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Raymond H Mak,
Brian M Alexander,
Kofi Asomaning,
Rebecca S Heist,
Chen-yu Liu,
Li Su,
Rihong Zhai,
Marek Ancukiewicz,
Brian Napolitano,
Andrzej Niemierko,
Henning Willers,
Noah C Choi,
David C Christiani
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ABSTRACT: This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.
A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.
With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.
This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
Cancer 12/2011; 118(14):3654-65. · 4.77 Impact Factor
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ABSTRACT: The addition of neoadjuvant chemoradiotherapy prior to surgical resection for esophageal cancer has improved clinical outcomes in some trials. Pathologic complete response (pCR) following neoadjuvant therapy is associated with better clinical outcome in these patients, but only 22% to 40% of patients achieve pCR. Because both chemotherapy and radiotherapy act by inducing DNA damage, we analyzed proteins selected from multiple DNA repair pathways, using quantitative immunohistochemistry coupled with a digital pathology platform, as possible biomarkers of treatment response and clinical outcome.
We identified 79 patients diagnosed with esophageal cancer between October 1994 and September 2002, with biopsy tissue available, who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsy samples to create tissue microarrays (TMA). TMA sections were stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1, and phosphorylated MAPKAP kinase 2 (pMK2). Stained TMA slides were evaluated using machine-based image analysis, and scoring incorporated both the intensity and the quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with clinical outcome.
Higher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. Staining of MLH1, PARP1, XPF, and PAR was associated with recurrence-free survival, and staining of PARP1 and FANCD2 was associated with overall survival on multivariable analysis.
DNA repair proteins analyzed by immunohistochemistry may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. These results are hypothesis generating and need confirmation in an independent data set.
International journal of radiation oncology, biology, physics 10/2011; 83(1):164-71. · 4.59 Impact Factor
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ABSTRACT: To characterize patterns in incidence, management, and costs of malignant spinal cord compression (MSCC) hospitalizations in the United States, using population-based data.
Using the Nationwide Inpatient Sample, an all-payer healthcare database representative of all U.S. hospitalizations, MSCC-related hospitalizations were identified for the period 1998-2006. Cases were combined with age-adjusted Surveillance, Epidemiology and End Results cancer death data to estimate annual incidence. Linear regression characterized trends in patient, treatment, and hospital characteristics, costs, and outcomes. Logistic regression was used to examine inpatient treatment (radiotherapy [RT], surgery, or neither) by hospital characteristics and year, adjusting for confounding.
We identified 15,367 MSCC-related cases, representing 75,876 hospitalizations. Lung cancer (24.9%), prostate cancer (16.2%), and multiple myeloma (11.1%) were the most prevalent underlying cancer diagnoses. The annual incidence of MSCC hospitalization among patients dying of cancer was 3.4%; multiple myeloma (15.0%), Hodgkin and non-Hodgkin lymphomas (13.9%), and prostate cancer (5.5%) exhibited the highest cancer-specific incidence. Over the study period, inpatient RT for MSCC decreased (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.61-0.81), whereas surgery increased (OR 1.48, 95% CI 1.17-1.84). Hospitalization costs for MSCC increased (5.3% per year, p < 0.001). Odds of inpatient RT were greater at teaching hospitals (OR 1.41, 95% CI 1.19-1.67), whereas odds of surgery were greater at urban institutions (OR 1.82, 95% CI 1.29-2.58).
In the United States, patients dying of cancer have an estimated 3.4% annual incidence of MSCC requiring hospitalization. Inpatient management of MSCC varied over time and by hospital characteristics, with hospitalization costs increasing. Future studies are required to determine the impact of treatment patterns on MSCC outcomes and strategies for reducing MSCC-related costs.
International journal of radiation oncology, biology, physics 07/2011; 80(3):824-31. · 4.59 Impact Factor
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ABSTRACT: To compare (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging characteristics in non-small cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutations.
We retrospectively identified NSCLC patients who underwent EGFR mutation testing and pretreatment FDG-PET and CT scans. The maximum standard uptake value (SUV(max)) of the primary tumor and any metastases was measured and normalized to the SUV of blood in the pulmonary artery. We compared normalized SUV(max) values between EGFR-mutant and wild-type patients and modeled radiographic and clinical predictors of EGFR mutation status. Receiver operator characteristic (ROC) curves were used to identify potential SUV cutoffs predictive of genotype.
