Hot off the presses! Mar 03 Cancer

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Latest Articles Include:

• CancerScope
  - Cancer 116(6):1393-1394 (2010)
  
• Increased cancer risk associated with breast tenderness during HRT
  - Cancer 116(6):1394-1395 (2010)
  
• Journey forward offers treatment plan for cancer survivors
  - Cancer 116(6):1395 (2010)
  
• Common sexual infection linked to aggressive prostate cancer
  - Cancer 116(6):1395 (2010)
  
• Guide for investigators conducting international cancer research involving developing nations
  Martin IK Awuah B Newman LA - Cancer 116(6):1396-1399 (2010)
  International studies of cancer will increasingly involve collaboration with underdeveloped countries. These research partnerships will also strengthen communication and understanding between diverse populations.
• The heterogeneity of epithelial ovarian cancer : Getting it right
  Gershenson DM - Cancer 116(6):1400-1402 (2010)
  Epithelial ovarian cancer is heterogeneous and comprises 4 major rare subtypes - mucinous, clear cell, low-grade serous, and endometrioid - all distinct from the more common high-grade serous carcinoma. Women with uncommon histotypes should be triaged to separate clinical trials.
• Refining the criteria for sentinel lymph node biopsy in patients with thinner melanoma : A roadmap for the future
  Messina JL Sondak VK - Cancer 116(6):1403-1405 (2010)
  Numerous studies validate the standard practice of sentinel lymph node biopsy for patients with melanoma, and recent results from the Sunbelt Melanoma Trial highlight its important prognostic role in patients with thinner (1.0 mm-2.0 mm) melanomas. Future studies including large, unselected groups of patients with thin melanoma undergoing thorough pathologic microstaging of both the primary and the sentinel node are necessary to address remaining questions and aid in refining selection criteria for this procedure.
• Pathogenesis of osteoblastic bone metastases from prostate cancer
  Toni I Flamini E Mercatali L Sacanna E Serra P Amadori D - Cancer 116(6):1406-1418 (2010)
  Prostate cancer is the second leading cause of cancer-related death in men. A typical feature of this disease is its ability to metastasize to bone. It is mainly osteosclerotic, and is caused by a relative excess of osteoblast activity, leading to an abnormal bone formation. Bone metastases are the result of a complex series of steps that are not yet fully understood and depend on dynamic crosstalk between metastatic cancer cells, cellular components of the bone marrow microenvironment, and bone matrix (osteoblasts and osteoclasts). Prostate cancer cells from primary tissue undergo an epithelial-mesenchymal transition to disseminate and acquire a bone-like phenotype to metastasize in bone tissue. This review discusses the biological processes and the molecules involved in the progression of bone metastases. Here we focus on the routes of osteoblast differentiation and activation, the crosstalk between bone cells and tumor cells, and the molecules involved in these proc! esses that are expressed by both osteoblasts and tumor cells. Furthermore, this review deals with the recently elucidated role of osteoclasts in prostate cancer bone metastases. Certainly, to better understand the underlying mechanisms of bone metastasis and so improve targeted bone therapies, further studies are warranted to shed light on the probable role of the premetastatic niche and the involvement of cancer stem cells. Cancer 2010. © 2010 American Cancer Society.
• Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase
  - Cancer 116(6):1419-1430 (2010)
  Identification of BCR-ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR-ABL inhibitor, is the standard of care for the first-line treatment of patients with chronic-phase CML because of its high long-term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard-dose imatinib (400 mg daily), imatinib dose escalation (600-800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR-ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second-generation tyrosine kinase inhibitors dasatini! b and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib-resistant or imatinib-intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.
• Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy : A single institutional experience with 359 cases
  Bhargava R Beriwal S Dabbs DJ Ozbek U Soran A Johnson RR Brufsky AM Lembersky BC Ahrendt GM - Cancer 116(6):1431-1439 (2010)
  BACKGROUND: Complete pathologic response to neoadjuvant chemotherapy (NACT) is predominantly seen in ERBB2 and basal-like tumors using expression profiling. We hypothesize that a similar response could be predicted using semiquantitative immunohistochemistry for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). METHODS: ER, PR, and HER2 were used to classify 359 tumors treated with NACT into 6 groups: luminal A (strong ER+, HER2 negative), luminal B (weak to moderate ER+, HER2 negative), triple negative (negative for ER, PR, and HER2), ERBB2 (negative for ER and PR, but HER2+), luminal A-HER2 hybrid (strong ER+ and HER2+), and luminal B-HER2 hybrid (weak to moderate ER+ and HER2+). Complete pathologic response was defined as absence of invasive carcinoma in the breast and regional lymph nodes. RESULTS: Thirteen percent (48 of 359) demonstrated complete pathologic response. The highest rate of complete pathologic response was seen in ERBB2 (33%; 19 of 57) and triple negative (30%; 24 of 79) tumor classes. Among the ER+ molecular group, the highest rate of complete pathologic response was seen among luminal B-HER2 hybrid tumors, 8% (2 of 24). Remainder of ER+ tumors demonstrated a very low rate of complete pathologic response, 1.5% (3 of 198). The 5-year survival for patients achieving complete pathologic response was 96% compared with 75% in patients that failed to achieve complete pathologic response. The overall survival was worse in the ER-negative group (ERBB2 and triple negative) compared with the ER-positive group. CONCLUSIONS: We confirm the recently defined triple negative paradox, or rather hormone receptor negative paradox, that despite the best response to NACT, ERBB2 and triple negative tumors show the worst overall survival because of higher relapse among those with residual disease. Cancer 2010. © 2010 American Cancer Society.
• A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3-times-daily regimen to treat patients with recurrent metastatic breast cancer
  Hortobagyi GN Heim W Hutchins L Rivera E Mason B Booser DJ Kirshner J - Cancer 116(6):1440-1445 (2010)
  BACKGROUND: A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m2, administered in 3 doses of 100 mg/m2 each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival. RESULTS: Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.
• Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer
  Overman MJ Kazmi SM Jhamb J Lin E Yao JC Abbruzzese JL Ho L Ajani J Phan A - Cancer 116(6):1446-1453 (2010)
  BACKGROUND: Docetaxel, cisplatin, and 5-flurouracil (DCF) administered every 3 weeks produces a high rate of treatment-related adverse events. The objective of the current study was to evaluate the efficacy and tolerability of a weekly formulation of DCF. METHODS: Data from 117 patients treated at The University of Texas M. D. Anderson Cancer Center from 2002 to 2006 with a weekly formulation of DCF were retrospectively collected. A total of 95 patients received front-line therapy with 20 mg/m2 of cisplatin, 350 mg/m2 of 5-fluorouracil, and 20 mg/m2 of docetaxel administered once weekly for 6 consecutive weeks followed by a 2-week break. RESULTS: Ninety-five patients (median age, 62 years [range, 33 to 87 years], with an Eastern Cooperative Oncology Group performance status of 1 or 2 in 67%) received a median of 10 weeks of DCF treatment (range, 3-41 weeks). Grade 3 or 4 hematologic toxicity (assessed according to National Cancer Institute Common Toxicity Criteria [version 3.0]) included granulocytopenia (4 patients) and anemia (9 patients). None of the patients developed a febrile neutropenic infection, but grade 3 or 4 non-neutropenic infections occurred in 8 patients. Eighty patients had measurable disease with an objective response rate determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of 34% (95% confidence interval [95% CI], 24-45%). The median follow-up was 9 months, with a median time to disease progression of 4.1 months (95% CI, 3.6-5.7 months) and a median overall survival of 8.9 months (95% CI, 7.7-10.8 months). CONCLUSIONS: In patients with advanced gastric and esophageal cancer who were not candidates for every-3-week DCF, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients. Cancer 2010. © 2010 American Cancer Society.
• Ability of integrated positron emission and computed tomography to detect significant colonic pathology : The experience of a tertiary cancer center
  Weston BR Iyer RB Qiao W Lee JH Bresalier RS Ross WA - Cancer 116(6):1454-1461 (2010)
  BACKGROUND: The ability of integrated positron emission tomography and computed axial tomography (PET-CT) to detect colonic pathology is not fully defined. The purpose of this study was to assess the ability of PET-CT to detect colonic pathology and to determine the significance of (18F)2-fluoro-2-deoxyglucose (18F-FDG) activity noted incidentally in the colon on PET-CT. METHODS: Records for all patients who underwent PET-CT and colonoscopy at our institution were reviewed. Patients with history of colonic malignancy or colon surgery were excluded. RESULTS: Fifty-eight patients had incidental colonic 18F-FDG activity on PET (Group A) and 272 had none (Group B). In Group A, 65% of patients had pathologic findings detected on colonoscopy that corresponded to the site of PET activity. Standardized uptake value (SUV) readings were not helpful in distinguishing true-positives from false-positives. In Group B, 11.8% of patients were found to have significant colonic findings. Lesions not detected by PET-CT included 4 colon cancers, 7 advanced adenomas, and 10 patients with colonic lymphoma. Overall, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET-CT for detecting significant pathology were 53%, 93%, 65%, 89%, and 85%, respectively. For detecting colon cancer and adenomas 10 mm or more, the sensitivity, specificity, PPV, NPV, and accuracy of PET-CT were 72%, 90%, 45%, 96%, and 88%, respectively. CONCLUSIONS: Incidental colonic activity detected by PET-CT warrants further evaluation with colonoscopy. However, negative PET-CT does not rule out significant colonic pathology including colon cancer, advanced adenomas, or lymphoma. Cancer 2010. © 2010 American Cancer Society.
• Mucinous but not clear cell histology is associated with inferior survival in patients with advanced stage ovarian carcinoma treated with platinum-paclitaxel chemotherapy
  Bamias A Psaltopoulou T Sotiropoulou M Haidopoulos D Lianos E Bournakis E Papadimitriou C Rodolakis A Vlahos G Dimopoulos MA - Cancer 116(6):1462-1468 (2010)
  BACKGROUND: Mucinous and clear cell histology have been associated with adverse prognosis in ovarian carcinomas. The authors compared the outcome of these subtypes with that of serous tumors in patients who were treated with combination paclitaxel/platinum at their center. METHODS: Four hundred twenty patients with histologically confirmed, serous (n = 367), mucinous (n = 24), or clear cell (n = 29) ovarian carcinomas, International Federation of Gynecology and Obstetrics stage III or IV disease, and who were treated with paclitaxel/platinum after cytoreductive surgery were included in this analysis. RESULTS: The median overall survival for each histological subtype was 47.7 months (95% confidence interval [CI], 37.7-57.7 months) for serous, 15.4 months (95% CI, 4.2-26.6 months) for mucinous, and 36.6 months (95% CI, 22.7-50.5 months) for clear cell carcinomas. Cox regression analysis showed that mucinous histology was an independent predictor of poor prognosis compared with serous tumors (hazard ratio, 0.360; 95% CI, 0.215-0.603; P = .001). In contrast, such a difference between clear cell and serous carcinomas was not found (P = .337). Median survival of patients with mucinous tumors and residual disease >2 cm was poor, averaging 7.1 months (95% CI, 4.6-9.6 months). CONCLUSIONS: Mucinous but not clear cell histology is associated with significantly worse prognosis in advanced ovarian cancer treated with combination platinum/paclitaxel. Different therapeutic strategies should be studied in this entity. Cancer 2010. © 2010 American Cancer Society.
