Hot off the presses! Jun 18 Cancer

The Jun 18 issue of the Cancer is now up on Pubget (About Cancer): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Centers search for clues with cancer genome sequencing : Pediatric cancer, glioblastomas are the focus of two separate projects
  - Cancer (Philad ) 116(13):3075-3077 (2010)
  
• Personalized blood tests for cancer that use whole-genome sequencing
  - Cancer (Philad ) 116(13):3076 (2010)
  
• Some cancer surgeries are safe at community hospitals
  - Cancer (Philad ) 116(13):3076 (2010)
  
• Myth: We can tailor palliative care to match life expectancy. Reality: No we can't
  - Cancer (Philad ) 116(13):3078-3079 (2010)
  The goal of palliative therapy is to palliate, not to cure. For the best palliative results for our patients (and their caregivers), this should be done as rapidly as possible.
• Early 21st Century renal cell carcinoma : A paradigm shift
  - Cancer (Philad ) 116(13):3080-3083 (2010)
  Individuals involved in the management of patients with small renal masses should acknowledge the role and the importance of active surveillance in older populations (aged >75 years) and minimally invasive ablative therapies. These new therapeutic strategies should be inculcated during medical training and practice so that they may become just as embedded as the emphasis on the oncologic outcome of standard treatment.
• Prognostic factors of survival in the trastuzumab era among women with breast cancer and brain metastases who receive whole brain radiotherapy : A Single-Institution Review
  - Cancer (Philad ) 116(13):3084-3092 (2010)
  BACKGROUND: The objective of this study was to review the outcome of women with breast cancer with known receptor status who were treated with whole brain radiotherapy for brain metastases and to determine factors that impact survival. METHODS: A total of 223 women with breast cancer and brain metastases, who received whole brain radiotherapy, were identified. All women with HER-2-positive disease had received trastuzumab. Kaplan-Meier product limit method was used to determine overall survival (OS) estimates. Cox proportional hazards models were then fitted to explore the association of OS with various patient and tumor characteristics. RESULTS: Median age at brain metastases diagnosis was 50 years. Sixty-seven (30.2%) patients had hormone receptor-positive/HER-2-negative disease, 101 (45.50%) had HER-2-positive disease, and 54 (24.3%) had triple receptor-negative disease. Median OS from brain metastases was 6 months, with 1-year survival of 30% (95% confidence interval [CI], 23%-36%). Women with hormone receptor-positive/HER-2-negative, HER-2-positive, and triple-negative tumors had median survivals of 5, 9, and 5 months, respectively (P = .0069). In the multivariate model, women with HER-2-positive disease had a significantly decreased risk of death compared with women with hormone receptor-positive/HER-2-negative disease (hazard ratio, 0.63; 95%CI, 0.42-0.94; P = .02). The risk of death among women with triple-negative disease compared with hormone receptor-positive/HER-2-negative disease was not significantly different (P = .54). Lower recursive partitioning analysis class and 30-gray brain radiation dose were a! lso significantly associated with a decreased risk of death. CONCLUSIONS: Breast tumor subtype has a significant prognostic role among women with breast cancer and brain metastases. In addition, in the trastuzumab era factors such as recursive partitioning analysis and adequate radiation dose continue to be important prognostic factors. Cancer 2010. © 2010 American Cancer Society.
• Is it useful to detect lymphovascular invasion in lymph node-positive patients with primary operable breast cancer?
  - Cancer (Philad ) 116(13):3093-3101 (2010)
  BACKGROUND: Lymphovascular invasion (LVI) is a widely recognized prognostic factor in lymph node-negative breast cancers. However, there are only limited and controversial data about its prognostic significance in lymph node-positive patients. METHODS: Among 931 patients operated on and monitored at the authors' institution for an invasive breast carcinoma between 1989 and 1992, all 374 lymph node-positive breast cancers entered the study (median follow-up, 126 months). RESULTS: LVI was present in 46% of tumors and was associated with age 40 years (P = .02), high histological grade (P = .01), and negative estrogen receptor status (P = .032), but not with tumor size, number of involved lymph nodes, or HER-2/neu status. LVI was an independent prognostic factor for distant metastases (P = .002). Furthermore, in HER-2/neu-negative/hormone receptor-positive (n = 287) tumors, the number of independent prognostic factors (LVI, age, histological grade, number of involved lymph nodes, and tumor size) was associated with a 5-years metastasis-free survival ranging from 100% if no factors (n = 25) to 89% ± 2% if 1 or 2 factors (n = 186) and 67% ± 6 if 3, 4, or 5 factors (n = 76) were present (P < .001). CONCLUSIONS: LVI is an independent prognostic factor in lymph node-positive breast cancer and merits further prospective investigations as a decision tool in the adjuvant chemotherapy setting. Cancer 2010. © 2010 American Cancer Society.
• Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment : A prospective study
  - Cancer (Philad ) 116(13):3102-3111 (2010)
  BACKGROUND: The incidence of chemotherapy-induced amenorrhea (CIA) and the time to subsequent menstrual bleeding in premenopausal breast cancer patients treated with current standard chemotherapy regimens was examined. METHODS: Four hundred sixty-six women ages 20 to 45 years at the time of diagnosis of a stage I to III breast cancer were recruited between January 1998 and July 2002. Patients completed monthly bleeding calendars from the time of study recruitment. Updated medical history data were obtained at 6-month intervals. RESULTS: Most women received doxorubicin and cyclophosphamide (AC); doxorubicin, cyclophosphamide, and paclitaxel (ACT); or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Approximately 41% of women experienced an initial 6 months of CIA, and an additional 29% had at least 1 year of CIA. Approximately half of the women with 6 months of CIA and 29% of those with 1 year of CIA resumed bleeding within the subsequent 3 years, usually in the year after their amenorrheic episode. Resumption of bleeding differed significantly by treatment regimen after 6 months of CIA (P = .002; 68% with AC, 57% with ACT, and 23% with CMF), but not after 1 year of CIA (P = .5). Of the 23% of women who experienced an initial 2-year period of CIA, 10% resumed bleeding within the ensuing 3 years after their amenorrheic episode, but none had regular menses. CONCLUSIONS: A considerable proportion of women treated with chemotherapy will experience periods of CIA, but many will resume bleeding. Newer treatment regimens such as ACT appear to have a higher resumption of bleeding compared with CMF. This finding may have implications for choice of anti-estrogen treatment and for future potential pregnancies/fertility. Cancer 2010. © 2010 American Cancer Society.
• Clinical significance of the 21-gene signature (Oncotype DX) in hormone receptor-positive early stage primary breast cancer in the Japanese population
  - Cancer (Philad ) 116(13):3112-3118 (2010)
  BACKGROUND: The 21-gene signature has been intensively studied and incorporated into major guidelines for treatment decision in early breast caner. However, it remains to be examined whether this system is applicable to Asian populations. METHODS: The authors collected 325 tumor tissues from estrogen receptor (ER)-positive primary breast cancer patients who had undergone surgery and were treated with tamoxifen between 1992 and 1998. The tissues were analyzed for the 21-gene signature, and the patients were classified into groups of low, intermediate, or high risk based on the Recurrence Score. RESULTS: A total of 280 patients were eligible, with adequate reverse transcription polymerase chain reaction profiles for the Recurrence Score. Of those, 200 and 80 patients had lymph node-negative and lymph node-positive disease, respectively. The proportions of lymph node-negative patients categorized as being at low, intermediate, or high risk were 48%, 20%, and 33%, respectively. In lymph node-negative patients, the Kaplan-Meier estimates of the distant recurrence rate at 10 years were 3.3% (95% confidence interval [95% CI], 1.1-10.0%), 0%, and 24.8% (95% CI, 15.7-37.8%) for those in the low-risk, intermediate-risk, and high-risk groups, respectively. The risk of distant recurrence in the low-risk group was significantly lower than that in the high-risk group when the entire Kaplan-Meier plots were compared (P < .001, log-rank test). There was a significant difference for overall survival between the low-risk and the high-risk groups (P = .008, log-rank test). CONCLUSIONS: This is the first report to show that the 21-gene signature has value in providing prognostic information in Asian populations with ER-positive, lymph node-negative breast cancer. Cancer 2010. © 2010 American Cancer Society.
• Active treatment of localized renal tumors may not impact overall survival in patients aged 75 years or older
  - Cancer (Philad ) 116(13):3119-3126 (2010)
  BACKGROUND: Although nephrectomy cures most localized renal cancers, this oncologic benefit may be outweighed by the renal functional costs of such an approach. In this study, the authors examined overall survival in 537 patients who had localized renal tumors 7 cm detected at age 75 years to investigate whether surgical intervention improved survival compared with active surveillance. METHODS: Clinical T1 renal tumors were managed with surveillance (20%), nephron-sparing interventions (53%), or nephrectomy (27%). Cox regression models were constructed based on age, comorbidity, management type, renal function, and other variables. RESULTS: The median follow-up was 3.9 years, and death from any cause occurred in 148 patients (28%). The most common cause of death was cardiovascular (29%), and cancer progression was responsible in only 4% of deaths. Kaplan-Meier analysis revealed decreased overall survival for patients who underwent surveillance and nephrectomy relative to nephron-sparing intervention (P = .01); however, surveilled patients were older and had greater comorbidity. In multivariate analysis, significant predictors of overall survival included age (P = .0004) and comorbidity (P < .0001) but not management type (P = .3). Preoperative renal function (P = .006) and comorbidity (P = .005) were predictors of cardiovascular mortality, and nephrectomy was associated with greatest loss of renal function. CONCLUSIONS: In patients aged 75 years, surgical management of clinically localized renal cortical tumors was not associated with increased survival. Patients died mostly of cardiovascular causes, similar to the general elderly population. Nephrectomy accelerated renal dysfunction, which was associated with cardiovascular mortality. Current paradigms suggest that there is over treatment of localized renal tumors, and further study will be required to evaluate the advisability of various options in patients with limited life expectancy. Cancer 2010. © 2010 American Cancer Society.
• Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma
  - Cancer (Philad ) 116(13):3127-3134 (2010)
  BACKGROUND: The authors evaluated the incidence of pathologic downstaging and complete remission (CR) in patients with high-grade ureteral and renal pelvic transitional cell carcinoma (TCC) (upper tract TCC) who received neoadjuvant chemotherapy followed by surgery. METHODS: The study group comprised patients with biopsy-demonstrated, high-grade disease who received neoadjuvant chemotherapy followed by nephrouterectomy from 2004 to 2008, during which time patients uniformly were considered for neoadjuvant chemotherapy. The control group comprised patients with biopsy-demonstrated, high-grade disease who underwent initial nephroureterectomy from 1993 to 2004, when patients uniformly underwent initial surgery. Multiple clinical and pathologic features were evaluated, and the primary endpoint was pathologic tumor classification. RESULTS: One hundred seven patients in the control group underwent initial surgery, and 43 patients in the study group received neoadjuvant chemotherapy. Baseline demographics were similar between the groups except for a higher rate of sessile tumor architecture in the study group (72.1% vs 49.5%; P = .018). There was significant downstaging in study group patients compared with the historic control group (P = .004). The incidence of tumors classified as pathologic T2 (pT2) or as pT3 or higher was significantly lower in the study group (pT2, 65.4% vs 48.8%; P = .043; pT3 or higher, 47.7% vs 27.9%; P = .029). Fourteen percent of patients who received neoadjuvant chemotherapy had a pathologic CR. CONCLUSIONS: Neoadjuvant chemotherapy was associated with a 14% CR rate and a significant rate of downstaging. While longer follow-up is awaited for survival data to mature, the current data provide justification for the sustained support of trials using this strategy. Cancer 2010. © 2010 American Cancer Society.
• Durable oncologic outcomes after radiofrequency ablation : Experience from treating 243 small renal masses over 7.5 years
  - Cancer (Philad ) 116(13):3135-3142 (2010)
  BACKGROUND: Long-term oncologic outcomes for renal thermal ablation are limited. The authors of this report present their experience with radiofrequency ablation (RFA) therapy for 243 small renal masses (SRMs) over the past 7.5 years. METHODS: The authors' institutional, prospectively maintained RFA database was reviewed to determine intermediate and long-term oncologic outcomes for patients with SRMs (generally <4 cm) who underwent RFA. Particular attention was placed on patients who had a minimum 3 years of follow-up. Patients were excluded from the analysis if they had received previous treatment for renal cell carcinoma (RCC) on the ipsilateral kidney or if they did not have at least 1 imaging study available for follow-up. RESULTS: Two hundred eight patients (with 243 SRMs) who had no evidence of previous ipsilateral renal cancer treatment underwent RFA and had follow-up imaging studies available for review. Overall, tumor size averaged 2.4 cm, and follow-up ranged from 1.5 months to 90 months (mean, 27 months). Of the 227 tumors (93%) that underwent preablation biopsy, RCC was confirmed in 79%. The initial treatment success rate was 97%, and the overall 5-year recurrence-free survival rate was 93% (90% for 160 patients who had biopsy-proven RCC). During follow-up, 3 patients developed metastatic disease, and 1 patient died of RCC, yielding 5-year actuarial metastasis-free and cancer-specific survival rates of 95% and 99%, respectively. CONCLUSIONS: RFA provided successful treatment of SRMs and produced a low rate of recurrence as well as prolonged metastasis-free and cancer-specific survival rates at 5 years after treatment. Although longer term follow-up of RFA will be required to determine late recurrence rates, the current results indicated a minimal risk of disease recurrence in patients who are >3 years removed from RFA. Cancer 2010. © 2010 American Cancer Society.
• Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma : A retrospective study
  - Cancer (Philad ) 116(13):3143-3151 (2010)
  BACKGROUND: This single-center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT). METHODS: Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3-week cycles of bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte-colony-stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria. RESULTS: Review of medical records identified 44 eligible patients (34 patients who were treated in the front-line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front-line patients, the ORR was 94%, which included a 56% VGPR rate (24% sCR/CR). The median CD34-positive stem cell collection was 10.67 × 106/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% VGPR rate (53% sCR/CR). Among all 44 patients, the median progression-free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2-year survival (80% ! vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis. CONCLUSIONS: BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long-term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.
• Imatinib front-line therapy is safe and effective in patients with chronic myelogenous leukemia with pre-existing liver and/or renal dysfunction
  - Cancer (Philad ) 116(13):3152-3159 (2010)
  BACKGROUND: Imatinib 400 mg daily is the standard treatment for patients with chronic myelogenous leukemia (CML). The safety and efficacy of imatinib in CML patients with pre-existing liver and/or renal dysfunction has not been analyzed. METHODS: The authors analyzed the outcome of 259 patients with early chronic phase CML treated with imatinib (starting dose 400 mg in 50, 800 mg in 209). Pre-existing liver and/or renal dysfunction was seen in 38 (15%) and 11 (4%) patients, respectively. RESULTS: Dose reductions were required in 91 (43%) of 210 patients with normal organ function, compared with 8 (73%) of 11 (P = .065) with renal dysfunction, and 19 (50%) of 38 (P = .271) with liver dysfunction. Grade 3-4 hematologic toxicities including anemia (29%, 10%, and 7% of patients with renal dysfunction, liver dysfunction, and normal organ function, respectively), neutropenia (57%, 30%, and 30%), and thrombocytopenia (43%, 30%, and 26%) were more frequent in patients with pre-existing renal dysfunction treated with high-dose imatinib. Grade 3-4 nonhematologic toxicities were observed at similar frequencies. Complete cytogenetic response rates, event-free survival, and overall survival were similar in all groups. CONCLUSIONS: Although patients with pre-existing liver and/or renal dysfunction might have a higher rate of hematologic toxicity and require more frequent dose reductions, most patients can be adequately managed, resulting in response rates and survival similar to those without pre-existing organ dysfunction. Cancer 2010. © 2010 American Cancer Society.
