The Predictive Value of the G8 Questionnaire in Older Patients with Lung Cancer or Mesothelioma before Systemic Treatment.

AIMS: The standard evaluation of older lung cancer or mesothelioma patients for systemic anti-cancer treatment, based on performance status, is inaccurate. We used the G8 questionnaire to assess a patient's fitness for chemotherapy and explored the correlations between G8 scores, treatment decisions and clinical outcomes. MATERIALS AND METHODS: In total, 201 older patients (≥70 years) with advanced lung cancer or mesothelioma were prospectively assessed by standard clinical methods and a G8 questionnaire. Treatment decisions before and after reviewing the G8 score were documented. Patients were divided into low (<11), intermediate (11-14) and high (>14) G8 score groups. Patients' characteristics, treatment plans and clinical outcomes among each G8 score group were compared. Similar analyses were compared between good (<2) and poor (≥2) performance status. RESULTS: 10.1% of patients' treatment plans changed after oncologists reviewed G8 scores. The G8 score correlated inversely with performance status. More patients with low G8 scores (22.5%) were offered the best supportive care compared with 4.5% in intermediate and 1.9% in high G8 score groups. More patients (30.1%) with low G8 scores had treatment changed from chemotherapy to best supportive care on the planned day of their treatment, compared with intermediate (7.5%) and high (6.1%) G8 score groups. High G8 score patients received higher chemotherapy intensity and survived longer than patients with intermediate or low G8 scores. CONCLUSIONS: The G8 score with two cut-off values can predict functional status, chemotherapy tolerability and prognosis in older patients with lung cancer or mesothelioma, thus supporting oncologists on treatment decisions for this population.

A randomised study comparing the effectiveness of acupuncture or morphine versus the combination for the relief of dyspnoea in patients with advanced non-small cell lung cancer and mesothelioma.

BACKGROUND: Dyspnoea is one of the commonest symptoms of lung cancer. Opioids can reduce dyspnoea. This study investigates acupuncture for relief of breathlessness in lung cancer. METHODS: We performed a single-centre, randomised phase II study of 173 patients with non-small cell lung cancer or mesothelioma with dyspnoea score of ≥4 on visual analogue scale (VAS). Randomisation was to acupuncture alone (A), morphine alone (M) or both (AM). Acupuncture was administered at upper sternal, thoracic paravertebral, trapezius trigger points and LI4. Manubrial semi-permanent acupuncture studs were inserted and massaged when symptomatic. Arm A patients received rescue morphine. Primary end-point was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 h. Measurements continued to day 14 and included VAS relaxation, line analogue rating (Lar) anxiety, hospital anxiety and depression and European Organisation for Research and Treatment of Cancer quality-of-life scores. RESULTS: Dyspnoea VAS improved ≥1.5 in 74%, 60% and 66% of arms A, M and AM, respectively, and was maintained in 45% at 2 weeks. There was no statistically significant difference between arms. VAS relaxation improved in arms A (1.06 points) and AM (1.48 points) compared to arm M (-0.19 points, p<0.001). At 7 d, the Lar anxiety score improved in arm A (1.5 points), arm AM (1.2 points) and arm M (no change, p=0.003). Fewer patients received at least one morphine dose in arm A compared with arm M or AM (21% versus 87% versus 87%, respectively, p<0.001). CONCLUSIONS: A, M and AM were effective in relieving dyspnoea. Acupuncture relieved anxiety and was morphine sparing, providing an alternative to morphine.

Mechanism and non-mechanism based imaging biomarkers for assessing biological response to treatment in non-small cell lung cancer.

Therapeutic options in locally advanced non-small cell lung cancer (NSCLC) have expanded in the past decade to include a palate of targeted interventions such as high dose targeted thermal ablations, radiotherapy and growing platform of antibody and small molecule therapies and immunotherapies. Although these therapies have varied mechanisms of action, they often induce changes in tumour architecture and microenvironment such that response is not always accompanied by early reduction in tumour mass, and evaluation by criteria other than size is needed to report more effectively on response. Functional imaging techniques, which probe the tumour and its microenvironment through novel positron emission tomography and magnetic resonance imaging techniques, offer more detailed insights into and quantitation of tumour response than is available on anatomical imaging alone. Use of these biomarkers, or other rational combinations as readouts of pathological response in NSCLC have potential to provide more accurate predictors of treatment outcomes. In this article, the robustness of the more commonly available positron emission tomography and magnetic resonance imaging biomarker indices is examined and the evidence for their application in NSCLC is reviewed.

