Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non-small cell lung cancer.

Objective: To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non-small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes. Methods: Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk-associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression. Results: We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114). Conclusions: The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.

Alliance Foundation Trial 09: A Randomized, Multicenter, Phase 2 Trial Evaluating Two Sequences of Pembrolizumab and Standard Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a "pick a winner" design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68-1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63-1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted.

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck.

INTRODUCTION: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors. AREAS COVERED: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN. Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.

Promotion of self-management for post treatment cancer survivors: evaluation of a risk-adapted visit.

PURPOSE: The LIFE Cancer Survivorship Program at NorthShore University HealthSystem provides risk-adapted visits (RAV) facilitated by an oncology nurse during which a survivorship care plan (SCP) is provided and discussed. In this report, we describe and evaluate RAV in promoting individualized health care and self-management during survivorship transition. METHODS: Patients complete a post-RAV questionnaire at their RAV and another ≥1 year after their RAV. RESULTS: One thousand seven hundred thirteen (1713) RAVs, majority for breast cancer, occurred from January 2007 to March 2014. One thousand six hundred fifteen (1615) "day-of" post-RAV questionnaires were completed. Respondents scaled statements as strongly agree/agree/disagree/strongly disagree. Combined strongly agree/agree ratings are 94 % felt more confident in communicating information about their treatments to other health care providers, 90 % felt more comfortable recognizing signs/symptoms to report to providers, and 98 % had a better appreciation for community programs/services. Of 488 respondents (RAV January 2007 to December 2012 n = 1366) to a questionnaire at least 1 year after the RAV, nearly 100 % found SCP useful to summarize medical information, 97 % to reinforce follow-up, 85 % to recognize symptoms of recurrence, 93 % to identify healthy lifestyle practices, 91 % to assist in identifying resources for support, 72 % discussed their SCP with their healthcare provider, and 97 % made at least one positive lifestyle change. CONCLUSIONS: Participation in LIFE RAV following treatment helps survivors to guide future self-care behavior. Data suggest that benefits may persist 1 year after the visit and support the feasibility of a nurse-led RAV to establish a SCP in cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Combined provision and discussion of SCPs help survivors construct a useful understanding of their cancer experience and may promote long-term self-management.

Lung cancer-a fractal viewpoint.

Fractals are mathematical constructs that show self-similarity over a range of scales and non-integer (fractal) dimensions. Owing to these properties, fractal geometry can be used to efficiently estimate the geometrical complexity, and the irregularity of shapes and patterns observed in lung tumour growth (over space or time), whereas the use of traditional Euclidean geometry in such calculations is more challenging. The application of fractal analysis in biomedical imaging and time series has shown considerable promise for measuring processes as varied as heart and respiratory rates, neuronal cell characterization, and vascular development. Despite the advantages of fractal mathematics and numerous studies demonstrating its applicability to lung cancer research, many researchers and clinicians remain unaware of its potential. Therefore, this Review aims to introduce the fundamental basis of fractals and to illustrate how analysis of fractal dimension (FD) and associated measurements, such as lacunarity (texture) can be performed. We describe the fractal nature of the lung and explain why this organ is particularly suited to fractal analysis. Studies that have used fractal analyses to quantify changes in nuclear and chromatin FD in primary and metastatic tumour cells, and clinical imaging studies that correlated changes in the FD of tumours on CT and/or PET images with tumour growth and treatment responses are reviewed. Moreover, the potential use of these techniques in the diagnosis and therapeutic management of lung cancer are discussed.

Buccal spectral markers for lung cancer risk stratification.