• Polymorphisms in ERCC2, MSH2, and OGG1 DNA repair genes and gallbladder cancer risk in a population of Northern India
  - Cancer (Philad ) 116(13):3160-3169 (2010)
  BACKGROUND: Genetic variants of DNA repair enzymes may lead to genetic instability and contribute to gallbladder (GB) carcinogenesis. METHODS: A case-control study (230 GB carcinogenesis patients and 230 controls) was undertaken to evaluate whether genetic variations in 3 DNA repair genes ERCC2 (Asp312Asn [rs1799793] and Lys751Gln [rs13181]), MSH2 (-118T>C [rs2303425] and IVS1 + 9G>C [rs2303426]), and OGG1 (Ser326Cys [rs1052133] and 748-15C>G [rs2072668]) are associated with GB carcinogenesis risk in a North Indian population. RESULTS: The authors found that the ERCC2 Asp312Asn AA, MSH2 IVS1 + 9G>C CC, OGG1 Ser326Cys GG and CG + GG, and OGG1 748-15C>G GG and CG + GG genotypes were significantly associated with an increased risk of GB carcinogenesis (odds ratio [OR], 2.1, 1.8, 2.5, 1.8, 2.0, and 1.6, respectively). In contrast, ERCC2 Lys751Gln, and MSH2 -118T>C markers showed no significant associations with GB carcinogenesis risk, although because of the small sample size their effects cannot be ruled out. Female GB carcinogenesis patients with the OGG1 748-15C>G GG, OGG1 Ser326Cys GG, and ERCC2 Asp312Asn genotypes had a greater risk for developing the disease (OR, 3.6, 7.7, and 2.7, respectively). There was a significant interaction between MSH2 IVS1 + 9G>C and OGG1 748-15C>G polymorphisms (P = .001). Furthermore, individuals with >6 variant alleles of the studied polymorphisms were at 4-fold increased risk for developing GB carcinogenesis. Classification and Regression Tree analysis revealed potential hi! gher-order gene-gene interactions and categorized a few higher-risk subgroups for GB carcinogenesis. CONCLUSIONS: These results suggest that genetic variants in the DNA repair pathways may be involved in GB carcinogenesis etiology. Cancer 2010. © 2010 American Cancer Society.
• Value of integrated positron emission tomography revised using a phantom study to evaluate malignancy grade of lung adenocarcinoma : A multicenter study
  - Cancer (Philad ) 116(13):3170-3177 (2010)
  BACKGROUND: The malignant biological behavior of small-sized lung adenocarcinomas remains obscure, although understanding this feature is important for selecting appropriate treatment. In the current study, the authors evaluated malignancy grades of small adenocarcinomas using fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) in addition to high-resolution CT (HRCT) and pathological analysis in a multicenter setting. METHODS: A total of 201 patients with clinical T1N0M0 adenocarcinoma underwent PET/CT and HRCT followed by complete surgical resection. Associations between components of bronchioloalveolar carcinoma (BAC) in specimens and maximum standardized uptake values (maxSUV) on PET/CT and ground-glass opacity (GGO) ratios and tumor disappearance rate (TDR) on HRCT were analyzed, as well as associations between these findings and pathological features of the tumors. Variations in maxSUV among institutions and the underestimations derived from small tumors, which are limitations of PET performed in multicenter studies, were adjusted using a phantom study. RESULTS: The maxSUV, BAC ratio, TDR, and GGO ratio (in that order) reflected the grade of tumor invasiveness and lymph node metastasis. The maxSUV and BAC ratio were found to be significant prognostic predictors derived from disease-free survival curves. Although the BAC ratio was found to be significantly associated with preoperative radiographic parameters, the maxSUV, GGO ratio, and TDR (all P < .0001), the degree of correlation with maxSUV (correlation coefficient [R2] = 0.1699) was much weaker than that reported with the GGO ratio (R2 = 0.5860) or TDR (R2 = 0.5082). CONCLUSIONS: Phantom studies can overcome the difficulties of multicenter studies using PET. A higher maxSUV appears to reflect aggressive malignant behavior in clinical T1N0M0 adenocarcinomas, independent of BAC components. Preoperative PET/CT assessment in addition to HRCT could be used to construct hypotheses for a future clinical study of strategies for the treatment of patients with small lung adenocarcinoma. Cancer 2010. © 2010 American Cancer Society.
• Comparison of classification systems in melanoma sentinel lymph nodes - An analysis of 697 patients from a single center
  - Cancer (Philad ) 116(13):3178 (2010)
  BACKGROUND: In melanoma, different classification systems have been proposed that predict overall survival (OS) and recurrence-free survival (RFS) based on findings in the sentinel lymph node (SLN). The authors of this report compared the RFS and OS of 697 melanoma patients as predicted by various classification systems. METHODS: The Rotterdam system (based on the greatest dimension of the largest tumor cell deposit), the Augsburg S-classification (based on tumor penetrative depth [TPD]), and the Hannover system (based on a combination of tumor load, TPD, and invasion of the capsule) were studied in 697 consecutive melanoma patients who underwent SLN biopsy at the authors' center. RESULTS: In univariate analyses, the Rotterdam and Hannover systems (but not the S-classification) identified 1 group of SLN-positive patients that had OS and RFS similar to the OS and RFS of SLN-negative patients. The intermediate groups from all classification systems did not differ significantly with regard to RFS and/or OS from the adjacent groups. In multivariate analysis using a Cox model, the greatest dimension of the largest tumor cell deposit (cutoff point, <0.1 mm vs 0.1 mm), the TPD (cutoff point, 2 mm vs >2 mm), and capsular involvement represented independent parameters for RFS; and TPD and capsular involvement also were independent parameters for OS. On the basis of these 3 parameters, a new scoring system for risk assessment in patients with melanoma is proposed that can distinguish 3 separate groups of patients that differed significantly in OS and RFS. CONCLUSIONS: Different parameters of independent prognostic significance were identified in SLNs from patients with melanoma. Combining these parameters, the prognosis of patients with melanoma was predicted more precisely by the new scoring system than by currently published classification systems. Cancer 2010. © 2010 American Cancer Society.