• Pelvic lymph node F-18 fluorodeoxyglucose uptake as a prognostic biomarker in newly diagnosed patients with locally advanced cervical cancer
  Kidd EA Siegel BA Dehdashti F Grigsby PW - Cancer 116(6):1469-1475 (2010)
  BACKGROUND: The objective of the current study was to evaluate the prognostic significance of the maximum standardized uptake value (SUVmax) of F-18 fluorodeoxyglucose (FDG) as measured by positron emission tomography (PET) in pelvic lymph nodes in patients with cervical cancer. METHODS: The authors studied cervical cancer patients with pelvic lymph node metastasis, as evidenced on FDG-PET, who were treated between November 2003 and October 2008. The maximum dimension and SUVmax for the most FDG-avid pelvic lymph node (SUVPLN) and the SUVmax of the primary cervical tumor (SUVcervix) were recorded from the FDG-PET/computed tomography (CT) scan. The SUVPLN was analyzed for its association with treatment response, pelvic disease recurrence, disease-specific survival, and overall survival. RESULTS: The population was comprised of 83 women with International Federation of Gynecology and Obstetrics (FIGO) stages IB1 to IIIB cervical cancer. The average SUVPLN was 6.9 (range, 2.1-33.0), whereas the average SUVcervix was 14.0 (range, 3.2-38.4). The SUVcervix and SUVPLN were found to be weakly correlated (correlation coefficient [R2] = 0.301). The average size of the pelvic lymph nodes was 2.1 cm (range, 0.6-7.9 cm), and was also found to be only weakly associated with the SUVPLN (R2 = 0.225). The SUVPLN was found to be correlated with an increased risk of persistent disease after treatment (P = .0025), specifically within the pelvic lymph node region (P = .0003). The SUVPLN was found to be predictive of an increased risk of ever developing pelvic disease recurrence (P = .0035). Patients with a higher SUVPLN were found to have significantly worse disease-specific (P = .0230) and overall survival (P = .0378) using Kaplan-Meier evaluation. A Cox proportional hazards model for! the risk of pelvic disease recurrence was performed including SUVPLN, patient age, and tumor stage, and found only an increased SUVPLN to be an independent predictor. CONCLUSIONS: SUVPLN is a prognostic biomarker, predicting treatment response, pelvic recurrence risk, and disease-specific survival in patients with cervical cancer. Cancer 2010. © 2010 American Cancer Society.
• Ten-year follow-up of a phase 2 study of dose-intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor-prognosis, advanced-stage epithelial ovarian cancer
  Sarosy GA Hussain MM Seiden MV Fuller AF Nikrui N Goodman A Minasian L Reed E Steinberg SM Kohn EC - Cancer 116(6):1476-1484 (2010)
  BACKGROUND: The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced-stage epithelial ovarian cancer (EOC) who were receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. METHODS: Patients with stage III/IV EOC received cyclophosphamide 750 mg/m2, followed by a 24-hour infusion of paclitaxel 250 mg/m2 and cisplatin 75 mg/m2 on Day 2. Filgrastim began on Day 3 at 10 g/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel. RESULTS: Sixty-two patients were enrolled. Thirty-two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent-to-treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow-up of 11.4 years, the median progression-free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel. CONCLUSIONS: The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose-dense or dose-intense paclitaxel regimens in women with newly diagnosed, advanced-stage EOC. Cancer 2010. © 2010 American Cancer Society.
