A phase I study of weekly doxorubicin and oral topotecan for patients with relapsed or refractory small cell lung cancer (SCLC): A Fred and Pamela Buffet Cancer Center Clinical Trials Network study.

BACKGROUND: Relapsed/refractory small cell lung cancer (SCLC) has a poor prognosis, with no good options. We evaluated a novel combination of topotecan and doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting. MATERIALS AND METHODS: Adult patients (>19 years) with relapsed/refractory SCLC, who had received at least one prior chemotherapy regimen were eligible. Patients received escalating doses of oral topotecan on days 1-5 of each three week cycle (maximum - 5 cycles). The dosing cohorts were: 0.85 mg/m2, 1.05 mg/m2, 1.35 mg/m2, 1.65 mg/m2 and 2.30 mg/m2. All patients received weekly doxorubicin 20 mg/m2 intravenously starting day 6 of the first cycle and continued weekly for a maximum of 15 weeks. In the absence of pre-specified dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. RESULTS: Twenty-two patients were enrolled, of which 20 were evaluable. Median age was 61 years; 74% were male and 95% were Caucasian. Hematologic side effects were the most common adverse events. There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL2: 1/6 (Grade 4 thrombocytopenia), DL3: 1/6 (AST elevation) and DL4: 2/4 (Grade 4 thrombocytopenia). Response rate was 20% (4/20) and disease control rate (SD + PR) was 36%. The median progression free and overall survival were 3.6 months and 6 months, respectively. CONCLUSIONS: The combination of topotecan and doxorubicin was safe and effective in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m2 when given concurrently with weekly doxorubicin.

Epidermal Growth Factor Receptor Mutational Status and Brain Metastases in Non-Small-Cell Lung Cancer.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables. METHODS: This retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors. RESULTS: EGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation-positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11). CONCLUSION: There is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases.

Weekly vinorelbine and paclitaxel in older patients with advanced non-small cell lung cancer: A phase II Fred and Pamela Buffet Cancer Center Clinical Trials Network study.

OBJECTIVE: Platinum-based doublet chemotherapy is the standard for most patients with advanced non-small cell lung cancer (NSCLC). Toxicity concerns limit chemotherapy for patients over 70years. Vinorelbine and paclitaxel are effective as single agents in advanced NSCLC. This phase II study evaluates safety and efficacy of a combination of these two agents in patients >70years with advanced NSCLC. MATERIALS AND METHODS: Patients with treatment naïve metastatic NSCLC received two cycles comprising 6 weekly doses of vinorelbine and paclitaxel, with restaging scans at week 8. Patients with radiographic progression came off study. The estimated sample size was 29. Toxicity analyses were conducted after 10 patients and again after 19 patients were enrolled. Outcomes were safety and efficacy, progression free (PFS) and overall survival (OS) and quality of life (QOL). RESULTS: The study closed at second interim analysis as 6/19 patients had ≥grade 4 non-hematologic toxicity (respiratory failure, sepsis, ischemic encephalopathy, pneumonia, hypoxemia, cardiopulmonary arrest, neutropenic fever, death). Of the 16 evaluable patients, 7 completed the study. Disease control rate (partial response+stable disease) was 47% (n=9); 37% (n=7) progressed. No complete responses were seen. Median PFS was 3.5months (95% CI: 1.4, 5.5) and OS 7.8months (95% CI: 1.9, 13.6). QOL did not change compared to baseline, at week 9, but increased at week 17. CONCLUSIONS: Although the combination met its response end points, increased toxicity makes this combination unsuitable for older patients. While QOL improved over the study, the small sample hinders interpretation.

Early Stage Non-Small-Cell Lung Cancer in Octogenarian and Older Patients: A SEER Database Analysis.