We included 100 patients (24 EGFR-mutant and 76 wild-type). There was a trend for higher normalized SUV(max) in the primary tumors among patients with EGFR-wild-type versus mutant (median, 3.4; range, 0.6-12.8; versus median, 2.9; range, 0.4-5.0; p = .09). Normalized SUV(max) of nodal and distant metastases, and CT characteristics were not associated with genotype. On multivariate analysis, low normalized SUV(max) of the primary tumor was predictive for EGFR mutation (odds ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .034). ROC curve analyses yielded an area under the curve of 0.62, and identified a potential cutoff of ≥ 5.0 to distinguish wild-type from mutant tumors.
In this retrospective study, high FDG avidity (normalized SUV(max) ≥ 5) correlated with EGFR-wild-type genotype. Although genotyping remains the gold standard, further work to validate FDG-PET as a surrogate for tumor genotype may provide useful information in patients without available tumor tissue.
The Oncologist 02/2011; 16(3):319-26. · 3.91 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) mutations identify a unique biological subtype of non-small cell lung cancer (NSCLC). Treatment outcomes for EGFR-mutant locally advanced NSCLC patients have not been well described.
We retrospectively examined outcomes after combined modality therapy including thoracic radiation therapy (RT) in 123 patients with locally advanced NSCLC and known EGFR mutation status. Outcomes were compared using Kaplan-Meier analysis, the log-rank test, and multivariate Cox regression models.
All 123 patients underwent thoracic RT; 25% had tumors with EGFR mutations and 94% had stage III disease. Overall, 81% received chemotherapy concurrent with RT and 55% underwent surgical resection. With a median follow-up of 27.5 months, the overall survival (OS) rate was significantly higher in patients with EGFR-mutant tumors than in those with wild-type EGFR tumors (2-year estimate: 92.6% versus 69.0%; p = .04). The 2-year relapse-free survival and distant recurrence rates did not differ significantly by genotype. The 2-year locoregional recurrence rate (LRR) was significantly lower in EGFR-mutant than in wild-type EGFR patients (17.8% versus 41.7%; p = .005). EGFR-mutant genotype was associated with a lower risk for LRR on multivariate analysis, but not OS, after adjusting for surgery and other potential confounders.
We observed that EGFR-mutant patients with locally advanced NSCLC treated with RT had lower rates of LRR than wild-type EGFR patients, raising the hypothesis that EGFR mutations may confer sensitivity to RT and/or chemotherapy. The association between mutation status and OS after combined modality therapy was less robust. Our data may serve as a useful baseline estimate of outcomes by EGFR genotype for future prospective studies.
The Oncologist 01/2011; 16(6):886-95. · 3.91 Impact Factor
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ABSTRACT: To compare outcomes in patients with squamous cell carcinoma (SCC) of the vulva treated with radiation (RT) and concurrent weekly platinum-based or every-3-4-week regimens containing 5-fluorouracil (5-FU).
Records of 44 patients with vulvar SCC treated with concurrent chemotherapy and radiation (chemoRT) from 1988 to 2008 were reviewed. Rates of disease-free survival (DFS), overall survival (OS), locoregional recurrence (LRR), and distant metastases (DM) were estimated using the Kaplan-Meier method.
The median age was 63 years (range, 44-90), 84.1% of patients had ECOG performance status 0-1, and patients had FIGO Stage II (n=6), III (n=31), or IVA (n=7) disease. Patients were treated preoperatively (n=10), postoperatively (n=10), or without surgery (n=24). The median RT dose to the vulva was 50.2 Gray (range, 22-75). Concurrent chemotherapy regimens included weekly platinum (n=16) or every 3-4 week regimens with 5-FU as the backbone (n=28). With a median follow-up of 31.5 months, there was no significant difference in 2-year OS (74.5% vs. 70.0%; p=0.65), DFS (61.9% vs. 56.0%; p=0.85), LRR (31.3% vs. 32.9%; p=0.93), or DM (6.3% vs. 10.6%; p=0.81) between the weekly platinum and every-3-4-week 5-FU regimens. Twenty patients (45.4%) recurred: 16 LRR, 2 DM, and 2 with both. The clinical and pathologic complete response rates were 58.8% (20/34), and 53.8% (14/26), respectively. There was a higher proportion of grade 3 or higher acute non-skin toxicities in patients receiving every-3-4-week 5-FU (46.1% vs. 13.3%; p=0.07), but more grade 3 or higher skin toxicity in patients receiving weekly platinum (62.5% vs. 32.0%; p=0.01).
