High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions.

PURPOSE: To report tumor control and toxicity for patients treated with image-guided intensity-modulated radiotherapy (RT) for spinal metastases with high-dose single-fraction RT. METHODS AND MATERIALS: A total of 103 consecutive spinal metastases in 93 patients without high-grade epidural spinal cord compression were treated with image-guided intensity-modulated RT to doses of 18-24 Gy (median, 24 Gy) in a single fraction between 2003 and 2006. The spinal cord dose was limited to a 14-Gy maximal dose. The patients were prospectively examined every 3-4 months with clinical assessment and cross-sectional imaging. RESULTS: The overall actuarial local control rate was 90% (local failure developed in 7 patients) at a median follow-up of 15 months (range, 2-45 months). The median time to local failure was 9 months (range, 2-15 months) from the time of treatment. Of the 93 patients, 37 died. The median overall survival was 15 months. In all cases, death was from progression of systemic disease and not local failure. The histologic type was not a statistically significant predictor of survival or local control. The radiation dose was a significant predictor of local control (p = 0.03). All patients without local failure also reported durable symptom palliation. Acute toxicity was mild (Grade 1-2). No case of radiculopathy or myelopathy has developed. CONCLUSION: High-dose, single-fraction image-guided intensity-modulated RT is a noninvasive intervention that appears to be safe and very effective palliation for patients with spinal metastases, with minimal negative effects on quality of life and a high probability of tumor control.

Epidermal growth factor receptor signaling in adenocarcinomas with bronchioloalveolar components.

BACKGROUND: Epidermal growth factor receptor (EGFR) has gained importance in non-small cell lung cancer given impressive responses to agents targeting this molecule, particularly in bronchioloalveolar carcinoma (BAC) and adenocarcinomas, mixed subtype, with BAC components (adeno/BAC). This study assesses EGFR signaling in these tumors. METHODS: One hundred fifty tumors were classified as BAC or adeno/BAC. Tumor marker expression was determined by immunohistochemistry. Correlations with expression were examined for all tumors (BAC and adeno/BAC), and by BAC and adeno/BAC subset analyses. RESULTS: Positive immunophenotype was observed in 40.6% of tumors for EGFR, 51.3% for p-AKT, 58.7% for p-ERK, and 28.0% for PTEN, with increased overexpression of EGFR (p = 0.025) and p-AKT (p < 0.0001) in adeno/BAC. Epidermal growth factor receptor immunophenotype was greater in never-smokers (p = 0.008) and correlated with improved overall survival (p = 0.018). On subset analysis, EGFR correlated with improved overall survival (p = 0.05) and disease-free interval (p = 0.044) only in adeno/BAC. Epidermal growth factor receptor independently predicted improved disease-free interval in adeno/BAC (p = 0.03; hazard ratio, 0.47; 95% confidence interval, 0.23 to 0.94). CONCLUSIONS: Overexpression of EGFR in lung adenocarcinomas with components of BAC histology correlate with never-smoker status and improved overall survival and disease-free interval. Epidermal growth factor receptor immunophenotype may be a useful predictor of clinical outcomes in this tumor subset.

Prognostic factors in the treatment of malignant pleural mesothelioma at a large tertiary referral center.

INTRODUCTION: Most studies describing the natural history and prognostic factors for malignant pleural mesothelioma antedate accurate pathologic diagnosis, staging by computed tomography, and a universal staging system. We conducted a large single-institution analysis to identify prognostic factors and assess the association of resection with outcome in a contemporary patient population. METHODS: Patients with biopsy-proven malignant pleural mesothelioma at our institution were identified and clinical data were obtained from an institutional database. Survival and prognostic factors were analyzed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis. A p value <0.05 was considered statistically significant. RESULTS: From 1990 to 2005, 945 patients were identified: 755 men, 190 women; median age, 66 years (range, 26-93). Extrapleural pneumonectomy was performed in 208 (22%), pleurectomy/decortication in 176 (19%). Operative mortality was 4% (16/384). Multimodality therapy including surgery was associated with a median survival of 20.1 months. Significant predictors of overall survival included histology, gender, smoking, asbestos exposure, laterality, surgical resection by extrapleural pneumonectomy or pleurectomy/decortication, American Joint Committee on Cancer stage, and symptoms. A Cox model demonstrated a hazard ratio of 1.4 without surgical resection when controlling for histology, stage, gender, asbestos exposure, smoking history, symptoms, and laterality (p = 0.003). CONCLUSIONS: In addition to tumor histology and pathologic stage, predictors of survival include gender, asbestos exposure, smoking, symptoms, laterality, and clinical stage. Surgical resection in a multimodality setting was associated with improved survival.

