Factors affecting the association between overall survival and progression-free survival in clinical trials of first-line treatment for patients with advanced non-small cell lung cancer

Purpose

New treatment strategies, particularly the introduction of molecular-targeted agents and appropriate patient selection based on histology and/or genotyping, have progressed markedly in recent years, and the overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients has improved. The aim of the study was to identify factors affecting longer OS than that estimated from progression-free survival (PFS) in first-line treatment for advanced NSCLC.

Methods

Sixty-five controlled trials for first-line treatment of advanced NSCLC were extracted for the study. Factors influencing higher than predicted OS were examined by logistic regression analysis between the OS-extended group and the OS-association group.

Results

PFS was moderately associated with OS. Twenty arms of 14 trials were categorized as an OS-extended group, in which the ratio of observed OS to estimated OS was found to be over 1.2. On multivariate logistic regression analysis, number of patients lower than 150, average age younger than 63 years, and percentage of squamous carcinoma <30 % were found to significantly affect this relationship.

Conclusion

We identified number of patients and well-known prognostic factors including age and histological cancer type as factors influencing longer OS. These factors should be considered for patient eligibility, when PFS is used as a surrogate primary endpoint for OS in randomized clinical trials of first-line treatment for patients with advanced NSCLC.     

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background

Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.

Patients and methods

This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged <65, ≥65, and ≥70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3–5 adverse events were also assessed.

Results

Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49–0.68] and OS (HR 0.85; 95% CI 0.74–0.97) in patients aged ≥65 years; patients aged ≥70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged ≥65 and ≥70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3–5 adverse events were observed.

Conclusions

In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients.     

Timing of chemotherapy-induced neutropenia is a prognostic factor in patients with metastatic non-small-cell lung cancer: a retrospective analysis in gemcitabine-plus-platinum-treated patients

Purpose

Chemotherapy-induced neutropenia (CIN) has been associated with better therapeutic results in studies of various tumors. Herein, we explored the relationship between timing (onset) of CIN and clinical outcomes of patients with metastatic non-small-cell lung cancer (NSCLC).

Methods

Patients with stage IV NSCLC receiving at least two cycles of first-line doublet chemotherapy (gemcitabine plus platinum) were reviewed retrospectively. Subjects were stratified by onset of CIN into two groups: early-onset (lowest neutrophil count of cycles 1–2 <2.0 × 10⁹/L) and non-early-onset. The non-early-onset group was further subdivided into late-onset (lowest neutrophil count of cycles 3–6 <2.0 × 10⁹/L) and absence of neutropenia.

Results

A total of 123 patients were studied. Significantly better disease control rate, progression-free survival (PFS), and overall survival (OS) were observed in early-onset versus non-early-onset patients. Median PFS of 5.1 and 3.8 months (p = 0.0016) and median OS of 16.7 and 11.2 months (p = 0.0004) were achieved for these groups, respectively. Patient subsets with late-onset and absence of neutropenia showed similarly poor clinical outcomes, with 4.8 and 3.8 months median PFS (p = 0.5067) and 13.0 and 11.2 months median OS (p = 0.6304), respectively.

Conclusions

Timing of CIN is predictive of prognosis in patients with metastatic NSCLC receiving gemcitabine/platinum doublet chemotherapy. Better clinical outcomes were achieved when onset of neutropenia was early versus late or absent altogether. Further research is warranted to determine whether above findings are applicable to other chemotherapeutic regimens.     

Clinical impact of radiotherapy for locally advanced pancreatic cancer

Background

Although a randomized controlled trial for locally advanced pancreatic cancer (PC) has demonstrated a survival advantage for treatment with gemcitabine alone, chemoradiotherapy remains the treatment of choice for locally advanced disease in Japan. The aim of this study was to compare the survival benefits associated with gemcitabine and concurrent chemoradiotherapy in locally advanced unresectable PC.

Patients

Seventy-seven patients with locally advanced unresectable PC were retrospectively enrolled from April 2001 to December 2006. All cases were histologically proven, and patients received gemcitabine chemotherapy (n = 30) or concurrent chemoradiotherapy (based on 5-fluorouracil, n = 28, or gemcitabine, n = 19, as a radiosensitizer) at Aichi Cancer Center Hospital.

Results

Patients who received chemoradiotherapy had significantly better performance status than those who had chemotherapy. Tumor response was 0% for chemotherapy and 13% chemoradiotherapy, but survival benefit was similar among patients in the chemotherapy group (overall response (OS) 12 months; progression-free survival (PFS), 3 months) and those in the chemoradiotherapy group (OS, 13 months; PFS, 5 months). Two-year survival was 21% for chemotherapy patients and 19% for chemoradiotherapy patients. Severe toxicities (Grade 3–4 National Cancer Institute-Common Toxicity Criteria, version 3.0) were significantly more frequent for chemoradiotherapy than for chemotherapy.

Conclusions

Gemcitabine chemotherapy showed similar survival benefit compared to 5-fluorouracil- and gemcitabine-based chemoradiotherapy.     

Validation study of a prognostic classification in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy

Purpose

Five prognostic factors had been previously identified in patients with metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted to validate this classification in an external validation cohort.

Methods

This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions.

Results

Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH ≥400 IU/L, progression-free survival of first-line therapy <6 months) remained highly significant in the validation cohort, although two (performance status 2 and peritoneal metastasis) were associated with borderline significance. The distribution of the three prognostic groups (low risk = no factors, intermediate risk = 1 factor, high risk = 2 or more factors) was low risk (n = 68; 35 %), intermediate risk (n = 80; 41 %), and high risk (n = 45; 23 %). The median OS of each group were 19.8, 11.0, and 7.9 months, respectively, with significant differences between groups, as found in the previous cohort.

Conclusion

The previous prognostic classification of patients with MCRC who received irinotecan-based second-line chemotherapy was validated in another independent cohort. Validation in prospective studies is warranted.     

High circulating VEGF level predicts poor overall survival in lung cancer

Purpose

Vascular endothelial growth factor (VEGF) is considered as the best-validated key regulator of angiogenesis, while the prognostic role of circulating VEGF in lung cancer remains controversial. We conducted a meta-analysis to evaluate the prognostic role of circulating VEGF.

Methods

Nineteen studies with a total number of 2,890 patients were analyzed in our meta-analysis. Hazard ratios (HRs) and their 95 % confidence intervals (CIs) were used to quantify the predictive ability of circulating VEGF on survival.

Results

The pooled HR of all 17 studies evaluating overall survival (OS) was 1.29 (95 % CI 1.19–1.40, p < 0.001), indicating high circulating VEGF predicted poor OS. When grouped by disease stages, the pooled HRs were 0.97 (95 % CI 0.47–1.47, p < 0.001) for operable stage and 1.34 (95 % CI 1.18–1.49, p < 0.001) for inoperable stage. The pooled HRs were 1.28 (95 % CI 1.15–1.42, p < 0.001) for serum and 1.31 (95 % CI 1.13–1.49, p < 0.001) for plasma, when categorized by blood sample. Meta-analysis of circulating VEGF related to progression-free survival (PFS) was performed in 7 studies, and the pooled HR was 1.03 (95 % CI 0.96–1.09).

Conclusions

Our results indicate that high level of circulating VEGF predicts poor OS in lung cancer, yet it does not predict poor PFS.     

The importance of gender in patients with peritoneal metastases of appendiceal origin treated by cytoreduction and intraperitoneal chemotherapy: an analysis of 257 consecutive patients from an Australian centre

Background and objectives

In the setting of colorectal cancer, female gender has been associated with superior long-term outcomes. Our aim is to investigate the gender differences for metastatic epithelial neoplasms of the appendix treated by cytoreductive surgery (CS) and intraperitoneal chemotherapy (IPC).

Methods

The survival outcomes of patients treated with CS/IPC from 1996 to 2013 at St. George Hospital, Sydney, Australia, for peritoneal metastases of appendiceal origin were retrospectively analysed.

Results

Two hundred and fifty-seven consecutive patients were followed for a median of 35.3 months. Baseline characteristics between genders were comparable, including age (p = 0.13) and peritoneal cancer index (p = 0.94). Median overall survival (OS) and progression-free survival (PFS) was not reached (NR) and 44.4 months, with a 3-, 5- and 10-year survival of 82, 74 and 64 %. OS and PFS for females was NR and 50.7 months, compared to NR (p = 0.007) and 31.5 months for males (p = 0.07). Three-, 5- and 10-year survival rates for females were 88, 84 and 72 % compared to 74, 61 and 53 % for males.

Conclusion

Observed gender differences for neoplasms of the appendix may direct future research in gender-specific tumour markers and the development of adjuvant therapies to improve patient outcomes.     

The Austrian experience with trabectedin in non-selected patients with metastatic soft tissue sarcoma (STS)

Purpose

The purpose of this retrospective analysis was to assess efficacy and tolerability of trabectedin in soft tissue sarcoma (STS) in the routine clinical setting.

Patients and methods

Efficacy and safety data of trabectedin were retrospectively evaluated in patients with advanced STS who had started treatment with trabectedin at six institutions in Austria between January 2008 and May 2012.

Results

Data of 101 adult patients were included in the present analysis. Patients had a median age of 56 years; 59 and 41 % received trabectedin as ≤2nd and ≥3rd chemotherapy line for advanced disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.6 months. Median PFS and OS were different in patients who received trabectedin as ≤2nd- or ≥3rd-line treatment: median PFS was 3.9 versus 3.6 months and OS was 15.2 versus 24.8 months, respectively. The extent and severity of trabectedin-induced toxicity were low and manageable.

Conclusions

The activity and tolerability of trabectedin in the routine clinical setting is comparable to outcomes reported in phase II trials already published. Regardless of whether trabectedin was given earlier or later in the course of disease, outcomes did not differ in the cohort of analysed patients.     

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial

Purpose

AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients.

Patients and methods

Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation.

Results

Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed.

Conclusion

Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.     

Treatment Outcomes in Elderly with Advanced-Stage Non-small Cell Lung Cancer

Purpose

Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome.

Methods

Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls.

Results

Fifty-six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups

Conclusions

In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR–TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known.     

Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist,in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised,double-blind,placebo-controlled trial

Purpose

This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).

Methods

Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).

Results

The hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29–1.08; P = 0.07) and 0.55 (95 % CI 0.3–1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26–0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31–1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3–1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation.

Conclusions

MGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703.     

Repeating of local therapy of distant metastases increases overall survival in patients with synchronous metastasized rectal cancer—a monocentric analysis

Purpose

The aim was to evaluate the outcome of treatment-naive patients with synchronous metastatic rectal cancer after chemotherapy with FOLFOXIRI followed by local therapeutic procedures of all tumor lesions as complete as possible.

Methods

We reviewed data of 30 patients with synchronous distant metastatic rectal cancer who underwent chemotherapy with FOLFOXIRI and subsequent local therapy in our institution.

Results

Median follow-up was 28 months (range: 8; 74). Cumulative overall survival (OS) and progression-free survival (PFS) was 93.3, 76.9, 55.6% and 46.2, 29.7, 29.7% after 1, 2, 4 years. Non-response to chemotherapy with FOLFOXIRI was associated with a highly significant decreased OS (p?<?0.0001). The consistent use of local ablative procedures led to a statistically significant increase in OS (p?<?0.0001), but not in PFS (p?=?0.635). Patients with ≤?4 distant metastases showed a better OS (p?=?0.033).

Conclusions

Response to intensified first-line chemotherapy with FOLFOXIRI, treatment of the primary rectal tumor, and repeated thorough local ablative procedures in patients with synchronous metastasized rectal cancer may lead to long-term survival, even in a subset of patients with unresectable disease at initial diagnosis.

     

Neoadjuvant chemotherapy using concurrent Docetaxel/CDDP/5-FU (DCF) in esophageal squamous cell carcinoma and its short-term prognosis

Background

Our aim in this study is to know whether clinical outcomes are improved by neoadjuvant chemotherapy (NAC) using Docetaxel/CDDP/5-FU (DCF) as compared to NAC using 5-FU/CDDP (FP).

Methods

Thirty-eight patients who underwent DCF NAC in cStage II/III esophageal squamous cell carcinoma (ESCC) were compared with the 41 counterparts treated by FP NAC. Docetaxel and CDDP were both given to 70–75 mg/m² with concurrent 5-FU at 750 mg/m² in 3 cycles. Median follow-up term of DCF NAC reached 27 months.