Lung cancer remains the leading cause of cancer deaths in the US with >150,000 deaths per year. In order to more effectively reduce lung cancer mortality, more sophisticated screening paradigms are needed. Previously, our group demonstrated the use of low-coherence enhanced backscattering (LEBS) spectroscopy to detect and quantify the micro/nano-architectural correlates of colorectal and pancreatic field carcinogenesis. In the lung, the buccal (cheek) mucosa has been suggested as an excellent surrogate site in the "field of injury". We, therefore, wanted to assess whether LEBS could similarly sense the presence of lung. To this end, we applied a fiber-optic LEBS probe to a dataset of 27 smokers without diagnosed lung cancer (controls) and 46 with lung cancer (cases), which was divided into a training and a blinded validation set (32 and 41 subjects, respectively). LEBS readings of the buccal mucosa were taken from the oral cavity applying gentle contact. The diagnostic LEBS marker was notably altered in patients harboring lung cancer compared to smoking controls. The prediction rule developed on training set data provided excellent diagnostics with 94% sensitivity, 80% specificity, and 95% accuracy. Applying the same threshold to the blinded validation set yielded 79% sensitivity and 83% specificity. These results were not confounded by patient demographics or impacted by cancer type or location. Moreover, the prediction rule was robust across all stages of cancer including stage I. We envision the use of LEBS as the first part of a two-step paradigm shift in lung cancer screening in which patients with high LEBS risk markers are funnelled into more invasive screening for confirmation.

Buccal microRNA dysregulation in lung field carcinogenesis: gender-specific implications.

MicroRNAs (miRNAs) have been shown to be reliable early biomarkers in a variety of cancers including that of lung. We ascertained whether the biomarker potential of miRNAs could be validated in microscopically normal and easily accessible buccal epithelial brushings from cigarette smokers as a consequence of lung cancer linked 'field carcinogenesis'. We found that compared to neoplasia-free subjects, a panel of 68 miRNAs were upregulated and 3 downregulated in the normal appearing buccal mucosal cells collected from patients harboring lung cancer (n=76). The performance characteristics of selected miRNAs (with ≥ 1-fold change) were excellent with an average under the receiver operator characteristic curve (AUROC) of >0.80. Several miRNAs also displayed gender specificity between the groups. These results provide the first proof-of-concept scenario in which minimally intrusive cheek brushings could provide an initial screening tool in a large at-risk population.

Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study.

PURPOSE: Survival of patients with completely resected non-small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). PATIENTS AND METHODS: Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. RESULTS: As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. CONCLUSION: Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

Molecular biomarkers for future screening of lung cancer.

The Landmark National Lung Screening Trial established the potential for low dose CT screening (LDCT) to reduce lung cancer-specific mortality in high-risk patients as defined by smoking history and age. However, the prevalence of lung cancer in asymptomatic smokers selected based on the NLST criteria is low. Recent advances have facilitated biomarker discovery for early diagnosis of lung cancer through the analysis of surrogate tissues, including airway epithelium, sputum, exhaled breath, and blood. Although a number of candidate diagnostic biomarkers have been described, none have been validated for use in the clinical setting. The NLST ACRIN biomarker repository is a valuable resource of annotated biological specimens that were collected during the NLST trial, which has the potential to facilitate validation of candidate biomarkers for early diagnosis identified in discovery trials. It will be important to perform retrospective and prospective analysis of biomarkers to screen for lung cancer. The review below summarizes some of our understanding of biomarkers in screening.

Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good. METHODS: A systematic literature review was performed to update the previous edition of the American College of Chest Physicians Lung Cancer Guidelines. RESULTS: The use of pemetrexed should be restricted to patients with nonsquamous histology. Similarly, bevacizumab in combination with chemotherapy (and as continuation maintenance) should be restricted to patients with nonsquamous histology and an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; however, the data now suggest it is safe to use in those patients with treated and controlled brain metastases. Data at this time are insufficient regarding the safety of bevacizumab in patients receiving therapeutic anticoagulation who have an ECOG PS of 2. The role of cetuximab added to chemotherapy remains uncertain and its routine use cannot be recommended. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line therapy are the recommended treatment of those patients identified as having an EGFR mutation. The use of maintenance therapy with either pemetrexed or erlotinib should be considered after four cycles of first-line therapy in those patients without evidence of disease progression. The use of second- and third-line therapy in stage IV NSCLC is recommended in those patients retaining a good PS; however, the benefit of therapy beyond the third-line setting has not been demonstrated. In the elderly and in patients with a poor PS, the use of two-drug, platinum-based regimens is preferred. Palliative care should be initiated early in the course of therapy for stage IV NSCLC. CONCLUSIONS: Significant advances continue to be made, and the treatment of stage IV NSCLC has become nuanced and specific for particular histologic subtypes and clinical patient characteristics and according to the presence of specific genetic mutations.