Duration of second or greater complete clinical remission in ovarian cancer: exploring potential endpoints for clinical trials.

OBJECTIVE: To explore benchmarks for future consolidation strategies, we evaluated a strictly defined (normal CA-125 and normal CT) second-complete-remission (CR) ovarian cancer population for 1) the median progression-free survival (PFS), 2) the frequency with which second remission exceeds first, and 3) the proportion of patients in remission at given time points. METHODS: Retrospective sampling was carried out at Memorial Sloan-Kettering (10/1993-12/2000) and the Royal Marsden Hospital (1/1995-4/2003) for the following: histological confirmation and elevated CA-125 at diagnosis; primary surgery; first-and second-line platinum-based chemotherapy with CR; and no maintenance therapy. RESULTS: In 35 patients 1) the duration of first PFS was 17.8 months (95% CI, 13.2-24.5 months) and second PFS was 10.8 months (95% CI, 9.6-12.2 months); 2) the number of patients with second response longer than first was 3/35 (9%); 3) the proportion of patients remaining in second complete remission was 100% (3 months), 100% (6 months), 83% (9 months), 34% (12 months), 23% (15 months) and 8.6% (18 months), respectively. CONCLUSION: 1) The median PFS from second complete remission is short. 2) A second response is rarely longer than the first even in this second CR population. 3) The number of patients with a second response longer than the first, or the proportion of patients remaining in complete remission at given time points could be evaluated as an outcome measure in future studies.

A phase II tolerability study of cisplatin plus docetaxel as adjuvant chemotherapy for resected non-small cell lung cancer.

INTRODUCTION: We undertook this phase II study to measure postoperative drug delivery and toxicity of cisplatin plus docetaxel in patients with resected stage I-III non-small cell lung cancer. METHODS: The primary endpoint was amount of cisplatin delivered over a planned four cycles of adjuvant chemotherapy. Statistical design required a cohort to close if the regimen proved unlikely to improve cisplatin delivery compared with published phase III data. The first cohort was treated with docetaxel 35 mg/m2 intravenously (IV) on days 1, 8, and 15, and cisplatin 80 mg/m2 IV on day 15, every 4 weeks for four planned cycles. A second cohort was treated with docetaxel 75 mg/m2 IV plus cisplatin 80 mg/m2 IV on day 1 every 3 weeks for four planned cycles. RESULTS: Sixteen patients were treated with weekly docetaxel and cisplatin every 4 weeks, with five of 16 (31%) unable to complete three cycles. Subsequently, 11 patients were treated with docetaxel and cisplatin every 3 weeks, with six of 11 (55%) unable to complete three cycles. Among the 11 patients who failed to complete three cycles, the reasons for stopping included one or more of the following: fatigue (n = 8), nausea (n = 4), febrile neutropenia (n = 1), hypotension (n = 1), and nephrotoxicity (n = 1). CONCLUSIONS: The combination of cisplatin at 80 mg/m2 with docetaxel 35 mg/m2 weekly or 75 mg/m2 every 3 weeks is no better tolerated than older chemotherapy regimens. The most common reason to stop chemotherapy was intolerable fatigue. These results suggest that the most common dose-limiting toxicities are attributable to the cisplatin, given similar problems were encountered whether the docetaxel was delivered as a single dose every 3 weeks or as a lower weekly dose.

A phase 1 study of pralatrexate in combination with paclitaxel or docetaxel in patients with advanced solid tumors.

PURPOSE: Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer. EXPERIMENTAL DESIGN: Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B(12) and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation. RESULTS: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m(2) plus docetaxel 35 mg/m(2) administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non-small-cell lung cancer. CONCLUSIONS: Pralatrexate (120 mg/m(2)) plus docetaxel (35 mg/m(2)) plus vitamin supplementation is well tolerated with signs of efficacy against non-small-cell lung cancer that merit phase 2 testing.

Phase II trial of pralatrexate (10-propargyl-10-deazaaminopterin, PDX) in patients with unresectable malignant pleural mesothelioma.