• Clinical outcome of children and adults with localized Ewing sarcoma : Impact of Chemotherapy Dose and Timing of Local Therapy
  - Cancer (Philad ) 116(13):3189-3194 (2010)
  BACKGROUND: As Ewing sarcoma (EWS) can affect children and adults, these patients can be treated at either a pediatric or an adult institution. This study investigated whether differences in therapeutic strategy undertaken in pediatric and adult specialty sarcoma centers correlated with clinical outcome. METHODS: Data from patients with localized EWS treated between 1990 and 2005 at tertiary care pediatric and adult institutions were reviewed. RESULTS: Fifty-three patients (24 adult and 29 pediatric) were treated. Pediatric patients received a median of 16 cycles of chemotherapy comprised of doxorubicin, vincristine, cyclophosphamide, ifosfamide, and etoposide. Adult patients received a median of 10 cycles of treatment, and a significantly lower total cumulative dose of ifosfamide and cyclophosphamide (P < .0001). There was no difference noted with regard to the total dose of doxorubicin, or in the type of local therapy offered (surgery or radiotherapy, vs both). However, local therapy occurred earlier in pediatric patients compared with adults (3.7 months vs 7.4 months; P = .0003). The 3-year event-free survival (EFS) rate in pediatric and adult patients was 70% ± 9% and 43% ± 13% (P = 0.1), respectively. The 3-year overall survival rate was 81% ± 7.7% and 59% ± 12% (P = .02) for pediatric and adult patients, respectively. Factors found to be significantly associated with EFS on univariate analysis included pelvic sit! e, cyclophosphamide dose, and time to local therapy. On multivariate analysis, only pelvic disease (hazard ratio [HR] 4.26; P = .018) and time to local therapy (HR, 1.19; P = .002) were found to be significant. CONCLUSIONS: Adults with localized EWS have an inferior outcome compared with pediatric patients. This difference may be related to lower doses of alkylating agents and the timing of local therapy. Cancer 2010. © 2010 American Cancer Society.
• Diagnostic and therapeutic delays among a multiethnic sample of breast and cervical cancer survivors
  - Cancer (Philad ) 116(13):3195-3204 (2010)
  BACKGROUND: Several publications reporting on health disparities document that ethnic minorities disproportionately experience delays in healthcare access, delivery, and treatment. However, few studies examine factors underlying access and receipt of healthcare among cancer survivors from the patient perspective. This study explores diagnostic and therapeutic care delays among a multiethnic sample of breast and cervical cancer survivors and examines contextual factors influencing diagnostic and therapeutic care delays. METHODS: Population-based sampling and a cross-sectional design were used to recruit 1377 survivors (breast cancer, n = 698; cervical cancer, n = 679). This multiethnic sample included 449 European American, 185 African American, 468 Latina American, and 275 Asian American survivors. RESULTS: Latina Americans were more likely to report diagnostic delays (P = .003), whereas African Americans were more likely to report therapeutic delays (P = .007). In terms of cancer type, cervical cancer survivors were more likely to report diagnostic (P = .004) and therapeutic delays (P = .000) compared with breast cancer survivors. Fear of finding cancer was the most frequently cited reason for diagnostic delays, and medical reasons were most frequently cited for therapeutic delays. CONCLUSIONS: Due in part to a higher proportion of diagnostic and therapeutic delays, ethnic minorities endure greater cancer burden, including poorer survival and survivorship outcomes. The medical community must recognize the impact of existing psychological and cultural dimensions on diagnostic care, as well as the personal and healthcare system level barriers that contribute to therapeutic delays. Cancer 2010. © 2010 American Cancer Society.
• Ethnicity and management of colon cancer in New Zealand : Do indigenous patients get a worse deal?
  - Cancer (Philad ) 116(13):3205-3214 (2010)
  BACKGROUND: Racial and ethnic inequalities in colon cancer treatment have been reported in the United States but not elsewhere. The authors of this report compared cancer treatment in a nationally representative cohort of Maori (indigenous) and non-Maori New Zealanders with colon cancer. METHODS: On the basis of cancer registry data, 301 Maori patients and 329 randomly selected non-Maori patients were identified who were diagnosed with colon cancer between 1996 and 2003. Medical notes were reviewed, and surgical and oncology treatments were compared by indigenous status. RESULTS: Maori and non-Maori patients had similar rates of surgical resection, although Maori patients were less likely to undergo extensive lymph node clearance and were more likely to die during the postoperative period. Maori patients were significantly less likely to receive chemotherapy for stage III disease (relative risk [RR], 0.69; 95% confidence interval [CI], 0.53-0.91) and were more likely to experience a delay of at least 8 weeks before starting chemotherapy (RR, 1.98; 95%CI, 1.23-3.16). Treatment disparities were not explained by differences in tumor characteristics or patient comorbidity. CONCLUSIONS: Maori New Zealanders with colon cancer were less likely to receive adjuvant chemotherapy and experienced a lower quality of care compared with non-Maori patients. The authors concluded that attention to health system factors is needed to ensure equal access and quality of cancer treatment for indigenous and ethnic minority populations. Cancer 2010. © 2010 American Cancer Society.