• Azacitidine for the treatment of lower risk myelodysplastic syndromes : A retrospective study of 74 patients enrolled in an Italian named patient program
  Musto P Maurillo L Spagnoli A Gozzini A Rivellini F Lunghi M Villani O Aloe-Spiriti MA Venditti A Santini V The "Ad Hoc" Italian Cooperative Study Group on Azacitidine in Myelodysplastic Syndromes Acute Leukemias - Cancer 116(6):1485-1494 (2010)
  BACKGROUND: Azacitidine induces responses and prolongs overall survival compared with conventional care regimens in patients who have high-risk myelodysplastic syndromes (MDS). However, limited data are available concerning the efficacy and safety of azacitidine in patients who have lower risk MDS. METHODS: The authors retrospectively evaluated 74 patients with International Prognostic Scoring System low-risk or intermediate 1-risk MDS, who received azacitidine on a national named patient program. At baseline, 84% of patients were transfusion-dependent, 57% had received erythropoietin, and 51% were aged >70 years. Azacitidine was administered subcutaneously for 5 days (n = 29 patients), 7 days (n = 43 patients), or 10 days (n = 2 patients) every month at a dose of 75 mg/m2 daily (n = 45 patients) or at a fixed dose of 100 mg daily (n = 29 patients) and for a median of 7 cycles (range, 1-30 cycles). RESULTS: According to the 2006 International Working Group criteria, overall response rate (ORR) was 45.9%, including complete responses (10.8%), partial responses (9.5%), hematologic improvements (20.3%), and bone marrow complete responses (5.4%). The ORR was 51.6% in 64 patients who completed 4 cycles of treatment. The median duration of response was 6 months (range, 1-30 months). After a median follow-up of 15 months, 71% of patients remained alive. A survival benefit was observed in responders versus nonresponders (94% vs 54% of patients projected to be alive at 2.5 years, respectively; P < .0014). The most common grade 3 or 4 adverse events were myelosuppression (21.6%) and infection (6.8%). CONCLUSIONS: The current results indicated that azacitidine may be a feasible and effective treatment for patients with lower risk MDS. Cancer 2010. © 2010 American Cancer Society.
• Phase 2 study of intrathecal, long-acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus-related non-Hodgkin lymphoma
  Spina M Chimienti E Martellotta F Vaccher E Berretta M Zanet E Lleshi A Canzonieri V Bulian P Tirelli U - Cancer 116(6):1495-1501 (2010)
  BACKGROUND: Patients with aggressive non-Hodgkin lymphoma (NHL) develop central nervous system (CNS) progression or recurrence during the course of their disease. Patients with human immunodeficiency virus (HIV)-NHL often develop CNS progression despite the use of prophylaxis. Liposomal cytarabine (DepoCyte) has shown activity in lymphomatous meningitis, but there are limited data for prophylaxis. METHODS: Between May 2006 and December 2008, a phase 2 study of intrathecal liposomal cytarabine was performed at the dose of 50 mg in 30 patients with HIV-NHL, with the aim of evaluating feasibility and activity for prophylaxis. RESULTS: Liposomal cytarabine was well tolerated, with headache grade I to III being the most frequent side effect in 40% of patients. With a median follow-up of 10.5 months, only 1 (3%) patient developed a combined systemic and meningeal recurrence. The use of liposomal cytarabine allowed significant reduction of the number of lumbar injections in comparison to the standard schedules (around 50%), improving the quality of life of patients and reducing the professional exposure risk. CONCLUSIONS: In this first study on prophylaxis of lymphomatous meningitis in HIV-NHL, liposomal cytarabine seems safe and active; it reduces by approximately 50% the number of lumbar punctures, and exposure risk for health staff as well. Cancer 2010. © 2010 American Cancer Society.
• Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy
  - Cancer 116(6):1502-1509 (2010)
  BACKGROUND: During chemotherapy, some colorectal liver metastases (LMs) disappear on serial imaging. This disappearance may represent a complete response (CR) or a reduction in the sensitivity of imaging during chemotherapy. The objective of the current study was to determine the fate of disappearing LMs (DLMs) and the factors that predict a true CR. METHODS: Between 2000 and 2003, 435 patients who were evaluated by hepatobiliary surgeons received chemotherapy before they were considered for resection. Inclusion criteria were <12 LMs before chemotherapy, at least 1 DLM on a computed tomography (CT) scan, and either surgical resection or 1 year of clinical follow-up after the disappearance of LMs. A true CR was defined as either a pathologic CR (no tumor detected in the resection specimen) or a durable clinical CR (did not reappear on follow-up imaging). Clinical and pathologic factors were analyzed to identify those associated with a true CR. RESULTS: During chemotherapy, 39 patients (9%) had a total of 118 DLMs on follow-up CT scans. Sixty-eight DLMs were resected, and 50 were followed clinically. Overall, 75 DLMs (64%) were true CRs, including 44 pathologic CRs and 31 durable clinical CRs. On multivariate analysis, the use of hepatic arterial infusion (HAI) chemotherapy (odds ratio [OR], 6.2; P = .02), the inability to observe the DLM on a magnetic resonance image (OR, 4.7; P = .005), and normalization of serum carcinoembryonic antigen levels (OR, 4.6; P = .006) were associated independently with a true CR. CONCLUSIONS: Approximately 66% of DLMs represented a true CR according to assessment by resection or radiologic follow-up. Predictive factors may help to stratify patients who are likely to harbor residual disease. Cancer 2010. © 2010 American Cancer Society.