BACKGROUND: Several previous clinical trials have shown that malignant pleural mesothelioma is responsive to antifolates. The dihydrofolate reductase inhibitor, pralatrexate, has a favorable toxicity profile, primarily limited to stomatitis, and has demonstrated activity in patients with non-small cell lung cancer. In mesothelioma cell lines and xenografts, pralatrexate demonstrated significant antitumor activity. METHODS: We conducted this phase II study to determine the response rate of malignant pleural mesothelioma to pralatrexate at a dose of 135 mg/m2 i.v. every 2 weeks. After a protocol amendment, patients were supplemented with vitamin B12 and folic acid at the time of starting therapy. RESULTS: A total of 16 assessable patients were enrolled. No complete or partial responses were observed. Two patients with epithelioid histology had minor responses. Three other patients remained on study with stable disease for 9, 9, and 48 months. The median time to progression was 3 months. The overall median survival time was 7 months (95% confidence interval: 3.2-16.2 months) and the one-year survival was 31% (95% confidence interval: 15%-65%). Three patients (19%) had grade 2 stomatitis, eight (50%) had grade 3, and one (6%) had grade 4. CONCLUSIONS: With this particular dose and schedule, pralatrexate as a single agent had no activity in malignant pleural mesothelioma.

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors.

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

Salvage re-irradiation for recurrent head and neck cancer.

PURPOSE: To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. METHODS AND MATERIALS: From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). RESULTS: With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. CONCLUSIONS: Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.

American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma.

PURPOSE: In patients with adenocarcinoma of the esophagus who receive preoperative chemoradiotherapy (CRT), American Joint Committee on Cancer (AJCC) stage, pathologic complete response (pCR), and estimated treatment response are various means used to stratify patients prognostically after surgery. However, none of these methods has been formally evaluated. The purpose of this study was to establish prognostic pathologic variables after CRT. PATIENTS AND METHODS: A retrospective review was performed of patients with esophageal adenocarcinoma who received CRT before esophagectomy. Data collected included demographics, CRT details, pathologic findings, and survival. Statistical methods included recursive partitioning and Kaplan-Meier analyses. RESULTS: Two hundred seventy-six patients were appropriate for this analysis. Kaplan-Meier analysis indicates that the current AJCC system poorly distinguishes between stages 0 to IIA (P = .52), IIB to III (P = .87), and IVA to IVB (P = .30). The presence of a pCR conferred improved survival over residual disease (P = .01). Recursive partitioning analysis indicates that involved lymph nodes and metastatic disease are the best predictors of survival and that depth of invasion and degree of treatment response are less predictive. CONCLUSION: The current AJCC staging system is not a good predictor of survival after CRT. Although patients with a pCR do have improved long-term survival relative to patients with residual disease, this method places too much emphasis on residual depth of invasion and fails to identify patients with residual disease who have good long-term survival. Recursive partitioning analysis more accurately identifies nodal disease and metastatic disease as the most important prognostic variables. Degree of treatment response is less prognostic than nodal involvement.

A Phase II study of SU5416 in patients with advanced or recurrent head and neck cancers.

BACKGROUND: SU5416 (semaxanib) is a synthetic small molecule inhibitor of the tyrosine kinase domain of vascular endothelial growth factor receptor 2 (VEGFR2). This Phase II study was conducted to determine the safety and efficacy of SU5416 in patients with recurrent or metastatic head and neck cancers. PATIENTS AND METHODS: This was an open label, single arm, Phase 2 study for patients who had received no more than 2 cytotoxic regimens. Thirty-five patients received intravenous SU5416 (145 mg/m(2)) twice per week by intravenous catheter. Radiologic imaging for response assessment was planned at the conclusion of each 8 week cycle. Serum VEGF levels and power Doppler ultrasound tumor imaging were explored as potential surrogate markers for SU5416 activity. RESULTS: Thirty-two patients had received prior radiotherapy, including 18 patients who received prior concurrent chemoradiotherapy. Twelve patients had received prior chemotherapy in the recurrent disease setting. Thirty-one patients were evaluable for response. There was one partial response and one minor response. The median number of 8-week cycles received was 1 (range 1-4). Median overall survival was 6.25 months. The most common > or = grade 3 toxicity was headache (31%). There was one fatal carotid artery hemorrhage. Fatigue, nausea, and vomiting were common grade 1-2 adverse events. Power Doppler ultrasound demonstrated decreased tumor vascularity in 5 of 7 patients. CONCLUSIONS: Treatment with SU5416 in patients with head and neck cancers is feasible, but objective responses are rare. Studies evaluating more potent anti-angiogenic agents in this disease are of interest.