• Comparative analysis of breast cancer risk factors among hispanic and non-hispanic white women
  - Cancer (Philad ) 116(13):3215-3223 (2010)
  BACKGROUND: Hispanic and non-Hispanic white (NHW) populations within the United States have different breast cancer incidence rates, yet there is limited research on how ethnic differences in the prevalence of established risk factors and their associations with breast cancer contribute to the observed differences. METHODS: Odds ratios and population-attributable risk estimates for breast cancer were determined for Hispanic and NHW women in the population-based, case-control 4-Corners Breast Cancer Study. RESULTS: When comparing NHW and Hispanic women, the authors observed differences in the prevalence of certain risk factors and in the magnitude and direction of their associations with breast cancer. Hispanic women were more likely to have characteristics associated with lower breast cancer risk, such as younger age at first birth, having more children, shorter height, less hormone use, and less alcohol consumption. Among premenopausal women, ethnic differences in risk were observed with taller height and positive family history, which were not associated with breast cancer among Hispanic women. Among postmenopausal women, associations for certain risk factors were either weaker or were not observed in Hispanics, such as recent estrogen plus progestin hormone therapy use and younger age at menarche. Among NHW women, an estimated 62% to 75% of breast cancers were attributed to the evaluated risk factors compared with 7% to 36% in Hispanic women. CONCLUSIONS: Breast cancer risk factors established in NHW populations had less influence on breast cancer risk in Hispanic women. These findings reflect the need to further evaluate breast cancer risk factors among different ethnic and racial populations. Cancer 2010. © 2010 American Cancer Society.
• Economic evaluation of erythropoiesis-stimulating agents for anemia related to cancer
  - Cancer (Philad ) 116(13):3224-3232 (2010)
  BACKGROUND: Erythropoiesis-stimulating agents (ESA) administered to cancer patients with anemia reduce the need for blood transfusions and improve quality-of-life (QOL). Concerns about toxicity have led to more restrictive recommendations for ESA use; however, the incremental costs and benefits of such a strategy are unknown. METHODS: The authors created a decision model to examine the costs and consequences of ESA use in patients with anemia and cancer from the perspective of the Canadian public healthcare system. Model inputs were informed by a recent systematic review. Extensive sensitivity analyses and scenario analysis rigorously assessed QOL benefits and more conservative ESA administration practices (initial hemoglobin [Hb] <10 g/dL, target Hb 12 g/dL, and chemotherapy induced anemia only). RESULTS: Compared with supportive transfusions only, conventional ESA treatment was associated with an incremental cost per quality-adjusted life year (QALY) gained of $267,000 during a 15-week time frame. During a 1.3-year time horizon, ESA was associated with higher costs and worse clinical outcomes. In scenarios where multiple assumptions regarding QOL all favored ESA, the lowest incremental cost per QALY gained was $126,000. Analyses simulating the use of ESA in accordance with recently issued guidelines resulted in incremental cost per QALY gained of >$100,000 or ESA being dominated (greater costs with lower benefit) in the majority of the scenarios, although greater variability in the cost-utility ratio was present. CONCLUSIONS: Use of ESA for anemia related to cancer is associated with incremental cost-effectiveness ratios that are not economically attractive, even when used in a conservative fashion recommended by current guidelines. Cancer 2010. © 2010 American Cancer Society.
• Signaling of ERBB receptor tyrosine kinases promotes neuroblastoma growth in vitro and in vivo
  - Cancer (Philad ) 116(13):3233-3243 (2010)
  BACKGROUND: ERBB receptor tyrosine kinases can mediate proliferation, migration, adhesion, differentiation, and survival in many types of cells and play critical roles in many malignancies. Recent reports suggest a role for EGFR signaling in proliferation and survival of neuroblastoma, a common form of pediatric cancer that often has an extremely poor outcome. METHODS: The authors examined ERBB family expression in neuroblastoma cell lines and patient samples by flow cytometry, western blot, and quantitative real time polymerase chain reaction (Q-PCR). Response to ERBB inhibition was assessed in vitro by cell-cycle analysis and western blot and in vivo by serial tumor-size measurements. RESULTS: A panel of neuroblastoma cell lines and primary patient tumors expressed EGFR, HER-3, and HER-4, with HER-2 in some tumors. HER-4 mRNA was expressed predominantly in cleavable isoforms. Whereas EGFR inhibition with erlotinib and pan-ERBB inhibition with CI-1033 inhibited EGF-induced phosphorylation of EGFR, AKT, and ERK1/2, only CI-1033 induced growth inhibition and dose-dependent apoptosis in vitro. Both CI-1033 and erlotinib treatment of neuroblastoma xenograft tumors resulted in decreased tumor growth in vivo, although CI-1033 was more effective. In vivo expression of EGFR was observed predominantly in vascular endothelial cells. CONCLUSIONS: Pan-ERBB inhibition is required for ERBB-related neuroblastoma apoptosis in vitro, although EGFR contributes indirectly to tumor growth in vivo. Inhibition of EGFR in endothelial cells may be an important aspect of erlotinib's impact on neuroblastoma growth in vivo. Our results suggest that non-EGFR ERBB family members contribute directly to neuroblastoma growth and survival, and pan-ERBB inhibition represents a potential therapeutic target for treating neuroblastoma. Cancer 2010. © 2010 American Cancer Society.
