Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study.

Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.

Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial.

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma.

BACKGROUND: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. MATERIALS AND METHOD: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963-2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). RESULTS: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. CONCLUSION: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.

Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.

BACKGROUND: Lung cancer in individuals who have never smoked tobacco products is an increasing medical and public-health issue. We aimed to unravel the genetic basis of lung cancer in never smokers. METHODS: We did a four-stage investigation. First, a genome-wide association study of single nucleotide polymorphisms (SNPs) was done with 754 never smokers (377 matched case-control pairs at Mayo Clinic, Rochester, MN, USA). Second, the top candidate SNPs from the first study were validated in two independent studies among 735 (MD Anderson Cancer Center, Houston, TX, USA) and 253 (Harvard University, Boston, MA, USA) never smokers. Third, further replication of the top SNP was done in 530 never smokers (UCLA, Los Angeles, CA, USA). Fourth, expression quantitative trait loci (eQTL) and gene-expression differences were analysed to further elucidate the causal relation between the validated SNPs and the risk of lung cancer in never smokers. FINDINGS: 44 top candidate SNPs were identified that might alter the risk of lung cancer in never smokers. rs2352028 at chromosome 13q31.3 was subsequently replicated with an additive genetic model in the four independent studies, with a combined odds ratio of 1.46 (95% CI 1.26-1.70, p=5.94x10(-6)). A cis eQTL analysis showed there was a strong correlation between genotypes of the replicated SNPs and the transcription level of the gene GPC5 in normal lung tissues (p=1.96x10(-4)), with the high-risk allele linked with lower expression. Additionally, the transcription level of GPC5 in normal lung tissue was twice that detected in matched lung adenocarcinoma tissue (p=6.75x10(-11)). INTERPRETATION: Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. Downregulation of GPC5 might contribute to the development of lung cancer in never smokers. FUNDING: US National Institutes of Health; Mayo Foundation.

Small-cell Lung Cancer in Very Elderly (≥ 80 Years) Patients.

BACKGROUND: This analysis was performed to describe the outcome of very elderly (≥ 80 years) patients with small-cell lung cancer (SCLC) as there is no published data regarding these patients. MATERIALS AND METHODS: One hundred forty-six very elderly patients with SCLC were identified from the Institutional Lung Cancer Database ranging in age from 80 to 92 years (median, 82 years). Of these, 47 (32%) patients had limited-stage SCLC (L-SCLC), and 99 (68%) had extensive-stage SCLC (E-SCLC). All were Caucasian, and the majority (64%) were female. Sixty-seven (46%) patients had Zubrod performance status (PS) of 0 to 1. RESULTS: Of the 146 patients, 44 (30%) received no therapy, 65 (45%) received chemotherapy alone, 27 (19%) received chemotherapy plus local therapy (thoracic radiotherapy [TRT] or surgery), and 10 (7%) received local therapy alone. The median survival was 5.4 months. On univariable analysis, age (P = .019), stage (L-SCLC vs. E-SCLC; P = .0002), PS (P < .0001), and treatment option (P < .0001) were associated with survival. On multivariable analysis, stage (P = .011), PS (P = .029), and treatment option (P < .0001) maintained significance. For entire cohort, the median survival was 1.3 months without active therapy, 6 months with local therapy alone, 7.2 months with chemotherapy alone, and 14.4 months with chemotherapy plus local therapy (P < .0001, univariable and multivariable). Similar survival findings in response to treatment were found when the L-SCLC and E-SCLC cohorts were separately analyzed. CONCLUSIONS: The survival of very elderly patients with SCLC was associated with stage (L-SCLC vs. E-SCLC), PS, and treatment option. Very elderly patients with SCLC often have limited functional reserve required to tolerate aggressive multimodality therapy but appeared to benefit from it. Geriatric assessments, careful monitoring, and extra support are warranted in elderly patients. Care should be individualized based on the desires and needs of each patient.

Efficacy of chest computed tomography prediction of the pathological TNM stage of thymic epithelial tumours.