The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system.

OBJECTIVE: The American Joint Committee on Cancer (AJCC) staging system for esophageal cancer is controversial because it relies on arbitrary definitions of the anatomic location of lymph nodes to establish N and M status. It has been proposed that the number of involved lymph nodes may better predict survival. We reviewed our experience to determine the prognostic impact of the number of involved nodes and the extent of lymphadenectomy on the current staging system. METHODS: Records of all patients who underwent resection of previously untreated adenocarcinoma and squamous cell carcinoma of the esophagus and gastroesophageal junction were reviewed. Overall survival according to the AJCC staging system and the number of involved lymph nodes was analyzed by the method of Kaplan and Meier and by recursive partitioning methods. RESULTS: Data were available on 336 patients operated on between January 1996 and September 2003. Recursive partitioning analysis using AJCC staging variables reproduced the AJCC staging system. When the number of involved lymph nodes is added, patients with more than 4 involved lymph nodes have survival similar to that of patients with M1 disease, and patients with no involved lymph nodes have the best prognosis. Recursive partitioning analysis identified 18 lymph nodes as the minimal number required for accurate staging. In patients who have 18 or more lymph nodes removed, survival is only predicted by the presence of nodal involvement and M1 disease. CONCLUSION: Our analysis suggests that revisions of the current AJCC staging system for esophageal cancer should include N staging based on the number of involved lymph nodes and minimal requirements for the extent of lymphadenectomy.

A comparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy for locally advanced oropharyngeal carcinoma.

PURPOSE: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma. METHODS AND MATERIALS: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors. RESULTS: Median follow-up was 46 months (range, 3-93 months) for the CBRT patients and 31 months (range, 20-64 months) for the IMRT group. Three-year actuarial local-progression-free, regional-progression-free, locoregional progression-free, distant-metastases-free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had > or =20 months follow-up, there was a significant difference in Grade > or =2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm. CONCLUSION: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT.

Mortality increases for octogenarians undergoing esophagogastrectomy for esophageal cancer.

BACKGROUND: As the general population ages, it becomes increasingly important to understand the potential contribution of chronologic age to mortality after esophagectomy. Because this risk is poorly defined, we sought to determine whether extreme age (>80 years) is an independent risk factor after esophagectomy. METHODS: We analyzed a prospectively maintained, single-institution database of 858 consecutive patients who underwent esophagectomy between January 1996 and May 2005. Data evaluated included patient demographics, medical comorbidity, types of resections performed, length of stay, postoperative adverse events, and overall survival. We used univariate, multivariate, and Kaplan-Meier analysis to determine the influence of age on postoperative morbidity, in-hospital survival, and overall survival. RESULTS: Of 858 patients, 31 (10 female, 21 male) were older than 80 years of age. Preliminary analysis indicated that patients younger than 50 years (n = 107) had significantly fewer comorbidities; these were excluded from the analysis. In the remaining 751 patients, the age older than 80 cohort was compared with patients aged 50 to 79. Patients aged 50 to 79 were grouped because of similar characteristics (length of stay, hospital death). There were no significant differences in comorbidities, types of resections, or postoperative complication type or severity between the two groups. Postoperative death, length of stay, and survival, however, were significantly worse in patients older than 80. In a logistic regression model controlling for comorbidity, age older than 80 was significantly associated with increased perioperative mortality (hazard-ratio, 3.9; p < 0.01). CONCLUSIONS: Patients older than 80 years have increased mortality risk after esophagectomy, independent of comorbidity. Octogenarian status should be a consideration in the management of these patients.

Evaluation of postradiotherapy PSA patterns and correlation with 10-year disease free survival outcomes for prostate cancer.