• Informed consent for pediatric phase 1 cancer trials: Physicians' perspectives
  - Cancer (Philad ) 116(13):3244-3250 (2010)
  BACKGROUND. This study was conducted to gather pediatric oncologists' opinions about and suggestions for improvement of informed consent (IC) in pediatric phase 1 cancer trials. METHODS. A questionnaire designed to elicit perspectives was distributed to 146 physicians at 6 participating institutions. A total of 103 completed surveys were returned for a 71% response rate. RESULTS. Pediatric oncologists believe providing information so families can decide about phase 1 study entry is the most important goal of the IC process (ICP). The majority of physicians (64%) report that they describe the phase 1 study without any attempt to influence parents' decisions. Several answers provided by physicians were associated with their gender and prior IC training. Male physicians were significantly more likely to endorse the no-attempt-to-influence approach, whereas female physicians were more likely to suggest to parents that other children will benefit from what is learned in phase 1 studies. Responses to an open-ended question provided 63 suggestions for improvement of the ICP, including document and training changes and tools to enhance physician-family communication. CONCLUSIONS. Pediatric oncologists tended to present phase 1 trials as an option rather than a strong recommendation and were reluctant to influence decisions of families about these studies. They believe most but not all parents understand key concepts involved in consent to this type of research, and had ample suggestions for how to improve the ICP. Future research and education efforts around this ethically challenging topic were warranted. Cancer 2010. © 2010 American Cancer Society.
• Palliative radiotherapy tailored to life expectancy in end-stage cancer patients : Reality or myth?
  - Cancer (Philad ) 116(13):3251-3256 (2010)
  BACKGROUND: The purpose of the study was to investigate the adequacy of palliative radiation treatment in end-stage cancer patients. METHODS: Of 216 patients referred for palliative radiotherapy, 33 died within 30 days and constitute the population of the study. Symptoms, Karnofsky Performance Status (KPS), laboratory tests, and survival estimates were obtained. Treatment course was evaluated by medical records. Univariate analyses were performed by using the 2-sided chi-square test. With significant variables, multiple regression analysis was performed. RESULTS: Median age was 65 years, and median survival was 15 days. Prevailing primary cancer types were lung (39%) and breast (18%). Metastases were present in 94% of patients, brain (36%), bone (24%) and lung (18%). In 91%, KPS was <50%. KPS, lactate dehydrogenase, dyspnea, leucocytosis, and brain metastases conveyed a poor prognosis. From 85 survival estimates, only 16% were correct, but 21% expected more than 6 months. Radiotherapy was delivered to 91% of patients. In 90% of radiation treatments, regimens of at least 30 Gy with fractions of 2-3 Gy were applied. Half of the patients spent greater than 60% of their remaining lifespan on therapy. In only 58% of patients was radiotherapy completed. Progressive complaints were noted in 52% and palliation in 26%. CONCLUSIONS: Radiotherapy was not appropriately customized to these patients considering the median treatment time, which resembles the median survival time. About half of the patients did not benefit despite spending most of their remaining lives on therapy. Prolonged irradiation schedules probably reflect overly optimistic prognoses and unrealistic concerns about late radiation damage. Single-fraction radiotherapy was too seldom used. Cancer 2010. © 2010 American Cancer Society.
• A national propensity-adjusted analysis of adjuvant radiotherapy in the treatment of resected pancreatic adenocarcinoma
  - Cancer (Philad ) 116(13):3257-3266 (2010)
  BACKGROUND: The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national-level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences. METHODS: Patients were identified from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2005 dataset). Multivariate analyses to determine the effect of RT on overall survival were performed using propensity-adjusted Cox proportional hazards and Kaplan-Meier analyses. RESULTS: In total, 5676 patients with resected pancreatic adenocarcinoma were identified, and 40.8% of those patients had received adjuvant RT. Univariate predictors of survival included age, race, marital status, disease stage, tumor size, tumor extension, tumor grade, lymph node status, year of diagnosis, type of resection, and receipt of RT (all P < .002). In a Cox model, independent predictors of improved survival included white race, married status, earlier stage, smaller tumors, well differentiated tumors, negative lymph node (N0) status, recent diagnosis, and receipt of RT (all P < .05). In a propensity-adjusted proportional hazards regression, the benefit of adjuvant treatment that included RT remained significant after adjusting for the likelihood of receiving RT (hazard ratio, 0.773; 95% confidence interval, 0.714-0.836; P < .0001). Within all 5 propensity strata, Kaplan-Meier survival differed significantly (P < .0001 [lowest and highest probability strata] and P = .0165 [! middle stratum with a pseudorandom probability of RT]). CONCLUSIONS: Adjuvant RT for resected pancreatic adenocarcinoma was associated with a significant survival advantage in a large national database, even after using propensity score methods to adjust for differences between treatment groups. The authors concluded that adjuvant RT should be considered for all appropriate patients who have resected pancreatic adenocarcinoma. Cancer 2010. © 2010 American Cancer Society.
• Cancer Quality-ASSIST supportive oncology quality indicator set : Feasibility, reliability, and validity testing
  - Cancer (Philad ) 116(13):3267-3275 (2010)
  BACKGROUND: Although measuring the quality of symptom management and end-of-life care could help provide a basis for improving supportive care for advanced cancer, few quality indicators in this area have been rigorously developed or evaluated. METHODS: The authors conducted a pilot evaluation of a comprehensive set of 92 supportive oncology quality indicators, Cancer Quality-ASSIST, including outpatient and hospital indicators for symptoms commonly related to cancer and its treatment and information and care planning. They operationalized the indicators and developed an electronic abstraction tool and extensive guidelines and training materials. Quality assurance nurses abstracted the medical records for 356 advanced cancer patients in 2 settings: a Veterans Administration hospital and an academic hospital and cancer center. The authors evaluated the indicators' feasibility, inter-rater reliability, and validity. RESULTS: The authors successfully evaluated 78 indicators across the domains; results were similar in the 2 settings. They could not feasibly evaluate 3 indicators because of low prevalence; 22 indicators had significant inter-rater reliability issues, 9 had significant validity issues, and 3 had both reliability and validity issues, leaving a set of 41 indicators most promising for further testing and use in this population, with an overall kappa score of 0.85 for specified care. CONCLUSIONS: Of 92 Cancer Quality-ASSIST quality indicators for symptoms, treatment toxicity, and information and care planning, 41 were sufficiently feasible, reliable, and valid to be used for patients with advanced cancer in these settings. This set of indicators shows promise for describing key supportive care processes in advanced cancer. Cancer 2010. © 2010 American Cancer Society.
• Nuclear factor B transcription factors are coexpressed and convey a poor outcome in ovarian cancer
  - Cancer (Philad ) 116(13):3276-3284 (2010)
  BACKGROUND: Recent work has suggested a role for nuclear factor B (NF-B) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-B in ovarian cancer is unknown. The authors hypothesized that the NF-B pathway is over activated in aggressive ovarian cancers. METHODS: The levels of 3 NF-B transcription factors, the activating inhibitors of NF-B (IB) kinases, and the NF-B target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-B pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. RESULTS: The presence of NF-B proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IB kinase , 1 component of a key trimolecular regulatory complex. Coexpression of the NF-B machinery suggested activity of NF-B signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. CONCLUSIONS: The deregulation of NF-B activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-B pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. Cancer 2010. © 2010 American Cancer Society.
• Radiofrequency field-induced thermal cytotoxicity in cancer cells treated with fluorescent nanoparticles
  - Cancer (Philad ) 116(13):3285-3293 (2010)
  BACKGROUND: Nonionizing radiation, such as radiofrequency field and near infrared laser, induces thermal cytotoxicity in cancer cells treated with gold nanoparticles. Quantum dots are fluorescent semiconducting nanoparticles that were hypothesized to induce similar injury after radiofrequency field irradiation. METHODS: Gold nanoparticles and 2 types of quantum dot (cadmium-selenide and indium-gallium-phosphide) conjugated to cetuximab (C225), a monoclonal antibody against human epidermal growth factor receptor (EGFR)-1, demonstrated concentration-dependent heating in a radiofrequency field. The authors investigated the effect of radiofrequency field exposure after targeted nanoparticle treatment in a coculture of 2 human cancer cell lines that have differential EGFR-1 expression (a high-expressing pancreatic carcinoma, Panc-1, and a low-expressing breast carcinoma, Cama-1). RESULTS: Radiofrequency revealed that Panc-1 or Cama-1 cells not containing gold nanoparticles or quantum dots had a viability of >92%. The viability of Panc-1 cells exposed to the radiofrequency field after treatment with 50 nM Au-C225 was 39.4% ± 8.3% without injury to bystander Cama-1 cells (viability was 93.7% ± 1.0%; P .0006). Panc-1 cells treated with targeted cadmium-selenide quantum dots were only 47.5% viable after radiofrequency field exposure (P<.0001 compared with radiofrequency only Panc-1 control cells). Targeted indium-gallium-phosphide quantum dots decreased Panc-1 viability to 58.2% ± 3.4% after radiofrequency field exposure (P = .0004 compared with Cama-1 and Panc-1 controls). CONCLUSIONS: The authors selectively induced radiofrequency field cytotoxicity in Panc-1 cells without injury to bystander Cama-1 cells using EGFR-1-targeted nanoparticles, and demonstrated an interesting bifunctionality of fluorescent nanoparticles as agents for both cancer cell imaging and treatment. Cancer 2010. © 2010 American Cancer Society.
• 1,25D3 Enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models
  - Cancer (Philad ) 116(13):3294-3303 (2010)
  BACKGROUND: 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin is a current standard chemotherapy regimen for bladder cancer. The authors investigated whether 1,25D3 could enhance the antitumor activity of gemcitabine and cisplatin in bladder cancer model systems. METHODS: Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by gemcitabine and cisplatin. Apoptosis was assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined by using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. RESULTS: 1,25D3 pretreatment enhanced gemcitabine and cisplatin-induced apoptosis and the activities of caspases 8, 9, and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced gemcitabine and cisplatin-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by gemcitabine and cisplatin or 1,25D3 and gemcitabine and cisplatin. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, gemcitabine and cisplatin, or 1,25D3 and gemcitabine and cisplatin. 1,25D3 and gemcitabine and cisplatin combination enhanced tumor regression compared with 1,25D3 or gemcitabine and cisplatin alone. CONCLUSIONS: 1,25D3 potentiates gemcitabine and cisplatin-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. Cancer 2010; 116:3294-303. © 2010 American Cancer Society.
• Depression as a predictor of disease progression and mortality in cancer patients : A meta-analysis
  - Cancer (Philad ) 116(13):3304 (2010)
  
• Reply to Depression as a predictor of disease progression and mortality in cancer patients : A meta-analysis
  - Cancer (Philad ) 116(13):3304-3305 (2010)