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ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial., Competing Interests: Disclosure None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the "accepted standard" biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of "plasma first" versus "tissue first" approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC., (Copyright © 2021. Published by Elsevier Inc.)

ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA-NSCLC) to concomitant durvalumab or no additional therapy, with both arms receiving 1 year of consolidative durvalumab. Radiation dose escalation failed to improve overall survival in RTOG 0617. However, conventionally fractionated radiation to 60 Gy with concomitant chemotherapy is associated with a high risk of local failure (38%-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we review conventional chemo/radiation therapy for LA-NSCLC, as well as the quickly evolving world of immunotherapy in the treatment of non-small cell lung cancer and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: This article provides an up-to-date assessment of how immunotherapy is reshaping the landscape of metastatic non-small cell lung cancer (NSCLC) and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. This article reviews the recent publications of chemo/radiation as well as those combining immunotherapy with chemotherapy and chemo/radiation, and provides a strategy for improving overall survival of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation., (© 2021 AlphaMed Press.)

To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Randomized controlled trial to evaluate synergy between taxane plus platinum chemotherapy and CADI-05, a Toll like receptor-2 agonist targeting desmocollin-3 as a first-line therapy in advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC (stage IIIB or IV) were randomized to cisplatin-paclitaxel (chemotherapy group, N = 112) or cisplatin-paclitaxel plus CADI-05 (chemoimmunotherapy group, N = 109). CADI-05 was administered a week before chemotherapy and on days 8 and 15 of each cycle and every month subsequently for 12 months or disease progression. Overall survival was compared using a log-rank test. Computed tomography was carried out at baseline, end of two cycles and four cycles. Response rate was evaluated using Response Evaluation Criteria in Solid Tumors criteria by an independent radiologist., Results: As per intention-to-treat analysis, no survival benefit was observed between two groups [208 versus 196 days; hazard ratio, 0.86; 95% confidence interval (CI) 0.63-1.19; P = 0.3804]. In a subgroup analysis, improvement in median survival by 127 days was observed in squamous NSCC with chemoimmunotherapy (hazard ratio, 0.55; 95% CI 0.32-0.95; P = 0.046). In patients receiving planned four cycles of chemotherapy, there was improved median overall survival by 66 days (299 versus 233 days; hazard ratio, 0.64; 95% CI 0.41 to 0.98; P = 0.04) in the chemoimmunotherapy group compared with the chemotherapy group. This was associated with the improved survival by 17.48% at the end of 1 year, in the chemoimmunotherapy group. Systemic adverse events were identical in both the groups., Conclusion: There was no survival benefit with the addition of CADI-05 to the combination of cisplatin-paclitaxel in patients with advanced NSCLC; however, the squamous cell subset did demonstrate a survival advantage., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study examined the day-to-day lives of early stage lung cancer survivors who were discharged from treatment between 2 and 24 months prior to the study. Lung cancer survivors were called on eight consecutive nights and completed an interview about their daily experiences. Repeated measures, multilevel analysis of the phone interview data was conducted. Survivors reported few daily stressor exposures or somatic symptoms. Daily moods were generally positive, and survivors reported living quite independently. Lung cancer survivors did not report experiencing health-related worry on a daily basis. The findings from this study create a much more positive picture of lung cancer survivorship relative to prior studies., (© The Author(s) 2015.)

Purpose: Current National Comprehensive Cancer Network guidelines recommend postoperative radiation therapy (PORT) for patients with resected non-small cell lung cancer (NSCLC) with N2 involvement. We investigated the relationship between nodal stage and local-regional recurrence (LR), distant recurrence (DR) and overall survival (OS) for patients having an R0 resection., Methods and Materials: A multi-institutional database of consecutive patients undergoing R0 resection for stage I-IIIA NSCLC from 1995 to 2008 was used. Patients receiving any radiation therapy before relapse were excluded. A total of 1241, 202, and 125 patients were identified with N0, N1, and N2 involvement, respectively; 161 patients received chemotherapy. Cumulative incidence rates were calculated for LR and DR as first sites of failure, and Kaplan-Meier estimates were made for OS. Competing risk analysis and proportional hazards models were used to examine LR, DR, and OS. Independent variables included age, sex, surgical procedure, extent of lymph node sampling, histology, lymphatic or vascular invasion, tumor size, tumor grade, chemotherapy, nodal stage, and visceral pleural invasion., Results: The median follow-up time was 28.7 months. Patients with N1 or N2 nodal stage had rates of LR similar to those of patients with N0 disease, but were at significantly increased risk for both DR (N1, hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.30-2.59; P=.001; N2, HR = 2.32, 95% CI: 1.55-3.48; P<.001) and death (N1, HR = 1.46, 95% CI: 1.18-1.81; P<.001; N2, HR = 2.33, 95% CI: 1.78-3.04; P<.001). LR was associated with squamous histology, visceral pleural involvement, tumor size, age, wedge resection, and segmentectomy. The most frequent site of LR was the mediastinum., Conclusions: Our investigation demonstrated that nodal stage is directly associated with DR and OS but not with LR. Thus, even some patients with, N0-N1 disease are at relatively high risk of local recurrence. Prospective identification of risk factors for local recurrence may aid in selecting an appropriate population for further study of postoperative radiation therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC)., Methods: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH)., Results: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes., Conclusions: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Stereotactic body radiotherapy (SBRT) is an alternative to surgery for clinical stage I non-small cell lung cancer (NSCLC), but comparing its effectiveness is difficult because of differences in patient selection and staging., Methods: Two databases were combined which contained patients treated from 1999 to 2008 by lobectomy (LR, n = 132), sublobar resection (SLR, n = 48), and SBRT (n = 137) after negative staging. Univariate and multivariate analysis were performed for survival (OS), total recurrence control (TRC comprises local-regional and distant control), and locoregional control (LRC) in our entire population. A matched-pair analysis was also performed that compared surgery and SBRT results. Median follow-up for the entire study population was 25.8 months., Results: On univariate analysis, OS was significantly worse with SBRT and also correlated with histology, the Charlson comorbidity index, tumor size, and aspirin use; TRC correlated only with histology; and no variable significantly correlated with LRC. OS was significantly poorer for SBRT in the matched-pair analysis than for patients treated with surgery, but TRC and LRC were not significantly different between these groups. Multivariate analyses including propensity score as a covariate (controlling for all factors affecting treatment selection) found that OS correlated only with Charlson comorbidity index, and TRC correlated only with tumor grade. LRC correlated only with tumor size with or without propensity score correction., Conclusions: This retrospective study has demonstrated similar OS, LRC, and TRC with SBRT or surgery after controlling for prognostic and patient selection factors. Randomized clinical trials are needed to better compare the effectiveness of these treatments., (© 2013 American Cancer Society.)