PURPOSE: To describe the prostate-specific antigen (PSA) pattern profiles observed after external beam radiotherapy with and without short-term neoadjuvant androgen deprivation therapy (ST-ADT) and to report the association of established posttreatment PSA patterns with long-term disease-free survival outcomes. METHODS AND MATERIALS: A total of 1,665 patients were treated with conformal external beam radiotherapy for clinically localized prostate cancer. Of 570 patients who had the requisite>10 consecutive PSA measurements for statistical analysis, 194 patients received a median of 3 months of ADT before radiotherapy and 376 were treated with radiotherapy alone. The median follow up was 103 months. RESULTS: In the group treated with ST-ADT, three distinct postradiotherapy PSA patterns were identified: a stable trend (44%), an increasing trend followed by stabilization of the PSA (25%), and an increasing trend (31%). Among the subgroup that demonstrated a rising and subsequent stabilizing patterns, PSA levels had gradually risen to a median value of 0.9 ng/mL after therapy, stabilized, and remained durably suppressed. The only identified trends among patients treated with external beam radiotherapy without ST-ADT were declining PSA levels followed by stable PSA trends or declining patterns followed by rising levels. Patients whose PSA levels stabilized after an initial rise or those with slowly rising PSA profiles had a lower incidence of distant metastasis compared to those with accelerated rises after therapy. CONCLUSIONS: For those treated with external beam radiotherapy in conjunction with ST-ADT, a significant percentage who develop a rising PSA after treatment are expected to manifest subsequent stabilization at plateaued levels of approximately 1.0 ng/mL, which can remain durably suppressed. The likelihood of distant metastasis in these patients is low despite the PSA stabilization at levels 1.0 ng/mL or higher and comparable to outcomes observed for those with lower nonrising PSA values.

A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer.

BACKGROUND: Preclinical studies have suggested that erlotinib at high doses may inhibit additional sites downstream of the epidermal growth factor receptor (EGFR), resulting in greater antitumor efficacy. The objective of this study was to determine the tolerability and efficacy of high-dose erlotinib administered on a weekly schedule to patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: The authors conducted a Phase I/II trial of weekly erlotinib in patients with progressive NSCLC who had received previous chemotherapy. In the Phase I portion, patients were enrolled in 3-patient cohorts at erlotinib dose levels of 1200 mg, 1600 mg, and 2000 mg once weekly. The Phase II portion was designed to determine the major objective response rate of the dose identified in the Phase I portion of the trial. RESULTS: Twenty-seven patients were enrolled. No dose-limiting toxicity was observed. Grade 1 and 2 rash and diarrhea were the principle toxicities, and each occurred in 92% of patients. Among 21 patients who were treated at the Phase II dose of 2000 mg weekly, a single objective response was identified, yielding a response rate of 5% (95% confidence interval, 0.2-22%). For this cohort, the median survival was 9.5 months. The sole radiographic response occurred in a patient whose pretreatment tumor specimen harbored an EGFR exon 19 deletion. CONCLUSIONS: Erlotinib at a dose of 2000 mg administered weekly was tolerated well by these patients with advanced NSCLC. The 5% objective response rate did not reach the stated objective at the interim efficacy analysis, prompting the closure of the study.

Prevalence of COPD in women compared to men around the time of diagnosis of primary lung cancer.

PURPOSES: COPD is a well-known independent risk factor that is associated with primary lung cancer. There is, however, a striking paucity of women in studies demonstrating this association. The purpose of this study was to compare the prevalence of COPD as determined by pulmonary function tests (PFTs) between women and men at around the time of lung cancer diagnosis. METHODS: We retrospectively reviewed patients with newly diagnosed primary lung cancer who had undergone PFTs prior to their treatment. The diagnosis of airflow obstruction was made according to American Thoracic Society guidelines. Comparisons of the prevalence of COPD between men and women were performed using univariate and multivariate logistic regression analysis. RESULTS: Of the 294 patients in the study, 151 patients (51.4%) were men and 143 patient (48.6%) were women. Of the men, 110 patients (72.8%) had COPD compared with 75 patients (52.5%) among the women. This represented a significantly lower prevalence of COPD in women than in men (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.25 to 0.67; p = 0.0003). When adjusted for age and smoking status, a sustained lower prevalence of COPD was noted in women compared to men (OR, 0.44; 95% CI, 0.26 to 0.74; p = 0.002). In a subset of 256 smokers, there remained a lower prevalence of COPD in women compared to men (OR, 0.45; 95% CI, 0.27 to 0.77; p = 0.003). Adjusted analysis to control for age and number of pack-years of smoking in this subset again showed a sustained reduction in the OR for women presenting with COPD (OR, 0.48; 95% CI, 0.28 to 0.83; p = 0.009). CONCLUSIONS: When COPD was examined as an end point among patients who had newly diagnosed lung cancer, a significantly higher proportion of women had normal PFT results. Gender-based differences on PFT results should be considered during the screening of lung cancer, because the stratification of high-risk patients based on the presence of COPD may miss a significant proportion of women with lung cancer.

Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma.

BACKGROUND: The benefit of cytoreductive surgery for patients with recurrent epithelial ovarian cancer has not been defined clearly. The objective of this study was to identify prognostic factors for survival in patients who underwent secondary cytoreduction for recurrent, platinum-sensitive epithelial ovarian cancer and to establish generally applicable guidelines and selection criteria. METHODS: The authors reviewed all patients who underwent secondary cytoreduction for recurrent epithelial ovarian cancer from 1987 to 2001. Potential prognostic factors were evaluated in univariate and multivariate analyses. RESULTS: In total, 157 patients underwent secondary cytoreduction, and 153 of those patients were evaluable. After secondary cytoreduction, the median follow-up was 36.9 months (range, 0.2-125.6 months), and the median survival was 41.7 months (95% confidence interval, 36.0-47.2 months). For patients who had a disease-free interval prior to recurrence of between 6 months and 12 months, the median survival was 30 months compared with 39 months for patients who had a disease-free interval between 13 months and 30 months and 51 months for patients who had a disease-free interval >30 months (P = .005). For patients who had a single site of recurrence, the median survival was 60 months compared with 42 months for patients who had multiple sites of recurrence and 28 months for patients who had carcinomatosis (P <.001). The median survival for patients who had residual disease that measured < or =0.5 cm was 56 months compared with 27 months for patients who had residual disease that measured >0.5 cm (P <.001). On multivariate analysis, disease-free interval (P = .004), the number of recurrence sites (P = .01), and residual disease (P <.001) were significant prognostic factors. CONCLUSIONS: In the authors' analysis of secondary cytoreduction for recurrent epithelial ovarian cancer, a significant survival benefit was demonstrated for residual disease that measured < or = 0.5 cm. The disease-free interval and the number of recurrence sites should be used as selection criteria for offering secondary cytoreduction.

Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas.

PURPOSE: Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers. METHODS: EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit > or = 1 year ago), or current smokers (quit < 1 year ago). RESULTS: We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively). CONCLUSION: The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

Phase I/II study of weekly paclitaxel plus carboplatin and gemcitabine as first-line treatment of advanced-stage ovarian cancer: pathologic complete response and longitudinal assessment of impact on cognitive functioning.

BACKGROUND: To determine the pathologic complete response rate of advanced ovarian cancer to weekly paclitaxel plus gemcitabine and carboplatin with filgrastim, and assess the longitudinal impact of this regimen on quality-of-life and cognitive functioning. METHODS: Fourteen patients with advanced ovarian, peritoneal, or fallopian tube cancer were treated in the phase I portion of the study. Initial doses were paclitaxel: 60 mg/m(2) days 1, 8, and 15; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: area under the curve (AUC) 5 day 1, every 21 days for 6 cycles with filgrastim. Twenty-seven patients were treated at the phase II dose. Pathologic response was assessed by second-look laparoscopy in patients with complete response. Patients completed longitudinal assessments of quality-of-life and cognitive functioning. RESULTS: Maximally tolerated doses were paclitaxel: 80 mg/m(2) days 1 and 8; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: AUC 5 day 1, every 21 days. Forty-eight percent of patients (13/27) experienced at least 1 grade 3 nonhematologic toxicity. Fifty percent (95% confidence interval [CI], 31-69%) of assessable patients achieved pathologic complete response. Median progression-free survival was 27.3 months (95% CI, 17.7 months to not reached), and overall survival 43.6 months (95% CI, 42 months to not reached). Cognitive functioning did not decline during or after chemotherapy. More highly educated women reported a perceived decline in concentration and memory while on chemotherapy. Quality-of-life scores were maintained during therapy. CONCLUSIONS: Fifty percent of patients with advanced-stage ovarian cancer achieved pathologic complete response to weekly paclitaxel plus gemcitabine and carboplatin. Cognitive functioning did not decline by objective measures, although highly educated women reported subjective impairment.