Long-term survival of stage T4N0-1 and single station IIIA-N2 NSCLC patients treated with definitive chemo-radiotherapy using individualised isotoxic accelerated radiotherapy (INDAR)

Background

Non-small cell lung cancer (NSCLC) stage T4N0-1 or single nodal station IIIA-N2 are two stage III sub-groups for which the outcome of non-surgical therapy is not well known. We investigated the results of individualised isotoxic accelerated radiotherapy (INDAR) and chemotherapy in this setting.

Methods

Analysis of NSCLC patients included in 2 prospective trials (NCT00573040 and NCT00572325) stage T4N0-1 or IIIA-N2 with 1 pathologic nodal station, treated with chemo-radiotherapy (CRT) using INDAR with concurrent or sequential platinum-based chemotherapy. Overall survival (OS) was updated and calculated from date of diagnosis (Kaplan–Meier). Toxicity was scored following CTCAEv3.0. To allow comparison with other articles the subgroups were also analysed separately for toxicity, progression free and overall survival.

Results

83 patients (42 T4N0-1 and 41 IIIA-N2) were identified: the median radiotherapy dose was 65 Gy. Thirty-seven percent of patients received sequential CRT and 63% received concurrent CRT. At a median follow-up of 48 months the median OS for T4N0-1 patients was 34 months with 55% 2-year survival and 25% 5-year survival. For stage IIIA-N2 at a median follow-up of 50 months the median OS was 26 months with 2- and 5-year survival rates of 53% and 24%, respectively.

Conclusion

Chemo-radiation using INDAR yields promising survival results in patients with single-station stage IIIA-N2 or T4N0-1 NSCLC.     

Evidence supporting contemporary post-operative radiation therapy (PORT) using linear accelerators in N2 lung cancer

Purpose

Post-operative radiotherapy (PORT) treatment for lung cancer declined since a meta-analysis failed to show benefit in patients with N2 disease. Because several included studies employed outmoded radiation planning and delivery techniques, we sought to determine whether PORT with modern technology benefits patients with N2 disease.

Methods

We conducted searches of the published literature. For inclusion, studies must have included patients with stage III-N2 lung cancer treated with PORT using only linear accelerators, used a control group that did not receive PORT, and reported outcome data for overall survival (OS). Prospective and retrospective analyses were included. Exclusion criteria were the use of cobalt devices or orthovoltage radiation.

Results

Data were evaluated with random-effects models. Three prospective and eight retrospective studies were included. The PORT and no-PORT groups included 1368 and 1360 patients, respectively. The PORT group had significantly improved OS over the no-PORT group (hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.62–0.96, P = 0.020). Locoregional recurrence-free survival (LRFS) in 10 studies for which data was available was also improved in the PORT group (HR = 0.51, CI 0.41–0.65, P < 0.001).

Conclusions

PORT was associated with significantly lower risk of death and locoregional recurrence in patients with N2 lung cancer. Our study was limited by lack of access to individual patient data, which would have enabled more detailed analyses. Regardless, data thus far suggest PORT may be associated with a survival benefit. Given a lack of large-scale prospective data, clinical trials evaluating PORT with modern technology are warranted.     

Post-operative radiotherapy in N2 non-small cell lung cancer: A retrospective analysis of 175 patients

Background and purpose

Post-operative radiotherapy (PORT) in radically resected non-small cell lung cancer (NSCLC) has the aim to reduce loco regional recurrence and to improve overall survival. PORT has been evaluated in several trials but indication to post-operative treatment in N2 patients is still debated.

Material and methods

We retrospectively analyzed 175 patients treated at University of Florence between 1988 and 2004 with completely resected NSCLC stages IIIA-IIIB, N2 disease. Surgery consisted in a lobectomy in 58.9% and in a bi-lobectomy or in a pneumonectomy in 41.1% of patients. One hundred and nineteen patients underwent PORT and 56 patients did not receive PORT (no-PORT).

Results

At a median follow-up of 27.6 months (range 4-233 months), we found a significant reduction in local recurrence (LR) in PORT group (log-rank test p = 0.015; HR: 0.45; 95%CI: 0.24-0.87). No statistical difference were found in terms of overall survival (OS) (log-rank test p = 0.92). Concerning other prognostic factors, male sex emerged as statistically significant (HR:4.33;1.04-18.02) on local progression free survival (LPFS) at univariate analysis. Acute and long-term toxicity was mild.

