A phase I study of pegylated liposomal doxorubicin and irinotecan in patients with solid tumors.

BACKGROUND: Preclinical studies have shown synergism between topoisomerase I and II inhibitors. METHODS: We conducted a phase I study evaluating the combination of pegylated liposomal doxorubicin and irinotecan in patients with previously treated solid tumors. RESULTS: Twelve patients were enrolled. The median age was 62 years (range 19-72). The most common grade 3/4 toxicities were neutropenia (dose-limiting toxicity), diarrhea and nausea/vomiting. The maximal tolerated dose and recommended schedule were pegylated liposomal doxorubicin 20 mg/m(2) over 60 min on day 1, followed by irinotecan 100 mg/m(2) over 90 min on days 1 and 8 of a 21-day cycle. There were no objective clinical responses, but 5 patients achieved stable disease lasting a median of 11 weeks duration (range 2-35). CONCLUSIONS: This regimen should be further studied in patients with tumors known to have a sensitivity to both topoisomerase I and II inhibitors such as ovarian and small cell carcinoma.

Response to bortezomib (velcade) in a case of advanced bronchiolo-alveolar carcinoma (BAC). A case report.

A 65-year-old male with 40-pack year smoking history presented with exertional dyspnea and was subsequently diagnosed with bronchiolo-alveolar carcinoma (BAC). He did not respond to first line therapy with geftinib, but he achieved disease stabilization with gemcitabine and carboplatin for 4 months before developing symptomatic worsening requiring oxygen supplementation. He responded dramatically to bortezomib with rapid symptom improvement. The follow-up computerized tomography revealed partial response that was maintained for 11 months. Based on observations like this and those seen in phase I studies with bortezomib, this agent is being studied now in patients with bronchio-alevolar cancer.

The role of docetaxel in N2 locally advanced non-small-cell lung cancer.

Patients with locally advanced non-small-cell lung cancer (NSCLC) are a heterogeneous group often treated with multimodality therapy. Docetaxel has an established role in the treatment of advanced-stage NSCLC and has demonstrated promising activity in the locally advanced setting. Herein, we review the available data on the role of docetaxel in locally advanced NSCLC. The phase I/II data regarding the use of docetaxel concomitantly with radiation as a single agent or combined with platinum compounds are reviewed. In addition, we discuss the role of docetaxel induction therapy before surgery or definitive radiation therapy. Additionally, we address the role of docetaxel in consolidation therapy in patients with locally advanced NSCLC.

Prognostic value of preoperative positron emission tomography in resected stage I non-small cell lung cancer.

PURPOSE: Approximately 20 to 40% of patients with surgically resected stage I non-small cell lung cancer (NSCLC) will develop recurrent disease. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is used often in staging NSCLC. We conducted this study to determine whether the preoperative maximum tumor standardized uptake value (SUVmax) was associated with recurrence in patients with resected stage I NSCLC. PATIENTS AND METHODS: We identified consecutive patients who underwent curative surgical resection for stage I NSCLC between 1999 and 2003 who had preoperative FDG-PET imaging. Patients were divided into two cohorts based on SUVmax above or below the median for the group. Recurrence rates were estimated by the Kaplan-Meier method and overall survival was analyzed as a secondary end point. RESULTS: Of 136 patients who met inclusion criteria, 77 (57%) had T1 and 59 (43%) had T2 tumors. The median follow-up time was 46 months and 32 patients had a disease recurrence. The median SUVmax was 5.5. The 5-year estimates of recurrence rates for patients with low and high SUVmax were 14% and 37%, respectively (p = 0.002), with 5-year overall survivals of 74% and 53%, respectively (p = 0.006). In multivariate analyses based on SUVmax, T-classification, age, and histology, high SUVmax was independently associated with recurrence (p = 0.002) and mortality (p = 0.041). CONCLUSION: High SUVmax (>or=5.5) on preoperative FDG-PET is an independent predictor of relapse and death in resected stage I NSCLC. Prospective trials of adjuvant chemotherapy in patients with stage I NSCLC and high SUVmax should be considered.

A clinical model to estimate recurrence risk in resected stage I non-small cell lung cancer.

OBJECTIVE: There are no reliable markers to predict recurrence in resected Stage I non-small cell lung cancer (NSCLC). A validated clinical model to estimate the risk of recurrence would help select patients for adjuvant therapy. METHODS: We reviewed the medical records of 715 patients who had a potentially curative resection for Stage I NSCLC at our institution from 1990 to 2000. Recurrence rates were estimated by the Kaplan-Meier method. A model to estimate risk of recurrence was developed by combining independent risk factors. RESULTS: With a median follow-up of 4.7 years, the 5-year survival rates for Stages IA and IB were 66% and 55% respectively, and 5-year recurrence rates were 19% and 30%, respectively. Four factors were independently associated with tumor recurrence: tumor size >3 cm (hazard ratio [HR] = 2.4), surgery other than lobectomy (HR = 2.0), nonsquamous histology (HR = 1.4), and high-grade cellular differentiation (HR = 1.4). A scoring system for recurrence was developed by assigning 2 points for each major risk factor (tumor size and surgery) and 1 point for each minor risk factor (histologic subtype and cellular grade). Scores were grouped as low (0-1), intermediate (2-3), and high (>3), yielding 5-year estimates of risk of recurrence of 14%, 27%, and 43%, respectively. CONCLUSION: This model, based upon readily available clinicopathologic characteristics, can estimate the risk of recurrence in Stage I NSCLC, independent of T classification. This model could be used to select patients for adjuvant therapy if validated in independent data sets.

Prognostic value of fluorodeoxyglucose positron emission tomography in non-small cell lung cancer: a review.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer morbidity and mortality. Adjuvant chemotherapy improves survival in resected early-stage NSCLC. However, a significant proportion of patients with early-stage lung cancer are cured by surgery alone. There are no reliable clinical or molecular markers to predict outcomes after surgery in early-stage NSCLC. Positron emission tomography with 2-[F]fluoro-2-deoxy-D-glucose (FDG-PET) improves the accuracy of staging work-up in NSCLC. The standardized uptake value, a commonly used semiquantitative measure of FDG uptake, correlates with tumor doubling time and indices of cell cycling. Therefore, FDG-PET may be a useful predictor of outcome independent of its role in tumor staging. In this review, we critically examine the published studies on the utility of FDG-PET as a prognostic tool in patients with NSCLC and provide direction for future research.

A phase II study of irinotecan and carboplatin in advanced non-small cell lung cancer with pharmacogenomic analysis: final report.

PURPOSE: We conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity. PATIENTS AND METHODS: Patients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1). RESULTS: Forty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia (p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes (p = 0.057). CONCLUSION: The combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity.