Prognostic factors in patients with advanced non-small cell lung cancer: data from the phase III FLEX study.

The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.

[Non-small-cell carcinoma of the lung with invasive Aspergillus infection after chemotherapy]. / Sepsis und Aspergillose bei einer Patientin mit nicht-kleinzelligem Lungenkarzinom.

HISTORY: A 56-year-old woman had two years previously undergone a neck dissection and subsequent adjuvant radiotherapy for an adenocarcinoma at the base of the tongue (pT2NOMOG2) when a percutaneous endoscopic gastrostomy (PEG) catheter had been placed. She was now admitted for chemotherapy, recent onset of severe pain in the left hip and knee having been caused by metastasis of a non-small-cell lung carcinoma (NSCLC). She was cachectic and in a reduced general condition (Karnofsky index 80), but had recently only occasionally used the PEG catheter. There were no inflammatory changes of the skin at the site of the PEG. TREATMENT, COURSE AND OUTCOME: The first chemotherapy cycle was initially without complication, but after a week the patient's general condition deteriorated and she developed nausea, fever and pain around the markedly inflamed site of the PEG catheter insertion. Laboratory tests indicated severe neutropenia. Intensive antibiotic and antimycotic treatment at first brought about some improvement, but she died 11 days after admission. Necropsy revealed invasive aspergillosis, with the PEG as the portal of entry and spreading to the stomach and intestines, where numerous hyphae were identified. There had also been a disseminated intravascular coagulopathy. CONCLUSION: Bacterial infections (and occasionally, but difficult to diagnose, fungal infection) are quite common as a result of neutropenia during chemotherapy of solid tumors. Various risk factors, including reduced general condition and weight loss, must be individually assessed in the prevention or treatment of associated infectious complications in such cases.

A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer.

BACKGROUND: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). METHODS: Patients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinum-based chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. RESULTS: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. CONCLUSION: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.

[Analysis of treatment outcomes in two patient cohorts (2004-2005 and 2007-2008) with limited and extensive disease small-cell lung cancer]. / Vergleich von Behandlungsergebnissen in zwei Patientengruppen (2004-2005 und 2007-2008) mit einem kleinzelligen Bronchialkarzinom im begrenzten und metastasierten Krankheitsstadium.

PURPOSE: The aim of this retrospective study was to compare patient characteristics, treatment patterns and treatment results in two groups of patients with limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC) in 2004 - 2005 vs. 2007 - 2008. PATIENTS AND METHODS: We included all patients with LD or ED SCLC in this retrospective analysis who were diagnosed in our department in the periods 2004 - 2005 and 2007 - 2008. We collected data on patient characteristics, chemotherapy, radiotherapy, treatment response and median survival. Statistical analyses were separately performed for patients in LD and ED SCLC. RESULTS: 109 patients had LD SCLC. The response rate on first-line therapy was 74 %. More than half of the cases had recurrent disease. Second-line treatment was given to about two thirds of these patients. Third-line therapy was administered in around 15 % of all cases. Prophylactic cranial irradiation was performed more frequently from 2007 - 2008. The median survival was 17 months. There were no statistically significant differences regarding patient characteristics and treatment results. ED SCLC was present in 188 patients. The response rate was around 68 %. All patients relapsed, second-line therapy was administered in half of these cases; third-line therapy in 10 % of all cases. No statistically significant differences were detected between the two time frames. Median survival was 10 months. CONCLUSION: Overall, no statistically significant differences were present for patients with LD and ED SCLC in 2004 - 2005 vs. 2007 - 2008. Prophylactic cranial irradiation was employed more frequently in LD SCLC from 2007.

Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer.