OS, response rates, and recurrence rates were not significantly different after RT with concurrent weekly platinum-based versus every-3-4-week regimens containing 5-FU for vulvar SCC.
Gynecologic Oncology 10/2010; 120(1):101-7. · 3.89 Impact Factor
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ABSTRACT: The German rectal study determined that preoperative radiation therapy (RT) as a component of combined-modality therapy decreased local tumor recurrence, increased sphincter preservation, and decreased treatment toxicity compared with postoperative RT for rectal cancer. We evaluated the use of preoperative RT after the presentation of the landmark German rectal study results and examined the impact of tumor and sociodemographic factors on receiving preoperative RT.
In total, 20,982 patients who underwent surgical resection for T3-T4 and/or node-positive rectal adenocarcinoma diagnosed from 2000 through 2006 were identified from the Surveillance, Epidemiology, and End Results tumor registries. We analyzed trends in preoperative RT use before and after publication of the findings from the German rectal study. We also performed multivariate logistic regression to identify factors associated with receiving preoperative RT.
Among those treated with RT, the proportion of patients treated with preoperative RT increased from 33.3% in 2000 to 63.8% in 2006. After adjustment for age; gender; race/ethnicity; marital status; Surveillance, Epidemiology, and End Results registry; county-level education; T stage; N stage; tumor size; and tumor grade, there was a significant association between later year of diagnosis and an increase in preoperative RT use (adjusted odds ratio, 1.26/y increase; 95% confidence interval, 1.23-1.29). When we compared the years before and after publication of the German rectal study (2000-2003 vs. 2004-2006), patients were more likely to receive preoperative RT than postoperative RT in 2004-2006 (adjusted odds ratio, 2.35; 95% confidence interval, 2.13-2.59). On multivariate analysis, patients who were older, who were female, and who resided in counties with lower educational levels had significantly decreased odds of receiving preoperative RT.
After the publication of the landmark German rectal study, there was widespread, rapid adoption of preoperative RT for locally advanced rectal cancer. However, preoperative RT may be underused in certain sociodemographic groups.
International journal of radiation oncology, biology, physics 10/2010; 80(4):978-84. · 4.59 Impact Factor
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ABSTRACT: While radical cystectomy (RC) remains the standard of care for muscle-invasive transitional cell carcinoma of the bladder, a series of single-institution and cooperative-group trials with a long-term follow-up have shown that combined modality therapy for bladder preservation can provide selected patients with an excellent chance for long-term survival with an intact, functioning bladder. Strategies for preserving the bladder have developed over the past 20 years, with continued refinements in radiation therapy, chemotherapy and patient selection. The hallmarks of modern bladder-preserving therapy include: (i) careful patient selection; (ii) combined therapy with maximum transurethral resection of bladder tumour, radiation and concurrent chemotherapy; (iii) cystoscopic assessment of the response to therapy with prompt salvage cystectomy for nonresponders; (iv) careful follow-up with cystoscopic surveillance and prompt cystectomy for invasive recurrence. Contemporary bladder-preserving approaches in patients with clinically staged muscle-invasive bladder cancer can achieve complete response rates of 60-85%, 5-year survival rates of 50-60%, and survival rates with an intact bladder of 40-45%. Although there are no randomized studies comparing RC with combined therapies for bladder preservation, long-term data show that overall and disease-specific survival rates in contemporary RC series of clinically staged patients with T2-T4a bladder cancer are comparable to those of bladder-preserving protocols. Thus, combined modality therapy for bladder preservation has become a safe, tested and effective alternative to RC in selected patients with muscle-invasive bladder cancer who desire to keep their bladders. Future work will continue to refine the bladder-preserving approach to improve survival and local control.
BJU International 12/2008; 102(9 Pt B):1345-53. · 2.84 Impact Factor