OBJECTIVES: The aim of this study is to evaluate the efficacy of chest computed tomography (CT) to predict the pathological stage of thymic epithelial tumours (TET) using the recently introduced tumour, node and metastasis (TNM) staging with comparison to the modified Masaoka staging. METHODS: Preoperative chest CT examinations in cases of resected TET with sampled lymph nodes (2006-2016) were retrospectively reviewed by 2 thoracic radiologists and radiologically (r) staged using both staging systems. A thoracic pathologist reviewed all cases for the pathological (p) stage. Concordance between r-staging and p-staging was assessed by % agreement and unweighted kappa statistics. Associations between r-stage and p-stage with outcomes were assessed using the Cox proportional hazards regression. RESULTS: Sixty patients with TET were included (47 thymomas, 12 thymic carcinomas and 1 atypical carcinoid tumour). Sixteen patients (26.7%) had received neoadjuvant therapy. Fifty-four patients (90.0%) had complete resection. The overall agreement between the r-stage and p-stage was 66.7% (κ = 0.46) for TNM staging and 46.7% (κ = 0.30) for modified Masaoka staging. Agreement between r-assessment and p-assessment of the T, N and M components of the TNM stage was 61.7% (κ = 0.28), 86.7% (κ = 0.48) and 98.3% (κ = 0.88), respectively. CT overstaged 12 patients (20.0%) for TNM staging and 12 patients (20.0%) for modified Masaoka staging and understaged 8 (13.3%) and 20 (33.3%) patients for TNM staging modified Masaoka staging, respectively. The r-TNM staging accuracy was lower for patients with neoadjuvant therapy (50.0% with vs 72.7% without). During a median follow-up of 2.6 years (range 0.1-10.5 years), 12 patients had metastases and/or recurrence; 11 patients died (4 of disease). The r-TNM stage and modified Masaoka stage were associated with overall survival and progression-free survival (P < 0.001). CONCLUSIONS: Preoperative chest CT is able to accurately predict p-TNM stage in two-thirds of surgically resected TET, with an agreement between radiological staging and pathological staging superior to the modified Masaoka staging.

Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51).

PURPOSE: This study assessed whether maintenance therapy with carboxyaminoimidazole (CAI), compared to placebo, prolonged overall survival in stage IIIB/IV NSCLC patients who had tumour regression or stable disease after treatment with one chemotherapy regimen. METHODS: After completion of chemotherapy, patients were randomized to receive daily oral CAI at 250mg or placebo. Treatment continued until patient refusal, disease progression or unacceptable adverse event (AE). Quality of life (QOL) was assessed by UNISCALE and Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L). RESULTS: Registration was halted early for slow accrual (targeted 360, randomized 186: 94 CAI, 92 placebo). All patients were off active treatment at time of analyses. Non-haematologic AEs (primarily grade 1, 2) observed significantly more often in the CAI group included fatigue (54.5% versus 29.3%), anorexia (31.1% versus 13.0%), nausea (62.2% versus 30.4%), vomiting (32.2% versus 14.1%), neurosensory (60.0% versus 44.6%) and ataxia (33.3% versus 16.3%). Patients discontinued treatment for AEs, death on study or refusal more often in the CAI group (36.0% versus 8.7%, p<0.0001). No significant differences in survival or time to progression were observed (median: CAI versus placebo: 11.4 months versus 10.5 months, log rank p=0.54; 2.8 months versus 2.4 months, log rank p=0.50). More patients receiving CAI reported a clinically significant (10-point) decline in QOL particularly on the functional (58% versus 37%, p=0.05) construct of FACT-L and UNISCALE (72% versus 51%, p=0.04). CONCLUSION: The addition of CAI following chemotherapy does not provide clinical benefit or improvement in QOL over placebo in advanced NSCLC.

Do patients with schizophrenia receive state-of-the-art lung cancer therapy? A brief report.

OBJECTIVE: Patients with schizophrenia sometimes receive substandard medical care. This study explored such disparities among lung cancer patients with underlying schizophrenia. METHODS: This retrospective study focused on patients with pre-existing schizophrenia (or in some instances schizoaffective disorder) and a lung cancer diagnosis made between 1980 and 2004. 'Disparity' was defined as a patient's having been prescribed less aggressive therapy for a potentially curable cancer based on state-of-the-art treatment standards for the time and for the cancer stage. Qualitative methods were used to assess healthcare providers' decision-making. RESULTS: 29 patients were included. The median age was 59 years; 38% were men. Twenty-three had non-small cell lung cancer and 6 small cell lung cancer; 17 had potentially curable cancers. Five of 17 had a 'disparity' in cancer care: (1) no cancer therapy was prescribed because of chronic obstructive pulmonary disease; (2) no cancer therapy was prescribed because of infection; (3) no chemotherapy was prescribed because the patient declined it; radiation was provided; (4) no chemotherapy was prescribed because of the patient's schizophrenia symptoms; radiation was administered; and (5) no surgery was performed because of disorientation from a lobotomy; radiation was prescribed. Comments from healthcare providers suggest reflection and ethical adjudication in decision-making. CONCLUSION: Schizophrenia was never the sole reason for no cancer treatment in patients with potentially curable lung cancer. This study provides the impetus for others to begin to assess the effect of schizophrenia on lung cancer management in other healthcare settings.

Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy.

OBJECTIVES: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO. METHODS: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO. RESULTS: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%).Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25-99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group.In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%. CONCLUSIONS: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis.

Transcleral orbital invasion by a radiation and chemotherapy-resistant choroidal metastasis of a pulmonary adenocarcinoma.

PURPOSE: To report transcleral orbital invasion by a radiation- and chemotherapy-resistant choroidal metastasis of a pulmonary adenocarcinoma. DESIGN: Interventional case report. METHODS: A 51-year-old female was found to have choroidal metastasis from a previously unknown primary pulmonary adenocarcinoma. She underwent external beam radiation treatment with a total dose of 40 Gray (Gy), delivered in 20 fractions over 28 days, followed by adjuvant chemotherapy with gemcitabine and carboplatin. After completing two of the three scheduled chemotherapy cycles, the choroidal lesion was observed to have increased in size. RESULTS: A transvitreal aspiration biopsy of the choroidal lesion confirmed the diagnosis of metastatic pulmonary adenocarcinoma. Enucleation was performed for intractable pain. Histopathology revealed invasion through scleral emissary channels to the retrobulbar tissue and through the optic nerve substance itself. CONCLUSIONS: Despite appropriate external beam radiation therapy (EBRT) and chemotherapy, pulmonary adenocarcinoma metastases to the choroid can continue to grow and may invade the orbit transclerally.

Radiologic Response to Neoadjuvant Treatment Predicts Histologic Response in Thymic Epithelial Tumors.

INTRODUCTION: Neoadjuvant treatment might increase resectability of thymic epithelial tumors (TETs). No standardized pathologic grading scheme for tumor response is available. Also, it is unclear whether radiologic treatment response can predict pathologic response. METHODS: Patients with unresectable TETs who underwent neoadjuvant treatment before surgery at Mayo Clinic Rochester (1942-2014) were included. The pathologic tumor response grade (TRG) was based on Mandard grading (1994), ranging from TRG 1 (no viable tumor) to TRG 5 (no regression). TRG was compared with response by computed tomography, including with the Response Evaluation Criteria in Solid Tumors, version 1.1 (Byrne modification). RESULTS: A total of 49 patients, including 29 men, with a median age of 47.6 years and thymomas (n = 28) or thymic carcinomas (n = 21) were included. In five cases, pretreatment tumor type differed from posttreatment diagnosis. Thymic carcinomas had a greater morphologic response to neoadjuvant treatment than did thymomas with a lower percent viable tumor (p < 0.0001) and lower TRG (p<0.0001). Agreement for TRG by three reviewers was good (Krippendorff α = 0.838). By imaging (n = 24), partial response and larger reduction in tumor longest diameter and volume were associated with lower TRG (p = 0.0093, p = 0.0042, and p = 0.0021, respectively) and lower percent viable tumor (p = 0.0041, p = 0.0034, and p =0.0019). TRG correlated with radiologic change in tumor longest diameter and volume (Spearman correlation coefficient = 0.59 and 0.61, respectively). Radiologic change in tumor longest diameter and volume reasonably predicted pathologic TRG of 3 to 5 versus 1 or 2 (area under the curve 0.73 and 0.71, respectively). Sixty-seven percent of patients' tumors were completely resected. CONCLUSIONS: Our proposed histologic TRG for TETs appears easy and reproducible and correlates with radiologic response. Radiologic response is useful to predict pathologic response.

Management of Multifocal Lung Cancer: Results of a Survey.

INTRODUCTION: Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns. METHODS: We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested. RESULTS: We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 [63%]) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation. CONCLUSIONS: This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians' specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity.

Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.

PURPOSE: To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity. PATIENTS AND METHODS: Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET). RESULTS: Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET. CONCLUSION: PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.

Risk factors for incident venous thromboembolism in active cancer patients: A population based case-control study.