• Proposed adjustments to pathologic staging of epithelial malignant pleural mesothelioma based on analysis of 354 cases
  Richards WG Godleski JJ Yeap BY Corson JM Chirieac LR Zellos L Mujoomdar A Jaklitsch MT Bueno R Sugarbaker DJ - Cancer 116(6):1510-1517 (2010)
  BACKGROUND: Several pathologic staging systems for malignant pleural mesothelioma (MPM) have been published, but none of them provide optimal survival stratification or stage distribution among patients treated with surgery. Interpretation of prior studies that correlate pathologic factors with outcome has been confounded by the inclusion of patients undergoing differing surgical procedures and with varied tumor histology. METHODS: We examined pathologic characteristics, previously included in published studies, and explored correlations with outcome among patients with epithelioid MPM who underwent extrapleural pneumonectomy (EPP) at Brigham and Women's Hospital (BWH). Comparisons of survival among patients with and without each tumor or lymph node feature guided adjustments to the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) classification criteria. Proportional hazards modeling of TN combinations guided adjustments to stage groupings. RESULTS: Three hundred fifty-four patients were resectable by EPP and had complete pathologic data. Overall median survival was 18 months from surgery. By AJCC/UICC criteria, 233 (66%) patients were stage III, whereas by BWH criteria, 194 (55%) patients were stage III. T classification criteria were adjusted based on prevalence and relation to survival. N status correlated significantly with survival. Regrouping of TN combinations based on relative hazard and Kaplan-Meier survival analysis resulted in improved stage distribution (stage I-IV: 8%, 43%, 33%, 16%, respectively) and survival stratification (51, 26, 15, 8 months, respectively). CONCLUSIONS: Proposed adjustments to TNM staging criteria improved outcome stratification of patients with epithelial tumor histology who received surgical therapy by EPP and complete pathologic assessment. Determining relevance to other treatment or staging modalities will require verification in additional cohorts. Cancer 2010. © 2010 American Cancer Society.
• Five-year lung cancer survival : Which advanced stage nonsmall cell lung cancer patients attain long-term survival?
  Wang T Nelson RA Bogardus A Grannis FW - Cancer 116(6):1518-1525 (2010)
  BACKGROUND: The core strategy of American College of Chest Physicians lung cancer guidelines is identification of the earliest symptoms of lung cancer and the immediate initiation of diagnosis and treatment. In the absence of screening, most symptomatic lung cancer is discovered at advanced stages, with the goal of long-term survival entirely dependent on effective treatment of stage III and IV lung cancer. METHODS: In a retrospective review, all patients diagnosed with stage IIIA, IIIB, and IV nonsmall cell lung cancer (NSCLC) between the years 1986 and 2001 at City of Hope National Medical Center who survived 5 years or longer were analyzed to identify parameters that might predict long-term survival. RESULTS: Of 846 patients presenting with stage III or IV disease, 56 (6.6%) survived 5 years or longer. Sixteen patients died of primary tumor progression beyond 5 years. Two 5-year survivors died of second tobacco-caused neoplasms, and 16 died from medical conditions potentially related to prior treatment. A substantial majority of survivors were from specific pathologic subsets including: 1) resectable N2 disease (n = 17, 30.4%), 2) multiple lung tumors (n = 7, 12.5%), 3) T3N0 (n = 5, 8.1%), and 4) single site distant metastasis (n = 8, 14.2%). CONCLUSIONS: Despite aggressive multimodality therapy, 5-year survival in patients with advanced stage NSCLC was very poor and limited to small pathological subsets. Patients with advanced stage NSCLC who did not belong to 1 of these subsets had a small chance of long-term survival. Cancer 2010. © 2010 American Cancer Society.
• A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin v3, ± dacarbazine in patients with stage IV metastatic melanoma
  Hersey P Sosman J O'Day S Richards J Bedikian A Gonzalez R Sharfman W Weber R Logan T Buzoianu M Hammershaimb L Kirkwood JM for the Etaracizumab Melanoma Study Group - Cancer 116(6):1526-1534 (2010)
  BACKGROUND: The alpha v beta 3 (v3) integrin is involved in intracellular signaling regulating cell proliferation, migration, and differentiation and is important for tumor-induced angiogenesis. METHODS: This phase 2, randomized, open-label, 2-arm study was designed to capture safety data and evaluate the antitumor efficacy of etaracizumab (Abegrin), an IgG1 humanized monoclonal antibody against the v3 integrin, in patients with previously untreated metastatic melanoma. The objective was to evaluate whether etaracizumab ± dacarbazine had sufficient clinical activity to warrant further study in a phase 3 clinical trial. RESULTS: One hundred twelve patients were randomized to receive etaracizumab alone (N = 57) or etaracizumab + dacarbazine (N = 55). Safety of etaracizumab ± dacarbazine was acceptable with infusion-related, gastrointestinal, and metabolic reactions being the most common adverse events (AEs). The majority of AEs were grade 1 or 2 in severity in both study arms; most events were not considered serious, except for cardiovascular (myocardial infarction, atrial fibrillation) and thromboembolic events, which occurred in 3 and 5 patients, respectively. None of the patients in the etaracizumab-alone study arm and 12.7% of patients in the etaracizumab + dacarbazine study arm achieved an objective response. The median duration of objective response in the etaracizumab + dacarbazine study arm was 4.2 months. Stable disease rate, time to progression (TTP), and progression-free survival (PFS) appeared to be similar between the 2 treatment arms. Stable disease occurred in 45.6% of patients in the! etaracizumab-alone study arm and 40.0% of patients in the etaracizumab + dacarbazine study arm. Median TTP and median PFS were both 1.8 months in the etaracizumab-alone study arm and 2.5 and 2.6 months in the etaracizumab + dacarbazine study arm, respectively. Median overall survival was 12.6 months in the etaracizumab-alone study arm and 9.4 months in the etaracizumab + dacarbazine study arm. CONCLUSIONS: The survival results in both treatment arms of this study were considered unlikely to result in clinically meaningful improvement over dacarbazine alone. Cancer 2010. © 2010 American Cancer Society.