Background: This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer (NSCLC)., Patients and Methods: The six symptom items' [average symptom burden index (ASBI)] mean at baseline was calculated using the lung cancer symptom scale (LCSS). Low and high symptom burden (LSB, ASBI < 25; HSB, ASBI ≥ 25) and performance status (PS: 0, 1) subgroups were analyzed for treatment effect on progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models adjusted for demographic/clinical factors., Results: Significantly longer PFS and OS for pemetrexed versus placebo occurred in LSB patients [PFS: median 5.1 versus 2.4 months, hazard ratio (HR) 0.49, P < 0.0001; OS: median 17.5 versus 11.0 months, HR 0.63, P = 0.0012] and PS 0 patients (PFS: median 5.5 versus 1.7 months, HR 0.36, P < 0.0001; OS: median 17.7 versus 10.3 months, HR 0.54, P = 0.0019). Significantly longer PFS, but not OS, occurred in HSB patients (median 3.7 versus 2.8 months, HR 0.50, P = 0.0033) and PS 1 patients (median 4.4 versus 2.8 months, HR 0.60, P = 0.0002)., Conclusions: ASBI and PS are associated with survival for non-squamous NSCLC patients, suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction.

Background: This phase Ib study evaluated volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC)., Patients and Methods: Three cohorts were treated with volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin-paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-volociximab antibodies were assessed., Results: A maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received volociximab, the most common grade≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5-8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment., Conclusions: Volociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.

Background: The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex., Patients and Methods: Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ≥60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort., Results: The median survival time (MST) for women ≥60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ≥60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men., Conclusions: In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ≥60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

While chemotherapy has been the standard of care for patients with advanced non-small cell lung cancer (NSCLC), efforts have shifted toward evaluating novel targeted agents in an attempt to improve outcome. These targeted agents are directed toward key components in several signalling pathways such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-IR). There is also increasing interest in using combinations of targeted agents to inhibit more than one pathway; for example, inhibition of VEGFR + EGFR and VEGFR + PDGFR + EGFR. Further investigation is needed to identify the most appropriate combinations of these targeted agents in select patient subgroups, and to define optimal treatment doses to thereby achieve the best therapeutic index. This review outlines the rationale for combining targeted agents for the treatment of advanced NSCLC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Non-small-cell lung cancer (NSCLC) represents a common health issue in the elderly population. Nevertheless, the paucity of large, well-conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The present paper reviews the currently available evidence regarding treatment of all stages of NSCLC in elderly patients. Surgery remains the standard for early-stage disease, though pneumonectomy is associated with higher incidence of postoperative mortality in elderly patients. Given the lack of demonstrated benefit for the use of adjuvant radiotherapy, it is also not recommended in elderly patients. Elderly patients seem to derive the same benefit from adjuvant chemotherapy as younger patients do, with no significant increase in toxicity. For locally advanced NSCLC, concurrent chemoradiotherapy may be offered to selected elderly patients as there is a higher risk for toxicity reported in the elderly population. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Unfortunately, with the exception of advanced/metastatic NSCLC, prospective elderly-specific NSCLC trials are lacking and the majority of recommendations made are based on retrospective data, which might suffer from selection bias. Prospective elderly-specific trials are needed.

Background: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen., Patients and Methods: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression., Results: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC., Conclusions: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of first-line therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen.

Introduction: This study evaluated the safety/efficacy of once-weekly (QW) epoetin alfa measured by quality of life (QOL), hemoglobin (Hb), transfusion incidence, tumor response, and survival in patients with chemotherapy-naïve, advanced non-small cell lung cancer (NSCLC)., Methods: Stage IIIB/IV NSCLC patients with Hb > or = 11 to < 15 g/dl scheduled for at least 8 weeks of first-line chemotherapy were randomized to subcutaneously receive 40,000 U of epoetin alfa QW at chemotherapy initiation (immediate) or no epoetin alfa unless Hb decreased to < or = 10 g/dl (delayed). The primary efficacy variable was change in QOL for immediate versus delayed intervention. Target accrual was 320 patients., Results: The study was terminated early because of slow accrual; of 216 patients enrolled, 211 were evaluable for efficacy. Hb was maintained in the immediate group, but it decreased in the delayed group (12.9 versus 11.6 g/dl final values, respectively). Numerically, fewer immediate patients required transfusions versus delayed patients. Mean QOL scores, modestly declining in both groups from baseline to final measurement, were not significantly different between groups. Tumor response and median overall survival were similar between groups. Epoetin alfa was well tolerated, with a similar thrombovascular event rate between groups., Conclusion: Epoetin alfa in subcutaneous doses of 40,000 U QW, given immediately at chemotherapy initiation for advanced NSCLC, was well tolerated, and it effectively maintained Hb, leading to a reduced transfusion incidence versus delayed epoetin alfa. Overall QOL scores were higher than typical in this population, decreasing slightly during treatment in both groups. Overall survival was similar between groups, with no evidence of a negative effect by early epoetin alfa intervention.