BACKGROUND: The study compared the efficacy of a first-line treatment with day 1 i.v. vinorelbine (NVBiv) and day 8 oral vinorelbine (NVBo) versus docetaxel (DCT) in a cisplatin-based combination in advanced non-small-cell lung cancer, in terms of time to treatment failure (TTF), overall response, progression-free survival (PFS), overall survival (OS), tolerance and quality of life (QoL). METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 (arm A) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks (arm B), for a maximum of six cycles in both arms. RESULTS: From 2 February 2004 to 1 January 2006, 390 patients were entered in a randomised study and 381 were treated. The patient characteristics are as follows (arms A/B): metastatic (%) 80.5/84.8; patients with three or more organs involved (%) 45.3/40.8; median age 59.4/62.1 years; male 139/146; squamous (%) 34.2/33.5; adenocarcinoma (%) 41.6/39.3; median TTF (arms A/B in months) [95% confidence interval (CI)]: 3.2 (3.0-4.2), 4.1 (3.4-4.5) (P = 0.19); overall response (arms A/B) (95% CI): 27.4% (21.2% to 34.2%), 27.2% (21.0% to 34.2%); median PFS (arms A/B in months) (95% CI): 4.9 (4.4-5.9), 5.1 (4.3-6.1) (P = 0.99) and median OS (arms A/B in months) (95% CI): 9.9 (8.4-11.6), 9.8 (8.8-11.5) (P = 0.58). The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B, respectively. Main haematological toxicity was grade 3-4 neutropenia: 24.4% (arm A) and 28.8% (arm B). QoL as measured by the Lung Cancer Symptom Scale was similar in both arms. CONCLUSIONS: Both arms provided similar efficacy in terms of response, time-related parameters and QoL, with an acceptable tolerance profile. In the current Global Lung Oncology Branch trial 3, NVBo was shown to be effective as a substitute for the i.v. formulation. This can relieve the burden of the i.v. injection on day 8 and can optimise the hospital's resources and improve patient convenience.

[Chemotherapy of malignant pleural mesothelioma: have we made any progress?]. / Systemtherapie des malignen Pleuramesothelioms: Gibt es Fortschritte?

Chemotherapy of malignant mesothelioma is of great importance because most patients with malignant pleural mesothelioma are diagnosed for the first time with widespread or advanced disease. Due to the small number of patients in clinical trials and due to difficulties in tumour assessment in the last 20 years, validation criteria for efficacy could only be defined with major limitations. After the introduction of modern antifolates in the chemotherapy for malignant mesothelioma and after the establishment of standardised response criteria, a significant prolongation of survival time by combination chemotherapy was shown in two randomised phase III trials. The combination of pemetrexed and cisplatin is the current standard of chemotherapy in malignant mesothelioma. Besides first-line therapy, there are also data to support the efficacy of chemotherapy in pretreated patients. In spite of the various results of preclinical trials which support the prognostic significance of certain targeted structures of intra- and intercellular signal transduction, no relevant efficacy could be shown for targeted therapies in mesothelioma up to now.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.

Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy.

This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H2O2 and nitric oxide (F(eNO)) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21-29). There were significant changes in the level of H2O2, F(eNO) and peripheral blood cell differentials over the visits. The level of H2O2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F(eNO) was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21-29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.

Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer.

PURPOSE: The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit. RESULTS: The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p=0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p=0.18). Median survival was significantly longer (p=0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively. CONCLUSION: VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative.

Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.

BACKGROUND: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival. PATIENTS AND METHODS: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups. RESULTS: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72). CONCLUSIONS: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.

[Phase II-trial of tirapazamine in combination with cisplatin and gemcitabine in patients with advanced non-small-cell-lung-cancer (NSCLC)]. / Tirapazamine, Cisplatin und Gemcitabine beim fortgeschrittenen nichtkleinzelligen Bronchialkarzinom - eine Phase II-Studie.

Despite improvements in chemotherapy of advanced and metastatic Non-Small-Cell-Lung-Cancer (NSCLC) the prognosis of these patients still remains poor with a 5-year-survival of 2 to 5 %. Due to the high level of hypoxic cells in solid tumors agents with activity in hypoxic milieu as the Benzotriazine compound Tirapazamine (SR 259 075) might improve the therapeutic results. We treated 45 patients with advanced or metastatic Non-Small-Cell-Lung-Cancer (stage IIIb: 20 patients, stage IV: 25 patients) with the combination TPZ 330 mg/m (2) (day 1), Cisplatin 75 mg/m (2) (day 1) and Gemcitabine 1250 mg/m (2) (day 1 and 8) every 3 weeks. With a response rate of 40 % median progression free survival was 6.7 months (4.8 - 8.1 months) and median survival was 8.1 months (7.5 - 12.5 months), (1-year-survival: 35 %). Hematologic and non-hematologic toxicity was moderate (neutropenia CTC grade 3 and 4: 20 %, thrombocytopenia CTC grade 3 and 4: 16 %, nausea and vomiting CTC 3: 5 %). Treatment of advanced and metastatic NSCLC with TPZ in combination with Gemcitabine/Cisplatin was well feasible and showed results recording to currently published data. The results of a following phase III-trial are awaited.

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.

BACKGROUND: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. PATIENTS AND METHODS: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. RESULTS: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. CONCLUSIONS: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed.

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

GLOB-1: a prospective randomised clinical phase III trial comparing vinorelbine-cisplatin with vinorelbine-ifosfamide-cisplatin in metastatic non-small-cell lung cancer patients.

BACKGROUND: The standard doublet, vinorelbine-cisplatin, was compared with a triplet of vinorelbine-ifosfamide-cisplatin, in terms of survival, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From February 1998 to June 1999, 259 chemonaïve patients entered the study and were randomised to receive either vinorelbine-cisplatin (NP; vinorelbine 30 mg/m(2) on days 1, 8 and 15 with cisplatin 80 mg/m(2) on day 1) or vinorelbine-ifosfamide-cisplatin (NIP; vinorelbine 25 mg/m(2) on days 1 and 8, ifosfamide 3 g/m(2) on day 1 and cisplatin 75 mg/m(2) on day 1), with both regimens being repeated every 3 weeks. All patients had stage IV or relapsed disease and a performance score of 0 or 1. RESULTS: The overall response rate was 34.6% for NP and 35.7% for NIP. Median and 1-year survival rates were 10.0 months and 38.4% for NP, and 8.2 months and 33.7% for NIP, respectively. A median of four cycles was administered in each arm. The major World Health Organization grade 3-4 toxicities for NP and NIP, respectively, were: neutropenia (20.3% compared with 9% of cycles), anaemia (4.1% compared with 5% of cycles), nausea and vomiting (22.2% compared with 19.4% of patients) and alopecia (5.6% compared with 29.8% of patients). Four toxic deaths occurred in the NP arm and eight in the NIP arm. CONCLUSIONS: The different schedules of vinorelbine in the two arms led to a greater survival in the NP arm without impairing the tolerance profile, although this is not statistically significant. This confirms that the two-drug combination NP is a reference treatment for metastatic NSCLC. The role of three-drug combinations remains questionable in this subset of patients.

Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial.

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m(2) (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m(2), all repeated every 3 weeks. Survival, toxicity and quality of life were also compared. PATIENTS AND METHODS: Patients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients. RESULTS: A total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 0-1), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 1-10 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 1-10 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m(2). The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.03-1.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.06-1.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms. CONCLUSIONS: This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.

Indications for chemotherapy in stage IV non-small cell lung cancer.

Treatment of stage IV NSCLC has been a controversial issue during the last decade. However, there is now clear evidence that cisplatin-containing chemotherapy regimens lead to prolonged survival with an increase of the 1-year survival rates at about 10%. New drugs like gemcitabine, the taxanes (paclitaxel, docetaxel), and vinorelbine have shown very promising single-agent activity and have been included into modern combination chemotherapy regimens achieving response rates of 40 to 50% and 1-year survival rates of between 30 and 40%. In comparison to single-agent cisplatin or cisplatin/etoposide as 'standard treatment approaches', most of these modern combinations could demonstrate advantages in terms of response, survival and improved QOL. Patients with favourable prognostic factors are at the moment frequently treated with platinum-based combination chemotherapy often including one of these newer active drugs. Patients with adverse prognostic factors such as elderly or stage IV patients with a reduced performance status are preferably treated with single agents such as gemcitabine, paclitaxel or vinorelbine.

Gemcitabine plus etoposide in chemonaive extensive disease small-cell lung cancer: a multi-centre phase II study.

BACKGROUND: Both gemcitabine and etoposide are active in the treatment of small-cell lung cancer (SCLC), and are characterised by mild toxicity profiles. The combination of both drugs was found to be feasible and active in a phase I dose-finding study in solid tumours. Therefore, a phase II trial was initiated to examine the activity and toxicity of this schedule in extensive disease SCLC. PATIENTS AND METHODS: Forty-two chemo-naïve extensive disease SCLC patients were enrolled to receive gemcitabine 1000 mg/m2, days 1, 8 and 15, and etoposide 80 mg/m2, days 8, 9 and 10 of a 28-day cycle. RESULTS: Thirty-seven patients were evaluable for efficacy (five received less than one cycle). No complete responses were observed, but partial responses were seen in 17 patients, yielding an overall response rate of 46%. The median duration of response was 5.8 months. Disease stabilisation was obtained in another 10 patients (27%). The median survival of the 37 protocol-qualified patients was 10.5 months (95% confidence interval (CI): 7.5-12.0). The levels of WHO grade 3 and 4 toxicities were low and clinically manageable. CONCLUSION: In comparison with standard platinum-based regimens, this combination of gemcitabine and etoposide resulted in a somewhat lower response rate, but a similar median survival time. Haematological toxicity was more pronounced than expected from the toxicity data of each agent individually. However, because of its mild non-haematological toxicity, and its ability to be administered in an outpatient setting, this combination provides a reasonable palliative option for patients with extensive disease SCLC.

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.