Conclusion

Our retrospective analysis showed that PORT may improve local disease control in N2 NSCLC patients with an acceptable treatment-related toxicity.     

A genetic sequence variant (GSV) at susceptibility loci of 5p15.33 (TERT-CLPTM1L) is associated with survival outcome in locally advanced and metastatic non-small-cell lung cancer (NSCLC)

Introduction

Lung cancer is a leading cause of cancer-related mortality in North America. In addition to tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether genetic sequence variants (GSVs) associated with lung cancer risk are associated with overall survival (OS) and progression-free survival (PFS) in stage-III-IV non-small-cell lung cancer (NSCLC) patients.

Methods

A total of 20 candidate GSVs in 12 genes previously reported to be associated with lung cancer risk were genotyped in 564 patients with stage-III or IV NSCLC. Multivariate Cox proportional hazard models adjusted for potential clinical prognostic factors were generated for OS and PFS.

Results

After taking into account multiple comparisons, one GSV remained significant: rs4975616 on chromosome 5p15.33, located near the TERT-CLPTM1L gene. The adjusted hazard ratio (aHR) for OS was 0.75 (0.69–0.91), p = 0.002; for PFS aHR was 0.74 (0.62–0.89), p < 0.001 for each protective variant allele. Results were similar in both Stage III (OS: aHR = 0.70; PFS: aHR = 0.71) and Stage IV patients (OS: aHR = 0.81; PFS: aHR = 0.77).

Conclusion

A GSV on 5p15.33 is not only a risk factor for lung cancer but may also be associated with survival in patients with late stage NSCLC. If validated, GSVs may define subsets of patients with different risk and prognosis of NSCLC.     

Target volume for postoperative radiotherapy in non-small cell lung cancer: Results from a prospective trial

Background and purpose

A previous prospective trial reported that three-dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT.

Materials and methods

The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV.

Results

Overall survival at 5 years was 27.1% with a median follow-up of 67 months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2–20.5%) including a failure rate of 2% (95% CI: 0–17%) in locations outside or at the border of the CTV.

Conclusions

The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients.     

Mid-ventilation based PTV margins in Stereotactic Body Radiotherapy (SBRT): A clinical evaluation

Purpose

Large tumor motion leads to large treatment volumes with an Internal Target Volume (ITV) based approach, whereas mid-ventilation (MidV) based Planning Target Volumes (PTV) margins typically lead to smaller treatment volumes. The purpose of this study was to evaluate the MidV approach on clinical outcome data of Stereotactic Body Radiotherapy (SBRT) in NSCLC.

Methods and materials

297 patients with 314 peripheral tumors treated from 2006 to 2012 were retrospectively analyzed. In all patients a 4D-CT was acquired and the MidV-CT-scan was selected. Tumor amplitudes were determined in left–right (LR), cranio–caudal (CC) and anterior–posterior (AP) direction, to calculate patient specific PTV margins.

Results

The median LR, CC and AP tumor amplitudes were 2 mm (0–16 mm), 4 mm (0–39 mm) and 3 mm (0–18 mm), respectively, yielding a median CTV-to-PTV margin of 8 mm. An ITV + 5 mm based PTV margin would have been bigger in 47% of the patients. After a median follow up of 22 months, local recurrence occurred in six patients (2%). Two year LC and OS were 98% and 67%, respectively.

Conclusions

Using the MidV approach combined with online image guidance an excellent LC of 98% was established with SBRT. This provides clinical support that incorporating respiratory motion into the PTV margin is a safe approach.     

Aggressive therapy for patients with non-small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival

Objectives

Optimal therapy for patients with non-small cell lung carcinoma (NSCLC) presenting with synchronous brain-only oligometastases (SBO) is not well defined. We sought to analyze the effect of differing therapeutic paradigms in this subpopulation.

Materials and methods

We retrospectively analyzed NSCLC patients with 1–4 SBO diagnosed between 1/2000 and 1/2011 at our institution. Patients with T0 tumors or documented Karnofsky Performance Status <70 were excluded. Aggressive thoracic therapy (ATT) was defined as resection of the primary disease or chemoradiotherapy whose total radiation dose exceeded 45 Gy. Cox proportional hazards and competing risks models were used to analyze factors affecting survival and first recurrence in the brain.

Results

Sixty-six patients were included. Median follow-up was 31.9 months. Intrathoracic disease extent included 9 stage I, 10 stage II and 47 stage III patients. Thirty-eight patients received ATT, 28 did not. Patients receiving ATT were younger (median age 55 vs. 60.5 years, p = 0.027) but were otherwise similar to those who did not. Receipt of ATT was associated with prolonged median overall survival (OS) (26.4 vs. 10.5 months; p < 0.001) with actuarial 2-year rates of 54% vs. 26%. ATT remained associated with OS after controlling for age, thoracic stage, performance status and initial brain therapy (HR 0.40, p = 0.009). On multivariate analysis, the risk of first failure in the brain was associated with receipt of ATT (HR 3.62, p = 0.032) and initial combined modality brain therapy (HR 0.34, p = 0.046).

Conclusion

Aggressive management of thoracic disease in NSCLC patients with SBO is associated with improved survival. Careful management of brain disease remains important, especially for those treated aggressively.     

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Background

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS).

Methods

Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation.

Results

OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n?≤?3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n?>?3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n?≤?3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n?>?3) but not for positive LNs (n?≤?3).

Conclusions

In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n?>?3), but not for patients with positive LNs (n?≤?3).

     

Outcomes following surgical treatment compared to radiation for stage I NSCLC: A SEER database analysis

Introduction

Outcomes following surgery are better than following radiation therapy (RT), for stage I NSCLC. Whether this is due to selection of healthier patients for surgery is unclear. This study was undertaken to compare outcomes between surgical patients and patients who were surgical candidates but did not receive surgery.

Methods

Data of patients with stage I NSCLC between 1988 and 2007, included in the SEER database were analyzed. Overall survival (OS) was examined by treatment type (surgery only, radiation only, surgery and radiation, and no treatment). OS was compared between RT patients who refused surgery and those not fit for surgery. Cox proportional hazards model was used to compare outcomes by treatment type.

Results

Data from 8579 patients with stage I NSCLC during 1988–2007 were analyzed. Use of RT alone increased during the study period. An increasing proportion of patients with stage I lung cancer chose to have no treatment. On multivariate analysis, OS was better among patients who had surgery. There was a 56% improvement in survival among patients who had surgery compared to fit patients who refused surgery (HR 0.437, 95% CI 0.301–0.632). Patients who refused surgery had a better OS than those who were not fit for surgery (log-rank p = 0.01). Patients who received RT alone or no treatment had a significant improvement in five-year OS during the latter part of the study period (1998–2002 vs. 1988–1992).

Conclusions

In medically fit patients, outcomes following surgery are better than those following conventional radiation. Hence surgery should be chosen over conventional radiation, whenever possible. Outcomes following RT show an improvement over time reflecting improvement in radiation techniques.     

Stereotactic Ablative Radiotherapy for stage I histologically proven non-small cell lung cancer: An Italian multicenter observational study

Objectives

Aim of this retrospective multicenter observational study was to provide data on outcomes and prognostic factors in patients affected with stage I histologically confirmed NSCLC treated with Stereotactic Ablative Radiotherapy (SABR, or Stereotactic Body Radiotherapy, SBRT) outside clinical trials.

Materials and Methods

We analyzed a cohort of 196 patients with histological/cytological diagnosis of NSCLC. Median age at treatment was 75 years old; median tumor diameter was 2.48 cm, and median GTV 13.3 cc. One hundred fifty-five patients had stage IA disease (79.1%) and 41 patients stage IB disease (20.9%). Total doses ranged from 48 to 60 Gy in 3–8 fractions. Primary endpoints of the study were safety (acute and late toxicity) and efficacy (Local Control, Disease-Free Survival, Overall and Cancer-Specific Survival).

