Guideline Concordance of Treatment and Outcomes Among Adult Non-Hodgkin Lymphoma Patients in Sub-Saharan Africa: A Multinational, Population-Based Cohort.

BACKGROUND: Although non-Hodgkin lymphoma (NHL) is the 6th most common malignancy in Sub-Saharan Africa (SSA), little is known about its management and outcome. Herein, we examined treatment patterns and survival among NHL patients. METHODS: We obtained a random sample of adult patients diagnosed between 2011 and 2015 from 11 population-based cancer registries in 10 SSA countries. Descriptive statistics for lymphoma-directed therapy (LDT) and degree of concordance with National Comprehensive Cancer Network (NCCN) guidelines were calculated, and survival rates were estimated. FINDINGS: Of 516 patients included in the study, sub-classification was available for 42.1% (121 high-grade and 64 low-grade B-cell lymphoma, 15 T-cell lymphoma and 17 otherwise sub-classified NHL), whilst the remaining 57.9% were unclassified. Any LDT was identified for 195 of all patients (37.8%). NCCN guideline-recommended treatment was initiated in 21 patients. This corresponds to 4.1% of all 516 patients, and to 11.7% of 180 patients with sub-classified B-cell lymphoma and NCCN guidelines available. Deviations from guideline-recommended treatment were initiated in another 49 (9.5% of 516, 27.2% of 180). By registry, the proportion of all patients receiving guideline-concordant LDT ranged from 30.8% in Namibia to 0% in Maputo and Bamako. Concordance with treatment recommendations was not assessable in 75.1% of patients (records not traced (43.2%), traced but no sub-classification identified (27.8%), traced but no guidelines available (4.1%)). By registry, diagnostic work-up was in part importantly limited, thus impeding guideline evaluation significantly. Overall 1-year survival was 61.2% (95%CI 55.3%-67.1%). Poor ECOG performance status, advanced stage, less than 5 cycles and absence of chemo (immuno-) therapy were associated with unfavorable survival, while HIV status, age, and gender did not impact survival. In diffuse large B-cell lymphoma, initiation of guideline-concordant treatment was associated with favorable survival. INTERPRETATION: This study shows that a majority of NHL patients in SSA are untreated or undertreated, resulting in unfavorable survival. Investments in enhanced diagnostic services, provision of chemo(immuno-)therapy and supportive care will likely improve outcomes in the region.

Clinical presentation and diagnosis of adult patients with non-Hodgkin lymphoma in Sub-Saharan Africa.

Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in Sub-Saharan Africa (SSA). Comprehensive diagnostics of NHL are essential for effective treatment. Our objective was to assess the frequency of NHL subtypes, disease stage and further diagnostic aspects. Eleven population-based cancer registries in 10 countries participated in our observational study. A random sample of 516 patients was included. Histological confirmation of NHL was available for 76.2% and cytological confirmation for another 17.3%. NHL subclassification was determined in 42.1%. Of these, diffuse large B cell lymphoma, chronic lymphocytic leukaemia and Burkitt lymphoma were the most common subtypes identified (48.8%, 18.4% and 6.0%, respectively). We traced 293 patients, for whom recorded data were amended using clinical records. For these, information on stage, human immunodeficiency virus (HIV) status and Eastern Cooperative Oncology Group Performance Status (ECOG PS) was available for 60.8%, 52.6% and 45.1%, respectively. Stage at diagnosis was advanced for 130 of 178 (73.0%) patients, HIV status was positive for 97 of 154 (63.0%) and ECOG PS was ≥2 for 81 of 132 (61.4%). Knowledge about NHL subclassification and baseline clinical characteristics is crucial for guideline-recommended treatment. Hence, regionally adapted investments in pathological capacity, as well as standardised clinical diagnostics, will significantly improve the therapeutic precision for NHL in SSA.

Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC. METHODS: In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS: The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug-drug interaction was implicated. CONCLUSIONS: Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.

Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial.

BACKGROUND: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma. METHODS: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366. FINDINGS: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin. INTERPRETATION: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT. FUNDING: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.

Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study.

BACKGROUND: Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). METHODS: We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00982111. FINDINGS: Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5-13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1-13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 [95% CI 0·84-1·21]; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51%] of 304 vs 127 [41%] of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3-4 rash (45 [15%] of 304 vs one [<1%] of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 [8%] vs seven [2%] patients), and grade 3 or higher venous thromboembolic events (23 [8%] vs 11 [4%] patients) than did those in the pemetrexed and cisplatin alone group. INTERPRETATION: Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. FUNDING: Eli Lilly and Company.

NCCN guideline-concordant cancer care in Sub-Saharan Africa A population-based multi-country study of five cancers.

BACKGROUND: To assess population-based quality of cancer care in Sub-Saharan Africa and to identify specific gaps and joint opportunities, we assessed concordance of diagnostic and treatment with NCCN harmonized guidelines for leading cancer types in 10 countries. METHODS: Adult patients with female breast cancer (BC), cervical cancer (CC), colorectal cancer (CRC), Non-Hodgkin lymphoma (NHL) and prostate cancer (PC) were randomly drawn from 11 population-based cancer registries. Guideline concordance of diagnostics and treatment was assessed using clinical records. In a sub-cohort of 906 patients with potentially curable cancer (stage I-III BC, CC, CRC, PC, aggressive NHL (any stage)) and documentation for >1 month after diagnosis, we estimated factors associated with guideline-concordant treatment or minor deviations (GCT). FINDINGS: Diagnostic information as per guidelines was complete for 1030 (31.7%)of 3246 patients included. In the sub-cohort with curable cancer, GCT was documented in 374 (41.3%, corresponding to 11.7% of 3246 included in the population-based cohort): aggressive NHL (59.8%/9.1% population-based), BC (54.5%/19.0%), PC (39.0%/6.1%), CRC (33.9%/9.5%), and CC (27.8%/11.6%). GCT was most frequent in Namibia (73.1% of curable cancer subset/32.8% population-based) and lowest in Kampala, Uganda (13.5%/3.1%). GCT was negatively associated with poor ECOG status, locally advanced stage, origin from low HDI countries, and a diagnosis of CRC or CC. INTERPRETATION: Quality of diagnostic workup and treatment showed major deficits, with considerable disparities among countries and cancer types. Improved diagnostic services are necessary to increase the share of curable cancer in SSA. Treatment components within NCCN guidelines synergetic for several cancers should be prioritized.

Open, randomized, phase II study of single-agent gemcitabine and docetaxel as first- and second-line treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Chemotherapy has been widely accepted as standard for palliation in advanced non-small-cell lung cancer. Gemcitabine and docetaxel are active as single agents. Our previous experience indicates that single-agent therapy, if given sequentially, could be an alternative to doublet combination chemotherapy and that sequence and schedule matter. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer were randomized to receive first-line 3-weekly gemcitabine or docetaxel. At progression, patients received second-line therapy with the other agent. Treatment was considered feasible if 30% of the evaluable patients had > or = 2 cycles of first-line and 2 cycles of second-line therapy and patient survival was > or = 7 months from the start of treatment. For efficacy, time to progression, overall survival, response, and quality of life were analyzed. RESULTS: Three hundred thirty patients received gemcitabine followed by docetaxel or docetaxel followed by gemcitabine. Treatment was feasible for 60 patients (38%) with gemcitabine followed by docetaxel and for 80 patients (49%) with docetaxel followed by gemcitabine; treatment favored docetaxel followed by gemcitabine (P = 0.03539). Median survival for gemcitabine followed by docetaxel and docetaxel followed by gemcitabine was 6.3 months and 8.6 months, and 1-year survival rate was 28% and 31%, respectively. Objective response rates were < or = 10% for both treatment strategies. Quality of life was significantly better in gemcitabine followed by docetaxel (P = 0.005). CONCLUSION: Single-agent gemcitabine and docetaxel are feasible as defined for both sequences but treatment favors docetaxel followed by gemcitabine. Thus, it is reasonable to state that single-agent therapy given sequentially might be a candidate for palliation and therefore should be investigated in comparison with combination therapy.

Necitumumab plus Gemcitabine and Cisplatin as First-Line Therapy in Patients with Stage IV EGFR- Expressing Squamous Non-Small-Cell Lung Cancer: German Subgroup Data from an Open-Label, Randomized Controlled Phase 3 Study (SQUIRE).

BACKGROUND: In the SQUIRE study, adding the anti-epidermal growth factor receptor (EGFR) IgG1 antibody necitumumab to first-line gemcitabine and cisplatin (GC + N) in advanced squamous non-small-cell lung cancer (sqNSCLC) significantly improved overall survival (OS); the safety profile was acceptable. We explored data for the German subpopulation (N = 96) of SQUIRE patients with EGFR-expressing tumors. PATIENT AND METHODS: Patients with stage IV sqNSCLC were randomized 1:1 to up to 6 cycles of open-label GC + N or GC alone. GC + N patients with no progression continued on necitumumab monotherapy until disease progression or intolerable toxicity. The primary endpoint was OS; the secondary endpoints included progression-free survival (PFS), safety and health-related quality of life (EQ-5D, Lung Cancer Symptom Scale (LCSS)). RESULTS: The 96 German SQUIRE patients with EGFR-expressing tumors (GC + N 42, GC 54) received a median of 4 GC cycles; the GC + N patients received 5 cycles of necitumumab. Adding necitumumab was associated with 41% risk reduction of death (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.94, p = 0.026) and 44% risk reduction of progression (HR 0.56, 95% CI 0.33-0.95, p = 0.029). Adverse events typically associated with EGFR antibody treatment (including rash, hypomagnesemia) were more common with GC + N. The time to deterioration of the EQ-5D and LCSS scores showed no notable differences between the treatment arms, except for appetite loss (delayed for GC + N). CONCLUSION: The survival benefit from adding necitumumab to first-line GC was more pronounced in the German SQUIRE subpopulation with EGFR-expressing tumors than in the overall (intention-to-treat) population; toxicity was manageable and consistent with the overall population.

Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: To investigate whether radiotherapy can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after four cycles of chemotherapy. PATIENTS AND METHODS: Between 1993 and 1998, patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study. Patients were randomly assigned to receive cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) + doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). RESULTS: Of 1,204 patients randomly assigned to treatment, 1,064 patients were informative and eligible for the arm comparison (532 patients in arm A; 532 patients in arm B). The median observation time was 54 months. Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%). In contrast, acute side effects including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity were more frequent in the EF arm. CONCLUSION: Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD.

Randomized multicenter phase II study of gemcitabine versus docetaxel as first-line therapy with second-line crossover in advanced-stage non-small-cell lung cancer.

BACKGROUND: A randomized phase II study was performed to determine whether single-agent gemcitabine or docetaxel with the introduction of the opposite agent in case of disease progression (ie, in the second-line setting) is feasible and effective in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The doses were 1,000 mg/m2 for gemcitabine and 35 mg/m2 for docetaxel, each given on days 1, 8, and 15 every 4 weeks. After a planned interim analysis, the docetaxel/gemcitabine arm (ie, docetaxel followed by gemcitabine) was closed after enrollment of 49 patients because of poor predefined feasibility. A total of 98 patients were recruited to the gemcitabine/docetaxel arm (ie, gemcitabine followed by docetaxel). RESULTS: Quality of life remained near baseline levels during the administration of 6 cycles of gemcitabine/docetaxel chemotherapy, whereas it deteriorated after 2 cycles of docetaxel/gemcitabine. Toxicity was comparable between arms. Median times to progression were 4.3 months and 2.2 months with gemcitabine/docetaxel and docetaxel/gemcitabine, respectively, and median overall survival times were 9 months (gemcitabine/docetaxel) and 5 months (docetaxel/gemcitabine; P=0.029, Wilcoxon rank-sum test). CONCLUSION: These results indicate that first-line gemcitabine followed by second-line weekly docetaxel is feasible, with promising survival in patients with advanced NSCLC.

Oral idarubicin, dexamethasone and vincristine in the treatment of multiple myeloma: final analysis of a phase II trial.

This prospective phase II study evaluated a regimen with vincristine, oral idarubicin and dexamethasone (VID) in 74 patients with multiple myeloma. A partial response was achieved in 57% (16/28) of patients with previously untreated disease and in 35% (16/46) with refractory diseases. VID chemotherapy is an effective and tolerable oral alternative in an outpatient setting for these patients.

Evaluation of antitumor activity using change in tumor size of the survivin antisense oligonucleotide LY2181308 in combination with docetaxel for second-line treatment of patients with non-small-cell lung cancer: a randomized open-label phase II study.

Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel-induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC. Patients (N = 162) eligible for second-line NSCLC treatment (stage IIIB/IV) with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomized 2:1 to receive LY2181308 (750 mg intravenously, weekly) and docetaxel (75 mg/m intravenously, day 1) or docetaxel alone every 21 days. CTS from baseline to the end of cycle 2 was compared between the two treatment arms. The mean (SD) tumor size ratio for LY2181308/docetaxel and docetaxel was 1.05 (0.21) and 1.00 (0.15) (p = 0.200), respectively, suggesting no significant improvement in antitumor activity between the arms. Because there was also no significant difference between the two arms for progression-free survival (PFS) (2.83 months with LY2181308/docetaxel and 3.35 months with docetaxel [p = 0.191]), both arms were combined. Using the combined arms, CTS correlated with PFS (PFS = 4.63 months in patients with decreased CTS compared with 2.66 months in patients with increased CTS), supporting its use in early decision-making in phase II studies.

Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

PURPOSE: Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC. PATIENTS AND METHODS: A total of 637 patients with refractory or sensitive SCLC were randomly assigned at a ratio of 2:1 to 21-day cycles of amrubicin 40 mg/m(2) intravenously (IV) on days 1 to 3 or topotecan 1.5 mg/m(2) IV on days 1 to 5. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival (PFS), and safety. RESULTS: Median OS was 7.5 months with amrubicin versus 7.8 months with topotecan (hazard ratio [HR], 0.880; P = .170); in refractory patients, median OS was 6.2 and 5.7 months, respectively (HR, 0.77; P = .047). Median PFS was 4.1 months with amrubicin and 3.5 months with topotecan (HR, 0.802; P = .018). ORR was 31.1% with amrubicin and 16.9% with topotecan (odds ratio, 2.223; P < .001). Grade ≥ 3 treatment-emergent adverse events in the amrubicin and topotecan arms were: neutropenia (41% v 54%; P = .004), thrombocytopenia (21% v 54%; P < .001), anemia (16% v 31%; P < .001), infections (16% v 10%; P = .043), febrile neutropenia (10% v 3%; P = .003), and cardiac disorders (5% v 5%; P = .759); transfusion rates were 32% and 53% (P < .001), respectively. NQO1 polymorphisms did not influence safety outcomes. CONCLUSION: Amrubicin did not improve survival when compared with topotecan in the second-line treatment of patients with SCLC. OS did not differ significantly between treatment groups, although an improvement in OS was noted in patients with refractory disease treated with amrubicin.

Efficacy and safety of bevacizumab-based therapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer in the phase III BO17704 study (AVAiL).