Results

In DCF NAC, grade 3 adverse effects were recognized in 97 %, and completion rate of the DCF NAC was 86 %. In terms of PR + CR rate, DCF NAC was better (87 %) than FP NAC (59 %) (p = 0.005). Five year progression-free survival (PFS) and overall survival (OS) of FP NAC were 32 and 69 %, respectively, and OS of FP NAC was excellent putatively due to adoption of definitive chemoradiation therapy for recurrent diseases. Furthermore, survival was in favor of DCF NAC as compared to FP NAC for OS (p = 0.02) and PFS (p = 0.10), while R0 resection rate was similar. The 1st multivariate prognostic analysis among all cases with NAC revealed that significant factors were resectability and NAC modality for OS and PFS. We then performed the 2nd stage multivariate prognostic analysis limited to R0 cases including pathologic factors, which again identified DCF NAC modality as an independent prognostic factor.

Conclusion

DCF NAC for ESCC demonstrated high response rates, and may improve patient survival with acceptable feasibility.     

The gefitinib dose reduction on survival outcomes in epidermal growth factor receptor mutant non-small cell lung cancer

Purpose

Gefitinib is safe for the treatment of non-small cell lung cancer (NSCLC), but some patients experience toxicities and require dose reduction. The purpose of this study was to evaluate the effect of gefitinib dose reduction on survival.

Methods

We retrospectively analyzed 263 patients with NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutation. All patients had recurred or metastatic disease and received gefitinib 250 mg daily as palliative chemotherapy.

Results

Of the 263 patients, 23 had gefitinib dose reduction due to toxicities (1 due to mucositis, 5 due to skin rash, 11 due to hepatotoxicity and 6 for both skin and hepatotoxicity). In the dose reduction group, the mean dose intensity was 0.84 (range 0.48–0.98). Patients with dose reduction showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those receiving the standard dose (median PFS: 14.0 vs. 10.6 months, P = 0.042, median OS: 54.5 vs. 29.6, P = 0.020). In multivariate analysis, the effect of dose reduction was not significantly associated with prolonged PFS [hazard ratio (HR) 0.619, 95 % confidence interval (CI) 0.357–1.073, P = 0.085], or OS (HR 0.625, 95 % CI 0.287–1.362, P = 0.237). However, patients receiving low-dose gefitinib tended to have superior survival outcomes compared to those receiving standard-dose gefitinib.

Conclusions

The patients experiencing gefitinib dose reduction or short-term treatment interruption due to toxicities did not show inferior survival, compared to those receiving full dose of gefitinib in NSCLC patients with EGFR mutation.     

Bevacizumab plus irinotecan in recurrent or progressive malign glioma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO)

Purposes

The overall prognosis for recurrent malignant glioma (MG) is extremely poor, and treatment options are limited. We evaluated our multicenter retrospective experience for patients with recurrent MG administering bevacizumab and irinotecan in combination therapy.

Methods

A total of 115 patients with grade IV glial tumor (n = 93) and grade III glial tumor (n = 22) were retrospectively evaluated at 14 centers in Turkey. Primary objectives of the study were to evaluate the efficacy and toxicity of the bevacizumab and irinotecan as salvage treatment based on response to therapy, progression-free survival (PFS), 6 months of PFS, overall survival (OS), and 6 months of OS (OS6).

Results

Bevacizumab and irinotecan were performed as second line (79.1 %) and third line treatment (20.9 %). Median chemotherapy cycle was 6 (range 1–37), and median follow-up was 6 months (range 1–36 months). Objective response rate was 39.1 %. Six-month PFS and OS6 were 46.3 % and 67.5 %, respectively. Median PFS was 6 months (95 % CI 2.5–9.5) and 6 months (95 % CI 4.9–7.1) in the grade III and IV groups, respectively (p = 0.773). Median OS was 9 months (95 % CI 7.1–10.9) and 8 months (95 % CI 6.6–9.4) in the grade III and IV groups, respectively (p = 0.450). Serious toxicities were observed in 7.8 % of patients. Treatment-related toxic death was observed in 3 patients. There was no treatment related to central nervous system hemorrhage or other serious hemorrhages.

Conclusions

Present study results were consistent with previous studies. In addition, we detected similar outcomes in grade III and IV glial tumors.     

PIK3CA mutation is associated with poor survival among patients with metastatic colorectal cancer following anti-EGFR monoclonal antibody therapy: a meta-analysis

Purpose

PIK3CA mutation appears to predict a lack of response to anti-EGFR monoclonal antibody (mAb) treatment in patients with metastatic colorectal cancer (mCRC). However, the predictive value of PIK3CA mutations for survival remains inconclusive. Here, we pooled the data from published studies to estimate the association between PIK3CA mutation and survival outcomes in mCRC patients treated with anti-EGFR mAbs.

Methods

Studies investigating the association of PIK3CA mutations with clinical survival outcomes of mCRC patients treated with anti-EGFR mAbs were systematically identified. The overall hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between trails.

Results

Eight studies that reported survival outcome in 839 mCRC patients were included. In unselected patients, we found that PIK3CA mutations were significantly associated with poorer PFS [8 studies, 839 patients; HR = 1.53; 95 % confidence interval (CI) 1.28–1.84; P < 0.001] and OS (5 studies; 587 patients; HR = 1.28; 95 % CI 1.05–1.56; P = 0.015). With increased predictive power in KRAS wild-type patients (3 studies; 275 patients), the overall HR for PFS was 2.44 (95 % CI 1.33–4.48; P = 0.004) and was statistically significant. We also observed a worse OS in KRAS wild-type patients with PIK3CA mutations (2 studies; 163 patients; HR = 1.37; 95 % CI 0.80–2.35; P = 0.258), although the result was not statistically significant due to small sample size.

Conclusions

PIK3CA mutation is a promising predictive biomarker for poor survival in mCRC patients treated with anti-EGFR mAbs, particularly in KRAS wild-type patients.     

Histology as a Potential Clinical Predictor of Outcome in Advanced Non-Small-Cell Lung Cancer Treated with Vinorelbine and Mitomycin Combination Chemotherapy

Background

The importance of clinical predictors in the treatment of non-small-cell lung cancer (NSCLC) has increased during the last decade. This retrospective study analyzed the combined patient-level data from two phase II trials that investigated the efficacy and safety of combination chemotherapy with vinorelbine and mitomycin in patients with locally advanced or metastatic NSCLC. The aim of this analysis was to determine if patients' baseline and disease characteristics, including histology, gender, smoking history, and expression of TTF-1, might be potential predictors of outcome.

Methods

Response rates, unadjusted survival times, and Cox covariate-adjusted hazard ratios (HRs) were calculated. Results were reported separately for each subgroup in each individual trial and in the pooled data set.

Results

A total of 175 patients were included in this analysis. Adjusted HRs for both overall survival (OS) and progression free survival (PFS) favored the nonadenocarcinoma histology subgroup, achieving a statistical significance for OS in the pooled data (n = 175; HR 0.68; 95 % CI 0.49–0.94; p = 0.019). TTF-1-negative immunohistochemistry was associated with a significantly higher response rate (25 vs. 0 %; p = 0.04) and with a nonsignificant advantage in OS (n = 33; HR 1.23; 95 % CI 0.56–2.73; p = 0.608). Gender and smoking history were not strongly related to outcome.

Conclusions

The results of this analysis indicate that patients with nonadenocarcinoma histology might get superior benefit from combination chemotherapy with vinorelbine and mitomycin. These results should be confirmed in a prospective study.     

Predictive value of excision repair cross-complementation group 1 expression for platinum-based chemotherapy and survival in gastric cancer: a meta-analysis

Purpose

The predictive value of excision repair cross-complementation group 1 (ERCC1) gene for survival and response to platinum-based chemotherapy in gastric cancer (GC) remains controversial. We performed a meta-analysis to clarify the precise estimation of the prognostic and predictive effect of ERCC1.

Methods

A systematic literature search was conducted using PubMed, ScienceDirect, Wiley and American Society of Clinical Oncology (ASCO) before March 2014. Studies analyzing survival data and/or chemotherapy response in GC by ERCC1 status were identified. The principal outcome measures were hazard ratios (HRs) for survival and relative risks (RRs) for chemotherapy response. Pooled HRs and RRs were calculated using fixed- or random-effects models according to the heterogeneity.

Results

Twenty-one studies involving 1,628 patients met our inclusion criteria. High ERCC1 expression was significantly associated with shorter overall survival (OS) and lower response to chemotherapy in advanced GC patients receiving palliative chemotherapy (HR 1.83; 95 % CI 1.45–2.31; P < 0.001; RR 0.49; 95 % CI 0.38–0.62; P < 0.001). There was no significant difference in survival between high and low ERCC1 expression in adjuvant setting (OS: HR 1.38; 95 % CI 0.77–2.45; P = 0.276; EFS 0.72; 95 % CI 0.38–1.33; P = 0.291). Some evidence of heterogeneity and possible publication bias were discovered in few meta-analyses.

Conclusions

High ERCC1 expression might be an adverse prognostic and a drug-resistance predictive factor for advanced GC patients. However, further studies with consistent ERCC1 assessment methodology are needed.     

Solid predominant histology predicts EGFR tyrosine kinase inhibitor response in patients with EGFR mutation-positive lung adenocarcinoma

Background

The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) differs in patients with lung adenocarcinoma harboring EGFR-activating mutations. Although lung adenocarcinoma with EGFR-activating mutations has heterogeneous morphologic features, the predictive role of histologic subtype of lung adenocarcinoma with regard to the effectiveness of EGFR-TKIs in patients with EGFR-activating mutations has not been well defined.

Methods

Among 134 postoperative recurrence patients with lung adenocarcinoma harboring EGFR-activating mutation (L858R or exon 19 deletion) treated with EGFR-TKIs, we retrospectively analyzed 61 patients treated with EGFR-TKIs as first-line chemotherapy. All the tumors were classified according to the new histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) into the following subtypes: lepidic, papillary, acinar, micropapillary, or solid predominant subtype. We evaluated the correlation between the histologic subtype and the clinical efficacy of EGFR-TKIs.

Results

In overall response rate, adenocarcinoma with solid predominant subtype is significantly worse than with non-solid predominant subtype (61 vs. 88 %, P = 0.03). The median progression-free survival (PFS) and overall survival after EGFR-TKI treatment were significantly shorter for the patients with solid predominant subtype than for those with non-solid predominant subtype (median PFS of 7.7 vs. 13.5 months, P = 0.002, and median OS of 21.5 vs. 31.0 months, P = 0.028).

Conclusions

This study indicated that among patients with lung adenocarcinoma harboring activating EGFR mutations treated with EGFR-TKIs, solid predominant subtype according to IASLC/ATS/ERS classification is a response predictor for EGFR-TKI.     

Prognostic significance of several biomarkers in epithelial ovarian cancer: a meta-analysis of published studies

Objective

Abnormal expression of several biomarkers might predict disease prognosis and response to chemotherapy in patients with epithelial ovarian cancer (EOC). However, the published data are inconsistent.

Methods

Eligible studies that investigated the association between survival or response to platinum-based chemotherapy in EOC and the expression status of Bcl-2, EGFR, GST, LRP, p16, p21, P-gp and TNF-α were identified by an electronic search of PubMed and Embase. The measures of interest were hazard ratio (HR) for survival or risk ratio for chemotherapy response. A meta-analysis was performed using the fixed-effect or random-effect models.

Results

The number of eligible studies analyzed was 27 for Bcl-2, 22 for EGFR, 29 for GST, 12 for LRP, 16 for p16, 22 for p21, 27 for P-gp and three for TNF-α. A meta-analysis showed that high EGFR and P-gp expression was associated with poor overall survival (OS) (pooled adjusted HR = 1.826 and HR = 1.822). Only high GST expression was associated with improved OS (HR = 0.780). Furthermore, high p16 and P-gp expression was associated with poor progression-free survival (PFS) (HR = 1.550 and HR = 2.136). High GST expression was associated with improved PFS (HR = 0.689). Among these factors, only LRP, P-gp and TNF-α were associated with response to platinum-based chemotherapy.

Conclusions

The markers we analyzed are unlikely to be useful as predictors of prognosis and response to platinum-based chemotherapy in EOC patients in clinical practice.