• Should all patients with melanoma between 1 and 2 mm Breslow thickness undergo sentinel lymph node biopsy?
  Mays MP Martin RC Burton A Ginter B Edwards MJ Reintgen DS Ross MI Urist MM Stromberg AJ McMasters KM Scoggins CR - Cancer 116(6):1535-1544 (2010)
  BACKGROUND: Sentinel lymph node (SLN) biopsy generally is recommended for patients who have melanoma with a Breslow thickness 1 mm. Most patients with melanoma between 1 mm and 2 mm thick have tumor-negative SLNs and an excellent long-term prognosis. The objective of the current study was to evaluate prognostic factors in this subset of patients and determine whether all such patients require SLN biopsy. METHODS: Patients with melanoma between 1 mm and 2 mm in Breslow thickness were evaluated from a prospective multi-institutional study of SLN biopsy for melanoma. Disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis to compare patients with melanoma that measured from 1.0 mm to 1.59 mm (Group A) versus patients with melanoma that measured from 1.6 mm to 2.0 mm thick (Group B). Univariate and multivariate analyses were performed to evaluate factors predictive of tumor-positive SLN status, DFS, and OS. RESULTS: The current analysis included 1110 patients with a median follow-up of 69 months. SLN status was tumor-positive in 133 of 1110 patients (12%) including 66 of 762 patients (8.7%) in Group A and 67 of 348 patients (19.3%) in Group B (P < .0001). On multivariate analysis, age, Breslow thickness, and lymphovascular invasion were independently predictive of a tumor-positive SLN (P < .05). DFS (P < .0001) and OS (P = .0001) were significantly better for Group A than for Group B. When tumor thickness was treated as either a continuous variable (P < 0.0001) or a categorical variable (P < .0001), it was significantly predictive of DFS and OS. On multivariate analysis, Breslow thickness, age, ulceration, histologic subtype, regression, Clark level, and SLN status were significant factors predicting DFS; and Breslow thickness, age, primary tumor location, sex, ulceration, and SLN status were significant factors predicting OS (P < .05). A subgroup of patients who had tumors <1.6 mm in B! reslow thickness, had no lymphovascular invasion, and were aged 59 years had a low risk (5%) of tumor-positive SLN. CONCLUSIONS: The current findings indicated that there is significant diversity in the biologic behavior of melanoma between 1 mm and 2 mm in Breslow thickness. SLN biopsy is recommended for all such patients to identify those with lymph node metastasis who are at the greatest risk of recurrence and mortality. Cancer 2010. © 2010 American Cancer Society.
• 5-Aminolevulinic acid is a promising marker for detection of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement
  Widhalm G Wolfsberger S Minchev G Woehrer A Krssak M Czech T Prayer D Asenbaum S Hainfellner JA Knosp E - Cancer 116(6):1545-1552 (2010)
  BACKGROUND: Because of intratumoral heterogeneity, diffusely infiltrating gliomas that lack significant contrast enhancement on magnetic resonance imaging are prone to tissue sampling error. Subsequent histologic undergrading may delay adjuvant treatments. 5-Aminolevulinic acid (5-ALA) leads to accumulation of fluorescent porphyrins in malignant glioma tissue, and is currently used for resection of malignant gliomas. The aim of this study was to clarify whether 5-ALA might serve as marker for visualization of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement for precise intraoperative tissue sampling. METHODS: 5-ALA was administered in 17 patients with diffusely infiltrating gliomas with nonsignificant contrast enhancement. During glioma resection, positive fluorescence was noted by a modified neurosurgical microscope. Intraoperative topographic correlation of focal 5-ALA fluorescence with maximum 11C-methionine positron emission tomography uptake (PETmax) was performed. Multiple tissue samples were taken from areas of positive and/or negative 5-ALA fluorescence. Histopathological diagnosis was established according to World Health Organization (WHO) 2007 criteria. Cell proliferation was assessed for multiregional samples by MIB-1 labeling index (LI). RESULTS: Focal 5-ALA fluorescence was observed in 8 of 9 patients with WHO grade III diffusely infiltrating gliomas. All 8 of 8 WHO grade II diffusely infiltrating gliomas were 5-ALA negative. Focal 5-ALA fluorescence correlated topographically with PETmax in all patients. MIB-1 LI was significantly higher in 5-ALA-positive than in nonfluorescent areas within a given tumor. CONCLUSIONS: The data indicate that 5-ALA is a promising marker for intraoperative visualization of anaplastic foci in diffusely infiltrating gliomas with nonsignificant contrast enhancement. Unaffected by intraoperative brain shift, 5-ALA may increase the precision of tissue sampling during tumor resection for histopathological grading, and therefore optimize allocation of patients to adjuvant treatments. Cancer 2010. © 2010 American Cancer Society.
• Prediction of pathologic fracture risk of the femur after combined modality treatment of soft tissue sarcoma of the thigh
  Gortzak Y Lockwood GA Mahendra A Wang Y Chung PW Catton CN O'Sullivan B Deheshi BM Wunder JS Ferguson PC - Cancer 116(6):1553-1559 (2010)
  BACKGROUND: The objective of the current study was to formulate a scoring system to enable decision making for prophylactic stabilization of the femur after surgical resection of a soft tissue sarcoma (STS) of the thigh. METHODS: A logistic regression model was developed using patient variables collected from a prospectively collected database. The study group included 22 patients who developed a radiation-related pathological fracture of the femur after surgery and radiotherapy for an STS of the thigh. The control group of 79 patients received similar treatment but did not sustain a fracture. No patients received chemotherapy. The mean follow-up was 8.6 years. The variables examined were age, gender, tumor size, radiation dose (low [50 grays (Gy)] vs high [60 Gy]), extent of periosteal stripping (<10 cm, 10-20 cm, and >20 cm), and thigh compartment involvement (posterior, adductor, anterior or other [ie, abductors and groin]). RESULTS: On the basis of an optimal regression model, the ability to predict radiation-associated fracture risk was 91% sensitive and 81% specific. The area under the receiver operating characteristic curve was 0.9, which supports this model as a very accurate predictor of fracture risk. CONCLUSIONS: Radiation-related fractures of the femur after combined surgery and radiotherapy for STS are uncommon, but are difficult to manage and their nonunion rate is extremely high. The results of the current study suggest that it is possible to predict radiation-associated pathological fracture risk using patient and treatment variables with high sensitivity and specificity. This would allow for the identification of high-risk patients and treatment with either close follow-up or prophylactic intramedullary nail stabilization. The presentation of this model as a nomogram will facilitate its clinical use. Cancer 2010. © 2010 American Cancer Society.
• Native American breast cancer survivors' physical conditions and quality of life
  - Cancer 116(6):1560-1571 (2010)
  BACKGROUND: Based on Survivors' Guidance, an interactive, Web-based, culturally relevant Native American cancer survivorship program, Native American Cancer Education for Survivors (NACES), was developed. The focus of the program is to improve quality of life (QOL) for Native American breast cancer survivors. METHODS: NACES is a community-driven research and education project, based on the Social Cognitive Theoretical Model. Participants complete a QOL survey that includes physical, psychosocial, spiritual, and social components. This publication focuses on the physical component of the survey collected by trained Native American patient advocates, and compares physical conditions among Native American breast cancer survivors who were diagnosed within 1 year, those diagnosed between 1 and 4 years, and those who are long-term survivors (diagnosed 5 years ago). RESULTS: For the first time, survivorship issues are reported specifically for Native American breast cancer patients (n = 266). Selected access issues document situations that contribute to disparities. Comorbidities such as high blood pressure and arthritis are common in the survivors, with more than a third having diabetes, in addition to breast cancer. Numerous side effects from cancer treatments are experienced by these survivors. CONCLUSIONS: These data describe what Native American breast cancer patients are experiencing based on self-reported information. Clearly there is need for much more work and long-term tracking of Native American patients to begin to document if or how the severity of physical symptoms lessens over time and if their experiences are significantly different from non-Native Americans. Cancer 2010. © 2010 American Cancer Society.
• The association of menstrual and reproductive factors with upper gastrointestinal tract cancers in the NIH-AARP cohort
  Freedman ND Lacey JV Hollenbeck AR Leitzmann MF Schatzkin A Abnet CC - Cancer 116(6):1572-1581 (2010)
  BACKGROUND: In most populations, incidence rates of upper gastrointestinal (UGI) tract cancers (head and neck, esophagus, and stomach) are higher among men than among women. Established risk factors do not appear to explain these differences, suggesting a possible role for sex hormones. METHODS: 201,506 women of the NIH-AARP Diet and Health cohort completed a questionnaire in 1995-1996. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models. RESULTS: During follow-up through 2003, 162 incident adenocarcinomas (ACs; esophagus, N = 25, and stomach, N = 137) and 353 incident squamous cell carcinomas (SCCs; head and neck, n = 297, and esophagus, N = 56) occurred. Among examined exposures, older age at menopause was associated inversely with SCC (Ptrend across categories = .013) but not AC (Ptrend = .501). Use of menopausal hormone therapy (MHT) was significantly associated with lower risk of SCC (hazard ratio [HR] = 0.77, 0.62-0.96) and nonsignificantly associated with lower risk of AC (HR = 0.81, 0.59-1.12). A subset (N = 127,386) of the cohort completed a more detailed MHT questionnaire a year after baseline. In 74,372 women with intact uteri, ever use of estrogen-progestin MHT conferred 0.47 (0.30-0.75) times the risk for SCC and 0.52 (0.26-1.07) times the risk for ACC. In 51,515 women with a hysterectomy before baseline, we found no associations between use of estrogen MHT and AC or SCC. CONCLUSIONS: Higher estrogen and progesterone levels may be related inversely to UGI cancers and in this way help explain lower incidence rates in women compared with men. Cancer 2010. © 2010 American Cancer Society.
• Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors
  Johnson FM Agrawal S Burris H Rosen L Dhillon N Hong D Blackwood-Chirchir A Luo FR Sy O Kaul S Chiappori AA - Cancer 116(6):1582-1591 (2010)
  BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society.
• Quality of life, self-esteem, fatigue, and sexual function in young men after cancer : A controlled cross-sectional study
  Greenfield DM Walters SJ Coleman RE Hancock BW Snowden JA Shalet SM Derogatis LR Ross RJ - Cancer 116(6):1592-1601 (2010)
  BACKGROUND: Androgen deficiency is increasingly recognized in young male cancer survivors; however, its impact on quality of life (QOL) is not established. The authors investigated the relationship between androgen levels, QOL, self-esteem, fatigue, and sexual function in young male cancer survivors compared with control subjects. METHODS: A cross-sectional, observational study of 176 male cancer survivors and 213 male controls aged 25 to 45 years was performed. Subjects completed 3 QOL scales (Medical Outcomes Study 36-Item Short-Form Health Survey version 2, the 12-item General Health Questionnaire [GHQ-12], and Aging Male Scale), and measures of self-esteem (Rosenberg Self-Esteem Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and sexual function (Derogatis Interview for Sexual Functioning-II Self-Report-Male). RESULTS: Cancer survivors had lower scores for all components of the Short-Form Health Survey, Aging Male Scale, and Functional Assessment of Chronic Illness Therapy-Fatigue, and for 4 of 5 subsections of the Derogatis Interview for Sexual Functioning than controls. The majority of these differences remained after adjusting by linear regression analysis. Levels of psychiatric disorder or self-esteem did not differ between the 2 groups. In cancer survivors, those with androgen deficiency (serum testosterone 10 nmol/L) had lower scores than those without for all components of the Short-Form Health Survey, the General Health Questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Derogatis Interview for Sexual Functioning. Serum testosterone only weakly correlated with health measures. CONCLUSIONS: Young male cancer survivors self-report a marked impairment in QOL, energy levels, and quality of sexual functioning, and this was exacerbated in those with androgen deficiency. However, psychological distress was not elevated, self-esteem was normal, and sexual relationships were not impaired. The relationship with testosterone is complex, and appears dependent on a threshold level rather than direct correlation. Interventional trials are needed to determine whether testosterone replacement would improve QOL in young male cancer survivors. Cancer 2010. © 2010 American Cancer Society.
• Nurses provide valuable proxy assessment of the health-related quality of life of children with Hodgkin disease
  Klaassen RJ Barr RD Hughes J Rogers P Anderson R Grundy P Ali SK Yanofsky R Abla O Silva M Carret AS Cappelli M - Cancer 116(6):1602-1607 (2010)
  BACKGROUND: We prospectively compared the proxy reporting of health-related quality of life (HRQL) by parents and nurses of children with Hodgkin disease to see how well they correlated with the children's report. METHODS: Children with all stages of Hodgkin disease, their parents, and the clinic nurse were all asked to complete 4 different HRQL measures at 4 time points: 2 weeks after the first course of chemotherapy, on the third day of the second course of chemotherapy, during the third week of radiation, and 1 year after diagnosis. RESULTS: Fifty-one patients from 12 centers across Canada were enrolled in the study between May 1, 2002 and March 31, 2005. Two patients were excluded. The children's Pediatric Quality of Life Inventory (PedsQL) generic scores increased from 64 at base line to 81 at the end of the study. There was substantial agreement (intraclass correlation coefficient >0.6) among the participants' scores at most time points except when the child was actively receiving inpatient chemotherapy. At that time, there was only fair to moderate agreement between the child and parent, with the parents on average rating the PedsQL generic score 5 points lower than the child. The nurses still had substantial agreement at that time point with the PedsQL generic and cancer module as well as the EuroQol EQ-5D visual analogue scale visual analogue scale. CONCLUSIONS: Over the course of treatment for Hodgkin disease, there was substantial agreement among the parent's, nurse's, and children's reported HRQL scores. Nurses contribute valuable additional information as proxy respondents. Cancer 2010. © 2010 American Cancer Society.
• Evaluating the ability to detect change of health-related quality of life in children with Hodgkin disease
  Klaassen RJ Krahn M Gaboury I Hughes J Anderson R Grundy P Ali SK Jardine L Abla O Silva M Barnard D Cappelli M - Cancer 116(6):1608-1614 (2010)
  BACKGROUND: We evaluated 4 different health-related quality of life (HRQL) measures prospectively to determine their ability to detect change over time: the Health Utilities Index Mark 2 and Mark 3, the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core and Cancer Module, the EuroQol EQ-5D visual analogue scale (EuroQol), and the Lansky Play-Performance Scale. METHODS: Children with all stages of Hodgkin disease from 12 centers across Canada were asked to complete the 4 measures at 4 time points: 2 weeks after the first course of chemotherapy, on the third day of the second course of chemotherapy, during the third week of radiation, and 1 year after diagnosis. RESULTS: Fifty-one patients were enrolled in the study between May 1, 2002 and March 31, 2005. Two patients were excluded: 1 patient died shortly after the first time point and the other patient failed to complete any of the questionnaires. All measures showed a significant change between Time 1 and Time 4 (<0.05). When the change in child scores was analyzed between the time points using the child's self-reported change in HRQL, the PedsQL and the EuroQol showed significant change at all time points. CONCLUSIONS: All of the measures were able to detect change in a diverse group of children with Hodgkin disease. The PedsQL and the EuroQol appeared to be the most sensitive to change. Cancer 2010. © 2010 American Cancer Society.
• Early changes in tumor size in patients treated for advanced stage nonsmall cell lung cancer do not correlate with survival
  Oxnard GR Schwartz LH - Cancer 116(6):1615 (2010)
  
• Reply to early changes in tumor size in patients treated for advanced stage nonsmall cell lung cancer do not correlate with survival
  Birchard KR Patz EE - Cancer 116(6):1616 (2010)