Results

Median follow-up time was 30 months. The percentage of grade ≥2 pulmonary toxicity was 3%, and the 30 and 60 days mortality rate was 0%. Local Recurrence-Free Survival was 89.7% at 3 years. Fifty-nine patients (30.1%) had at least one failure (local and/or nodal and/or distant), with a Disease-Free Survival (DFS) rate at 3 years of 65.5%. Overall Survival (OS) and Cancer-Specific Survival (CSS) rates were 68% and 82.1% at 3 years, respectively. Median time to any recurrence was 15 months, while median overall survival time was 54 months. At multivariate analysis, stage IB was the only variable associated to a decrease in DFS, OS and CSS (HR 2.77, p = 0.006; HR 2.38, p = 0.009; HR 4.06, p ≤ 0.001, respectively). A difference in survival according to stage was also evident at the log-rank test (p ≤ 0.0001 for CSS and OS).

Conclusion

The results of the present study support the routine use of SABR for stage I NSCLC in a daily practice environment. The only prognostic factor that has been confirmed by our analysis was tumor stage (IA vs. IB).     

Nuclear and cytoplasmic cellular distribution of survivin as survival predictor in resected non-small-cell lung cancer

Aim

Survivin is a member of the inhibitors of apoptosis (IAP) gene family that acts through pathways different from those involving the bcl-2 family. Largely undetectable in normal adult tissues, survivin is deregulated in most human cancers including non-small-cell lung cancer (NSCLC) and may represent a tumor marker with prognostic and therapeutic implications. Aim of our study was to determine the prognostic role of survivin as an apoptosis-related biomarker in a series of resected NSCLC patients.

Methods

A retrospective series of resected NSCLC patients were retrieved from the files of the Regina Elena National Cancer Institute. Survivin was detected by immunohistochemistry (IHC) using a polyclonal antibody. Survivin displayed two kinds of immunoreactivity: (i) a diffuse cytoplasmic staining and (ii) a distinct nuclear staining. A score-scale to distinguish positive (score 1–2) vs. negative (score 0) pattern was applied. Clinical and biological (nuclear and cytoplasmic survivin staining) covariables were screened for a prognostic relationship with overall survival (OS) and disease-free survival (DFS) into the univariate and multivariate analyses.

Results

Data referring to 116 NSCLC patients who underwent surgery for stage I–IIIA NSCLC were collected. Multivariate analyses identified tumor size, nodal status and nuclear, but not cytoplasmic, expression of survivin as significant independent predictors of OS, with a hazard ratio of 2.40 (95% CI 1.44, 3.99, p = 0.001), 2.03 (95% CI 1.26, 3.26, p = 0.003) and 1.83 (95% CI 1.01, 3.30, p = 0.044), respectively. Median OS for nuclear survivin positive (score 1–2) and negative (score 0) patients were 23 months (95% CI 15, 31) and 36 months (95% CI 1, 76), respectively (p = 0.01); five-year survival for score 1–2 and score 0 patients were 20% and 44.5%, respectively. Conversely, no significant impact on survival is found when patients are stratified according to cytoplasmic survivin expression.

Conclusions

Data presented herein open the issue that prognosis of stage I–IIIA NSCLC can be linked to the cellular pattern of distribution of survivin.     

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.     

Cross-validation analysis of the prognostic significance of mucin expression in patients with resected non-small cell lung cancer treated with adjuvant chemotherapy: Results from IALT,JBR.10 and ANITA

Introduction

CALGB 9633 was a randomized trial of observation versus adjuvant chemotherapy for patients with stage IB non-small cell lung cancer (NSCLC). In CALGB 9633, the presence of mucin in the primary tumor was associated with shorter disease-free survival (DFS; hazard ratio (HR) = 1.9, p = 0.002) and overall survival (OS; HR = 1.9, p = 0.004).

Methods

To validate these results, mucin staining was performed on primary tumor specimens from 780 patients treated on IALT, 351 on JBR.10 and 150 on ANITA. The histochemical technique using mucicarmine was performed. The prognostic value of mucin for DFS and OS was tested in a Cox model stratified by trial and adjusted for clinical and pathological factors. A pooled analysis of all 4 trials was performed for the predictive value of mucin for benefit from adjuvant chemotherapy.

Results

The cross-validation group had 48% squamous, 37% adenocarcinoma and 15% other NSCLC compared with 29%, 56%, and 15%, respectively in CALGB. Among 1262 patients with assessable results, mucin was positive in IALT 24%, JBR.10 30%, ANITA 22% compared with 45% in CALGB. Histology was the only significant covariate (p < 0.0001) in multivariate analysis with mucin seen more commonly in adenocarcinoma (56%) compared with squamous (5%) and other NSCLC (15%). Mucin was a borderline negative prognostic factor for DFS (HR = 1.2 [1.0–1.5], p = 0.06) but not significantly so for OS (HR = 1.1 [0.9–1.4], p = 0.25). Prognostic value did not vary according to histology: HR = 1.3 [1.0–1.6] in adenocarcinoma vs. 1.6 [1.2–2.2] for DFS in other histology (interaction p = 0.69). Mucin status was not predictive for benefit from adjuvant chemotherapy (test of interaction: DFS p = 0.27; OS p = 0.49).

Conclusions

Mucin was less frequent in the cross-validation group due to its higher percentage of squamous cell carcinomas. The negative impact of mucin was confirmed for DFS but not for OS. Mucin expression was not predictive of overall survival benefit from adjuvant chemotherapy.     

Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: Efficacy and safety outcomes of a randomized,multi-center phase II study investigating

Background

Modest benefits from concurrent chemoradiotherapy in patients with locally advanced NSCLC warrant further clinical investigations to identify more effective treatment regimens. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. We report on the safety and efficacy of the combination of daily dose Cisplatin and concurrent radiotherapy with or without weekly Cetuximab.

Patients and methods

Patients received high dose accelerated radiotherapy (66 Gy in 24 fractions) and concurrent daily Cisplatin (6 mg/m²) without (Arm A) or with (Arm B) weekly Cetuximab (400 mg/m² loading dose one week prior to radiotherapy followed by weekly 250 mg/m²). The primary endpoint of the trial was objective local control rate (OLCR) determined at 6–8 weeks after treatment. Toxicity was reported as well.

Results

Between February 2009 and May 2011, 102 patients were randomized. Median follow up was 29 months. The OLCR was 84% in Arm A and 92% in Arm B (p = 0.36). The one-year local progression free interval (LPFI) and overall survival (OS) were 69% and 82% for Arm A and 73% and 71% for Arm B, respectively (LPFI p = 0.39; OS p = 0.99). Toxicity compared equally between both groups.

Conclusion

The addition of Cetuximab to radiotherapy and concurrent Cisplatin did not improve disease control in patients with locally advanced NSCLC but increased treatment related toxicity.     

Benefits of postoperative radiotherapy in multimodality treatment of resected small-cell lung cancer with lymph node metastasis

Aim

The purpose of this study is to evaluate the role of postoperative radiotherapy (PORT) in resected small-cell lung cancer (SCLC).Methods: This study retrospectively analyzed 143 patients with completely resected SCLC in our institution between 1996 and 2011. The primary endpoint was overall survival (OS). The log-rank test and Cox regression model were used to evaluate the factors influencing local-regional recurrence (LRR) and OS.

Results

The median OS for the entire population was 34 months, and the 5-year OS rate was 34.6%. In multivariate analysis, age, surgical procedure, pathology stage, adjuvant chemotherapy and distant relapse were significant factors for survival. For the whole population, PORT had no effect on OS, with a median OS of 40 months in the PORT group versus 27 months in the non-PORT group (p = 0.260). However, in patients with N1 disease, the median OS were 40 months in the PORT group versus 14 months in the non-PORT group (p = 0.032). The corresponding OS in N2 patients were 35 months versus 17 months, respectively (p = 0.040). Similarly, PORT significantly reduced the LRR in patients with positive lymph node. For patients with N1 disease, the 3-year LRR rate was 0.0% in the PORT group versus 14.3% in the non-PORT group (p = 0.037). The corresponding LLR rate in N2 patients was 4.2% versus 56.6% (p < 0.001).

Conclusion

PORT significantly reduced LRR and improved OS in patients with regional metastasis SCLC. We suggest supplementing PORT in the multimodality treatment of resected SCLC with lymph node metastasis.     

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.     

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.     

Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer

Objectives

Retrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC). The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB.

Materials and methods

Chinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500 mg/m² + cisplatin 75 mg/m² (day 1), or gemcitabine 1250 mg/m² (days 1 and 8) + cisplatin 75 mg/m² (day 1).

Results

In JMIL, 256 Chinese patients were randomized (PC, n = 126; GC, n = 130). Patient baseline characteristics were balanced between treatment arms. In the combined dataset, PC was superior to GC in prolonging OS, with adjusted hazard ratio (HR) of 0.87 (95% CI: 0.77–0.98, p = 0.023) and median OS of 11.76 versus 10.94 months. In the JMIL-only population, no significant OS difference observed between treatment arms (adjusted HR = 1.03 [95% CI: 0.77–1.39, p = 0.822]; unadjusted HR = 0.996 [95% CI: 0.74–1.33, p = 0.980]), nor for other secondary efficacy endpoints. Significantly fewer patients in the PC arm experienced drug-related grade 3/4 toxicities, 54 (43.2%) versus 71 (55.9%) for GC (p = 0.045), with significantly lower rates of leukocytopenia, thrombocytopenia, and fatigue.

Conclusion

This study showed that in the combined population, OS of PC was superior to GC, while in the Chinese-only population, no significant difference was observed; a better safety and risk/benefit profile was found in the PC arm. A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.     

Stereotactic ablative radiotherapy (SABR) using 70 Gy in 10 fractions for non-small cell lung cancer: Exploration of clinical indications

Background and purpose

We report our outcomes for patients with NSCLC treated with SABR to 70 Gy in 10 fractions and propose indications for this regimen as well as new dose–volume constraints.

Materials and methods

Volumetric image-guided SABR was used to treat 82 patients with clinical challenging NSCLC, not suitable for 50 Gy in 4 fractions, to a final dose of 70 Gy in 10 fractions. Endpoints included overall survival (OS), toxicity, and disease control.

Results

At a median follow-up time of 21.1 months, 2-year OS and local control rates were 66.9% and 96.2%, respectively. The most common side effects were radiation pneumonitis (14.6% grade 2, 2.4% grade 3), followed by chest wall pain (4.9% grade 2, 1.2% grade 3). Multivariate analysis revealed chest wall V50 > 60 cm³ to be associated with chest wall pain. No patient developed brachial plexopathy. One patient with bronchial tree tumor invasion died of hemoptysis.

Conclusions

SABR with 70 Gy in 10 fractions appears to achieve excellent local control and acceptable toxicity for clinically challenging cases with improved tolerance of the chest wall and brachial plexus as compared with 50 Gy in 4 fractions. This regimen may not be suitable in patients with tumor invading critical central structures. More studies are needed to validate our conclusions.     

Randomized,double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC)

Objectives

Adding nitroglycerin to the combination of vinorelbine plus cisplatin has been reported to improve the overall survival (OS) of Asian patients with stage IIIB/IV non-small cell lung cancer (NSCLC) probably due to better drug delivery based on changed vascular tonus. The main objective of our study was to evaluate the effect of adding nitroglycerin to vinorelbine and cisplatin in a Caucasian population.

Methods

66 chemonaïve patients with stage IIIB/IV NSCLC received oral vinorelbine (first cycle 60 mg/m², subsequent cycles: 80 mg/m² in the absence of any hematological toxicity ≥grade 3 in cycle 1) once daily on days 1 and 8 of each cycle and cisplatin (80 mg/m² i.v.) on day 1 of each cycle (q3w). Nitroglycerin (arm A, n = 34) or placebo patches (arm B, n = 32) were administered once daily from day −3 to day 2 of each cycle and were removed about 12 h after administration. One nitroglycerin patch contained 25 mg nitroglycerin.

Results

Median age was 62.5 (33–82) years. In the overall population (n = 66), the objective response rate (ORR) was 27.3% (all PR; 95%CI: 17.0–39.6), with a disease control rate (DCR) of 57.6% (95%CI: 44.8–69.7), a median time to progression (TTP) of 4.8 months (n = 58; 95%CI: 3.4–5.9) and a median overall survival (OS) of 11.5 months (95%CI: 7.9–13.6). ORR and DCR were numerically higher in arm A than in arm B (35.3% vs. 18.8% and 61.8% vs. 53.1%, respectively), whereas TTP and OS were comparable. The main hematological and non-hematological toxicities grade ≥3 were moderate with no significant differences between the two treatment arms.

Conclusions

Overall, oral vinorelbine plus cisplatin showed a high level of efficacy and adequate tolerability in first line treatment of NSCLC. Despite the low sample size per group the results seem to confirm the previous results reported in Asian patients.