A randomized phase II trial of first-line treatment with gemcitabine, erlotinib, or gemcitabine and erlotinib in elderly patients (age ≥70 years) with stage IIIB/IV non-small cell lung cancer.

INTRODUCTION: Single-agent gemcitabine is a standard of care for elderly patients with advanced non-small cell lung cancer, but novel therapies are needed for this patient population. METHODS: We performed a noncomparative randomized phase II trial of gemcitabine, erlotinib, or the combination in elderly patients (age ≥70 years) with stage IIIB or IV non-small cell lung cancer. Patients were randomized to arms: A (gemcitabine 1200 mg/m on days 1 and 8 every 21 days), B (erlotinib 150 mg daily), or C (gemcitabine 1000 mg/m on days 1 and 8 every 21 days and erlotinib 100 mg daily). Arms B and C were considered investigational; the primary objective was 6-month progression-free survival. RESULTS: Between March 2006 and May 2010, 146 eligible patients received protocol therapy. The majority of the patients (82%) had stage IV disease, 64% reported adenocarcinoma histology, 90% reported current or previous tobacco use, and 28% had a performance status of 2. The 6-month progression-free survival rate observed in arms A, B, and C was 22% (95% confidence interval [CI] 11-35), 24% (95% CI 13-36), and 25% (95% CI 15-38), respectively; the median overall survival observed was 6.8 months (95% CI 4.8-8.5), 5.8 months (95% CI 3.0-8.3), and 5.6 months (95% CI 3.5-8.4), respectively. The rate of grade ≥3 hematological and nonhematological toxicity observed was similar in all three arms. The best overall health-related quality of life response did not differ between treatment arms. CONCLUSIONS: Erlotinib or erlotinib and gemcitabine do not warrant further investigation in an unselected elderly patient population.

Proteomic characterization of non-small cell lung cancer in a comprehensive translational thoracic oncology database.

BACKGROUND: In recent years, there has been tremendous growth and interest in translational research, particularly in cancer biology. This area of study clearly establishes the connection between laboratory experimentation and practical human application. Though it is common for laboratory and clinical data regarding patient specimens to be maintained separately, the storage of such heterogeneous data in one database offers many benefits as it may facilitate more rapid accession of data and provide researchers access to greater numbers of tissue samples. DESCRIPTION: The Thoracic Oncology Program Database Project was developed to serve as a repository for well-annotated cancer specimen, clinical, genomic, and proteomic data obtained from tumor tissue studies. The TOPDP is not merely a library-it is a dynamic tool that may be used for data mining and exploratory analysis. Using the example of non-small cell lung cancer cases within the database, this study will demonstrate how clinical data may be combined with proteomic analyses of patient tissue samples in determining the functional relevance of protein over and under expression in this disease. Clinical data for 1323 patients with non-small cell lung cancer has been captured to date. Proteomic studies have been performed on tissue samples from 105 of these patients. These tissues have been analyzed for the expression of 33 different protein biomarkers using tissue microarrays. The expression of 15 potential biomarkers was found to be significantly higher in tumor versus matched normal tissue. Proteins belonging to the receptor tyrosine kinase family were particularly likely to be over expressed in tumor tissues. There was no difference in protein expression across various histologies or stages of non-small cell lung cancer. Though not differentially expressed between tumor and non-tumor tissues, the over expression of the glucocorticoid receptor (GR) was associated improved overall survival. However, this finding is preliminary and warrants further investigation. CONCLUSION: Though the database project is still under development, the application of such a database has the potential to enhance our understanding of cancer biology and will help researchers to identify targets to modify the course of thoracic malignancies.

Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening.

We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs.

A multicenter phase II trial of carboplatin and cetuximab for treatment of advanced nonsmall cell lung cancer.

PURPOSE: To investigate the activity of carboplatin and cetuximab in NSCLC. PATIENTS AND METHODS: This was a single arm, multicenter phase II trial, and the primary objective was response rate. RESULTS: The overall response rate observed was 9% (95% confidence interval [CI], 3-19), the progression-free survival was 2.9 months (95% CI, 1.9-3.6), the median overall survival was 8.2 months (95% CI, 4.9-10.5), and 1-year survival rate was 33% (95% CI, 21-45). CONCLUSION: The combination of carboplatin and cetuximab demonstrated lower activity than double agent platinum-based therapy and does not warrant further development.

Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer.

PURPOSE: This study evaluated the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB (effusion) or stage IV nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received pemetrexed 500 mg/m(2), carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for six cycles. For patients with response or stable disease, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity. RESULTS: Fifty patients were enrolled and received treatment. The median follow-up was 13.0 months, and the median number of treatment cycles was seven (range, one to 51). Thirty patients (60%) completed > or = six treatment cycles, and nine (18%) completed > or = 18 treatment cycles. Among the 49 patients assessable for response, the objective response rate was 55% (95% CI, 41% to 69%). Median progression-free and overall survival rates were 7.8 months (95% CI, 5.2 to 11.5 months) and 14.1 months (95% CI, 10.8 to 19.6 months), respectively. Grade 3/4 hematologic toxicity was modest-anemia (6%; 0), neutropenia (4%; 0), and thrombocytopenia (0; 8%). Grade 3/4 nonhematologic toxicities were proteinuria (2%; 0), venous thrombosis (4%; 2%), arterial thrombosis (2%; 0), fatigue (8%; 0), infection (8%; 2%), nephrotoxicity (2%; 0), and diverticulitis (6%; 2%). There were no grade 3 or greater hemorrhagic events or hypertension cases. CONCLUSION: This regimen, involving a maintenance component, was associated with acceptable toxicity and relatively long survival in patients with advanced nonsquamous NSCLC. These results justify a phase III comparison against the standard-of-care in this patient population.

Relationship between symptom change, objective tumor measurements, and performance status during chemotherapy for advanced lung cancer.

PURPOSE: Our objective was to identify which symptoms of advanced lung cancer are most likely to change with objective tumor measurements (progressions and responses) or changes in performance status (PS). PATIENTS AND METHODS: Eighty patients with advanced non-small-cell lung cancer were studied during the first 12 weeks of chemotherapy. Symptoms were assessed weekly through telephone administration of the Functional Assessment of Cancer Therapy-Lung Symptom Index-12. Data on PS were collected from patients every 3 weeks. Symptom reports were mapped onto clinical events (progression or response as determined by clinicians) and PS assessments. RESULTS: Disease progression and declining PS were associated with worsening of several symptoms. Pain, shortness of breath, cough, weight loss, and appetite loss worsened most from before to after progression. Patients with an objective response to chemotherapy reported more fatigue and difficulty breathing at response than before response. However, unlike patients who experienced progression, patients responding to chemotherapy never or rarely complained of clinically significant pain, weight loss, cough, chest tightness, nausea, or confusion before, during, or after response. With the exception of bother with side effects of treatment, confusion, and difficulty breathing, symptoms tracked fairly closely over the 12 weeks with changes in PS. Declining PS was associated with considerably more symptom worsening than unchanged or improved PS, independent of treatment response. CONCLUSION: These data can help the clinician identify symptoms of lung cancer most reliably associated with objective responses and perceived changes in functional status during chemotherapy. Symptom self-reports could be used by clinicians to monitor patient status and possibly inform treatment modification.

Prevalence of poor performance status in lung cancer patients: implications for research.