AKT inhibition synergistically enhances growth-inhibitory effects of gefitinib and increases apoptosis in non-small cell lung cancer cell lines.

OBJECTIVES: EGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR-mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines. MATERIALS AND METHODS: Drug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p-EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis. RESULTS: The combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p=0.0048), 0.56 (p=0.036), 0.75 (p=0.13) and 0.64 (p=0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p=0.0087) and 0.22 (p<0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated. CONCLUSION: Dual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild-type non-small cell lung cancer.

An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity.

BACKGROUND: Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non-pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels. PATIENT AND METHOD: Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30 days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity. RESULTS: In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30 days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3 months vs 7 months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients. CONCLUSIONS: The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted. TRIAL REGISTRATION NUMBER: EudracCT 2005-002736-10 ISRCTN8734355.

Patient factors, health care factors and survival from lung cancer according to ethnic group in the south of London, UK.

International and UK data suggest that there are ethnic differences in survival for some malignancies. The aim of the present study was to identify any health inequalities related to lung cancer and ethnicity. Data on 423 patients with a diagnosis of lung cancer treated at a large specialist cancer hospital in London UK were analysed. Data on stage of disease at diagnosis, co-morbidities, socio-economic status, treatments received and survival were collected and examined for differences by ethnic group. There was a significant difference between black and minority ethnic (BME) patients and White-European patients in socio-economic status (Chi-square test P-value < 0.001). BME patients were over-represented in the most deprived socio-economic groups and under-represented in the most affluent. There were no significant differences in histology, stage of disease, co-morbidities and performance status or treatments received between the different ethnic groups. Ethnicity was not associated with survival. Significant prognostic factors for overall survival were performance status (P < 0.001), stage of disease (P = 0.001) and gender (P = 0.003). Our findings suggest that patients from BME groups are over-represented in more deprived socio-economic groups; however, this did not impact on significant prognostic factors or the treatments that they received. Importantly ethnicity did not influence survival.

A phase II study of ¹8F-fluorodeoxyglucose PET-CT in non-small cell lung cancer patients receiving erlotinib (Tarceva); objective and symptomatic responses at 6 and 12 weeks.

BACKGROUND: The aim of this study was to assess if (18)F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)-CT scanning could minimise the time non-responding patients were exposed to erlotinib (Tarceva). METHODS: Patients were selected for clinical factors that would predict response to erlotinib. A FDG PET-CT and diagnostic contrast-enhanced (traditional) CT scan were carried out at baseline, and then a FDG PET-CT at 6 weeks and a traditional CT at 12 weeks were repeated. The primary end-point was rate of early progression in patients after 6 weeks, of which a minimum 12 out of 35 were required to make the study worthwhile. The responses at 6 (PET-CT) and 12 weeks (traditional CT) were compared and correlated with symptomatic response at both these time points. RESULTS: Forty seven patients were recruited with 38 and 33 patients assessable by FDG PET-CT at 6 weeks and traditional CT at 12weeks, respectively. There was good correlation between Partial response (PR) at both time points and all 10 patients who had a PR at 12 weeks had a PR at 6 weeks. Of the 13 patients with progressive disease (PD) at 12 weeks, seven had PD at 6 weeks and could have had their treatment stopped early. No evaluable patient with stable disease (SD) (8/38) or PD (9/38) on FDG PET-CT at 6 weeks went on to have a later response. Symptomatic response at 6 or 12 weeks did not correlate well with objective response on scanning at either time point. CONCLUSIONS: The primary end-point of this study was met as >12 (15/38) patients could have stopped treatment early on the basis of the FDG PET-CT scan result. A FDG PET-CT evaluable response of SD or PD at 6 weeks does predict future lack of response. No correlation was found between response and symptomatic response at either 6 or 12 weeks.

Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease--a short communication.

