Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials

Background

EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC.

Methods

Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results

Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR = 1.37, 95% CI = 1.20–1.56, P < 0.00001). However, this significant difference did not translate into OS (HR = 1.02, 95% CI = 0.87–1.20, P = 0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR = 1.77, 95% CI = 0.90–3.50, P = 0.10).

Conclusions

Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild-type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully.     

Radical treatment of synchronous oligometastatic non-small cell lung carcinoma (NSCLC): Patient outcomes and prognostic factors

Objectives

Metastatic non-small cell lung carcinoma (NSCLC) generally carries a poor prognosis, and systemic therapy is the mainstay of treatment. However, extended survival has been reported in patients presenting with a limited number of metastases, termed oligometastatic disease. We retrospectively reviewed the outcomes of such patients treated at two centers.

Materials and methods

From September 1999–July 2012, a total of 61 patients with 1–3 synchronous metastases, who were treated with radical intent to all sites of disease, were identified from records of two cancer centers. Treatment was considered radical if it involved surgical resection and/or delivery of radiation doses ≥13 × 3 Gy.

Results

Besides the primary tumor, 50 patients had a solitary metastasis, 9 had two metastases, and 2 had three metastases. Locations of metastases included the brain (n = 36), bone (n = 11), adrenal (n = 4), contralateral lung (n = 4), extra-thoracic lymph nodes (n = 4), skin (n = 2) and colon (n = 1). Only one patient had metastases in two different organs. Median follow-up was 26.1 months (m), median overall survival (OS) was 13.5 m, median progression free survival (PFS) was 6.6 m and median survival after first progression (SAFP) was 8.3 m. The 1- and 2-year OS were, 54% and 38%, respectively. Significant predictors of improved OS were: smaller radiotherapy planning target volume (PTV) (p = 0.004) and surgery for the primary lung tumor (p < 0.001). Factors associated with improved SAFP included surgery for the primary lung tumor, presence of brain metastases, and absence of bone metastases. No significant differences in outcomes were observed between the two centers.

Conclusion

Radical treatment of selected NSCLC patients presenting with 1–3 synchronous metastases can result in favorable 2-year survivals. Favorable outcomes were associated with intra-thoracic disease status: patients with small radiotherapy treatment volumes or resected disease had the best OS. Future prospective clinical trials, ideally randomized, should evaluate radical treatment strategies in such patients.     

A randomized,double-blind,placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naïve metastatic/unresectable non-small cell lung cancer

Introduction

Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC).

Methods

Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0–1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety.

Results

97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n = 25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo.

Conclusions

Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients. Clinical trials identifier: NCT00991796.     

EGFR mutations and clinical outcomes of chemotherapy for advanced non-small cell lung cancer: A meta-analysis

Background

This meta-analysis was performed to assess whether epidermal growth factor receptor (EGFR) mutation status was associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy.

Method

We systematically identified eligible articles investigating the effects of chemotherapy in patients with NSCLC stratified by EGFR mutation status. The summary risk ratio (RR) for ORR and hazard ratios (HRs) for both PFS and OS were calculated using the inverse variance formula of meta-analysis.

Results

Identification for the current meta-analysis: 5 prospective studies (n = 875) and 18 retrospective studies (n = 1934) for ORR; 2 prospective studies (n = 434) and 10 retrospective studies (n = 947) for PFS; 2 prospective studies (n = 438) and 7 retrospective studies (n = 711) for OS. The ORR was significantly higher in patients with EGFR mutations in prospective studies (RR = 1.42; 95% confidence interval [CI], 1.16–1.74; P = 0.001), but not in retrospective studies (RR = 1.12; 95% CI, 0.96–1.32; P = 0.146). There was no obvious association between EGFR mutations and PFS both in prospective (HR = 0.84; 95% CI: 0.65–1.09; P = 0.197) and retrospective (HR = 1.02; 95% CI: 0.87–1.18; P = 0.838) studies. Association between EGFR mutations and OS was also not seen in prospective studies (HR = 0.74; 95% CI: 0.27–2.05; P = 0.566), but was seen in retrospective studies (HR = 0.48; 95% CI: 0.33–0.72; P < 0.001; I² = 75.9%; P < 0.001) with significant heterogeneity.

Conclusion

EGFR mutations in advanced NSCLC may be associated with higher ORRs to chemotherapy, but may have nothing to do with PFS and OS. Further prospective studies are required to identify the influence of EGFR mutations on chemotherapy effects in advanced NSCLC.     

A prospective,phase II,open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC)

Introduction

The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). This phase II, single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC.

Methods

Eligible patients received erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival (PFS) and safety.

Results

A high degree of concordance was observed between different mutation testing methodologies, suggesting feasibility of early, rapid detection of EGFR mutations. Median PFS was 11.8 months (95% confidence interval [CI]: 9.7–15.3) at data cut-off (1 June 2012) (n = 102). Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations; T790M mutations were tentatively linked with shorter PFS. The safety profile was as expected: rash (any grade; 83%) and diarrhea (any grade; 81%) were most common. Six interstitial lung disease (ILD)-like cases were reported, and 5 were confirmed as ILD-like events by the extramural committee. Two patients died of treatment-related pneumonitis (JAPIC Clinical Trials Information number: Japic CTI-101085).

Conclusion

Erlotinib should be considered for first-line treatment in this subset of Japanese patients, with close monitoring for ILD-like events.     

Evaluation of EGFR protein expression by immunohistochemistry using H-score and the magnification rule: Re-analysis of the SATURN study

Introduction

The phase III SATURN study demonstrated that first-line maintenance erlotinib extended progression-free survival (PFS) and overall survival (OS) versus placebo in patients with advanced non-small cell lung cancer (NSCLC). Analysis of epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) found no significant interaction between EGFR IHC status and PFS (p = 0.63) or OS (p = 0.52). The FLEX study of first-line cetuximab plus chemotherapy demonstrated that EGFR IHC expression was predictive of improved OS with cetuximab when assessed by H-score with a magnification rule. This novel method was used to reassess samples from SATURN.

Methods

The H-score method assigned a score of 0–300 to each patient, based on the percentage of cells stained at different intensities viewed at various magnifications. The discriminatory threshold was set at 200, per the FLEX study, and existing samples were re-read and classed as low (H-score < 200) or high (≥200) EGFR expression. PFS and OS were re-analyzed based on these new classifications.

Results

In the overall and EGFR wild-type populations, erlotinib provided a consistent survival benefit versus placebo. Hazard ratios (HRs) in the overall population were similar between EGFR IHC-positive and -negative patients for median PFS (HR 0.68 [95% confidence interval (CI) 0.53–0.86] and 0.76 [95% CI 0.62–0.93], respectively) and OS (HR 0.80 [95% CI 0.62–1.05] and 0.80 [95% CI 0.64–1.01] for IHC-positive and IHC-negative, respectively). In the EGFR wild-type population, HRs were again similar between EGFR IHC-positive and -negative subpopulations for PFS (HR 0.69 [95% CI 0.51–0.95] and 0.84 [95% CI 0.63–1.12], respectively) and OS (HR 0.78 [95% CI 0.55–1.10] and 0.76 [95% CI 0.55–1.05], respectively).

Conclusions

These data suggest that EGFR IHC does not have value as a marker to predict erlotinib benefit in the first-line maintenance setting for advanced NSCLC.     

Serum reactive oxygen species modulator 1 (Romo1) as a potential diagnostic biomarker for non-small cell lung cancer

Objectives

Reactive oxygen species modulator 1 (Romo1) is a novel protein that localizes in the mitochondrial membrane and induces mitochondrial reactive oxygen species (ROS) generation. Romo1 is increased in most cancer cell lines and is related with resistance to chemotherapy in vitro. However, data on its expression in patients with malignancy is very limited. We evaluated the usefulness of serum Romo1 as a potential diagnostic biomarker in non-small cell lung cancer (NSCLC).

Materials and methods

We initially assessed the expression of Romo1 using Western blotting and enzyme-linked immunosorbent assay in paired lung tissue and serum specimen from NSCLC patients who underwent surgical resection. Then we evaluated and compared serum Romo1 level in a healthy population (n = 55), patients with benign lung diseases (n = 63) and NSCLC patients (n = 58). We explored the correlation between Romo1 expression and clinical parameters and assessed diagnostic performance of serum Romo1 for NSCLC using receiver operating characteristic (ROC) curve analysis.

Results

Romo1 expression in lung cancer tissues was significantly increased compared with non-tumorous tissues (p < 0.001). Romo1 expression in cancer tissues positively correlated with that in serum (r = 0.68, p = 0.009). Serum Romo1 level in NSCLC patients significantly increased compared with that of healthy population or patients with benign lung diseases (both p < 0.001). ROC curve analysis using an optimal cutoff value of 329.7 pg/mL revealed sensitivity and specificity for the diagnosis of NSCLC of 81.9% and 89.8%, respectively, with an area under the curve of 0.847 (95% confidence interval: 0.789–0.892, p < 0.001). Serum Romo1 level was not related with age, gender, smoking status, tumor differentiation, histological type or stage.

Conclusions

Serum Romo1 discriminated NSCLC patients from the population without cancer with considerable sensitivity and specificity. Serum Romo1 could be a potential diagnostic biomarker for NSCLC.     

Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer (NSCLC)?

Background

Clinical implications of KRAS mutational status in advanced non-small cell lung cancer (NSCLC) remain unclear. To clarify this point, we retrospectively explored whether KRAS mutations could impact tumor response, and disease control rate (DCR) to first-line platinum-based chemotherapy (CT) as well as progression-free survival (PFS) or overall survival (OS).

Methods

Between June 2009 and June 2012, 340 patients with advanced (stage IIIB/IV) NSCLC were reviewed in a single institution (Institut Gustave Roussy). Two hundred and one patients had a biomolecular profile and received a platinum-based first-line CT. Patients with an unknown mutational status or with actionable alterations were excluded. We retained two groups: patients with KRAS mutated tumor (MUT) and patients with wild-type KRAS/EGFR (WT). Multivariate analyses with Cox model were used. Survival curves were calculated with Kaplan–Meier method.

Results

One hundred and eight patients were included in the analysis: 39 in the MUT group and 69 in the WT group. Baseline radiological assessment demonstrated more brain (P = 0.01) and liver (P = 0.04) metastases in MUT patients. DCR was 76% for MUT vs. 91% for WT group (P = 0.03), regardless of the type of platinum-based CT (use of pemetrexed or not). Although no statistically significant differences were found, shorter PFS (4.9 vs. 6.0 months; P = 0.79) and OS (10.3 vs. 13.2 months; P = 0.40) were observed for patients with KRAS mutated tumors in univariate analysis.

Conclusions

KRAS mutant tumors had a lower DCR after the first-line platinum-based CT, but this difference did not translate in PFS or OS. The presence of KRAS mutations may confer a more aggressive disease, with greater baseline incidence of hepatic and cerebral metastases.     

EGFR expression and survival in patients given cetuximab and chemoradiation for stage III non-small cell lung cancer: A secondary analysis of RTOG 0324

Purpose

We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab + chemoradiation for stage III non-small cell lung cancer.

Methods

Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP).

Results

Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n = 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP.

Conclusions

Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials.     

A single-arm confirmatory study of amrubicin therapy in patients with refractory small-cell lung cancer: Japan Clinical Oncology Group Study (JCOG0901)

Objectives

We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC).

Patients and methods

Patients with chemotherapy-refractory SCLC received 40 mg/m² AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results

Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1–22 cycles). ORR was 32.9% [P < 0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9–44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0–4.3 months) and 8.9 months (95% CI, 7.6–11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P = 0.034), PFS (median, 2.9 v 5.1 months; P = 0.0009), and OS (median, 7.9 v 13.1 months; P = 0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred.

Conclusions

AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy.     

Immunohistochemistry evaluation of biomarker expression in non-small cell lung cancer (Pharmacogenoscan study)

Objectives

Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments.

Materials and methods

The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III β-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS).

Results

A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P = 0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR.

Conclusion

In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.     

Platinum rechallenge in patients with advanced NSCLC: A pooled analysis

Introduction

The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established.

Methods

Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I² index.

Results

Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7–46.7%) for TAXs-based treatment vs. 22% (range, 13.4–34.1%) for PEM-based combinations; (p < 0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p < 0.0001) and similar OS for PEM vs. TAXs-based doublets.

Conclusions

With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets.     

Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): A randomized controlled trial

Background

The pediatric diffuse intrinsic pontine glioma (DIPG) outcome remains dismal despite multiple therapeutic attempts.

Purpose

To compare the results of treatment of pediatric diffuse intrinsic pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy.

Patients and methods

Seventy-one newly diagnosed DIPG children were randomized into hypofractionated (HF) (39 Gy/13 fractions in 2.6 weeks) and conventional (CF) arm (54 Gy/30 fractions in 6 weeks).

Results

The median and one-year overall survival (OS) was 7.8 months and 36.4 ± 8.2% for the hypofractionated arm, and 9.5 and 26.2 ± 7.4% for the conventional arm respectively. The 18-month OS difference was 2.2%. The OS hazard ratio (HR) was 1.14 (95% CI: 0.70–1.89) (p = 0.59).The hypofractionated arm had a median and one-year progression-free survival (PFS) of 6.6 months and 22.5 ± 7.1%, compared to 7.3 and 17.9 ± 7.1% for the conventional arm. The PFS HR was 1.10 (95% CI: 0.67–1.90) (p = 0.71). The 18-month PFS difference was 1.1%. These differences exceed the non-inferiority margin.The immediate and delayed side effects were not different in the 2 arms.

Conclusions

Hypofractionated radiotherapy offers lesser burden on the patients, their families and the treating departments, with nearly comparable results to conventional fractionation, though not fulfilling the non-inferiority assumption.     

Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: A meta-analysis

Background

We hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC).

Methods

To investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. Non-individual patient data were used to model the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection.

Results

Of the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 (p = 0.01) and 0.76 (p = 0.02) for PORT vs. controls, respectively).Four trials (357 patients) were suitable to assess LR rates in stage III NSCLC treated with surgery, in most cases after induction chemotherapy. LR as first relapse was 30% (105/357) after 5 years. In the modeling part, PORT with linear accelerators was estimated to reduce LR rates to 10% as first relapse and to increase the absolute 5-year OS by 13%.

Conclusions

This modeling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.     

Retrospective evaluation of thromboembolic events in patients with non-small cell lung cancer treated with platinum-based chemotherapy

Objectives

Thromboembolic events (TE) are common in patients with cancer and are potentially life-threatening. In lung cancer, little is known about thrombosis during chemotherapy treatment. The aim of this study was to describe the incidence of TE in patients with non-small cell lung cancer (NSCLC), occurring during treatment with platinum-based chemotherapy.

Methods

We retrospectively selected patients with NSCLC treated with platinum-based chemotherapy at the VU University Medical Center Amsterdam between 2000 and 2012. Patients who underwent recent surgery were excluded. All TE were included that occurred from start of chemotherapy treatment until 30 days after last administration.

Results

Among 784 included patients, 63 (8.0%) patients had 69 TE during treatment. Forty-five venous TE (VTE) and 24 arterial TE (ATE). Six patients had multiple events within treatment period, 3 of which had simultaneous ATE and VTE. In total, 613 patients were treated with cisplatin, 119 patients received carboplatin and 52 patients received both in first- or second-line treatment. In 8% (55/665) of the patients exposed to cisplatin a TE had occurred vs. 5% (8/171) in patients exposed to carboplatin (p = 0.42). The majority of TE occurred in the first 2 cycles (70%). History of TE was related to occurrence of TE during chemotherapy (p < 0.01). Median PFS was similar in patients with and without TE (6.2 vs. 7.2 months, respectively; p = 0.10). Median OS was significantly shorter in patients with TE (9.5 vs. 12.9 months, respectively; p = 0.03).

Conclusion

In our series, both ATE and VTE were a common finding during chemotherapy. TE was a poor prognostic factor. No difference in TE incidence was found between patients treated with cisplatin or carboplatin.     

Positive prognostic impact of miR-210 in non-small cell lung cancer

Objectives

miR-210 is an important regulator of the cellular response to hypoxia. Therefore, we aimed to explore the prognostic significance of miR-210 in non-small cell lung cancer (NSCLC) patients with stage I-IIIA disease.

Materials and methods

In addition to clinicopathological and demograpic information, tumor tissues were collected and tissue micro arrays (TMAs) were constructed from 335 patients with stage I-IIIA NSCLC. Expression of miR-210 in cancer cells and stromal cells of the tumor was assessed by in situ hybridization.

Results

In univariate analyses, high cancer cell (p = 0.039) and high stromal cell expression (p = 0.008) of miR-210 were both significantly associated with an improved disease-spesific survival (DSS). High co-expression of miR-210 in cancer and stromal cells was also a positive prognostic factor for DSS (p = 0.010). In multivariate analysis, miR-210 in stromal cells (p = 0.011), and miR-210 co-expressed in cancer and stromal cells was an independent prognosticator for DSS (p = 0.011).

Conclusions

We show that miR-210 in stromal cells, and co-expressed in cancer cells and stromal cells mediates an independent prognostic impact. It is a candidate marker for prognostic stratification in NSCLC.     

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor

Objectives

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Materials and methods

This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed.

Results

In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P = 0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P < 0.001), while the RR (76.5% vs. 68.9%, P = 0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR) = 3.06; 95% CI = 2.12–4.42, P < 0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P < 0.001). The adjusted HR for death in the study group was 1.91 (95% CI = 1.33–2.76; P < 0.001).

Conclusion

In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials.     

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Objectives

Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression.

Methods

Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population.

Results

Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT.

Conclusions

The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.     

Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer

Objective

More tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC.

Materials and methods

From December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75–84 years, ≥85 years). Kaplan–Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD).

Results

A total of 9907 patients were eligible for safety assessment (<75 years, n = 7848; 75–84 years, n = 1911; ≥85 years, n = 148) and 9651 for efficacy assessment (<75 years, n = 7701; 75–84 years, n = 1815; ≥85 years, n = 135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75–84 years), and 3.4% (≥85 years). The mortality rate due to ILD was ≤1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62–68) for patients aged <75 years, 74 days (95% CI, 69–82) for patients aged 75–84 years, and 72 days (95% CI, 56–93) for patients aged ≥85 years.

Conclusions

Efficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC.