Latest Articles Include:
- Adult survivors of childhood and adolescent cancer have more heart disease
- Cancer (Philad ) 116(11):2507 (2010)
- Phase 3 study of immunotherapy to treat advanced prostate cancer
- Cancer (Philad ) 116(11):2507 (2010)
- Patterns of questionable quality care in nonmuscle invasive bladder cancer
Gore JL Porter MP - Cancer (Philad ) 116(11):2508-2510 (2010)
Understanding those factors associated with the rising cost of bladder cancer care may inform guidelines dedicated to defining the best bladder cancer practices. In the care of noninvasive bladder cancer patients, we have yet to define the services that are being underutilized or overutilized. - Impact of chemotherapy on quality of life in patients with metastatic esophagogastric cancer
Al-Batran SE Ajani JA - Cancer (Philad ) 116(11):2511-2518 (2010)
BACKGROUND: Health-related quality of life (HRQoL) is a key issue in patients with metastatic esophagogastric cancer, a disease associated with survival times rarely exceeding 10 months. The objective of the current review was to evaluate the effects of chemotherapy on the HRQoL of patients with metastatic or locally advanced, inoperable esophagogastric cancer. METHODS: A systematic MEDLINE search was performed to address a predefined question list: Does chemotherapy improve or maintain HRQoL? Do available data favor a particular chemotherapy? What relation exists between HRQoL and the efficacy and tolerability of therapy? RESULTS: The majority of studies, including large randomized studies, indicated no significant improvements in mean HRQoL scores versus baseline after chemotherapy. However, scores were maintained and symptomatic relief or improved performance status was observed in many patients. HRQoL was maintained in approximately 50% of patients for up to 6 months but deteriorated in the remaining patients. In randomized phase 3 trials, only cisplatin/fluorouracil plus either docetaxel or epirubicin were found to provide superior HRQoL versus comparators. Between-regimen differences in HRQoL scores appeared to correspond to differences in the efficacy rather than the toxicity of treatment regimens. CONCLUSIONS: Chemotherapy maintained HRQoL in a substantial proportion of patients with advanced esophagogastric cancer. This effect appeared to correspond to the efficacy of the treatment. Cancer 2010. © 2010 American Cancer Society. - Human mesenchymal stem cells and their use in cell-based therapies
Motaln H Schichor C Lah TT - Cancer (Philad ) 116(11):2519-2530 (2010)
The human population is increasingly facing various diseases, including types of cancer, that cannot be cured with conventional drugs. Advanced drug targeting of tumor cells is also often impossible when treating highly invasive and infiltrative tumors such as glioblastoma or pulmonary cancer, because of tumor cells' high migration and invasiveness. Pluripotent human mesenchymal stem cells (hMSCs) have been extensively studied, and strategies are being proposed for treating incurable cancers and injury/disease-affected organs. Because of their own intrinsic properties, involving homing and immunomodulatory potency, hMSCs could be used as an excellent cell/drug delivery vehicle in those cell-based therapies. Their unprecedented use has been shadowed, however, by their spontaneous transformation, which links them to cancer-initiating cells during tumor development. How malignant initiation proceeds in vivo, and what are the exact characteristics of the cancer-initiating ! cells, still remain to be investigated. In the present review, the authors summed up the most recent knowledge about hMSC characteristics, their malignant transformation, and outlined the possibilities of their safe use in novel cell-based therapies. Cancer 2010. © 2010 American Cancer Society. - Cervical cancer prevention : New tools and old barriers
Scarinci IC Garcia FA Kobetz E Partridge EE Brandt HM Bell MC Dignan M Ma GX Daye JL Castle PE - Cancer (Philad ) 116(11):2531-2542 (2010)
Cervical cancer is the second most common female tumor worldwide, and its incidence is disproportionately high (>80%) in the developing world. In the United States, in which Papanicolaou (Pap) tests have reduced the annual incidence to approximately 11,000 cervical cancers, >60% of cases are reported to occur in medically underserved populations as part of a complex of diseases linked to poverty, race/ethnicity, and/or health disparities. Because carcinogenic human papillomavirus (HPV) infections cause virtually all cervical cancer, 2 new approaches for cervical cancer prevention have emerged: 1) HPV vaccination to prevent infections in younger women (aged 18 years) and 2) carcinogenic HPV detection in older women (aged 30 years). Together, HPV vaccination and testing, if used in an age-appropriate manner, have the potential to transform cervical cancer prevention, particularly among underserved populations. Nevertheless, significant barriers of access, acceptability, ! and adoption to any cervical cancer prevention strategy remain. Without understanding and addressing these obstacles, these promising new tools for cervical cancer prevention may be futile. In the current study, the delivery of cervical cancer prevention strategies to these US populations that experience a high cervical cancer burden (African-American women in South Carolina, Alabama, and Mississippi; Haitian immigrant women in Miami; Hispanic women in the US-Mexico Border; Sioux/Native American women in the Northern Plains; white women in the Appalachia; and Vietnamese-American women in Pennsylvania and New Jersey) is reviewed. The goal was to inform future research and outreach efforts to reduce the burden of cervical cancer in underserved populations. Cancer 2010. © 2010 American Cancer Society. - A phase I study to assess the feasibility and oncologic safety of axillary reverse mapping in breast cancer patients
Bedrosian I Babiera GV Mittendorf EA Kuerer HM Pantoja L Hunt KK Krishnamurthy S Meric-Bernstam F - Cancer (Philad ) 116(11):2543-2548 (2010)
BACKGROUND: Axillary reverse mapping (ARM) is a novel technique to preserve upper extremity lymphatics that may reduce the incidence of lymphedema after axillary lymph node dissection. Early reports have suggested that ARM lymph nodes do not contain metastatic disease from breast cancer; however, these studies were conducted in early stage patients with low likelihood of lymph node metastasis. This study reported a phase 1 trial conducted in patients with cytologically documented axillary metastasis undergoing axillary lymph node dissection to determine the feasibility and oncologic safety of ARM. METHODS: Thirty patients, 23 (77%) of whom received preoperative therapy (chemotherapy in 22 patients and hormonal therapy in 1 patient), were enrolled. Blue dye was injected in the upper inner ipsilateral arm. The presence of blue lymphatics was noted, and blue lymph nodes were sent separately for pathologic evaluation. RESULTS: The average time between blue dye injection and axillary exposure was 35 minutes (range, 15-60 minutes). Blue lymphatics were identified in 21 patients (70%) and blue lymph nodes in 15 patients (50%). The median number of ARM lymph nodes was 1 (range, 0-3 lymph nodes) and the median number of axillary lymph nodes was 26 (range, 6-47 lymph nodes). Axillary metastases were noted in 60% (18 of 30) of patients. Of 11 patients who had axillary metastasis and at least 1 ARM lymph node identified, 2 (18%) had metastasis to the ARM lymph node. CONCLUSIONS: ARM appears to be a feasible technique with which to identify upper arm lymphatics during axillary surgery. However, the high prevalence of disease involving ARM lymph nodes in this small cohort suggested that preservation of these lymphatics is not oncologically safe in women with documented axillary lymph node metastasis from breast cancer. Cancer 2010. © 2010 American Cancer Society. - Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes : A population-based study and first report
Lund MJ Butler EN Hair BY Ward KC Andrews JH Oprea-Ilies G Bayakly AR O'Regan RM Vertino PM Eley JW - Cancer (Philad ) 116(11):2549-2559 (2010)
BACKGROUND: Although US year 2000 guidelines recommended characterizing breast cancers by human epidermal growth factor receptor 2 (HER2), national cancer registries do not collect HER2, rendering a population-based understanding of HER2 and clinical triple subtypes (estrogen receptor [ER] / progesterone receptor [PR] / HER2) largely unknown. We document the population-based prevalence of HER2 testing / status, triple subtypes and present the first report of subtype incidence rates. METHODS: Medical records were searched for HER2 on 1842 metropolitan Atlanta females diagnosed with breast cancer during 2003-2004. HER2 testing/status and triple subtypes were analyzed by age, race/ethnicity, tumor factors, socioeconomic status, and treatment. Age-adjusted incidence rates were calculated. RESULTS: Over 90% of cases received HER2 testing: 12.6% were positive, 71.7% negative, and 15.7% unknown. HER2 testing compliance was significantly better for women who were younger, of Caucasian or African-American descent, or diagnosed with early stage disease. Incidence rates (per 100,000) were 21.1 for HER2+ tumors and 27.8 for triple-negative tumors, the latter differing by race (36.3 and 19.4 for black and white women, respectively). CONCLUSIONS: HER2 recommendations are not uniformly adhered to. Incidence rates for breast cancer triple subtypes differ by age/race. As biologic knowledge is translated into the clinical setting eg, HER2 as a biomarker, it will be incumbent upon national cancer registries to report this information. Incidence rates cautiously extrapolate to an annual burden of 3000 and 17,000 HER2+ tumors for black and white women, respectively, and triple-negative tumors among 5000 and 16,000 respectively. Testing, rate, and burden variations warrant population-based in-depth exploration and clinical translation. Cancer 2010. © 2010 American Cancer Society. - Clinical and pathologic factors that predict lymph node yield from surgical specimens in colorectal cancer : A population-based study
- Cancer (Philad ) 116(11):2560-2570 (2010)
BACKGROUND: The National Quality Forum endorses the recommendation of examining at least 12 lymph nodes (LNs) from colorectal cancer (CRC) specimens. However, heterogeneity in LN harvest exists. The objective of this study was to investigate the clinicopathologic factors that influence LN yield. METHODS: The authors used the Surveillance, Epidemiology, and End Results database to identify patients who were diagnosed with stage I, II, and III CRC between 1994 and 2005. Poisson regression was used to model the number of LNs examined as a function of individual clinicopathologic factors, including age, sex, race, year of diagnosis, geographic region, anatomic site, preoperative radiation, tumor size, tumor classification, tumor differentiation, and LN positivity. RESULTS: In total, 153,483 patients with CRC were identified. The mean number of LNs examined (± standard deviation) was 12 (±9.3). Separate multivariate analyses revealed that age, year of diagnosis, tumor size, and tumor classification were significant predictors of LN yield for colon and extraperitoneal rectal cancers (P < .01 for all covariates). Tumor location and radiotherapy were significant predictors of LN yield in patients with colon cancer and rectal cancer, respectively. Overall LN yields increased between 2% and 3% annually. CONCLUSIONS: Despite the increasing yields observed over time, patients with rectal cancer and older patients who had distally located, early colon cancer were less likely to meet the benchmark yield of 12 LNs. Further investigation into how LN yield is influenced by alterable factors, such as the extent of mesenteric resection and the pathologic technique, as well as nonalterable factors, such as patient age and tumor location, may reveal innovative ways to improve current staging methods. Cancer 2010. © 2010 American Cancer Society. - Log odds of positive lymph nodes : A novel prognostic indicator superior to the number-based and the ratio-based N category for gastric cancer patients with R0 resection
Sun Z Xu Y Li DM Wang ZN Zhu GL Huang BJ Li K Xu HM - Cancer (Philad ) 116(11):2571-2580 (2010)
BACKGROUND: Log odds of positive lymph nodes (LODDS) is defined as the log of the ratio between the probability of being a positive lymph nodes and the probability of being a negative lymph nodes when one lymph node is retrieved. The value of LODDS staging system on prognostic assessment for gastric cancer patients with R0 resection is still unclear. METHODS: Clinicopathologic and prognostic data of 2547 gastric cancer patients underwent D2 or D3 lymphadenectomy with R0 surgery were retrospectively studied. RESULTS: Multivariate analysis indentified LODDS stage was an independent prognostic factor, but not pN classification or rN classification. The scatter plots of the relationship between LODDS and the number, the ratio of nodes metastasis, suggested that the LODDS stage had power to divide patients with the same number or ratio of nodes metastasis into different groups. For patients in each of the pN or rN classifications, significant differences in survival could always be observed among patients in different LODDS stages. However, for patients in each LODDS stage, prognosis was highly homologous between those in different pN or rN classifications. A minimum number of 10, 15, 20, 25, and 10 nodes retrieved should be met for patients in the pN0, pN1, pN2, pN3, and rN0-3 classifications, respectively, unless the hazard risks of death would be underestimated or overestimated. However, LODDS stage could discriminate among 5 groups of patients with highly homologous prognosis, regardless! how many nodes retrieved. CONCLUSIONS: The LODDS system is more reliable than the Union Internationale Contre le Cancer and American Joint Committee on cancer pN system and the rN system for prognostic assessment. Cancer 2010. © 2010 American Cancer Society. - Loss of SM22 is a characteristic signature of colon carcinogenesis and its restoration suppresses colon tumorigenicity in vivo and in vitro
Yeo M Park HJ Kim DK Kim YB Cheong JY Lee KJ Cho SW - Cancer (Philad ) 116(11):2581-2589 (2010)
BACKGROUND: We previously found the down-expression of SM22 in an experimental animal model of colorectal cancer by performing a proteomic analysis. In this study, we addressed the expression and molecular mechanisms of SM22 in human colorectal cancer. METHODS: To evaluate the expression of SM22 in colon cancers, Western blot and immunohistochemistry were performed in 13 normal, 14 adenomas, and 44 adenocarcinomas. To address the role of SM22 in colon carcinogenesis, SM22 was restored in the colon cancer cells by the transfection with the pIRES2 vector containing full-length SM22 cDNA and tested for tumorigenicity in vivo and in vitro. RESULTS: SM22 was found to be significantly down-regulated in adenocarcinoma (58%) compared with adenoma (21.4%) and normal (15.3%). The loss of SM22 correlated with poor differentiation of tumor (P = 0.009) and lymph node metastasis (P = 0.029). Restoration of SM22 expression inhibited cell migration, colony-forming ability of cancer cells, and induced retardation of in vivo tumor growth in a xenograft model. CONCLUSIONS: Loss of SM22 is a molecular signature of colon cancer and is closely associated with progression, differentiation, and metastasis of colon cancer. The restoration of SM22 leads to an inhibition of colon carcinogenesis in vivo and in vitro, suggesting that SM22 might potentially function as a novel tumor suppressor. Cancer 2010. © 2010 American Cancer Society. - Prostate cancer-specific mortality and the extent of therapy in healthy elderly men with high-risk prostate cancer
Hoffman KE Chen MH Moran BJ Braccioforte MH Dosoretz D Salenius S Katin MJ Ross R D'Amico AV - Cancer (Philad ) 116(11):2590-2595 (2010)
BACKGROUND: The risk of prostate cancer-specific mortality (PCSM) in healthy elderly men may depend on extent of treatment. The authors of this report compared the use of brachytherapy alone with combined brachytherapy, external-beam radiation to the prostate and seminal vesicles, and androgen-suppression therapy (CMT) in this population. METHODS: The study cohort comprised 764 men aged 65 years with high-risk prostate cancer (T3 or T4N0M0, prostate-specific antigen >20 ng/mL, and/or Gleason score 8-10) who received either brachytherapy alone (n = 206) or CMT (n = 558) at the Chicago Prostate Cancer Center or at a 21st Century Oncology facility. Men either had no history of myocardial infarction (MI) or had a history of MI treated with a stent or surgical intervention. Fine and Gray regression analysis was used to identify the factors associated with PCSM. RESULTS: The median patient age was 73 years (interquartile range, 70-77 years). After a median follow-up of 4.9 years, 25 men died of prostate cancer. After adjusting for age and prostate cancer prognostic factors, the risk of PCSM was significantly less (adjusted hazard ratio, 0.29; 95% confidence interval, 0.12-0.68; P = .004) for men who received CMT than for men who received brachytherapy alone. Other factors that were associated significantly with an increased risk of PCSM included a Gleason score of 8 to 10 (P = .017). CONCLUSIONS: Elderly men who had high-risk prostate cancer without cardiovascular disease or with surgically corrected cardiovascular disease had a lower risk of PCSM when they received CMT than when they received brachytherapy alone. These results support aggressive locoregional treatment in healthy elderly men with high-risk prostate cancer. Cancer 2010. © 2010 American Cancer Society. - The incidence of venous thromboembolism and its effect on survival among patients with primary bladder cancer
Sandhu R Pan CX Wun T Harvey D Zhou H White RH Chew HK - Cancer (Philad ) 116(11):2596-2603 (2010)
BACKGROUND: The incidence, risk factors, time course, and impact on survival of venous thromboembolism (VTE) in a large, population-based study of patients with bladder cancer have not been identified previously. METHODS: The California Cancer Registry was merged with the California Patient Discharge Data Set to determine the incidence of VTE in patients with newly diagnosed bladder cancer within a 6-year period. Cox proportional hazards models were used to determine the risk factors for VTE and the effects of VTE on survival. RESULTS: Among 24,861 patients with bladder cancer, the 2-year incidence of VTE was 1.9%. The highest incidence of VTE occurred in the first 6 months regardless of age, sex, race, tumor stage, or histologic subtype. In a multivariate model, significant risk factors for the development of VTE included major surgery, advancing disease stage, and increasing number of comorbidities. Compared with the general population, the 1-year standardized incidence ratio for VTE in the bladder cancer cohort was 5.3 (95% confidence interval, 4.8-5.9). Among patients with bladder cancer, significant risk factors for death included advancing disease stage, increasing comorbidities, African-American race, nontransitional cell carcinoma histology, and the development of VTE. CONCLUSIONS: Patients with bladder cancer had a 1.9% 2-year incidence of VTE. Metastatic disease was the strongest predictor of both VTE and death. It was noteworthy that cancer-associated surgery was associated with a higher risk of VTE, which differed from the results reported from other studies in solid tumors. VTE was a significant predictor of death in the first 2 years. Cancer 2010. © 2010 American Cancer Society. - Patterns of care for early stage bladder cancer
Strope SA Ye Z Hollingsworth JM Hollenbeck BK - Cancer (Philad ) 116(11):2604-2611 (2010)
BACKGROUND: Early stage bladder cancer is a heterogeneous disease with a variable risk of progression and mortality. Uncertainty surrounding the optimal care for these patients may result in a mismatch between disease risk and treatment intensity. METHODS: Using Surveillance, Epidemiology, End Results-Medicare data, we identified patients diagnosed with early stage bladder cancer (n = 24,980) between 1993 and 2002. We measured patients' treatment intensity by totaling all Medicare payments made for bladder cancer in the 2 years after diagnosis. Using multiple logistic regression, we assessed relationships between clinical characteristics and treatment intensity. Finally, we determined the extent to which a patient's disease risk matched with their treatment intensity. RESULTS: The average per capita expenditures increased from $6,936 to $7,642 over the study period (10.2% increase; P < .01). This increase was driven by greater use of intravesical therapy (2.6 vs 3.7 instillations per capita, P < .01) and physician office visits (3.0 vs 4.8 visits per capita, P < .01). Generally, treatment intensity was appropriately aligned with many clinical characteristics, including age, comorbidity, tumor stage, and grade. However, treatment intensity matched disease risk for only 55% and 49% of the lowest and highest risk patients, respectively. CONCLUSIONS: The initial treatment intensity of early stage bladder cancer is increasing, primarily through greater use of intravesical therapy and office visits. Treatment intensity matches disease risk for many, but up to 1 in 5 patients may receive too much or too little care, suggesting opportunities for improvement. Cancer 2010. © 2010 American Cancer Society. - Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate-specific antigen : Data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden
Vickers AJ Cronin AM Aus G Pihl CG Becker C Pettersson K Scardino PT Hugosson J Lilja H - Cancer (Philad ) 116(11):2612-2620 (2010)
BACKGROUND: Risk models to predict prostate cancer on biopsy, whether they include only prostate-specific antigen (PSA) or other markers, are intended for use in all men of screening age. However, the association between PSA and cancer probably depends on a man's recent screening history. METHODS: The authors examined the effect of prior screening on the ability to predict the risk of prostate cancer by using a previously reported, 4-kallikrein panel that included total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2 (hK2). The study cohort comprised 1241 men in Gothenburg, Sweden who underwent biopsy for elevated PSA during their second or later visit for the European Randomized Study of Screening for Prostate Cancer. The predictive accuracy of the 4-kallikrein panel was calculated. RESULTS: Total PSA was not predictive of prostate cancer. The previously published 4-kallikrein model increased predictive accuracy compared with total PSA and age alone (area under the curve [AUC], 0.66 vs 0.51; P < .001) but was poorly calibrated and missed many cancers. A model that was developed with recently screened men provided important improvements in discrimination (AUC, 0.67 vs 0.56; P < .001). Using this model reduced the number of biopsies by 413 per 1000 men with elevated PSA, missed 60 of 216 low-grade cancers (Gleason score 6), but missed only 1 of 43 high-grade cancers. CONCLUSIONS: Previous participation in PSA screening dramatically changed the performance of statistical models that were designed to predict biopsy outcome. A 4-kallikrein panel was able to predict prostate cancer in men who had a recent screening history and provided independent confirmation that multiple kallikrein forms contribute important diagnostic information for men with elevated PSA. Cancer 2010. © 2010 American Cancer Society. - Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer
Nakayama N Nakayama K Shamima Y Ishikawa M Katagiri A Iida K Miyazaki K - Cancer (Philad ) 116(11):2621-2634 (2010)
BACKGROUND: This study examined the clinical significance of CCNE1 (Cyclin E1) amplification and assessed whether CCNE1 is a potential therapeutic target in ovarian cancer. METHODS: CCNE1 expression and amplification in ovarian cancer was assessed by immunohistochemistry, fluorescence in situ hybridization and clinical data collected by retrospective chart review. CCNE1 gene knockdown using silencing RNA and a CCNE1 gene transfection system were used to asses CCNE1 function in tissue samples of ovarian cancer. RESULTS: Gene amplification was identified in 18 (20.4%) of 88 ovarian carcinomas. CCNE1 copy number significantly correlated with CCNE1 protein expression (r = 0.522, P < .0001). CCNE1 amplification significantly correlated with shorter disease-free survival and overall survival (P < .001). There were nonsignificant trends between high protein expression and poor disease-free survival (P = .2865) and overall survival (P = .1248). Multivariate analysis showed gene amplification was an independent prognostic factor for disease-free survival and overall survival after standard platinum-taxane chemotherapy (P = .0274, P = .0023). Profound growth inhibition and apoptosis were observed in silencing RNA-treated cancer cells with gene amplification compared with results in cancer cells with CCNE1 moderate expression without gene amplification or with low CCNE1 expression. CCNE1 overexpression stimulated proliferation in ovarian cancer cell lines ES2 and TOV-21G, which have lower endogenous ! CCNE1 expression. CONCLUSIONS: These findings indicate that CCNE1 overexpression is critical to growth and survival of ovarian cancer tumors with CCNE1 gene amplification. Furthermore, they suggest that CCNE1 silencing RNA-induced phenotypes depend on amplification status of ovarian cancers. Therefore, CCNE1-targeted therapy may benefit ovarian cancer patients with CCNE1 amplification. Cancer 2010. © 2010 American Cancer Society. - Trends in oropharyngeal and oral cavity cancer incidence of human papillomavirus (HPV)-related and HPV-unrelated sites in a multicultural population : The British Columbia experience
Auluck A Hislop G Bajdik C Poh C Zhang L Rosin M - Cancer (Philad ) 116(11):2635-2644 (2010)
BACKGROUND: There is a growing recognition of the involvement of human papilloma virus infection in the etiology of head and neck cancers at some sites, mainly the base of the tongue, tonsils, and other oropharynx (hereafter termed oropharyngeal cancer). Other oral sites (hereafter termed oral cavity cancer [OCC]) show a stronger association with tobacco and alcohol. Little is known about the ethnic variation in incidence for these cancers. This study determined incidence rates of OCC and oropharyngeal cancer among South Asian, Chinese, and the general population in British Columbia, Canada. METHODS: Patients with OCC and oropharyngeal cancer diagnosed from 1980 to 2006 were identified through the British Columbia cancer registry, and surname lists were used to establish ethnicity. Age-adjusted incidence rates were determined for these cancers by sex, topographical site, and ethnicity, and temporal trends were examined. RESULTS: Age-adjusted incidence rates have been decreasing for OCC and increasing for oropharyngeal cancer in the general population for both sexes, with men having higher incidence rates than women. Ethnic differences were found, with the highest age-adjusted incidence rates for OCC for men in South Asians and for women in Chinese, and with the highest age-adjusted incidence rates for oropharyngeal cancer for men in Chinese and for women in the general population. Differences were also found for OCC topographical sites by sex and ethnicity. CONCLUSIONS: The incidence of oropharyngeal cancer has now surpassed OCC in the British Columbia male population. Ethnic minorities are at higher risk than the general population for both OCC and oropharyngeal cancer for men, and for OCC for women. Cancer 2010. © 2010 American Cancer Society. - Intensity-modulated radiotherapy outcomes for oropharyngeal squamous cell carcinoma patients stratified by p16 status
Shoushtari A Meeneghan M Sheng K Moskaluk CA Thomas CY Reibel JF Levine PA Jameson MJ Keene K Read PW - Cancer (Philad ) 116(11):2645-2654 (2010)
BACKGROUND: Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with intensity-modulated radiotherapy (IMRT) were stratified by p16 status, neck dissection, and chemotherapy to correlate these factors with outcomes. METHODS: A total of 112 patients with OPSCC treated with IMRT from 2002 to 2008 were retrospectively analyzed. All patients received RT to 66-70 Gray. Forty-five of the tumors were p16 positive (p16+), 27 were p16 negative (p16-), and 41 had unknown p16 status. Sixty-two patients had postradiation neck dissections. Nine patients with p16- tumors and 28 patients with p16+ tumors received chemotherapy. The distribution of T, N, and stage grouping among the p16+ and p16- patients was not significantly different, and 87.5% patients had stage III/IV disease. RESULTS: The median follow-up was 26.3 months. For patients with p16+ tumors, p16- tumors, and the overall cohort, the actuarial 3-year locoregional progression-free survival rate was 97.8%,73.5%, and 90.5% respectively (P = .006) and the disease-free survival rate was 88.2%, 61.4%, and 81.7%, respectively (P = .004). Patients with p16+ tumors had an 89.5% and 87.5% pathologic complete response (CR) on neck dissection with and without chemotherapy, respectively. In contrast, patients with p16- tumors had a 66.7% and 25.0% pathologic CR on neck dissection with and without chemotherapy, respectively. CONCLUSIONS: In this series, p16 status was found to be a significant predictive biomarker and patients with p16+ tumors had much better outcomes than patients with p16- tumors. Further investigation is warranted to determine whether less intense therapy is appropriate for selected patients with p16+ OPSCC, whereas more aggressive strategies are needed to improve outcomes in patients with p16- disease. Cancer 2010. © 2010 American Cancer Society. - Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma
Ruan J Martin P Coleman M Furman RR Cheung K Faye A Elstrom R Lachs M Hajjar KA Leonard JP - Cancer (Philad ) 116(11):2655-2664 (2010)
BACKGROUND: Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL). METHODS: RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells. RESULTS: Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (6 months, 31 months, 48 months, and 50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occu! rred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment. CONCLUSIONS: RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients. Cancer 2010. © 2010 American Cancer Society. - Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance
Kantarjian H Coutre PL Cortes J Pinilla-Ibarz J Nagler A Hochhaus A Kimura S Ottmann O - Cancer (Philad ) 116(11):2665-2672 (2010)
BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society. - Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy
- Cancer (Philad ) 116(11):2673-2681 (2010)
BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response wi! th imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined. Cancer 2010. © 2010 American Cancer Society. - KRAS mutation status in primary nonsmall cell lung cancer and matched metastases
Cortot AB Italiano A Burel-Vandenbos F Martel-Planche G Hainaut P - Cancer (Philad ) 116(11):2682-2687 (2010)
BACKGROUND: The objective of this study was to determine whether the mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) differed between primary tumors and matched distant metastases in nonsmall cell lung cancer (NSCLC). METHODS: Patients who underwent resection for both primary NSCLC and matched distant metastases were included in the study. KRAS and EGFR mutation status were assessed by polymerase chain reaction (PCR) amplification and direct sequencing on both primary tumors and metastases. For KRAS analysis, mutant-enriched PCR (ME-PCR) was performed in case of discordance between a primary tumor and its matched metastasis. RESULTS: Twenty-one patients were included. No EGFR mutations were detected. KRAS mutations were detected in 6 patients (28%). In all patients, the mutations identified by direct sequencing were discordant between the primary tumor and the matched metastasis. The use of ME-PCR allowed a resolution of the discordance in 3 of the 6 cases by demonstrating the presence of low levels of mutant KRAS in lesions that were negative by direct sequencing. CONCLUSIONS: Highly sensitive tools are required to identify biomarkers. The KRAS mutation status mostly was concordant between primary tumors and matched distant metastases. In a few patients, KRAS mutation status differed between different tumor sites. Cancer 2010. © 2010 American Cancer Society. - Association between YKL-40 and adult primary astrocytoma
- Cancer (Philad ) 116(11):2688-2697 (2010)
BACKGROUND: The YKL-40 coding chitinase 3-like 1 gene is 1 of the most overexpressed genes in human glioblastomas. The objectives of this study were to explore YKL-40 protein expression status and World Health Organization (WHO) pathologic grades of primary human astrocytoma and to investigate the role of YKL-40 in the proliferation of both established and primary astrocytoma cells in vitro. METHODS: WHO grade 1, 2, 3, and 4 primary astrocytomas (210 patients) were evaluated for YKL-40 protein expression status in immunohistochemical analyses. In addition, after transfection with a plasmid that contained YKL-40 small-interfering RNA (siRNA), cell proliferation and the cell cycle were measured with a cell-viability assay and flow cytometry. Expression levels of phosphorylated, total mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) were detected by Western blot analysis. RESULTS: The percentage of positive cells and the staining intensity differed significantly between different pathologic tumor grades (P < .001). The YKL-40 immunoreactivity score increased markedly with increased pathologic grade (F = 18.89; P < .001). In the in vitro experiment, the cell cycle was arrested in G1 phase. An inhibitor of the p38 MAPK, SB203580, could partially abrogate the cell proliferation inhibition effect by siRNA treatment. The expression levels of phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated AKT were notably decreased in siRNA-transfected U87 cells. In contrast, the expression levels of phosphorylated p38 and phosphorylated c-jun N-terminal kinase 1 and 2 increased significantly (P < .01). CONCLUSIONS: YKL-40 expression status correlated well with the pathologic grade of primary astrocytomas. The current results also indicted that YKL-40 plays a pivotal role in glioma cell proliferation through activation of the MAPK and AKT pathways. YKL-40 may be an attractive target for glioma therapy. Cancer 2010. © 2010 American Cancer Society. - Race versus place of service in mortality among Medicare beneficiaries with cancer
Onega T Duell EJ Shi X Demidenko E Goodman DC - Cancer (Philad ) 116(11):2698-2706 (2010)
BACKGROUND: Evidence suggests that excess mortality among African-American cancer patients is explained in part by the healthcare setting. The objective of this study was to compare mortality among African-American and Caucasian cancer patients and to evaluate the influence of attendance at a National Cancer Institute (NCI)-designated comprehensive or clinical cancer center. METHODS: The authors conducted a retrospective cohort analysis of Medicare beneficiaries with an incident diagnosis of lung, breast, colorectal, or prostate cancer between 1998 and 2002 who were identified from Surveillance, Epidemiology, and End Results data. Multivariate logistic regression models were used to assess the impact of NCI cancer center attendance and race on all-cause and cancer-specific mortality at 1 year and 3 years after diagnosis. RESULTS: The likelihood of 1-year and 3-year all-cause and cancer-specific mortality was higher for African Americans than for Caucasians in crude and adjusted models (cancer-specific adjusted: Caucasian referent, 1-year odds ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.19; 3-year OR, 1.23; 95% CI, 1.17-1.30). By cancer site, cancer-specific mortality was higher among African Americans at 1 year for breast and colorectal cancers and for all cancers at 3 years. NCI cancer center attendance was associated with significantly lower odds of mortality for African Americans (1-year OR, 0.63; 95% CI, 0.56-0.76; 3-year OR, 0.71; 95% CI, 0.62-0.81). With Caucasians as the referent group, the excess mortality risk among African Americans no longer was observed for all-cause or cancer-specific mortality risk among patients who attended NCI cancer centers (cancer-specific mortality:1-year OR, 0.95; 95% CI, 0.76-1.19; 3-year OR, 1.00; 95% CI, 0.82-1.21). CONCLUSIONS: African-American Medicare beneficiaries with lung, breast, colorectal, and prostate cancers had higher mortality compared with their Caucasian counterparts; however, there were no significant differences in mortality by race among those who attended NCI cancer centers. The results of this study suggested that place of service may explain some of the cancer mortality excess observed in African Americans. Cancer 2010. © 2010 American Cancer Society. - Risk factors for fatigue severity in primary brain tumor patients
Armstrong TS Cron SG Bolanos EV Gilbert MR Kang DH - Cancer (Philad ) 116(11):2707-2715 (2010)
BACKGROUND: In addition to neurologic symptoms, fatigue is commonly reported in patients with primary brain tumors during radiation therapy and in long-term survivors of low-grade brain tumors. Other factors have not been explored. The aim of this study was to identify demographic and clinical factors that predict fatigue severity and to evaluate the association of fatigue with other symptoms throughout the disease trajectory. METHODS: Two hundred one patients with primary brain tumors completed the M. D. Anderson Symptom Inventory-Brain Tumor Module and a demographic checklist. Clinical data, including treatment, tumor grade, and performance status, were also collected. Correlations among fatigue and other recorded symptoms were evaluated. Logistic regression modeling was performed to evaluate factors associated with fatigue severity. RESULTS: Fatigue severity was associated with symptoms including pain, drowsiness, distress, difficulty sleeping, and weakness as well as overall symptom severity and interference. Poor performance status (Karnofsky scale) (odds ratio [OR], 5.73; P = .001), female sex (OR, 2.48; P = .005), and disease status (OR, 2.20; P = .013) were the strongest predictors of fatigue. Severity of fatigue for women was primarily predicted by disease status (OR, 3.33; P = .01) For men, antidepressant use (OR, 4.43; P = .013) in addition to opioids (OR, 3.46; P = .017) and performance status (OR, 12.47; P = .0001) predicted fatigue severity. CONCLUSIONS: Fatigue should not be considered a solitary symptom with 1 root cause, but a complex symptom related to the severity of other symptoms and potentially having various etiologies. Future studies should consider these factors in planning interventions and assessing response. Cancer 2010. © 2010 American Cancer Society. - Efficacy of radiotherapy for painful bone metastases during the last 12 weeks of life : Results from the Dutch Bone Metastasis Study
Meeuse JJ van der Linden YM van Tienhoven G Gans RO Leer JW Reyners AK for the Dutch Bone Metastasis Study Group - Cancer (Philad ) 116(11):2716-2725 (2010)
BACKGROUND: Radiotherapy is an effective treatment for painful bone metastases. Whether this applies also in patients with limited survival remains to be investigated. This study analyzed the effect of radiotherapy for painful bone metastases in patients with a survival 12 weeks. METHODS: In the Dutch Bone Metastasis Study, 1157 patients with painful bone metastases were randomized to single fraction (1 × 8 grays [Gy]) or multiple fraction (6 × 4 Gy) radiotherapy. Patients who died within 12 weeks after randomization were included in this analysis. Patients were classified as responders or nonresponders, based on their pain response to radiotherapy. This response was calculated considering changes in pain intensity (measured with an 11-point numeric rating scale) and analgesic usage. Cox proportional hazards models were used to analyze pain response and survival. RESULTS: Two hundred seventy-4 patients were included in this analysis. At randomization, the mean pain intensity score (±standard deviation) was 7 (±2). The proportion showing a pain response did not differ between the single fraction and multiple fraction groups. Toward death, pain intensity score decreased to 5 (±3) in responders (45%), whereas in nonresponders (55%) no change was observed. Despite the benefit in responders, in 60% of all patients pain intensity remained 5 after randomization. CONCLUSIONS: Pain responded in about half of the patients who survived 12 weeks after randomization into the Dutch Bone Metastasis Study. When considering radiotherapy, single fraction should be preferred. Additional palliative measures remain essential for adequate pain control. Cancer 2010. © 2010 American Cancer Society. - Erratum
- Cancer (Philad ) 116(11):2726 (2010)
- Erratum
- Cancer (Philad ) 116(11):2727 (2010)
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