early Stage Non-Small Cell Lung Cancer after Stereotactic Body Radiation Therapy(Elsevier, 2019) Cerra-Franco, Alberto; Liu, S.; Azar, M.; Shiue, Kevin; Freije, S.; Hinton, J.; Deig, Christopher R.; Edwards, D.; Estabrook, Neil C.; Ellsworth, S. G.; Huang, K.; Diab, K.; Langer, Mark P.; Zellars, Richard; Kong, Feng-Ming; Wan, Jun; Lautenschlaeger, Tim; Radiation Oncology, School of MedicineIntroduction/Background Many early-stage non-small cell lung cancer (ES-NSCLC) patients undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. Materials and Methods We included 363 patients with ES-NSCLC who received SBRT; median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): sex; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. Results A total of 111/406 (27.3%) lesions metastasized. GTV volume and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (p<0.001 and HR=1.02 per mL, p<0.05 and HR=0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV volume and prescription dose was built: [risk score=(0.01611 x GTV)–(0.00525 x dose (BED10))]. Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk-score identified significant differences in time to metastases between low-, medium-, and high-risk patients (p<0.001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. Conclusion GTV volume and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.Item Principal component analysis identifies patterns of cytokine expression in non-small cell lung cancer patients undergoing definitive radiation therapy(PLOS, 2017-09-21) Ellsworth, Susannah G.; Rabatic, Bryan M.; Chen, Jie; Zhao, Jing; Campbell, Jeffrey; Wang, Weili; Pi, Wenhu; Stanton, Paul; Matuszak, Martha; Jolly, Shruti; Miller, Amy; Kong, Feng-Ming; Radiation Oncology, School of MedicineBackground/Purpose Radiation treatment (RT) stimulates the release of many immunohumoral factors, complicating the identification of clinically significant cytokine expression patterns. This study used principal component analysis (PCA) to analyze cytokines in non-small cell lung cancer (NSCLC) patients undergoing RT and explore differences in changes after hypofractionated stereotactic body radiation therapy (SBRT) and conventionally fractionated RT (CFRT) without or with chemotherapy. Methods The dataset included 141 NSCLC patients treated on prospective clinical protocols; PCA was based on the 128 patients who had complete CK values at baseline and during treatment. Patients underwent SBRT (n = 16), CFRT (n = 18), or CFRT (n = 107) with concurrent chemotherapy (ChRT). Levels of 30 cytokines were measured from prospectively collected platelet-poor plasma samples at baseline, during RT, and after RT. PCA was used to study variations in cytokine levels in patients at each time point. Results Median patient age was 66, and 22.7% of patients were female. PCA showed that sCD40l, fractalkine/C3, IP10, VEGF, IL-1a, IL-10, and GMCSF were responsible for most variability in baseline cytokine levels. During treatment, sCD40l, IP10, MIP-1b, fractalkine, IFN-r, and VEGF accounted for most changes in cytokine levels. In SBRT patients, the most important players were sCD40l, IP10, and MIP-1b, whereas fractalkine exhibited greater variability in CFRT alone patients. ChRT patients exhibited variability in IFN-γ and VEGF in addition to IP10, MIP-1b, and sCD40l. Conclusions PCA can identify potentially significant patterns of cytokine expression after fractionated RT. Our PCA showed that inflammatory cytokines dominate post-treatment cytokine profiles, and the changes differ after SBRT versus CFRT, with vs without chemotherapy. Further studies are planned to validate these findings and determine the clinical significance of the cytokine profiles identified by PCA.Item Survival impact of postoperative therapy modalities according to margin status in non–small cell lung cancer patients in the United States(Elsevier, 2017) Smeltzer, Matthew P.; Lin, Chun Chieh; Kong, Feng-Ming; Jemal, Ahmedin; Osarogiagbon, Raymond U.; Department of Radiation Oncology, IU School of MedicineObjective Unlike complete (R0) resection guidelines, current National Comprehensive Cancer Network (NCCN) adjuvant therapy guidelines after incomplete (R1/R2) resection of non–small cell lung cancer (NSCLC) are based on low-level evidence. We attempted to validate them. Methods Patients with pathologic stage I-IIIA NSCLC from 2004 to 2011 in the National Cancer Database were stratified by margin status, NCCN-specified stage groupings, and adjuvant therapy exposure (none, radiotherapy, chemotherapy, or both). Five-year overall survival (OS) and hazard ratios, adjusted for patient and institutional characteristics, were compared. We used a parallel analysis of R0 resections to validate our methodology. Results We analyzed 3461 R1/R2, and 78,979 R0 resections. After R0 resection, the NCCN-recommended option was associated with the best survival across all stage groups, supporting our analytic approach. Patients with R1/R2 stage IA treated with radiation had a 26% OS, compared with 58% with no treatment (P = .003). In patients with stage IB/IIA(N0) R1/R2, radiation was associated with a 25% OS compared with 47% with no treatment (P = .025) and 62% with chemotherapy (P < .007). Chemoradiation was not associated with a survival benefit in either group. Patients with IIA(N1)/IIB and IIIA had better survival with chemotherapy or chemoradiation. No group had a survival benefit with radiation alone. Conclusions NCCN adjuvant therapy guidelines after complete resection, based on high-level evidence, are validated, but not guidelines for patients with incompletely resected early-stage NSCLC, which are based on low-level evidence. Monomodality postoperative radiotherapy was not validated for any stage. Specific studies are needed to determine optimal management after incomplete resection.