BACKGROUND AND AIM: The use of zoledronic acid (ZA) is now recommended for patients with NSCLC and metastatic bone disease (MBD). We thus examined the rates of ZA administration in NSCLC looking specifically at the use of this drug with systemic chemotherapy (ZCt) and comparing overall survival between patients who had ZCt from diagnosis to those who had chemotherapy (Ct) alone. METHOD: In this retrospective audit, we analysed the data of 114 consecutive patients with stage IV NSCLC and MBD at presentation. Forty-three of these patients had received zoledronic acid and chemotherapy (ZCt) and 71 had received chemotherapy alone (Ct). RESULTS: Forty-three (37.7%, 43/114) of NSCLC patients diagnosed with MBD received ZA with their first chemotherapy (ZCt). Patients on ZCt, after adjustment for the planned prognostic factors (sites of disease, histology and PS), had better overall survival (OS), with a median of 34 weeks, compared to those who received chemotherapy alone, who had a median of 19 weeks (p = 0.03), HR = 0.60 (95%CI: 0.38-0.96). After adjusting for prognostic factors (sex, age. single versus doublet chemotherapy), ZCt patients still maintained a trend to better OS (p = 0.06) HR 0.63 (95%CI: 0.39-1.02) 34 versus 21 weeks. CONCLUSIONS: The percentage of patients with MBD treated with ZA at first chemotherapy (37.7%) is low. The addition of ZA increased OS in NSCLC patients with MBD in this audit. More formal policies and dedicated trials on the treatment of MBD in NSCLC patients need to be put in place.

Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy.

BACKGROUND: Creatinine clearance (CrCl) estimation by Cockcroft-Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [(51)Cr]-ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates. METHODS: Retrospective analysis of co-morbidity, nephrotoxic drug use, chemotherapy toxicity, and correlation between paired CG and EDTA, in 388 lung cancer and mesothelioma patients receiving platinum-based chemotherapy. RESULTS: Potentially nephrotoxic co-morbidity or medication use occurred in 47% of patients, and was twice as likely in those aged >70 years (OR=2.07; 95%CI: 1.25-3.44, p=0.003). Patients with co-morbidity or nephrotoxic medication use had a lower EDTA compared to those without these baseline factors (p=0.02), but were not significantly more likely to experience chemotherapy toxicity. CG and EDTA correlation was high (r(2)=0.68), but reduced in patients with ETDA<50 ml/min (r(2)=0.26, p=0.02) or >120 ml/min (r(2)=0.32, p=0.09), and in those with CG>120 ml/min (r(2)=0.20, p=0.01). The correlation between CG and EDTA was not significantly altered in patients with co-morbidity or nephrotoxic medication use. CG bias (mean percentage error) and precision (mean absolute percentage error, MAPE) were 7% and 26%, respectively, and precision was impaired in patients with abnormally raised serum creatinine (MAPE 65%, p<0.0001). CONCLUSION: CG estimation of CrCl is accurate and safe in lung cancer patients with potentially nephrotoxic co-morbidity or concomitant medication, but should not be used when values are outside the range 50-120 ml/min, or with abnormally elevated serum creatinine.

Histology classification is not a predictor of clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with vinorelbine or gemcitabine combinations.

BACKGROUND: Until recently, histology has not been clearly or consistently described in the literature as a prognostic or predictive variable in advanced NSCLC studies. We have categorised patients treated with vinorelbine and gemcitabine based first line chemotherapy regimes for advanced NSCLC as either squamous or non-squamous, and also as either adenocarcinoma and non-adenocarcinoma, and compared outcome. MATERIAL AND METHODS: 420 patients treated with platinum/gemcitabine, platinum/vinorelbine or single agent gemcitabine or vinorelbine as first line chemotherapy for advanced NSCLC were identified. The influence of pathology on progression free survival (PFS) and overall survival (OS) has been investigated by means of a Cox regression analysis. Hazard ratios with 95% CIs have been given for each pathological type after adjusting for the effects of age, gender, stage (III vs. IV), PS (0/1 vs. 2/3) and treatment type (platinum doublet vs. single agent). RESULTS: Neither univariate nor multivariate analysis suggested that there was a significant difference in the response rates for adenocarcinoma vs. non-adenocarcinoma or between squamous and non-squamous pathology. There was no difference in PFS between adenocarcinoma and non-adenocarcinoma pathologies until 8 months (p = 0.98), and there was a statistically significant advantage in PFS for squamous vs. non-squamous pathologies (p = 0.04). Using multivariate Cox regression analysis to adjust for the effects of age, gender, stage, PS, and treatment type, the pathology subtype was not significant. There was no difference in OS in any group. CONCLUSIONS: These results suggest that histology may not be considered as a predictor of clinical outcome using these drugs.

Treatment options for small cell lung cancer - do we have more choice?

Small cell lung cancer (SCLC) is a significant health problem worldwide because of its high propensity for relapse. This review discusses existing and future therapies for the treatment of SCLC.

Time and chemotherapy treatment trends in the treatment of elderly patients (age>or=70 years) with non-small cell lung cancer.

AIMS: Palliative chemotherapy in non-small cell lung cancer (NSCLC) has been established since 1995 and little chemotherapy treatment was given to these patients before 1990. This retrospective study investigates the treatment outcome of elderly patients (age>or=70 years) with NSCLC over the past 13 years in a large UK cancer centre. MATERIALS AND METHODS: A comparison of all-cause survival between the time periods 1990-1994, 1995-1999 and 2000-2004 was adjusted for age, gender, stage and performance status. A comparison of survival was also made between three age groups: 70-74, 75-79 and 80+ years. RESULTS: Between 1990 and 2004, 302 patients>or=70 years had NSCLC. There were differences in age and performance status between the time periods. There was no improvement in median survival between the three time periods (P=0.6). There was little difference in outcome between the three age cohorts. CONCLUSIONS: The analysis shows that there has been no significant improvement in survival for elderly patients with advanced lung cancer treated with chemotherapy in the past 13 years.

Successful immunotherapy with Mycobacterium vaccae in the treatment of adenocarcinoma of the lung.

Immunotherapy with a heat-killed suspension of Mycobacterium vaccae (SRL172), given with chemotherapy, in a phase III trial against non-small-cell-lung cancer showed no improvement in the primary endpoint of survival over chemotherapy alone in the initial published analysis. Compliance was poor, with on average only 53% of patients receiving more than 2 injections in the SRL172 arm of the study. Quality of life was, however, improved in those receiving SRL172. Secondary analyses based on compliance with therapy showed that immunotherapy led to significantly improved survival times of patients with adenocarcinoma but, by contrast, had no beneficial effect on survival times of patients with squamous cell carcinoma. Survival of adenocarcinoma patients receiving SRL172 was increased by a mean of 135 days (p=0.0009, Kaplan-Meier log rank test) and survival after 4 or 5 doses of SRL172 showed a difference of greater than 100 days (p<0.05, Mantel-Hänszel log rank test) in the group receiving SRL172 in addition to chemotherapy. Despite the problems inherent in a secondary analysis, these results encourage further research on the role of killed preparations of adjuvant-rich micro-organisms, including saprophytic mycobacteria such as M. vaccae, and members of related genera in the therapy of a range of cancers.

Symptoms and weight loss in patients with gastrointestinal and lung cancer at presentation.

INTRODUCTION: Weight loss is an independent prognostic factor for decreased survival in cancer patients. The effectiveness of treatment is impaired in patients with weight loss. The aetiology of this weight loss is complex and poorly characterised. Decreased calorie intake may be important. The reasons for decreased intake are unknown. AIMS AND METHODS: To determine in adult patients with cancer, who had not started chemotherapy or radiotherapy, the prevalence of symptoms which carry a risk to nutritional status and how these relate to weight loss, tumour burden and primary tumour site. New patients referred for treatment of any form of gastrointestinal (GI) cancer, non-small cell lung cancer or lung mesothelioma completed a validated questionnaire recording symptoms contributing to weight loss (Patient-generated Subjective Global Assessment--PG-SGA). In a subset of patients without metastatic disease, computed tomography scans were assessed to determine tumour burden. RESULTS: Between August and October 2004, 122 patients with GI and 29 with lung cancers were recruited. There were 48% of GI and 28% of lung cancer patients who had lost weight. Sixty-two percent of the patients had one or more symptoms at presentation. The frequency of symptoms varied according to the site of disease. The most common symptom at all tumour sites was loss of appetite (38%). There was a weak but significant correlation between the number of symptoms and amount of weight loss (r=0.347). Patients reporting a reduced food intake had more symptoms than patients who had not lost weight. Tumour burden did not correlate with weight loss. CONCLUSION: The symptoms in cancer patients occur across different types of primary tumours, may affect food intake and have a part in causing weight loss. More information on the role of symptom management in improving nutritional status is needed.

Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients.

No national benchmark figures exist for early mortality due to chemotherapy unlike for surgical interventions. Deaths within 30 days of chemotherapy during a 6-month period were identified from the Royal Marsden Hospital electronic patient records. Treatment intention--curative or palliative, cause of death and number of previous treatments--were documented. Between April 2005 and September 2005, 1976 patients received chemotherapy with 161 deaths within 30 days of chemotherapy (8.1%). Of these, 124 deaths (77.0%) were due to disease progression. Of the other 37 deaths, 12 (7.5%) were related to chemotherapy, six each for solid tumours and haematological malignancies, of which seven (4.3%) were due to neutropenic sepsis. For the remaining 25 deaths (15.5%) there was insufficient information. There were more deaths after third and subsequent lines of therapy than with first and secondlines of therapy. Only 12 of the 161 deaths occurred in patients who were receiving potentially curative chemotherapy to give a mortality rate in breast and gastrointestinal malignancy of 0.5 and 1.5%, respectively. It is possible to audit mortality within 30 days of chemotherapy and this should become a benchmark for standard practice nationally. Most deaths were due to disease progression in the palliative setting. We practice this form of audit each quarter and feed back to the treating teams so that deaths are discussed and practice monitored.

A randomised trial in malignant mesothelioma (M) of early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED trial.

BACKGROUND: Prior phase II trials have demonstrated the therapeutic activity of cytotoxic chemotherapy in mesothelioma. Currently there are few randomised data assessing the role of chemotherapy versus best supportive care (BSC) in the management of patients with stable symptoms after control of any pleural effusion. A policy of observation is often adopted over initial use of chemotherapy. In this prospective randomised trial we assess the use of early versus delayed cytotoxic therapy. The study opened in 1998, and closed in view of a competing national study (MSO 1) in 2003. METHODS: Eligible patients had a performance status3 months and had stable symptoms for at least 4 weeks prior to randomisation. Patients were randomised to receive immediate chemotherapy or initial BSC with the addition of chemotherapy at time of symptomatic progression. All patients received the same platinum-based chemotherapy regimen, MVP [mitomycin C 8 mg/m2 cycles 1, 2, 4 and 6, vinblastine 6 mg/m2, maximum 10 mg, and cisplatin 50 mg/m2 (or carboplatin AUC 5)], every 3 weeks for up to six cycles. RESULTS: A total of 43 patients were recruited, of which 21 were randomised to the early treatment group and 22 to the delayed treatment group. The median ages were 59 years (range 50-78) and 67 years (range 48-75), respectively (P=0.1); other baseline parameters were well matched between the two groups. All 21 patients in the early group received chemotherapy versus 17 patients in the delayed group. Median time to symptomatic progression was 25 weeks in the early group compared with 11 weeks for the delayed group (P=0.1). Median survival was 14 months (1-year survival 66%) for the early group compared with 10 months (1-year survival 36%) for the delayed group (P=0.1). Quality of life was in general better maintained for early treatment and the health resources use was similar in both arms. CONCLUSIONS: In this patient group, presenting with stable symptoms after control of pleural effusion, the early use of chemotherapy provided an extended period of symptom control, and in this small trial a trend to survival advantage.

Time and chemotherapy treatment trends in the treatment of elderly patients (age >/=70 years) with small cell lung cancer.