INTRODUCTION: The placebo-controlled, phase III AVAiL trial evaluated bevacizumab plus cisplatin and gemcitabine as first-line therapy in patients with advanced, nonsquamous non-small cell lung cancer. A retrospective subgroup analysis was performed to assess the efficacy and safety of bevacizumab-based therapy in elderly patients aged 65 years or older in AVAiL. METHODS: Patients received cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles plus 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, or placebo every 3 weeks until disease progression. The primary end point was progression-free survival. Secondary endpoints included objective response rate, overall survival, and safety. RESULTS: Data were evaluated for 304 patients aged 65 years or older (median age 68 years). Most of the patients were Caucasian (87%) and the majority had adenocarcinoma (83%). In the combined bevacizumab arms, 143 patients (79%) completed ≥4 cycles of chemotherapy. Patients who received bevacizumab derived an improvement in progression-free survival compared with placebo (7.5 mg/kg bevacizumab: hazard ratio [HR] = 0.71, p = 0.023; 15 mg/kg bevacizumab: HR = 0.84, p = 0.25). Objective response rates were 40, 29, and 30% in the 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, and placebo arms, respectively. Overall survival was similar for each bevacizumab arm versus placebo (7.5 mg/kg bevacizumab: HR = 0.84, p = 0.31; 15 mg/kg bevacizumab: HR = 0.88, p = 0.44). There were no particular safety signals of concern in elderly patients. CONCLUSIONS: This analysis of the randomized, phase III AVAiL trial shows that bevacizumab-based therapy improves outcomes for elderly patients with non-small cell lung cancer. Furthermore, bevacizumab-based therapy is well tolerated in elderly patients.

Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.

PURPOSE: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves survival when combined with carboplatin/paclitaxel for advanced nonsquamous non-small-cell lung cancer (NSCLC). This randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine (CG) plus bevacizumab in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m2 and gemcitabine 1,250 mg/m(2) for up to six cycles plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The trial was not powered to compare the two doses directly. The primary end point was amended from overall survival (OS) to progression-free survival (PFS). Between February 2005 and August 2006, 1,043 patients were randomly assigned (placebo, n = 347; low dose, n = 345; high dose, n = 351). RESULTS: PFS was significantly prolonged; the hazard ratios for PFS were 0.75 (median PFS, 6.7 v 6.1 months for placebo; P = .003) in the low-dose group and 0.82 (median PFS, 6.5 v 6.1 months for placebo; P = .03) in the high-dose group compared with placebo. Objective response rates were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus CG, respectively. Duration of follow-up was not sufficient for OS analysis. Incidence of grade 3 or greater adverse events was similar across arms. Grade > or = 3 pulmonary hemorrhage rates were < or = 1.5% for all arms despite 9% of patients receiving therapeutic anticoagulation. CONCLUSION: Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.

Randomized phase II trial of a toll-like receptor 9 agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer.

PURPOSE: This study assessed the efficacy of the combination of standard taxane plus platinum chemotherapy with the synthetic Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB to IV NSCLC were randomly assigned (one to two ratio) to receive four to six cycles of taxane/platinum chemotherapy alone or with 0.2 mg/kg of subcutaneous PF-3512676 on days 8 and 15 of each 3-week cycle. The primary end point was objective response rate (ORR). RESULTS: Baseline demographics were similar between treatment arms, although significantly more patients in the PF-3512676 arm had stage IV disease (85% compared with 62% in the chemotherapy-alone arm). The modified intent-to-treat analysis (n = 111) demonstrated a 38% ORR (confirmed and unconfirmed) in the PF-3512676 arm (n = 74) and 19% in the chemotherapy-alone arm (n = 37) by investigator evaluation. Blinded, independent radiologic review for 90 patients showed a similar trend in confirmed response rate (19% and 11%, respectively). Median survival was 12.3 months in the PF-3512676 arm and 6.8 months in the chemotherapy-alone arm, and 1-year survival was 50% and 33%, respectively. Mild to moderate local injection site reactions and flu-like symptoms were the most common PF-3512676-related adverse events, but grade 3/4 neutropenia, thrombocytopenia, and anemia were all reported more commonly for patients in the PF-3512676 arm. CONCLUSION: The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.

High-dose chemotherapy with autologous peripheral blood stem cell support for recurrent primary AFP-producing intracranial germinoma.

We report of a 34-year old man with second intracranial relapse of a suprasellar germinoma. Despite of extensive pretreatment with radiation and conventional chemotherapy relapse occurred and was treated with sequential high-dose chemotherapy followed by transfusion of autologous peripheral stem cells. The high-dose chemotherapy course was complicated by refractory derailment of pineal gland insufficiency. The patient achieved a complete remission after high dose chemotherapy which lasted for 13 months. Subsequently, he developed a third relapse and died.