Introduction: Gemcitabine and paclitaxel (Taxol) each provides an efficacious non-platinum option for the treatment of advanced non-small-cell lung cancer (NSCLC), but the optimal dosage and schedule of the two agents used in combination are not well defined., Methods: Previously untreated patients with advanced NSCLC were randomized to receive gemcitabine-paclitaxel on a traditional three-weekly schedule (Arm A) or a novel weekly schedule (Arm B) as follows-Arm A (three-weekly): gemcitabine 1000 mg/m2 infused>30 min on days 1 and 8 and paclitaxel 200 mg/m2 infused>3 h on day 1 of a 21-day cycle or Arm B (weekly): gemcitabine 1000 mg/m2 infused>30 min and paclitaxel 100 mg/m2 infused>1 h, both administered on days 1 and 8 of a 21-day cycle., Results: One hundred patients received at least one dose of treatment. The weekly schedule, Arm B, was more efficacious and less hematologically toxic than Arm A. Confirmed complete and partial response rates were 28.2% and 26.8%, respectively. Median survival was 10.3 months on Arm B and 7.9 months on Arm A (log-rank P=0.10); 1- and 2-year survival rates also favor Arm B: 42.0% versus 34.0% and 18.0% versus 6.0%. Progression-free survival was 5.8 versus 4.8 months, again favoring Arm B (log-rank P=0.06). There was a two-fold lower frequency of grade 3/4 hematologic events with Arm B as follows: neutropenia (16% versus 30%), thrombocytopenia (4% versus 8%), and anemia (2% versus 6%). One patient (2%) in each treatment group developed febrile neutropenia., Conclusion: In this trial, both schedules were efficacious and tolerable, although the weekly schedule resulted in improved survival and lower hematologic toxicity compared with a three-weekly schedule. The weekly schedule of gemcitabine-paclitaxel indicates an improved therapeutic index.

We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; (P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.

Background: The present study was designed to evaluate the efficacy and safety of the regimen of carboplatin plus paclitaxel (investigational arm) versus the reference regimen of cisplatin plus etoposide for the treatment of advanced or metastatic non-small-cell lung cancer., Patients and Methods: A total of 369 patients were enrolled, 179 on arm A (cisplatin 75 mg/m2 and etoposide 100 mg/m2) and 190 on arm B (carboplatin AUC=6 mg/ml min and paclitaxel 225 mg/m2), with cycles repeated every 3 weeks. The arms were well balanced with respect to age, performance status, weight loss, stage of disease and disease measurability. However, significantly more women were randomized to arm A than to arm B (P=0.039)., Results: The objective response rate (ORR) was 15% on arm A compared with 23% on arm B (P=0.061). Median survival time, time to progression and 1-year survival rates for arms A and B were 274 days and 233 days (P=0.086), 111 days and 121 days (P=0.877), and 37% and 32%, respectively. The most prevalent toxicities were neutropenia and leukopenia and they occurred at a higher rate in arm A than in arm B., Conclusion: There was no statistically significant survival advantage for carboplatin-paclitaxel compared with cisplatin-etoposide. However, there was an overall benefit in quality of life with the carboplatin-paclitaxel regimen.

Background: Gefitinib (Iressa) is active as a single agent in the treatment of select patients with recurrent non-small cell lung cancer (NSCLC). The clinical characteristics of patients treated with gefitinib on an Expanded Access Program (EAP) at our institution identified predictive variables associated with better outcome., Patients and Methods: Patients (n=199) with advanced NSCLC were treated with gefitinib (250 mg) upon progression with chemotherapy. Baseline patient characteristics were: median age, 69 years; males, 57%; adenocarcinoma, 56%., Results: Partial responses were noted in two patients (1%) and disease stabilization in 66 (35%) patients. The median survival (MS) was 5.9 months [95% confidence interval (CI) 4.1-7.1] and median time to progression was 3 months (95% CI 2.0-3.0). The predictive factors analyzed were gender, skin rash, diarrhea, tumor histology and performance status (PS). Patients who developed skin rash (any grade) had MS of 10.8 months versus 4.0 months for those without rash (P <0.0001, log rank test). Patients with PS 0, 1 and 2 had MS of 8.4, 6.2 and 2.8 months, respectively (P <0.0002). The other factors did not impact survival., Conclusions: Occurrence of skin rash and baseline PS of 0/1 were associated with improved survival with gefitinib for recurrent NSCLC patients at our institution.

Objective: Treatment options for patients with non-small cell lung cancer who are not surgical candidates or who refuse operation are limited. Radiofrequency ablation represents a potential less invasive option for these patients. Our initial experience with radiofrequency ablation for peripheral, primary non-small cell lung cancer is reported., Methods: We treated 21 tumors in 18 patients. Median age was 75 (range 58-86) years. Cancer stages were I (n = 9), II (n = 2), III (n = 3), and IV (n = 4). Patients with stage IV disease included 3 with recurrence after previous lobectomies and 1 with a synchronous liver metastasis also treated with radiofrequency ablation. Median tumor diameter was 2.8 cm (range 1.2-4.5 cm). Radiofrequency ablation was delivered by minithoracotomy in 2 cases and by a computed tomography-guided percutaneous approach in 16 patients. Computed tomographic and positron emission tomographic scans were used to evaluate recurrence and radiographic response in ablated nodules., Results: One postoperative death occurred from pneumonia after open radiofrequency ablation. Median hospital stay was 2.5 days. A chest tube or pigtail catheter was required in 7 patients (38.9%) for procedure-related pneumothoraces. At a median follow-up of 14 months, 15 patients (83.3%) were alive. Local progression occurred in 8 nodules (38.1%). Mean and median progression-free intervals were 16.8 and 18 months, respectively. For stage I cancers, mean progression-free interval was 17.6 months. Median progression-free interval was not reached., Conclusion: This study demonstrates the feasibility of radiofrequency ablation for small, peripheral non-small cell lung cancer tumors. Local control is comparable to, if not better than, that provided by radiotherapy. Radiofrequency ablation should continue to be evaluated by thoracic surgeons as a noninvasive therapy for the high-risk patient with non-small cell lung cancer.

Inconsistencies in the treatment planning process leading to dosimetric uncertainties may affect conclusions drawn from interinstitutional radiation oncology clinical trials. The purpose of this study was to assess the dosimetric uncertainties resulting from the process of reconstructing three-dimensional dose distributions from two-dimensional treatment plan information provided by participating institutions in a randomized clinical trial. This study was based on American College of Radiology Protocol #427, Locally Advanced Multi-Modality Protocol; a multi-institutional phase II randomized study involving radiation therapy for patients with inoperable non-small cell lung cancer. Several sources of dosimetric uncertainty were identified and analyzed, including image quality of hard-copy computed tomography (CT) images, slice spacing of CT scans, treatment position, interpretations of target volumes by radiation oncologists, the contouring of normal anatomic structures, and the use of common beam models for all dose calculations. Each source of uncertainty was investigated using a set of plans, with the ideal characteristics of digital images with 3-mm axial slice spacing and a flat couch, consisting of eight cases from Vanderbilt University Medical Center with electronically transferred CT data. The target volume DVH values were dependent on the additional uncertainty introduced by differences in delineation of the target volumes by the participating radiation oncologists. The DVH values for the lungs and heart were dependent on image quality and treatment position. Esophagus DVH values were not dependent on any of the sources of uncertainty. None of the structure DVH values were dependent on slice thickness or variations in the contouring of normal anatomic structures. Reconstruction of three-dimensional dose distributions from two-dimensional treatment plan information may be useful in cases for which digital CT data is not available or for historical data review. However, dosimetric accuracy will depend on image quality of the treatment planning CT data and consistency in the delineation of tumor volumes.

Background: This phase II study was conducted to evaluate the safety and efficacy of the combination of paclitaxel and topotecan for patients with extensive stage small-cell lung cancer (ED-SCLC)., Patients and Methods: Previously untreated ED-SCLC patients with Eastern Coperative Oncology Group performance status <2 were eligible. Treatment consisted of topotecan 1 mg/m2 (first three patients received 1.25 mg/m2), on days 1-5, and paclitaxel 135 mg/m2 over 24 h on day 5, every 4 weeks. Prophylactic granulocyte colony-stimulating factor was administered to all patients., Results: Thirty-two patients received a median of four cycles of chemotherapy. Grade 4 anemia, neutropenia and thrombocytopenia occurred in 13, 31 and 18 patients, respectively. Thirty episodes of febrile neutropenia occurred in 22 patients. Grade 3 fatigue, esophagitis, stomatitis and hypotension occurred in one patient each. Of 26 patients eligible for response evaluation, there were six complete and 12 partial responses (overall response rate 69%). The median survival was 54 weeks. The 1-, 2- and 3-year survival rates were 50%, 10% and 3%, respectively., Conclusions: The combination of topotecan and paclitaxel is active as initial therapy in SCLC, but the efficacy is similar to 'standard therapy'. This combination was associated with a high incidence of myelosuppression and febrile neutropenia, at the doses evaluated.

Background: Eastern Cooperative Oncology Group (ECOG) Study E1594 compared paclitaxel and cisplatin with three newer chemotherapy doublets in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). The accrual of patients with an ECOG performance status (PS) of 2 was discontinued due to a perceived rate of unacceptable toxicity., Methods: Patients were stratified by PS and randomized to one of the following treatments: 1) paclitaxel (135 mg/m2) over 24 hours with cisplatin (75 mg/m2) on a 21-day cycle; 2) cisplatin (100 mg/m2) with gemcitabine (1 g/m2) on Days 1, 8, and 15 on a 28-day cycle; 3) cisplatin (75 mg/m2) with docetaxel (75 mg/m2) on a 21-day cycle; and 4) paclitaxel (225 mg/m2) over 3 hours with carboplatin (area under the curve, 6). All tests of statistical significance were two-sided., Results: Sixty-eight patients with an ECOG PS of 2 were enrolled, and 64 patients were evaluable for toxicity and response. Fifty-six percent of 64 evaluable patients were male, and 81% had Stage IV disease. Grade 3-4 hematologic toxicities occurred in > 50% of the patients in each treatment group. Nonhematologic Grade 3-4 toxicities occurred significantly less often in the paclitaxel and carboplatin arm (P = 0.0032). The overall rate of toxicity did not differ significantly from the rate of toxicity in the PS-0 or PS-1 cohorts. There were 5 deaths (7.35%) among 68 patients with a PS of 2 during therapy; however, only 2 of those deaths were attributed to therapy. The overall response rate for the 64 evaluable patients was 14%. The overall median survival of all 68 patients with a PS of 2, as determined by an intent-to-treat analysis, was 4.1 months., Conclusions: Patients with advanced NSCLC and a PS of 2 experienced a large number of adverse reactions and overall poor survival. A comparison with patients with a PS of 0-1 suggests that these events and the shorter survival were related to disease process rather than treatment. Alternative strategies need to be explored with therapy specifically tailored for this group of patients., (Copyright 2001 American Cancer Society.)

This multi-institutional randomized phase II study was designed to compare the efficacy and toxicity of three different weekly paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin schedules in patients with advanced and metastatic non-small cell lung cancer. The second part of the trial evaluated the role of maintenance weekly paclitaxel for those with response or stable disease after 16 weeks of initial treatment. Patients in arm 1 received paclitaxel 100 mg/m(2)/wk for 3 weeks along with carboplatin (area under the curve of 6) on day 1 every 4 weeks. The treatment in arm 2 was the same as in arm 1 except that carboplatin was also administered weekly (area under the curve of 2) for 3 weeks. Patients in arm 3 received paclitaxel 150 mg/m(2)/wk and carboplatin (area under the curve of 2 per week) during the second 8-week cycle. The total duration of this initial therapy was 16 weeks. All regimens were well tolerated. Arm 1 has the best therapeutic index and will exceed the median survival seen in previous phase III trials with traditional schedules of paclitaxel and carboplatin., (Copyright 2001 by W.B. Saunders Company.)

In the TAX 326 trial, 1,220 chemotherapy-naive patients with advanced or metastatic non--small cell lung cancer have been randomized to receive one of three regimens: docetaxel 75 mg/m(2) plus cisplatin 75 mg/m(2) every 3 weeks; docetaxel 75 mg/m(2) plus carboplatin to an area under the curve of 6 mg/mL x min every 3 weeks; or a control arm of vinorelbine 25 mg/m(2) weekly plus cisplatin 100 mg/m(2) monthly. The treatment and toxicity data presented are based on a planned preliminary analysis conducted after 601 patients had been enrolled. The median age of patients randomized was 60 years and 73% were male. The majority of patients had a Karnofsky score of 80 or greater, two thirds had stage IV disease and 35% had three or more sites of organ involvement. While the relative dose intensity for docetaxel was 0.97 both when combined with cisplatin and when combined with carboplatin, the corresponding figure for vinorelbine was 0.68, reflecting the frequent need for dose reduction when combined with cisplatin on the schedule used. Hematologic toxicities were tolerable and comparable across the three arms of the trial, and the rate of febrile neutropenia was below 5% in all cases. The incidence of nonhematologic toxicities also was similar, although nausea and vomiting appeared to be less frequent among patients assigned to docetaxel plus carboplatin than among patients receiving comparator regimens. Semin Oncol 28 (suppl 9):10-14., (Copyright 2001 by W.B. Saunders Company.)

Docetaxel (Taxotere; Aventis, Antony, France) is among the most effective agents for the treatment of non-small cell lung cancer and its use in combination with cisplatin is a logical development. Docetaxel has been combined with cisplatin and is well-tolerated with promising activity in phase II studies. Extensive phase II investigations in the first-line setting recorded response rates of 32% to 52% survival (median, 8 to 12 months) with 33% to 48% of patients alive at 1 year. Neutropenia is dose-limiting. However, the incidence of severe neuropathy is low and clinically significant nephrotoxicity is uncommon. Following these encouraging findings, the combination of docetaxel with cisplatin has been studied in two randomized phase III trials that compare the new combination against reference regimens. These studies have completed accrual and data are expected shortly. The combination of docetaxel with carboplatin is also active and feasible. Neutropenia is the main adverse event and grade II or III neurotoxicity is uncommon. In phase II trials combining doses of 65 to 100 mg/m2 docetaxel with doses of carboplatin designed to maintain an area under the curve of 5 to 7.5 mg/mL/min, response rates have ranged from 30% to 67%.

Purpose: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days., Results: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects., Conclusions: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

Over the last decade, we have witnessed improved outcome among patients with non-small cell lung cancer (NSCLC), principally through the use of new and novel treatment programs. A meta-analysis of randomized clinical trials comparing combined chemotherapy and radiation to radiation therapy alone clearly has shown a survival benefit with platinum-based combination chemotherapy administered sequentially or concurrently with thoracic radiation therapy over radiation therapy alone. In addition, combining thoracic radiation therapy with novel drugs or new drug combinations has yielded improvements in median survival duration and long-term survival rates in locally advanced unresectable NSCLC. Paclitaxel and carboplatin are two novel agents that have undergone extensive clinical evaluation at various doses and schedules in combination with thoracic radiation therapy in patients with locally advanced disease. There remains a need, however, for further improvement in metastatic control and prevention of locoregional recurrences. This will likely be achieved through the optimization of chemotherapy regimens to be used in combined modality therapy with thoracic radiation therapy.

Paclitaxel, the first of the taxanes, has exhibited unique and encouraging single-agent activity in the treatment of non-small cell lung cancer (NSCLC). Yet, with single-agent response rates approaching 25%, it was logical to examine the impact of paclitaxel in combination chemotherapy regimens. In trials evaluating the activity of paclitaxel in combination with one of the platinum compounds, cisplatin or carboplatin, response rates have ranged from 35 to > 50% and were significantly better than response rates observed with etoposide/cisplatin, the previous standard regimen for treatment of NSCLC. Docetaxel is a newer taxane that also has exhibited notable single-agent activity and response rates ranging from 20 to 50% when combined with cisplatin. Future research will look to refine the use of taxane combinations in NSCLC and to examine the potential of these unique and promising drugs when combined with newer agents that are active against this disease.

Purpose: Although several new chemotherapeutic agents are promising as primary therapy in non-small-cell lung cancer (NSCLC), few have demonstrated activity in platinum-refractory disease. Based on encouraging results reported in two single-institution studies of docetaxel in this setting, we performed a multicenter phase II trial evaluating this novel taxane in previously treated NSCLC patients prospectively categorized by platinum response status., Patients and Methods: Eighty patients with NSCLC previously treated with platinum-based chemotherapy received docetaxel at a dose of 100 mg/m(2) intravenously over 1 hour, repeated every 21 days, accompanied by dexamethasone 8 mg orally twice daily for 5 days. Forty-seven patients (59%) were defined as platinum-refractory based on response status to prior therapy., Results: The median number of cycles delivered per patient was four (range, one to 21 cycles). Partial response was observed in 13 (16%) of 80 of patients, with similar response rates in platinum-sensitive and platinum-refractory patients. The median survival time was 7 months, and the 1-year survival rate was 25%. Docetaxel was relatively well tolerated in this previously treated population. Grade IV neutropenia was common in patients (77%) but typically of brief duration. Febrile neutropenia was observed in 11 patients (14%), with no fatal infections. Severe fluid retention was rare (4% of patients)., Conclusions: This multicenter phase II trial confirms antitumor activity and encouraging survival with docetaxel therapy in platinum-treated and platinum-refractory NSCLC. To validate these results, a phase III trial randomizing platinum-treated patients to docetaxel or best supportive care is underway.

The options for treating non-small cell lung cancer (NSCLC) were expanded by the introduction of the taxanes. As a single agent, docetaxel produced response rates ranging from 15 to 22% in evaluable patients in the second-line setting, with median duration of responses ranging from 5.6 to 7.5 months. To confirm the results observed in the phase II studies, a phase III trial was conducted. Three-hundred and seventy-three patients with advanced NSCLC who had failed prior platinum-based chemotherapy were randomized to receive docetaxel 100 mg/m2, docetaxel 75 mg/m2 or a reference arm consisting of vinorelbine or ifosfamide. Efficacy, safety and quality of life (using the Lung Cancer Symptom Scale) were assessed. Data from this study are forthcoming and may confirm the benefits provided by the inclusion of docetaxel in the second-line treatment of NSCLC. Docetaxel is also an active single agent in the first-line setting, with response rates ranging from 24 to 38% in evaluable patients, with a median survival of 6-13 months. Based on the single-agent activity, it was logical to evaluate the efficacy of docetaxel in combination with other active agents. As such, docetaxel has been studied in with numerous other agents such as vinorelbine, gemcitabine, platinums, etc. Notably cisplatin and carboplatin has shown promising rates of response and response duration in phase II trials. These combinations have now entered randomized phase III study.

The combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) with cisplatin is feasible, has manageable toxicity, and is active in stage IIIB/IV non-small cell lung cancer. The four phase II trials completed to date show response rates ranging from 32% to 48% and median survival durations of 8 to 13 months. Based on these results, regimens combining 75 to 100 mg/m2 docetaxel with 75 to 100 mg/m2 cisplatin are now being assessed in randomized phase III comparisons with platinum-containing combinations. The combination of docetaxel and carboplatin also has promising activity, with response rates of 48% (1 complete response and 12 partial responses) seen in 27 evaluable patients. Overall, this combination is also well tolerated. However, it will be necessary to use both docetaxel/platinum regimens at earlier stages in the disease if a significant impact is to be made on survival.

Lung cancer remains the leading cause of cancer deaths in industrialized countries. Efforts toward the development of new cytotoxic drugs and more active combination regimens for non-small cell lung cancer (NSCLC) are ongoing. Nevertheless, specific targeting of malignant cells poses a major challenge; toxicities of normal tissues continue to be dose limiting. Cytoprotective agents, such as amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), that can shield normal tissues from cytotoxic effects are now the subject of intense clinical investigation. Amifostine has been shown to selectively protect normal tissues when used in combination with a large number of chemotherapeutic agents, including cisplatin, carboplatin, and paclitaxel. The addition of amifostine to paclitaxel or carboplatin has been shown to reduce the dose-limiting toxicities associated with each chemotherapeutic agent. However, now the combination regimen of carboplatin/paclitaxel is commonly used in NSCLC. To improve the tolerance of this regimen, a large, phase III, multicenter, randomized trial has been initiated that compares carboplatin/paclitaxel with or without amifostine in patients with locally advanced and metastatic NSCLC. The main objective is to evaluate the impact of amifostine on myelotoxicity and neurotoxicity. The addition of cytoprotective agents such as amifostine to other active NSCLC regimens may also reduce overall toxicity and improve the therapeutic index.

Combined chemotherapy and thoracic radiation therapy has emerged as a primary treatment option for locally advanced, unresectable non-small cell lung cancer (NSCLC). Randomized trials and subsequent metaanalyses have shown a clear survival benefit with platinum-based combination chemotherapy administered sequentially or concurrently with hyperfractionated thoracic radiation over radiation alone. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin recently have been evaluated in numerous phase 1/11 trials at various doses in both sequential and concurrent schedules with thoracic radiation in patients with locally advanced and unresectable NSCLC. The patterns of failure in patients treated with concurrent paclitaxel/carboplatin and thoracic radiation suggest the need for additional chemotherapy either at the front end or after completion of the concurrent regimen. A large multicenter randomized study (Locally Advanced Multimodality Protocol) has been initiated to address these issues of improvement in distant control and to further refine the combined-modality approach for patients with locally advanced NSCLC. Several other combined-modality regimens incorporating a platinum compound and a novel agent like gemcitabine, vinorelbine, paclitaxel, or docetaxel have been recently completed or are in progress. The hope for the immediate future is to define an "effective" and "optimal" regimen that can be given simultaneously with thoracic radiation and can result in improved local and systemic control in patients with regionally advanced NSCLC. Numerous phase II and III trials are currently planned or under way to further define the efficacy of this novel combination of paclitaxel/carboplatin in combined-modality programs in an attempt to determine the optimal administration sequence of chemotherapy and thoracic radiation. These combined-modality programs are now being integrated into trials for early stage, potentially resectable disease. Thus, NSCLC is in fact a systemic disease requiring a multidisciplinary approach for optimal management.

Purpose: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects., Patients and Methods: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC., Results: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support., Conclusion: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.

A five-field conformal technique with three-dimensional radiation therapy treatment planning (3-DRTP) has been shown to permit better definition of the target volume for lung cancer, while minimizing the normal tissue volume receiving greater than 50% of the target dose. In an initial study to confirm the safety of conventional doses, we used the five-field conformal 3-DRTP technique. We then used the technique in a second study, enhancing the therapeutic index in a series of 42 patients, as well as to evaluate feasibility, survival outcome, and treatment toxicity. Forty-two consecutive patients with nonsmall-cell lung carcinoma (NSCLC) were evaluated during the years 1993-1997. The median age was 60 years (range 34-80). The median radiation therapy (RT) dose to the gross tumor volume was 6,300 cGy (range 5,000-6,840 cGy) delivered over 6 to 6.5 weeks in 180-275 cGy daily fractions, 5 days per week. There were three patients who received a split course treatment of 5,500 cGy in 20 fractions, delivering 275 cGy daily with a 2-week break built into the treatment course after 10 fractions. The stages of disease were II in 2%, IIIA in 40%, IIIB in 42.9%, and recurrent disease in 14.3% of the patients. The mean tumor volume was 324.14 cc (range 88.3-773.7 cc); 57.1% of the patients received combined chemoradiotherapy, while the others were treated with radiation therapy alone. Of the 42 patients, 7 were excluded from the final analysis because of diagnosis of distant metastasis during treatment. Two of the patients had their histology reinterpreted as being other than NSCLC, 2 patients did not complete RT at the time of analysis, and 1 patient voluntarily discontinued treatment because of progressive deterioration. Median follow-up was 11.2 months (range 3-32.5 months). Survival for patients with Stage III disease was 70.2% at 1 year and 51.5% at 2 years, with median survival not yet reached. Local control for the entire series was 23.3+/-11.4% at 2 years. However, for Stage III patients, local control was 50% at 1 year and 30% at 2 years. Patients who received concurrent chemotherapy had significantly improved survival (P = 0.002) and local control (P = 0.004), compared with RT alone. Late esophageal toxicity of > or =Grade 3 occurred in 14.1+/-9.3% of patients (3 of 20) receiving combined chemoradiotherapy, but in none of the 15 patients treated with RT alone. Pulmonary toxicity limited to Grades 1-2 occurred in 6.8% of the patients, and none developed > or =Grade 3 pulmonary toxicity. Patients with locally advanced NSCLC, who commonly have tumor volumes in excess of 200 cc, presenta challenge for adequate dose delivery without significant toxicity. Our five-field conformal 3-DRTP technique, which incorporates treatment planning by dose/volume histogram (DVH) was associated with minimal toxicity and may facilitate dose escalation to the gross tumor.

Purpose: A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Forty-four patients with stage IIIB/IV NSCLC were treated with a combination of tirapazamine and cisplatin. Patients received tirapazamine 260 mg/m2 administered intravenously over 2 hours, followed 1 hour later by cisplatin 75 mg/m2 administered over an additional hour, repeated every 21 days. The duration of therapy was meant to be limited to four cycles for nonresponders and eight cycles for responders., Results: Ten of 44 patients (23%) showed a partial response. The estimated median survival for all patients was 37 weeks. Toxicities were treatable and included grade 3 nausea or vomiting (25%), fatigue (27.3%), and muscle cramps (4.5%). No dose reductions were necessary., Conclusion: The results show that tirapazamine can safely be added to cisplatin. Both the median survival and response rate observed strongly suggest that tirapazamine with cisplatin is more active than cisplatin alone.

The options available to patients with advanced non-small cell lung cancer (NSCLC) resistant or refractory to first-line chemotherapy are very limited. The older-generation drugs (etoposide, vindesine, epirubicin, and cisplatin) that are active against previously untreated NSCLC do not achieve a response rate greater than 10% when used in the second-line setting. The newer-generation agents with activity in previously untreated NSCLC include carboplatin, paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Although NSCLC remains relatively resistant to chemotherapy, the fact that second-line chemotherapy is being considered is tribute to the progress being made with first-line therapy. The taxanes have clearly become the agents of the 1990s. The activity of paclitaxel in the second-line setting is not well-defined, and the response rates have ranged from 0% to 3 31% using various schedules. However, docetaxel achieved response rates of 15% to 22% in five phase II trials, with a clinically meaningful survival rate of 25% at 1 year in one of the studies. Randomized trials of docetaxel versus best supportive care and of docetaxel versus vinorelbine or ifosfamide are in progress. The efficacy of vinorelbine and irinotecan in the second-line setting have been dismal. Gemcitabine demonstrated a response rate of 25% in a recently reported trial and needs further investigation. Further progress may come from a wider investigation of novel agents and their combination with biological and other selective therapies.

Chemotherapeutic intervention in advanced and metastatic non-small-cell lung cancer (NSCLC) has changed over the past 2 decades. The improvements offered by cisplatin (Platinol)-based regimens, though significant in terms of survival and quality of life, were modest at best. Carboplatin (Paraplatin), which possesses a toxicity profile favorable to that of its parent analogue cisplatin, yielded survival rates superior to that of the cisplatin-combination chemotherapy arms in a large randomized study of patients with metastatic non-small-cell lung cancer. With the introduction of taxanes in the early 1990s, paclitaxel (Taxol) demonstrated single-agent activity of 21% to 24%, with a 40% 1-year survival rate in metastatic disease. The next generation of phase I/II studies evaluated the efficacy of paclitaxel in combination with carboplatin. Results with this regimen have shown substantial promise, and 1-year survival rates as high as 54% have been reported. Full doses of both agents have been combined without any additional toxicity, and there appears to be a dose-response effect with paclitaxel. The combination of paclitaxel and carboplatin has been incorporated as the investigational arm of all the ongoing multicenter and cooperative group studies. While the results from these randomized studies are awaited, this combination has become the most widely used regimen in community practice for patients with non-small-cell lung cancer. It is also being evaluated for treatment at earlier disease stages, in the setting of minimal tumor burden, and in combined-modality regimens.

Irradiation therapy for lung cancer is mostly restricted to conventional methods. To improve therapeutic ratio, we have combined a treatment planning and a gene therapy approach. Three-dimensional conformal radiotherapy is described as carried out by methods of gene therapy for radiation protection using the manganese-superoxide-dismutase transgene delivered by inhalation gene transfer. These methods may improve therapeutic outcomes in lung cancer.

The role of multimodality management in locally advanced non-small cell lung cancer (NSCLC) continues to evolve and is a subject of ongoing clinical research. Induction chemotherapy followed by surgical resection with or without thoracic radiotherapy has proved superior to surgical resection alone in patients with ipsilateral mediastinal (N2) disease. Whether surgery alone still plays a role in these patients is the subject of an ongoing intergroup study. As no definitive, optimal effective chemotherapy regimen currently exists for NSCLC, future studies will attempt to incorporate novel and active agents like the taxanes, irinotecan, vinorelbine, and gemcitabine into combined-modality therapy for locally advanced NSCLC. Thoracic radiation therapy by itself provides local control and effective palliation of tumor-related symptoms but has minimal impact on the survival of patients with locally advanced disease. Novel schemes such as hyperfractionated radiotherapy and continuous hyperfractionated accelerated radiotherapy are currently being investigated and appear promising but need to be tested in combination with chemotherapeutic agents. Randomized studies have demonstrated the benefit of concurrent or sequential chemoradiation in selected patients with a good performance status and minimal weight loss. The exact sequence of combined-modality therapy has yet to be determined. The combination of paclitaxel and platinum compounds has shown impressive activity in advanced NSCLC in both phase II and III randomized studies. We have incorporated weekly low-dose paclitaxel and carboplatin with concurrent thoracic radiation in treating patients with locally advanced, inoperable NSCLC, and long-term follow-up has shown remarkable survival rates. Confirmation of these phase II combined-modality studies is needed. Combination sequential chemotherapy followed by concurrent chemoradiation in patients with advanced NSCLC has the potential to improve overall survival by increasing both local and distant control.

Until recently, chemotherapeutic intervention in advanced and metastatic non-small cell lung cancer (NSCLC) has been viewed with a certain degree of nihilism. Although meta-analysis of randomized clinical studies from the 1970s and 1980s comparing cisplatin-based chemotherapy to best supportive care in metastatic NSCLC showed improvement in survival, it was modest at best. A number of novel agents have been developed with significant activity against NSCLC in the past 5 to 6 years and are being incorporated into the therapy of this disease. These agents include paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. Clearly there has been improvement in response rates, and in some cases the responses have been durable with an increase in the number of 1- and 2-year survivors. The next generation of studies has evaluated combinations of these novel agents with either cisplatin or carboplatin for patients with NSCLC and the results have been provocative, with 1-year survival rates as high as 54%. A randomized phase III study of the Eastern Cooperative Oncology Group has shown the superiority of paclitaxel-cisplatin regimens over etoposide-cisplatin for patients with advanced and metastatic NSCLC. The vinorelbine-cisplatin regimen has also proven to have significant, albeit modest benefit in survival when compared with cisplatin alone. These combination regimens have now become the reference regimens in ongoing randomized studies. There is continued interest in developing new agents, or selective approaches that effect novel targets with the hope of showing improved therapeutic activity. Some of these approaches include gene therapy, monoclonal antibodies, and introduction of antisense oligodeoxynucleotides. With better understanding of the molecular and cellular biology of lung cancer, the hope for the future is to combine the mechanistic approaches with new drug development to define an effective, optimal, and definitive regimen for NSCLC.

Docetaxel (Taxotere) is a semisynthetic taxoid that possesses significant activity as a single agent in the treatment of patients with non-small-cell lung cancer. In previously untreated patients with non-small-cell lung cancer, 100 mg/m2 of docetaxel administered as an intravenous infusion over 1 hour once every 3 weeks produced response rates that ranged from 21% to 38% and median survivals of 25.2 to 47.0 weeks. In patients with advanced non-small-cell lung cancer who had previously failed cisplatin (Platinol)-based chemotherapy, docetaxel produced median response rates of 20% to 21% and median survival of 28 to 42 weeks. This review summarizes results from key phase I and II studies demonstrating the antitumor activity and tolerability of docetaxel combined with platinum compounds for patients with advanced non-small-cell lung cancer. Phase I trials determined that 75 mg/m2 of docetaxel and 75 mg/m2 of cisplatin is the recommended dose for phase II and III trials. Overall, response rates with docetaxel and cisplatin have ranged from 21% to 48% and median survival of 8 to 13 months has been achieved in phase II trials. Regarding docetaxel and carboplatin, results from phase I trials in patients with nonhematologic solid tumors indicate that this combination is well tolerated. The maximum tolerated dose of docetaxel in combination with carboplatin (target area under the time-concentration curve of 6 mg/mL.min) is 90 mg/m2 without granulocyte-colony stimulating factor (G-CSF) (filgrastim [Neupogen]) support and 100 mg/m2 with G-CSF support. The combination of docetaxel and carboplatin is presently being evaluated in a multicenter phase II study for patients with advanced non-small-cell lung cancer.

Based on superior results observed with combined-modality therapy over radiotherapy alone and on the authors' previous work with carboplatin and standard daily thoracic radiotherapy in patients with advanced, unresectable non-small cell lung cancer, a phase II study was designed to incorporate radiosensitizing doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into the carboplatin/radiotherapy regimen, to improve the therapeutic index and define the toxicities. Thirty-two patients have been entered. Paclitaxel 45 mg/m2/wk was administered over 3 hours prior to carboplatin (100 mg/m2/wk) and thoracic radiotherapy (1.8 Gy/d 5 days a week; total dose, 60 to 65 Gy). No grade 4 toxicities occurred. Seven patients had chemotherapy doses delayed because of grade 3 neutropenia, and one patient had grade 3 mucositis/esophagitis that required hospitalization. Median survival has not yet been reached, and all patients are being followed. These preliminary data demonstrate the feasibility of combined concurrent chemoradiotherapy, with acceptable toxicities. Further investigation is needed to optimize carboplatin dosage with adaptive control using formulas based on pharmacokinetics and pharmacodynamics. Full-dose induction chemotherapy regimens to maximize the systemic effects of chemotherapy should precede concurrent chemoradiotherapy in future studies.

Given their known activity against non-small cell lung cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin were combined in this phase I study of patients with metastatic disease to determine the maximum tolerated dose and the dose-limiting toxicity of the combination. The initial dose of paclitaxel was fixed at 135 mg/m2 given as a 24-hour infusion with carboplatin administered in escalating doses in cohorts using Calvert's formula-dose (mg) = target AUC x (GFR + 25), where AUC is area under the concentration-time curve and GFR is glomerular filtration rate-based on target AUCs of 5, 7, 9, or 11 mg/mL.min. Dose escalations were based on cycle 1 toxicities. Filgrastim was not administered with the first cycle until two or more patients developed grade 4 or febrile neutropenia at the preceding dose level. Dose-limiting toxicity occurred in two patients at level 2 (cycle 1), and filgrastim was administered thereafter for the next four dose levels. Grade 4 thrombocytopenia was seen at level 4; thus, the carboplatin dose was de-escalated thereafter, and the paclitaxel dose escalated. Rare nonhematologic toxicities include fatigue, diarrhea, and nausea and vomiting. Among the first 30 patients, one had a complete response and 14 had partial responses, for an overall response rate of 50%. The combination of paclitaxel and carboplatin is active in non-small cell lung cancer, and the recommended phase II dose without filgrastim support is paclitaxel 175 mg/m2 via a 24-hour infusion with the carboplatin dose targeted to achieve an AUC of 7 mg/ mL.min.