Platinum-based treatment for small cell lung cancer (SCLC) has been established since 1995. This study investigates treatment outcome of elderly patients (age >/=70 years) with SCLC over the past 20 years in a large UK cancer centre. Comparison of all-cause survival was assessed in patients presenting between two predefined time periods: 1982-1994 and 1995-2003. All the survival analysis were adjusted for stage and performance status and age if appropriate. Survival between different chemotherapy treatment regimens was compared. A total of 322 elderly patients (31% of all) registered between 1982-2003 received chemotherapy for SCLC. Patients presenting in 1995-2003 had an overall better median survival (43 vs 25 weeks) and a 1-year survival (37 vs 14%) than patients presenting in 1982-1994 (P<0.001). This applied to patients with both limited and extensive stage disease and all age groups. There was a trend towards the use of more platinum-based treatments in the later cohort but the use of radiotherapy remained constant. Patients who received platinum combinations (Carboplatin or Cisplatin) had significantly improved survival over those who received single agents or other combinations (P<0.001) and there was no significant difference between carboplatin and cisplatin (P=0.7). The analysis demonstrates that there has been a significant improvement in survival for elderly patients with lung cancer treated by chemotherapy in the past 20 years despite more very elderly patients being treated with a poorer performance status. This change is probably multifactorial and may be due to the increased use of platinum-based treatment and improved supportive care.

Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2).

BACKGROUND: Vinorelbine is active and well tolerated against advanced breast cancer but there are no published efficacy studies in early breast cancer. We have therefore carried out a randomised phase III neoadjuvant trial in operable breast cancer. PATIENTS AND METHODS: Patients with > or =3 cm operable breast carcinoma were randomised to receive either vinorelbine 25 mg/m(2) on days 1 and 8 and epirubicin 60 mg/m(2) on day 1, 3 weekly for six cycles (VE) or doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) i.v. on day 1, 3 weekly for six cycles (AC), prior to standard local therapy, and adjuvant endocrine therapy as appropriate. RESULTS: A total of 451 patients were randomised. Results for AC and VE, respectively, were: overall clinical response 73% and 74%, complete clinical remission 20% and 24%, pathological complete remission 12% and 12%, mastectomy rate 52% and 55%. None of these differences were significant. Dose reduction was required in 8% for AC and 20% for VE (P <0.001) (GSCF support not used). Significantly more grade 3/4 toxicity for nausea, vomiting and alopecia (despite scalp cooling) was seen for AC compared with VE but significantly less grade 3/4 thrombophlebitis and neuropathy. CONCLUSIONS: Neoadjuvant VE is as effective as AC in early breast cancer and was better tolerated except for thrombophlebitis and neuropathy.

Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer.

BACKGROUND: Recent dose-intensity studies of small-cell lung cancer (SCLC) have yielded conflicting results. We carried out a phase III randomized trial in patients with better-prognosis SCLC (i.e., prognostic score of 0-1) to investigate whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support improves survival, compared with standard ICE chemotherapy. METHODS: We studied 318 patients with pathologically proven SCLC who were randomly assigned to receive six cycles of ICE chemotherapy with a 4-week (standard arm) or 2-week (dose-dense arm) interval between cycles. Patients in the dose-dense arm received filgrastim subcutaneously daily on days 4 through 14 and had autologous blood collected before cycles 2 through 6, which was returned 24 hours after treatment. Toxicities, including hematologic toxicity and incidence of neutropenic sepsis, were monitored. Survival was calculated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The delivered median dose intensity was 99% (interquartile range = 96%-100%) for the standard arm and 182% (interquartile range = 163%-196%) for the dose-dense arm. After a median follow-up of 14 months, overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm, a statistically non-significant difference. Median overall survival was 13.9 months (95% confidence interval [CI] = 12.9 to 15.8 months) in the standard arm and 14.4 months (95% CI = 12.7 to 16.0) in the dose-dense arm, and the 2-year survival was 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively--neither difference being statistically significant. The median treatment free time was 286 days (95% CI = 229 to 343 days) for the standard arm and 367 days (95% CI = 321 to 413 days) for the dose-dense arm (difference = 81 days; P = .109). Statistically significantly more hematologic toxicity was reported in the dose-dense arm than in the standard arm, but the number of cycles complicated by neutropenic sepsis was statistically significantly higher in the standard arm than in the dose-dense arm (15.3% versus 11.6%, respectively; difference = 3.7%, 95% CI = -4.1% to 11.5%; P = .03). CONCLUSIONS: Dose-dense ICE chemotherapy for SCLC led to shorter treatment duration and less neutropenic sepsis than did standard ICE but did not improve overall survival.