BACKGROUND: Independent risk factors for cancer-associated incident venous thromboembolism (VTE) and their magnitude of risk are not fully characterized. AIM: To identify non-cancer and cancer-specific risk factors for cancer-associated incident VTE. METHODS: In a population-based retrospective case-control study, we used Rochester Epidemiology Project and Mayo Clinic Cancer Registry resources to identify all Olmsted County, MN residents with active cancer-associated incident VTE, 1973-2000 (cases; n=570) and 1-3 residents with active cancer matched to each case on age, sex, date and duration of active cancer (controls; n=604). Using conditional logistic regression, we tested cancer and non-cancer characteristics for an association with VTE, including a cancer site VTE risk score. RESULTS: In the multivariable model, higher cancer site VTE risk score (OR=1.4 per 2-fold increase), cancer stage≥2 (OR=2.2), liver metastasis (OR=2.7), chemotherapy (OR=1.8) and progesterone use (OR=2.1) were independently associated with VTE, as were BMI<18.5kg/m(2) (OR=1.9) or ≥35kg/m(2) (OR=4.0), hospitalization (OR=7.9), nursing home confinement (OR=4.7), central venous (CV) catheter (OR=8.5) and any recent infection (OR=1.7). In a subgroup analysis, platelet count≥350×10(9)/L at time of cancer diagnosis was marginally associated with VTE (OR=2.3, p=0.07). CONCLUSION: Cancer site, cancer stage≥2, liver metastasis, chemotherapy, progesterone, being underweight or obese, hospitalization/nursing home confinement, CV catheter, and infection are independent risk factors for incident VTE in active cancer patients.

Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer.

PURPOSE: This phase II study was undertaken to define the efficacy and pharmacodynamics of R115777, a farnesyl transferase inhibitor, in the first-line treatment of patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Forty-four patients with measurable stage IIIB (pleural effusion) or stage IV disease received 193 courses of treatment (median, 2.0; range, 1 to 22) with R115777 300 mg administered orally twice daily for 21 of every 28 days. Buccal mucosa samples and peripheral blood mononuclear cells (PBMCs) were collected before and after 8 days of treatment to evaluate inhibition of farnesyl transferase in vivo. RESULTS: No objective complete or partial responses were documented. Seven patients (16%; 95% confidence interval [CI], 8% to 31%) had disease stabilization for greater than 6 months. Median survival was 7.7 months (95% CI, 6.5 to 10.5) and time to progression was 2.7 months (95% CI, 1.9 to 3.1). The most severe toxicity was neutropenia (9% grade 3, 7% grade 4) and the most common toxicities were anemia (50% grade 1 or 2, 5% grade 3) and anorexia (50% grade 1 or 2, 2% grade 3). Mild peripheral neuropathy occurred in 25% of patients. Evidence of farnesyl transferase inhibition was documented in 83% of patients. CONCLUSION: Single-agent R115777 was well tolerated in patients with advanced NSCLC, but demonstrated minimal clinical activity. Inhibition of farnesylation in vivo was consistently documented. On the basis of promising results of farnesyl transferase inhibitor combinations with standard chemotherapy agents, future studies of this agent in NSCLC should be in combination with systemic chemotherapy.

Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003.

STUDY OBJECTIVES: To improve the current understanding of the etiology and natural history of primary lung cancer, we need to study the dynamic changes of clinical presentation and prognosis among a large number of patients with newly diagnosed lung cancer. In this report, we present the clinical features and survival rates up to 5 years of a patient cohort. DESIGN: We identified 5,628 primary lung cancer patients between 1997 and 2002 and followed them through 2003 using multiple, complementary resources. MEASUREMENTS AND RESULTS: Of the 5,628 patients, 58% were men with a mean age at lung cancer diagnosis of 66 years, and 42% were women with a mean age at diagnosis of 64 years. Ten percent were < 50 years, and 8% were > 80 years at diagnosis. A tobacco smoking history was present in 89% of patients, and 40% were smoking at the time of diagnosis. The estimated overall 5-year survival rates of patients with non-small cell lung cancer (NSCLC) by disease stage was as follows: IA, 66%; IB, 53%; IIA, 42%; IIB, 36%; IIIA, 10%; IIIB, 12%; and IV, 4%. The 5-year survival rate of patients with small cell lung cancer was 22% for limited disease and 1% for extensive disease. Approximately 50% of all patients are participants in one or more research studies, and nearly 75% of these patients have donated biological specimens for research. CONCLUSION: The survival rate of this cohort of lung cancer patients was slightly improved compared with earlier reports, particularly for patients with low-stage NSCLC. Our patient and biospecimen resource has enabled us to obtain timely results from clinical and translational research of lung cancer.

Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk.

OBJECTIVE: Imbalance between alpha(1)-antitrypsin and neutrophil elastase is an underlying cause of lung tissue damage that may create a favorable host environment for carcinogenesis. We conducted a case-control study to investigate whether genetic variations indicative of alpha(1)-antitrypsin deficiency (A1ATD) or an excess of neutrophil elastase modify lung cancer risk DESIGN: The case patients were 305 consecutively identified primary lung cancer patients, and the control subjects were 338 community residents. Protease inhibitor-1 (PI1), encoding alpha(1)-antitrypsin, was typed by an isoelectric focusing assay. Neutrophil elastase-2 (ELA2), encoding neutrophil elastase, was typed by two single-nucleotide polymorphism sites. Multivariable logistic regression models tested the independent and interactive effects of PI1, ELA2, tobacco smoke exposure, COPD, and family history of lung cancer RESULTS: Sex and ethnicity were comparable between case patients and control subjects, but case patients were more likely to be smokers, and to have a history of COPD, environmental tobacco smoke exposure, and a positive family history of lung cancer. Haplotype analysis indicated an overall strong association between the two ELA2 markers and lung cancer risk. Our best-fitting model showed significant and independent effects of the PI1-deficient allele (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4 to 3.0) and the ELA2 T-G haplotype (OR, 4.1; 95% CI, 1.9 to 8.9) on lung cancer risk, and an increased risk (OR, 2.6; 95% CI, 2.4 to 2.8) for individuals carrying both a PI1-deficient allele and a G-G haplotype CONCLUSIONS: Genotypes indicative of A1ATD and/or an excess of neutrophil elastase are significantly associated with lung cancer risk. Our findings may provide opportunities to better understand the mechanisms of lung cancer development and risk reduction.

Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590.

To determine the influence of adjuvant therapy on the risk of DID following resection of NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or CPORT (PORT plus four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently). The study accrued 488 patients, 242 to the PORT only arm and 246 to the CPORT arm. The overall 4 years actuarial rate of DID for the two arms combined, with a median follow-up of 82 months, was 12.9%, not significantly different from the 10.1% expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status (p=0.16). Survival distributions with regard to DID did not differ between the two treatment arms (p=0.96). DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or weight loss in the previous 6 months. The risk of DID following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or CPORT.

A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer.

PURPOSE: This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty patients with solid tumors received a median of 2.5 cycles (range 1-30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777. RESULTS: Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients. CONCLUSION: The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.

Risk of site-specific cancer in incident venous thromboembolism: a population-based study.

BACKGROUND: The risk of venous thromboembolism (VTE) by cancer site is uncertain. OBJECTIVE: To estimate VTE risk by tumor site. METHODS: We enumerated observed active cancers by cancer site for Olmsted County, MN residents with incident VTE over the 13-year period, 1988-2000 (n = 345 of 1417). We used 1988-2000 Iowa State Surveillance, Epidemiology, and End Results (SEER) data to estimate the expected age-specific prevalence of cancer by cancer site for all VTE cases; standardized Morbidity Ratios (SMR) for each cancer site were estimated by dividing the observed number of cancers in the VTE incident cohort by the expected number. Relative risk regression was used to model the observed number of cancers of each site, adjusting for the expected value based on SEER prevalence data, using generalized linear regression with a Poisson error and the natural log of the age- and sex-group expected count as an offset. RESULTS: For men and women with VTE, all cancer sites had an increased SMR, ranging from 4.1 for head neck cancer to 47.3 for brain cancer. Among women, the SMR for breast, ovarian and other gynecologic cancers were 8.4, 13.0 and 8.4, respectively; for men, prostate cancer SMR was 7.9. Adjusting for age and sex, the relative risk (RR) of cancer in VTE cases was associated with cancer site in a multivariable model (p < 0.001). Adjusting for age and sex, pancreatic, brain, other digestive cancers, and lymphoma had significantly higher RRs than the grouped comparison cancers. CONCLUSIONS: Incident VTE risk can be stratified by cancer site.