Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)†.

BACKGROUND: Nitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity. PATIENTS AND METHODS: In this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)-paclitaxel (200 mg/m(2))-bevacizumab 15 mg/kg on day 1 every 3 weeks with or without NTG patches 15 mg (day -2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed. RESULTS: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6-7.3) and 5.1 months (4.2-5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96-1.67). Overall survival (OS) was 11.6 months (8.8-13.6) in control arm and 9.4 months (7.8-11.3) in experimental arm, HR 1.02 (95% CI 0.71-1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG). CONCLUSION: Adding NTG to first-line carboplatin-paclitaxel-bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.

A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small-cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49-0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. CONCLUSIONS: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. STUDY REGISTRATION NUMBER: NCT00835471.

Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study.

BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. PATIENTS AND METHODS: A total of 181 chemotherapy-naive patients [≥70 years, performance score (PS) of 0-2] with stage III-IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. RESULTS: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. CONCLUSIONS: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic.

COPD in cancer patients: higher prevalence in the elderly, a different treatment strategy in case of primary tumours above the diaphragm, and a worse overall survival in the elderly patient.

The purpose of this study was to document the influence of chronic obstructive pulmonary diseases (COPD) on stage at diagnosis, treatment strategy, and survival for unselected cancer patients (35 years and older) diagnosed between 1995 and 2004 in the Eindhoven Cancer Registry. Follow-up of all patients was complete up to January 1st, 2006. Twelve percent of all cancer patients had COPD at the time of cancer diagnosis, being about 15% in elderly patients (65+) and up to 30% among lung cancer patients, middle-aged males and all females with oesophageal and laryngeal cancer, and middle-aged women with renal cancer. Stage at diagnoses was not significantly different between cancer patients with or without COPD, except for lung cancer patients who were diagnosed at an earlier stage. Nevertheless, non-small cell lung cancer (NSCLC) patients with COPD less frequently underwent surgery, and chemotherapy, and more often radiotherapy. In the presence of COPD, women with oesophageal cancer underwent surgery less often, and patients with laryngeal cancer received radiotherapy more often. The effect of COPD on the type of oncological treatment was not different for middle-aged (35-64 years) and elderly cancer patients. In a multivariate Cox-regression model, COPD was associated with a significantly worse survival, especially for elderly patients with colon, rectum, larynx, prostate or urinary bladder cancer. In conclusion, not surprisingly, COPD is related with age and smoking-associated tumours. Therapy of cancer patients with COPD was different for head and neck tumours and primary tumours in the chest organs (above the diaphragm), for whom radiotherapy, as an alternative treatment option, was available. As COPD, especially at older age, is frequently associated with a worse prognosis, further prospective investigation of interactions seems warranted. Further, closer involvement of pulmonologists and COPD nurses in elderly cancer patients might be warranted.

Negligible influence of comorbidity on prognosis of patients with small cell lung cancer: a population-based study in the Netherlands.

Management of small cell lung cancer (SCLC) among elderly is complex because of decreased organ functions and interactions with comorbidity. Since elderly patients are often excluded from clinical trials, little is known about the way they are treated and outcome. We evaluated the prognostic effects of rising age and comorbidity in unselected Dutch SCLC patients (Eindhoven Cancer Registry). Elderly patients received chemotherapy less often and the dose was also reduced more often. Cardiovascular diseases, hypertension or diabetes lowered the proportion receiving combined chemotherapy and radiotherapy among patients with limited disease. About 80% of the patients receiving chemotherapy suffered from a side effect, which was not related to age. After adjustment for age, gender, stage and treatment modality, comorbidity had a negligible prognostic effect. Chemotherapy (in combination with radiotherapy) seemed to improve survival, however, toxicity and quality of life in these patients should be evaluated thoroughly in future randomized studies.

Is a patient's self-reported health-related quality of life a prognostic factor for survival in non-small-cell lung cancer patients? A multivariate analysis of prognostic factors of EORTC study 08975.

BACKGROUND: The aim of this prognostic factor analysis was to investigate if a patient's self-reported health-related quality of life (HRQOL) provided independent prognostic information for survival in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Pretreatment HRQOL was measured in 391 advanced NSCLC patients using the EORTC QLQ-C30 and the EORTC Lung Cancer module (QLQ-LC13). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap validation technique was used to assess the stability of the outcomes. RESULTS: The final multivariate Cox regression model retained four parameters as independent prognostic factors for survival: male gender with a hazard ratio (HR) = 1.32 (95% CI 1.03-1.69; P = 0.03); performance status (0 to 1 versus 2) with HR = 1.63 (95% CI 1.04-2.54; P = 0.032); patient's self-reported score of pain with HR= 1.11 (95% CI 1.07-1.16; P < 0.001) and dysphagia with HR = 1.12 (95% CI 1.04-1.21; P = 0.003). A 10-point shift worse in the scale measuring pain and dysphagia translated into an 11% and 12% increased in the likelihood of death respectively. A risk group categorization was also developed. CONCLUSION: The results suggest that patients' self-reported HRQOL provide independent prognostic information for survival. This finding supports the collection of such data in routine clinical practice.

Multicenter phase II trial of accelerated cisplatin and high-dose epirubicin followed by surgery or radiotherapy in patients with stage IIIa non-small-cell lung cancer with mediastinal lymph node involvement (N2-disease).

To assess the therapeutic activity of accelerated cisplatin and high-dose epirubicin with erythropoietin and G-CSF support as induction therapy for patients with stage IIIa-N2 non-small-cell lung cancer (NSCLC). Patients with stage IIIa-N2 NSCLC were enrolled in a phase II trial. They received cisplatin 60 mg m(-2) and epirubicin 135 mg m(-2) every 2 weeks for three courses combined with erythropoietin and G-CSF. Depending on results of clinical response to induction therapy and restaging, patients were treated with surgery or radiotherapy. In total, 61 patients entered from March 2001 to April 2004. During 169 courses of induction chemotherapy, National Cancer Institute of Canada (NCI-C) grade III/IV leucocytopenia was reported in 35 courses (20.7%), NCI-C grade III/IV thrombocytopenia in 26 courses (15.4%) and NCI-C grade III/IV anaemia in six courses (3.6%). Main cause of cisplatin dose reduction was nephrotoxicity (12 courses). Most patients received three courses. There were no chemotherapy-related deaths. Three patients were not evaluable for clinical response. Twenty-eight patients had a partial response (48.3%, 95% CI: 36-61.1%), 24 stable disease and six progressive disease. After induction therapy, 30 patients underwent surgery; complete resection was achieved in 19 procedures (31.1%). Radical radiotherapy was delivered to 25 patients (41%). Six patients were considered unfit for further treatment. Median survival for all patients was 18 months. Response rate of accelerated cisplatin and high-dose epirubicin as induction chemotherapy for stage IIIa-N2 NSCLC patients is not different from more commonly used cisplatin-based regimen.

Docetaxel and cisplatin as induction chemotherapy in patients with pathologically-proven stage IIIA N2 non-small cell lung cancer: a phase II study of the European organization for research and treatment of cancer (EORTC 08984).

The objective of this phase II study was to document activity and toxicity of docetaxel and cisplatin as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) before definitive local treatment. Forty-six chemotherapy-nai ve patients (median age 60 years) were included. Treatment consisted of 3 cycles of docetaxel (85 mg/m2 on day 1), followed by cisplatin (40 mg/m2/day on days 1 and 2) every 21 days. Grade 3-4 leukopenia and neutropenia occurred in 45.7% and 65.2% of the patients, respectively. Among 8 cases of febrile neutropenia (17.4%), one (2.2%) resulted in early death. Common grade 3-4 non-haematological toxicities were nausea (17.4%) and vomiting (13%). Eighty-five percent of the patients received three courses; six stopped prematurely due to toxicity, one due to protocol violation. Response rate was the primary endpoint of this study. Considering eligible patients (n=40), 18 responses (1 complete and 17 partial responses) were observed (response rate 45%; 95% Confidence interval (CI): 29.3%-61.5%). In stage IIIA-N2 NSCLC patients, docetaxel-cisplatin could be administered and demonstrated manageable toxicity with modest efficacy.

A randomised phase II trial of docetaxel vs docetaxel and irinotecan in patients with stage IIIb-IV non-small-cell lung cancer who failed first-line treatment.

Response rate and toxicity of second-line therapy with docetaxel (75 mg m(-2)) or docetaxel, irinotecan, and lenogastrim (60 mg m(-2), 200 mg m(-2), and 150 microg m(-2) day(-1), respectively) were compared in 108 patients with stage IIIb-IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity.

Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer. an EORTC phase II study (EORTC 08958).

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naïve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%-76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1-31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2-81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

The value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in the selection of patients with stage IIIA-N2 non-small cell lung cancer for combined modality treatment.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.

Economic evaluation of antibiotic prophylaxis in small-cell lung cancer patients receiving chemotherapy: an EORTC double-blind placebo-controlled phase III study (08923).

BACKGROUND: To determine whether the cost of prophylactic antibiotics during chemotherapy is offset by cost savings due to a decreased incidence of febrile leukopenia (FL). PATIENTS AND METHODS: Small-cell lung cancer (SCLC) patients were randomised to standard or intensified chemotherapy with granulocyte colony-stimulating factor to assess the impact on survival (n = 244). In addition, patients were randomised to prophylactic ciprofloxacin and roxithromycin or placebo to assess the impact on FL (n = 161). The economic evaluation examined the costs and effects of patients taking antibiotics versus placebo. Medical resource utilisation was documented prospectively, including 33 patients from one centre in The Netherlands (NL) and 49 patients from one centre in Germany (GE). The evaluation takes the perspective of the health insurance systems and of the hospitals. Sensitivity analyses were performed. RESULTS: In the main trial, prophylactic antibiotics reduced the incidence of FL, hospitalisation due to FL and use of therapeutic antibiotics by 50%. In GE, the incidence of FL was not reduced by prophylaxis. This resulted in an average cost difference of only 35 Euros [95% confidence interval (CI) (-)1.713-2.263] in favour of prophylaxis (not significant). In NL, prophylaxis reduced the incidence of FL by nearly 50%, comparable with the results of the main trial, resulting in a cost difference of 2706 Euros [95% CI 810-5948], demonstrating savings in favour of prophylactic antibiotics of nearly 45%. Sensitivity analyses indicate that with an efficacy of prophylaxis of 50%, and with expected costs of antibiotic prophylaxis of 500 Euros or less, cost savings will incur over a broad range of baseline risks for FL; that is, a risk >10-20% for FL per cycle. CONCLUSIONS: Giving oral prophylactic antibiotics to SCLC patients undergoing chemotherapy is the dominant strategy in both GE and NL, demonstrating both cost-savings and superior efficacy. The sensitivity analyses demonstrate that, due to the efficacy of prophylactic antibiotics and their low unit cost, cost savings will incur over a broad range of baseline risks for FL. We recommend the use of prophylactic antibiotics in patients at risk for FL during chemotherapy.

Accelerated cisplatin and high-dose epirubicin with G-CSF support in patients with relapsed non-small-cell lung cancer: feasibility and efficacy.

The purpose of this study is to determine whether it is feasible to administer high-dose epirubicin (135 mg m(-2)) combined with a fixed dose of cisplatin every 2 weeks with G-CSF support in patients with metastatic non-small-cell lung cancer (NSCLC). Subsequently, the efficacy of the recommended dose of this regimen was tested in a phase II study in patients with relapsed NSCLC. In the initial feasibility study at least 6 patients were entered at each of the 4 dose levels tested. A fixed dose of cisplatin 60 mg m(-2) was given. Epirubicin was administered at 120 mg m(-2) on dose level 1, 135 mg m(-2) on dose level 2 and 3 and 135 mg m(-2) on dose level 4. Patients treated at dose level 3 and 4 received G-CSF support on days 3-12. Cycles were repeated every 3 weeks on the first 3 dose levels and every 2 weeks on the fourth dose level. A total of 27 patients were then treated on dose level 4, which appeared to be feasible in the initial study. In the initial study, a total of 86 courses were administered. Haematological toxicity was the principal side effect. None of the patients encountered dose-limiting toxicity in the first course, which confirmed that epirubicin 135 mg m(-2) could be combined with cisplatin 60 mg m(-2) and accelerated by G-CSF support to a 14-day-schedule. In the subsequent phase II study with this schedule, 89 courses were administered. The relative dose intensity of cisplatin and epirubicin was 0.90 and 0.91, respectively. Myelosuppression was frequent with 70% and 63% of patients experiencing WHO grade III or IV leukocytopenia and thrombocytopenia, respectively. 6 cases of febrile neutropenia were observed, with 2 treatment-related deaths. Non-haematological toxicity consisted mainly of nausea and vomiting, which was grade III in 22% of patients. Renal toxicity grade I and II occurred in 37% and 4% of patients, respectively. 55% of these patients had received prior cisplatin-containing chemotherapy. On an intention-to-treat basis 9 partial responses were recorded in 27 patients (33%; 95% confidence interval, 15%-51%). Accelerated cisplatin and high-dose epirubicin with G-CSF support is a feasible and promising regimen in relapsed NSCLC. Myelosuppression limits the use of this regimen in the second-line setting to a selected group of patients with a good performance status. Since the activity of this regimen is encouraging, it is probably best studied in untreated patients.

Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study.

BACKGROUND: CDE (cyclophosphamide, doxorubicin, etoposide) is one of the standard chemotherapy regimens in the treatment of small-cell lung cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this trial the impact of prophylactic antibiotics on incidence of febrile leucopenia (FL) during chemotherapy for SCLC was evaluated. PATIENTS AND METHODS: Patients with chemo-naïve SCLC were randomized to standard-dose CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v., q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks, x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on survival (n = 240 patients). Patients were also randomized to prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150 mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163 patients). This manuscript focuses on the antibiotics question. RESULTS: The incidence of FL during the first cycle was 25% of patients in the placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an overall incidence through all cycles of 43% vs. 24% respectively (P = 0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative (20 vs. 5) and clinically documented (38 vs. 15) infections in the antibiotics arm. The use of therapeutic antibiotics was reduced (P = 0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17 patients, P = 0.013: 1-sided). However, the overall number of days of hospitalization was not reduced (P = 0.05; 1-sided). The number of infectious deaths was nil in the antibiotics vs. five (6%) in the placebo arm (P = 0.022; 2-sided). CONCLUSIONS: Prophylactic ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the incidence of FL, the number of infections, the use of therapeutic antibiotics and hospitalizations due to FL by approximately 50%, with reduced number of infectious deaths. For patients with similar risk for FL, the prophylactic use of antibiotics should be considered.

A dose and schedule finding study of gemcitabine and etoposide in patients with progressive non-small cell lung cancer after platinum containing chemotherapy.

BACKGROUND: Combination chemotherapy improves survival in patients with disseminated non-small cell lung cancer (NSCLC). Gemcitabine is active against NSCLC and etoposide has an additive effect in vitro. We describe a dose finding study for the combination of these drugs. PATIENTS AND METHODS: NSCLC patients progressive after chemotherapy received gemcitabine (1000 mg/m2 days 1, 8, 15) and one of five etoposide schedules in doses ranging from 60 to 100 mg/m2 per day administered on days 1-3 (schedules 1-2) or 8-10 (schedules 3-5). RESULTS: 23 patients (median age 59 years) were entered. Number of patients and cycles evaluable for toxicity was 22 and 75. Non-hematological toxicity was mild. In cycle 1 leukocytopenia grade III/IV was observed in 33 and 56% of the patients treated with etoposide 60 and 80 mg/m2 days 1-3 and in 50% treated with etoposide 60 and 80 mg/m2 days 8-10. During cycle 1 thrombocytopenia grade III/IV was observed in 0, 33, 0 and 33% of these patients, respectively. Both patients treated at etoposide 100 mg/m2 days 8-10 experienced febrile leukocytopenia. During cycle 1 single doses of gemcitabine were administered as planned more frequently in patients receiving etoposide 80 mg/m2 per day on days 8-10 compared to etoposide days 1-3 (83 versus 70%). Postponement of combination gemcitabine and etoposide was not necessary. The overall response rate was 21% (95% confidence interval 3-39%) with a median duration of 7.5 + months in this dose finding study. CONCLUSIONS: Combined gemcitabine etoposide is feasible in patients with progressive NSCLC. The optimal combination was gemcitabine 1000 mg/m2 per day on days 1, 8 and 15 and etoposide 80 mg/m2 per day on days 8-10 of each 28-day cycle. The response rate of 21% warrants further investigation in patients with advanced NSCLC.

Paclitaxel and carboplatin in the treatment of small-cell lung cancer patients resistant to cyclophosphamide, doxorubicin, and etoposide: a non-cross-resistant schedule.

PURPOSE: To evaluate the efficacy of paclitaxel and carboplatin (PC) in small-cell lung cancer (SCLC) patients resistant to cyclophosphamide, doxorubicin, and etoposide (CDE). PATIENTS AND METHODS: We performed a phase II study with PC in SCLC patients who relapsed within 3 months after first-line treatment with CDE. Paclitaxel administration (175 mg/m2 by a 3-hour intravenous infusion) was followed by a 30-minute infusion of carboplatin (area under the curve 7; Chatelut formula) once every 3 weeks for five cycles. Dexamethasone, clemastine, and ranitidine were standard premedication before every cycle. RESULTS: Included were 35 patients (median age, 59 years; 16 with limited disease and 19 with extensive disease; Eastern Cooperative Oncology Group performance status of < or = 1; median time off treatment 6 weeks) who were previously treated with CDE (n = 33), oral etoposide (n = 2), and reinduction CDE (n = 15); only one patient had received three CDE treatments of five cycles. The CDE regimen was followed by local thoracic radiotherapy in seven patients. Hematologic toxicity of grade 3 or 4, for leukopenia was 27% and 6%, for thrombocytopenia 21% and 13%, and for anemia 17% and 0%, respectively, for a total of 132 cycles. Two patients had neutropenic fever; no toxic death occurred. Nonhematologic toxicity was paresthesia CTC grade 3, diarrhea grade 4, and myalgia grade 3 in one patient each. Reversible paresthesia (CTC grade 1 and 2) in toes and fingers was reported in 69% of patients. Thirty-four patients were assessable for response: complete response in two patients, partial response in 23 patients, stable disease in eight patients, and progressive disease in one patient (response rate, 73.5%; 95% confidence interval, 59% to 88%). One patient was found to have atypical carcinoid at pathologic review and was excluded. Median time to progression was 21 weeks (range, 3 to 40 weeks). Median survival was 31 weeks (range, 6 to 112 weeks). One-year survival was 9%. CONCLUSION: Second-line PC in CDE-resistant SCLC patients yields a high response rate and seems non-cross-resistant to CDE. Toxicity was mild in these poor-prognosis patients.

Enhanced myelotoxicity due to granulocyte colony-stimulating factor administration until 48 hours before the next chemotherapy course in patients with small-cell lung carcinoma.

PURPOSE: To evaluate the impact of granulocyte colony-stimulating factor (G-CSF) priming on peripheral-blood cell counts during standard-dose chemotherapy. PATIENTS AND METHODS: Twelve patients with relapsed small-cell lung carcinoma (SCLC) were treated with two chemotherapy courses. Six patients received G-CSF priming only before the first course (group A) and the other six patients only before the second course (group B). Each patient served as his own control. Patients were treated with cyclophosphamide, epirubicin, and etoposide (CEE), or with vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. G-CSF was administered subcutaneously 5 microg/kg/d for 6 days until 48 hours before the first or second chemotherapy course. RESULTS: Priming caused a lowering of the WBC nadir, with a median value of 0.95 x 10(9)/L (P = .004), and of absolute neutrophil nadir, with a median value of 0.48 x 10(9)/L (P = .03). There was a trend for a lower platelet (PLT) nadir after G-CSF priming (P = .09). G-CSF priming resulted in a prolonged duration of WBC count less than 3.0 x 10(9)/L of +4.25 days (P = .04), and of WBC count less than 1.0 x 10(9)/L of +0.50 days (P = .03). The duration of neutropenia less than 0.5 x 10(9)/L seemed longer in primed courses (+3.75 days, P = .18). The duration of PLT counts less than 100 x 10(9)/L was prolonged by 1.5 days (P = .04). Hemoglobin (Hgb) levels were not influenced by G-CSF priming. CONCLUSION: G-CSF administration until 48 hours before the next chemotherapy course increases chemotherapy-associated leukocytopenia and thrombocytopenia. This may be of special concern when G-CSF is administered during dose-densified chemotherapy.

A phase II study of paclitaxel in heavily pretreated patients with small-cell lung cancer.

The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate.