Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer

BackgroundWeekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles.Patients and methodsIn this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb–IV EOC were randomised to six cycles PCw (paclitaxel 90 mg/m², cisplatin 70 mg/m² or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175 mg/m², cisplatin 75 mg/m² or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity.ResultsOf 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3 years (range 7.1–14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9–21.0) months for PCw and 16.4 (95% CI 13.5–19.2) months for PC3w (p = 0.78). Median OS was 44.8 (95% CI 33.1–56.5) months for PCw and 41.1 (95% CI 34.4–47.7) months for PC3w (p = 0.98).ConclusionsThere was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

Long-term results of weekly paclitaxel carboplatin induction therapy: An effective and well-tolerated treatment in patients with platinum-resistant ovarian cancer

BackgroundWeekly paclitaxel/cisplatin is effective in platinum-resistant epithelial ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin.Patients and methodsPatients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m² and carboplatin area under the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. End-points were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity.ResultsMedian progression free interval after last platinum was 9 (0–81) months in 108 patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin <6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 1–21) and 13 (1–46) months, median OS 15 (1–69) and 26 (4–93) months, respectively. The 13 platinum-resistant patients with a platinum-therapy free interval <6 months had a significant shorter PFS (4 versus 10 months, p = 0.035) and OS (9 versus 15 months, p = 0.002).ConclusionSix cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.     

Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian cancer: Analysis of prospective randomised phase III trials

Background and AimsSurgery followed by platinum-taxane chemotherapy is the current standard approach to treat advanced ovarian cancer. The impact of the time interval between surgery and initiation of chemotherapy for clinical outcome has not been clarified yet.MethodsIndividual patient data analysis of 3326 patients from three prospective randomised phase III trials conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Time to chemotherapy (TTC) was analysed and correlated with outcome.ResultsMedian TTC was 19 days (range 1–56). The effect of TTC differed significantly for patients with or without residual disease for progression-free (PFS; interaction p = 0.004) and for overall survival (OS; interaction p = 0.028). A delayed start of chemotherapy was associated with earlier disease recurrence (HR 1.038, 95% CI 0.973; 1.106, p = 0.257 per week delay) and a significantly decreased OS (HR 1.087, 95% CI 1.005; 1.176 p = 0.038) in patients with no residual tumour after surgery. In contrast, in patients with residual disease, a longer TTC was significantly associated with later progression (HR 0.931, 95% CI 0.895; 0.969, p < 0.001) and no effect towards OS (HR 0.983, 95% CI 0.940; 1.028, p = 0.452).ConclusionsOur results provide evidence that early initiation of chemotherapy might result in slightly improved survival in patients with complete cytoreduction while patients with residual disease after surgery did not benefit from earlier chemotherapy. A prospective study randomising patients to different time intervals could clarify the definitive relevance of the time between surgery and chemotherapy.     

Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review

BackgroundFluoropyrimidine-based chemotherapy is considered standard treatment of advanced colorectal cancer. Recent studies indicate benefit to the addition of bevacizumab, a recombinant monoclonal antibody targeting vascular endothelial growth factor.MethodsMedline, EMBASE, Cochrane Library, and conference proceedings were searched to identify randomized trials in advanced colorectal cancer comparing chemotherapy plus bevacizumab with chemotherapy alone. A meta-analysis of published data was carried out.ResultsFive trials comparing chemotherapy plus bevacizumab with chemotherapy alone as first- or second-line treatment were identified. Our meta-analysis indicates an advantage in favor of the addition of bevacizumab to chemotherapy in terms of overall survival (OS) [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.69–0.90; P = 0.0005], progression-free survival (PFS) (HR 0.63; 95% CI 0.49–0.81, P = 0.0004), and response rate (RR 1.50; 95% CI 1.06–2.10, P = 0.02). The most commonly observed adverse effects related to bevacizumab included hypertension, proteinuria, bleeding, and thrombosis. Gastrointestinal perforation and poor wound healing were also observed; however, their incidence was rare.ConclusionsFor patients with advanced colorectal cancer receiving first- or second-line fluoropyrimidine-based chemotherapy, the addition of bevacizumab improves PFS and OS at the expense of increased incidence of toxicity. The magnitude of benefit may differ based on the chemotherapy regimen with which bevacizumab is partnered.     

KRAS mutations are associated with inferior clinical outcome in patients with metastatic colorectal cancer,but are not predictive for benefit with cediranib

PurposeThe prognostic potential of KRAS mutations in advanced colorectal cancer (CRC) patients and the impact of KRAS mutation status on the effectiveness of chemotherapy or vascular endothelial growth factor (VEGF) signalling inhibitor therapy remain unclear. KRAS mutation status was evaluated retrospectively as a potential prognostic/predictive marker of clinical outcomes using tumour samples from patients with metastatic CRC receiving cediranib or placebo plus FOLFOX/XELOX in a Phase III trial (HORIZON II; NCT00399035).MethodsKRAS codon 12 and 13 mutation analyses were performed using a commercially available, allele-specific, amplification refractory mutation system (ARMS)-based polymerase chain reaction (PCR) assay. Retrospective analyses of progression-free survival (PFS) and overall survival (OS) according to KRAS mutation status were performed for patients randomised to cediranib 20 mg or placebo.ResultsKRAS status was determined in 599/1076 patients (cediranib 20 mg, n = 285/502; cediranib 30 mg, n = 110/216; placebo, n = 204/358). Baseline characteristics were similar across KRAS mutant (n = 258; 24.0%), wild-type (n = 341; 31.7%) and status unknown (n = 477; 44.3%) groups. There was a trend towards improved PFS and OS in the wild-type versus mutant subgroups independent of treatment (cediranib 20 mg and placebo: PFS hazard ratio (HR) = 0.85 [median PFS: wild-type = 8.5 months; mutant = 8.3 months]; OS HR = 0.71 [median OS: wild-type = 20.9 months; mutant = 16.9 months]). Treatment effects were similar between KRAS subgroups for cediranib 20 mg versus placebo (PFS: wild-type HR = 0.78, mutant HR = 0.82; OS: wild-type HR = 0.92, mutant HR = 1.01).ConclusionData from this large randomised Phase III study show that KRAS codon 12/13 mutations have negative prognostic value in metastatic CRC patients receiving treatment with FOLFOX/XELOX, but KRAS mutation status is not predictive of treatment benefit with cediranib, using PFS or OS.     

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival,surgery, and organ preservation

BackgroundLocally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points.Patients and methodsThese outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy.ResultsAmong 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31–not reached] versus 24 months (95% CI: 13–42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41–0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12–59) versus 11 months (95% CI: 8–14) for PF (HR: 0.66; 95% CI: 0.45–0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030).ConclusionsIn locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.     

Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis

BackgroundThe role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients is highly controversial and it is not endorsed by current guidelines. Our meta-analysis aimed to better elucidate its activity, efficacy and safety.Material and methodsA systematic search of Medline, Web of Science and conferences proceedings up to 30 October 2017 was carried out to identify randomized controlled trials (RCTs) investigating platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients. Using the fixed and random effects models, pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for pathological complete response (pCR, defined as ypT0/is pN0), event-free survival (EFS), overall survival (OS) and grade 3 and 4 adverse events (AEs: neutropenia, anemia, thrombocytopenia and neuropathy).ResultsNine RCTs (N = 2109) were included. Overall, platinum-based neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1% (OR 1.96, 95% CI 1.46–2.62, P < 0.001). Platinum-based neoadjuvant chemotherapy remained significantly associated with increased pCR rate also after restricting the analysis to the three RCTs (N = 611) that used the same standard regimen in both groups of weekly paclitaxel (with or without carboplatin) followed by anthracycline and cyclophosphamide (OR 2.53, 95% CI 1.37–4.66, P = 0.003). Conversely, among the 96 BRCA-mutated patients included in two RCTs, the addition of carboplatin was not associated with significantly increased pCR rate (OR 1.17, 95% CI 0.51–2.67, P = 0.711). Two RCTs (N = 748) reported survival outcomes: no significant difference in EFS (HR 0.72, 95% CI 0.49–1.06, P = 0.094) and OS (HR 0.86, 95% CI 0.46–1.63, P = 0.651) was observed.A significant higher risk of grade 3 and 4 hematological AEs, with no increased risk of grade 3 and 4 neuropathy was observed with platinum-based neoadjuvant chemotherapy.ConclusionIn TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities. Platinum-based neoadjuvant chemotherapy may be considered an option in TNBC patients.PROSPERO registration numberCRD42018080042.     

Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: Results from the multicenter,randomised trial Fédération Francophone de Cancérologie Digestive 9601

ObjectiveTo assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC).DesignAmong the 294 patients with non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test.ResultsAmong the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 [4.6–5.6] versus 2.9 [2.2–4.1] months; p = 0.001) and OS (16.3 [13.7–19.2] versus 9.6 [7.4–12.5]; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n = 43).ConclusionResection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.     

Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group,EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064)

BackgroundSwitch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC.MethodsPatients with non-progressive disease after 4–6 cycles of chemotherapy were randomised to receive either pazopanib 800 mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety.ResultsA total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n = 50) or placebo (n = 52). Median age was 64 years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40–1.28]; p = 0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43–1.03], p = 0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1–2. Grade 3–4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE.ConclusionsSwitch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.     

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BackgroundPaclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy.MethodsA total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed.ResultsThe median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5–9.6 months) and 26.9 months (95% CI: 23.6–30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1–6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13–10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity.ConclusionGenetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.     

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized,double-blind,multicenter phase 2 trial

BackgroundIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).DesignPatients (n = 130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m²)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.ResultsPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64; P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.ConclusionThese results suggest further investigation of ipilimumab in ED-SCLC.     

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

BackgroundThere is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs.Patients and methodsWe reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied.ResultsThe study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p < 0.001).ConclusionThe previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.     

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO

BackgroundNeutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.Patients and methodsPts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.ResultsNLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05–1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25–1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14–1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95–1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64–1.08)] and high [HR 0.73 (95% CI 0.54–0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62–1.12) for low NLR; HR 0.82 (95% CI 0.59–1.12) for high NLR].ConclusionThis study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.     

Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer

BackgroundCBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy.Patients and methodsGerm-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided.ResultsMedian progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46–9.00] months for GP arm and 6.07 (95% CI 5.32–6.83) months for GT arm (P = 0.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, P = 0.008; 10.37 versus 4.30 months, P = 0.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, P = 0.086; 8.90 versus 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks.ConclusionsGP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients.Trial registrationClinicalTrials.gov, NCT01287624.     

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy

BackgroundPaclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure.Methods and materialsPatients were randomized 1 : 1 to DHP107 (200 mg/m² orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m² day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25.ResultsBaseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7–4.0) months for DHP107 and 2.6 (95% CI 1.8–2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64–1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70–1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 − 11.5) months for DHP107 versus 8.9 (95% CI 7.1–12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76–1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%).ConclusionsDHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC.ClinicalTrials.govNCT01839773.     

nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial

BackgroundMetastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC.Patients and methodsPatients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m² plus C AUC 2, nab-P 125 mg/m² plus G 1000 mg/m², or G 1000 mg/m² plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety.ResultsIn total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38–0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37–0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47–1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52–1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic.ConclusionsFirst-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.     

A randomised trial comparing preoperative to perioperative chemotherapy in early-stage non-small-cell lung cancer (IFCT 0002 trial)

HypothesisThere will be a detectable increase in overall survival (OS) using preoperative (PRE) as opposed to perioperative (PERI) chemotherapy in resectable Stage I–II non-small-cell lung cancer (NSCLC).MethodsThis multicenter, open-label, randomised trial with a 2 × 2 factorial design first compared two chemotherapy strategies (PRE versus PERI), then two chemotherapy regimens (gemcitabine–cisplatin [GP] versus paclitaxel–carboplatin [TC]). The PRE group received two preoperative cycles followed by two additional preoperative cycles, while the PERI group underwent two preoperative cycles followed by two postoperative cycles, the 3rd and 4th cycles being given only to responders in both cases.ResultsA total of 528 patients were randomised, 267 of which were assigned to the PRE group and 261 to the PERI group. Three-year OS did not differ between the two groups (67.4% and 67.7%, respectively; hazard ratio (HR) = 1.01 [0.79–1.30], p = 0.92), nor did 3-year disease-free survival, response rates, toxicity, or postoperative mortality. Pathological complete response was observed in 22 (8.2%) and 16 patients (6.1%), respectively. Although quality of life did not differ significantly, chemotherapy compliance was significantly higher in the PRE group. The proportion of responders who received Cycles 3 and 4 was significantly higher in the PRE group (90.4% versus 75.2%, p = 0.001). In responders, the dose intensity of Cycles 3 and 4 was higher in the PRE group than in the PERI group (mean relative dose intensity of 90.4% versus 82.6%, respectively; p = 0.0007). There was no difference between GP and TC in 3-year OS (HR = 0.97 [95% confidence interval (CI): 0.76–1.25], p = 0.80) or response rates. However, the regimens’ toxicity profiles differed.ConclusionsThis study failed to demonstrate any difference in survival between patients receiving preoperative and perioperative chemotherapy in early-stage NSCLC. The increase from two to four preoperative chemotherapy cycles did not increase the pathological response rate.     

Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study

BackgroundCediranib is a highly potent vascular endothelial growth factor (VEGF) signalling inhibitor with activity against VEGF receptors 1, 2 and 3. This Phase II, randomised, double-blind, parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor.MethodsPatients were randomised (3:1) to cediranib 45 mg/day or placebo. The primary objective was comparison of change from baseline in tumour size after 12 weeks of therapy. Secondary objectives included response rate and duration, progression-free survival (PFS) and safety and tolerability. Patients in the placebo group could cross over to open-label cediranib at 12 weeks or earlier if their disease had progressed. This study has been completed and is registered with ClinicalTrials.gov, number NCT00423332.FindingsPatients (n = 71) were randomised to receive cediranib (n = 53) or placebo (n = 18). The primary study outcome revealed that, after 12 weeks of therapy, there was a significant difference in mean percentage change from baseline in tumour size between the cediranib (–20%) and placebo (+20%) arms (p < 0.0001). Eighteen patients (34%) on cediranib achieved a partial response and 25 (47%) experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo (hazard ratio (HR) = 0.45, 90% confidence interval: 0.26–0.76, p = 0.017; median PFS 12.1 versus 2.8 months). The most common adverse events in patients receiving cediranib were diarrhoea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%).InterpretationCediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma. The adverse event profile was consistent with previous studies of cediranib 45 mg.     

Comparison of survival and hospitalization rates between Medicare patients with advanced NSCLC treated with bevacizumab–carboplatin–paclitaxel and carboplatin–paclitaxel: A retrospective cohort study

ObjectiveThe use of bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC) is controversial among elderly patients. This study aimed to compare overall survival for Medicare patients diagnosed with NSCLC and treated with either first-line bevacizumab–carboplatin–paclitaxel (BCP) or carboplatin–paclitaxel (CP).MethodsPatients ≥65 years old, first diagnosed with non-squamous NSCLC stage IIIB/IV between 2006 and 2009, and treated with either first-line BCP or CP, were selected from the SEER-Medicare database that links cancer registry and US Medicare claims data. Kaplan–Meier estimates were used to evaluate survival. Multivariable Cox proportional hazards models were used to compare the effect of BCP versus CP on the hazard of death. Age-stratified analyses were conducted for patients aged 65–74 and ≥75 years.ResultsOf 1706 patients in the study sample, 592 (34.7%) received BCP and 1114 (65.3%) received CP; 692 (40.6%) were ≥75 years. Adjusted median survival time in the BCP versus CP cohorts was 10.5 versus 8.5 months (p = 0.008). The difference in median survival favoring the BCP cohort was statistically significant for both patients aged ≥75 years (2.8 months, p = 0.019), and patients aged 65–74 years (1.5 months, p = 0.018). The adjusted hazard of death did not differ between the cohorts (HR: 0.96, 95% CI: 0.86–1.06); however, during the first year of follow-up, when most deaths (>60%) occurred, the hazard of death was 18% lower for the BCP cohort (HR: 0.82, 95% CI: 0.71–0.94). BCP patients also had 18% fewer hospital admissions than CP patients (adjusted incidence rate ratio (IRR): 0.82, 95% CI: 0.72–0.94) and 23% fewer inpatient days (IRR: 0.77, 95% CI: 0.65–0.91).ConclusionsIn this retrospective analysis of Medicare patients in the SEER database, first-line therapy with BCP was associated with longer survival and fewer hospitalizations than CP.