BACKGROUND: The median age at diagnosis of lung cancer is 70 years. However, the evidence guiding the management of octogenarians and older patients with non-small-cell lung cancer (NSCLC), is based on data derived from younger patients and may not be appropriate. METHODS: Patients ≥ 80 years diagnosed with clinical stages I and II NSCLC, between 1988 and 2007, were identified from the SEER database. Patients were classified according to treatments received: no treatment, surgery only, radiation only, and surgery + radiation. Factors associated with survival were assessed using the Cox proportional hazards model. RESULTS: There were 1338 cases of early stage NSCLC in octogenarians. Surgery was the most common treatment modality. The median overall survival was 3.8 years for patients who had surgery, compared with 1.6 years, 1.6 years, and 0.9 years for those who received surgery + radiation, radiation alone, and no treatment, respectively (P < .0001). Factors significantly associated with worse overall survival following surgery included increasing age (hazard ratio [HR], 1.08; P = .0005), male gender (HR, 1.33; P = .01), stage II (HR, 2.21; P < .0001), and squamous histology (HR, 1.36; P = .01). CONCLUSION: Surgical resection is associated with long-term survival outcomes in a substantial proportion of octogenarian and older patients with early stage lung cancer and should not be withheld on the basis of age alone.

Effect of Surgical Intervention on Survival of Patients With Clinical N2 Non-Small Cell Lung Cancer: A Veterans' Affairs Central Cancer Registry (VACCR) Database Analysis.

BACKGROUND: Optimal management of locally advanced non-small cell lung cancer (NSCLC) lacks consensus. A retrospective analysis of patient data entered in the Veterans Affairs Central Cancer Registry was conducted to evaluate these issues. PATIENTS AND METHODS: Data of patients with cT1-4, cN2, and cM0 NSCLC diagnosed in the VA Health System between 1995 and 2003 were evaluated. Age, sex, race, smoking history, TNM stage, treatment, and overall survival were abstracted. Survival was compared using multivariate Cox proportional hazards regression analysis. RESULTS: Of the 7328 patients analyzed, 7218 (98.5%) were male, 6061 (82.7%) were white, and 321 (4.4%) were never smokers. The treatment received included: none, 23.8%; chemotherapy alone, 14.3%; radiation alone, 23%; and chemoradiation (sequential or concurrent), 31.4%. Only 7.5% of patients had a surgical resection, with or without multimodality therapy. The median survival (months) of these patient groups were: surgery, 19.3; chemoradiation, 13; chemotherapy alone, 9.2; radiation alone, 7.3; and no treatment, 4 (P<0.0001). African Americans had a significantly decreased risk of mortality compared with whites (hazard ratio 0.92; 95% confidence interval, 0.87-0.98). CONCLUSIONS: Inclusion of surgical resection as a treatment modality was associated with a better overall survival. Also, African Americans appeared to do better than whites. These hypothesis-generating findings should be useful in the ongoing pursuit of better treatment strategies for locally advanced NSCLC.

Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute myeloid leukemia.

Philadelphia chromosome-positive acute myeloid leukemia (Ph(+)-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy with imatinib and allogeneic stem cell transplantation (allo-SCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph(+)-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph(+)-AML.

Association between race and survival of patients with non--small-cell lung cancer in the United States veterans affairs population.

BACKGROUND: Racial disparities in outcomes of non-small-cell lung cancer (NSCLC) patients in the United States are well documented. A retrospective analysis of patients in the Veterans Affairs Central Cancer Registry was conducted to determine whether similar disparities exist in a population with a single-payer, accessible health care system. PATIENTS AND METHODS: Demographic data of patients diagnosed with NSCLC between January 1995 and February 2009 were analyzed using Kruskal-Wallis test or the χ(2) test. Multivariate Cox proportional hazards regression analysis was used to compare survival among races. RESULTS: Of the 82,414 patients, 98% were male, 82% had a smoking history, and 81% were Caucasian. Caucasian individuals had better prognostic features compared with African-American individuals (stage I/II [24% vs. 21%]; Grade I/II [21% vs. 17%]). A larger proportion of Caucasian compared with African-American individuals received stage-appropriate treatment (surgery for stage I [48% vs. 41%; P < .001]; chemotherapy for stage IV [18% vs. 16%; P = .003]). African-American individuals had a lower risk of mortality compared with Caucasian individuals (hazard ratio, 0.94; 95% confidence interval, 0.92-0.96). CONCLUSION: Although African-American patients had a higher stage and grade of NSCLC, they had a better overall survival than Caucasian patients. In a single-payer system with accessible health care, previously described racial differences in lung cancer outcomes were not observed.

Outcomes following surgical treatment compared to radiation for stage I NSCLC: a SEER database analysis.

INTRODUCTION: Outcomes following surgery are better than following radiation therapy (RT), for stage I NSCLC. Whether this is due to selection of healthier patients for surgery is unclear. This study was undertaken to compare outcomes between surgical patients and patients who were surgical candidates but did not receive surgery. METHODS: Data of patients with stage I NSCLC between 1988 and 2007, included in the SEER database were analyzed. Overall survival (OS) was examined by treatment type (surgery only, radiation only, surgery and radiation, and no treatment). OS was compared between RT patients who refused surgery and those not fit for surgery. Cox proportional hazards model was used to compare outcomes by treatment type. RESULTS: Data from 8579 patients with stage I NSCLC during 1988-2007 were analyzed. Use of RT alone increased during the study period. An increasing proportion of patients with stage I lung cancer chose to have no treatment. On multivariate analysis, OS was better among patients who had surgery. There was a 56% improvement in survival among patients who had surgery compared to fit patients who refused surgery (HR 0.437, 95% CI 0.301-0.632). Patients who refused surgery had a better OS than those who were not fit for surgery (log-rank p = 0.01). Patients who received RT alone or no treatment had a significant improvement in five-year OS during the latter part of the study period (1998-2002 vs. 1988-1992). CONCLUSIONS: In medically fit patients, outcomes following surgery are better than those following conventional radiation. Hence surgery should be chosen over conventional radiation, whenever possible. Outcomes following RT show an improvement over time reflecting improvement in radiation techniques.

Non-small cell lung cancer.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.

The impact of signet-ring cell carcinoma histology on bladder cancer outcome.

BACKGROUND: Signet-ring cell carcinoma (SRCC) of the urinary bladder is a rare entity. No previous studies have directly compared the cancer-specific survival of patients with SRCC to patients with urothelial carcinoma (UC) of the urinary bladder. MATERIALS AND METHODS: Patients with diagnosis of urinary bladder SRCC and UC were identified in the Surveillance, epidemiology, and end results program (SEER) (2001-2004). Demographic of patients and clinical characteristics at diagnosis were compared. Differences in cancer-specific survival were compared using univariate and multivariate analysis. RESULTS: A total of 103 patients with SRCC and 14,648 patients with UC were indentified. Patients with SRCC were younger (P < 0.001), more commonly presented with higher-grade histology (P < 0.001) and advanced stage disease (P < 0.001), in comparison with patients with UC. The 3-year cancer-specific survival rate was 67.0% for patients with UC and 33.2% for SRCC. On multivariate analysis, there was an increased mortality risk in patients with SRCC versus UC (HR 1.49, 95% CI 1.11-2.00, P < 0.01). CONCLUSIONS: Even after adjusting for demographic, surgical, and pathological factors, cancer-specific survival rate was significantly worse in patients with SRCC compared to UC. Further research into the biology of this rare tumor is required to explain these results.

The natural history and outcomes of the patients with carcinosarcoma involving kidney and renal pelvis.

Background. The objective of this paper was to examine the epidemiology, natural history, and prognostic factors of carcinosarcoma of the kidney and renal pelvis (CSKP) using population-based registry. Patients and Methods. Forty-three patients with CSKP, diagnosed between January 1973 and December 2007, were identified from the national Surveillance, Epidemiology, and End Results (SEER) database and reviewed. Results. 79% of all patients with known SEER stage were classified as having regional or distant stage; almost all the patients with known histology grade had poorly or undifferentiated histology. The median cancer specific survival was 6 months (95% CI 4-9). The 1-year cancer-specific survival rate for entire cohort was 30.2%. There were no differences in terms of age at diagnosis, histological grade, tumor stage on presentation, and frequency of nephrectomy between carcinosarcoma of kidney (CSK) or renal pelvis (CSP). In multivariate analysis, age at diagnosis, tumor stage, and year of diagnosis were found to be significant predictors for cancer-specific survival. Conclusion. CSKP commonly presented as high-grade, advanced stage disease, and was associated with a poor prognosis regardless of location.

Systemic therapy for disseminated basal cell carcinoma: an uncommon manifestation of a common cancer.

While basal cell carcinoma (BCC) is the most common human malignancy, distant metastases from this are rare. Current therapy for disseminated BCC is based on anecdotal reports in the absence of clinical trials to guide management. For many years, platinum based cytotoxic chemotherapy was the mainstay of treatment. Advances in the understanding of the biology of BCC have led to the development of targeted therapies (e.g. inhibitors of the hedgehog and the epidermal growth factor receptor pathways) that are currently being investigated in this disease. This review summarizes the available data on the epidemiology and management of disseminated BCC.

Predictive ability of Charlson comorbidity index on outcomes from lung cancer.

BACKGROUND: The effect of age and/or comorbidities on management decisions in lung cancer patients has been debated. The Charlson Comorbidity Index (CCI) was developed to help predict mortality from chronic medical conditions. This study was undertaken to evaluate whether CCI is correlated with survival in lung cancer. PATIENTS AND METHODS: A retrospective chart review of 617 lung cancer patients diagnosed between 1994 and 2007 was conducted. CCI was calculated for each patient with and without the inclusion of age. Multivariate Cox proportional hazard regression analysis was used to evaluate the relationship between CCI and survival while adjusting for other prognostic factors. RESULTS: Six patients were excluded from the final analysis due to missing outcome or comorbidity data. The median age at diagnosis was 64 years (range, 16-89 y). Five hundred fourteen patients (84%) had nonsmall cell lung cancer and 97 patients (16%) had small cell lung cancer. Using multivariate analysis, no correlation was found between CCI and risk of death whether or not age was included in the index score. CONCLUSIONS: CCI did not provide predictive validity for survival of lung cancer patients. Development of accurate and predictive prognostic models to help estimate a patient's prognosis is needed.

Current concepts in the diagnosis and management of small-cell lung cancer.

Despite a decreasing incidence in the United States, small-cell lung cancer (SCLC) remains a major clinical problem, with approximately 30,000 new cases each year. The diagnosis of SCLC is usually not difficult. The Veterans Administration Lung Study Group (VALSG) staging system is less accurate than the American Joint Committee of Cancer tumor-node-metastasis (TNM) system (7th edition) at predicting survival in SCLC, especially in lower stage disease. Surgery has not played a major part in the management of SCLC, but emerging data suggest that resection may have a role in earlier stage disease. While the frontline treatment of SCLC has not changed significantly in the past decade, newer agents that are currently being investigated provide hope for better treatment of relapsed/refractory disease for the future.

Outcome of combined hepatocellular and cholangiocarcinoma of the liver.

Background. The objective of this study was to examine the epidemiology, natural history, and prognostic factors of combined hepatocellular and cholangiocarcinoma (cHCC-CC) using population-based registry. Methods. The Surveillance, Epidemiology, and End Results Program database (1973-2004) was used to identify cases of cHCC-CC. Multivariable logistic regression was used to evaluate factors associated with cancer-directed surgery (CDS). The influence of CDS on cancer specific survival was evaluated using Kaplan-Meier curves and Cox proportional hazards modeling. Results. A total of 380 cases of cHCC-CC were identified, which account for approximately 0.87% of primary liver tumors. Of all patients, 69.8% of patients had regional or distant stage; 65.6% of patients had poorly or undifferentiated histology. Only 44.9% of patients with localized disease, received CDS. By logistic regression analysis, being widowed, advanced stage, and earlier diagnosis year were associated with lower rate of utilization of CDS. In multivariate analysis, tumor stage, receipt of CDS, and recent year of diagnosis were found to be significant predictors for cancer-specific survival. Conclusions. Patients with localized cHCC-CC who are selected for CDS were strongly associated with improved survival. However, many patients with localized tumors did not receive potentially curative cancer-directed surgery. Further study is warranted to address the barriers to the delivery of appropriate care to these patients.