INTRODUCTION: Performance status (PS) is a standard functional classification in oncology research and practice. However, despite its widespread use, little is known about the prevalence of poor PS in lung cancer patients, in relation to other cancers, based on the assessments of health care providers and patients. METHODS: Data from two quality of life studies were pooled for analysis. Analyses were performed on the subset of patients with lung cancer (n = 503) from the entire population of cancer patients (n = 2885). The prevalence of poor PS (defined as PS = 2-4 on a 0-4 scale) was determined for lung cancer patients. RESULTS: Prevalence of poor PS among lung cancer patients was 34% when estimated by providers and 48% when estimated by patients themselves. Agreement between providers and patients was only fair (weighted [kappa] = 0.41). For both advanced and early stage disease, lung cancer patients were at the highest risk for poor PS compared with other common cancers. CONCLUSIONS: The prevalence of poor PS is quite high in lung cancer patients. Providers tend to underestimate poor PS. Specific clinical trials and treatment guidelines for this patient population are urgently needed.

The feasibility of adjuvant carboplatin and docetaxel in patients with curatively resected non-small cell lung cancer.

INTRODUCTION: Adjuvant cisplatin-based chemotherapy improves overall survival; however, chemotherapy compliance has been difficult. Carboplatin (C) is better tolerated than cisplatin, and carboplatin-based adjuvant therapy may have better chemotherapy compliance. METHODS: The primary end point of this multicenter phase II trial was the feasibility of delivering carboplatin and docetaxel (C/D). An "adequate exposure" was defined as receiving four cycles of C/D within 12 weeks of initiating adjuvant therapy. A sample size of 72 patients provided 88% power to detect a true adequate exposure of rate of at least 80%. Patients with resected non-small cell lung cancer, a good functional status, and preserved organ function were eligible. Adjuvant therapy was initiated between 2 and 8 weeks after surgery, and consisted of four cycles C (area under the curve = 6), and D 75 mg/m every 3 weeks. RESULTS: Seventy-two patients were treated, and the patient demographics were: median age 65 years (range 47-84), gender male/female 67%/33%, stage I (40%), II (36%) IIIA (22%) and IIIB (1%), and the two most common histologies were: adenocarcinoma (44%), and squamous cell carcinoma (42%). Fifty-seven patients (79%) received four cycles within 12 weeks, and 15 (21%) of patients did not complete four cycles for the following reasons: adverse events (n = 5), patient refusal (n = 5), disease progression during active therapy (n = 3), and intercurrent illness (n = 2). No treatment related deaths were observed and the primary toxicities were hematologic (grade 4 neutropenia 42% and febrile neutropenia 11% of patients). Twenty-six patients (36%) received growth colony stimulating factor (G-CSF) supportive therapy during their treatment, and G-CSF supportive therapy was used in 21.6% of all cycles. CONCLUSIONS: C/D has an acceptable toxicity profile with the use of G-CSF supportive therapy and the majority of patients completed four cycles of therapy within 12 weeks.

Should health-related quality of life be measured in cancer symptom management clinical trials? Lessons learned using the functional assessment of cancer therapy.

There are several advantages to including comprehensive health-related quality of life (HRQL) in symptom trials in oncology. The most obvious is to test the hypothesis that HRQL will be improved in addition to the symptom benefit. We should not "require," however, that a successful symptom intervention also improve other dimensions of HRQL. On the other hand, we should expect that it will not make other dimensions worse through side effects or exacerbation of disease, even if it improves the symptom. HRQL assessment in the trial helps evaluate the competing risks of any therapy. Furthermore, assessment of HRQL is now accomplished with very brief assessment (usually 30 questions or less), and the knowledge gained is valuable. With HRQL, one can compare cancer patients with those with other conditions and can determine the contribution of symptoms and side effects to the more broadly defined HRQL. Examples using the Functional Assessment of Cancer Therapy measurement system will demonstrate how HRQL assessment has contributed to our understanding of common cancer symptoms and their place in the conceptualization of HRQL. The prevalence of clinically significant symptoms is greatest in poor performance status (PS) patients compared with patients with good PS. Symptom improvement trials specifically designed for these patients should be encouraged, particularly with interventions that can provide symptomatic relief and improve multidimensional HRQL.