Postoperative Recurrent Non-small Cell Lung Cancer Research Articles

Clinical usefulness of gefitinib for non-small-cell lung cancer with a double epidermal growth factor receptor mutation.

The aim of this study was to investigate whether the pattern of epidermal growth factor receptor (EGFR) gene mutations affects sensitivity to gefitinib treatment. We investigated 44 surgically resected non-small-cell lung cancer (NSCLC) specimens obtained between 2001 and 2012 at the Tokyo Medical University Hospital. The specimens were obtained from patients treated with gefitinib as 1st-, 2nd-, or 3rd-line therapy for postoperative recurrent NSCLC. We detected EGFR mutations using the cycleave PCR technique. In addition, the specimens from non-responders were stained with antibodies against hepatocyte growth factor receptor (HGFR; MET) and hepatocyte growth factor (HGF). We assessed the progression of non-responders over a period of 2 months. Intermediate responders were considered to be patients who responded (exhibiting at least stable disease) to gefitinib therapy for 3-11 months, while long-term responders were defined as those who responded to gefitinib therapy for >12 months. The NSCLCs were histologically classified as 43 adenocarcinomas and one large-cell neuroendocrine carcinoma. One patient had an exon 18 point mutation, 23 an exon 19 deletion, 2 an exon 20 point mutation, 16 an exon 21 point mutation and 2 patients had both exon 20 and 21 point mutations. There were 4 non-responders, including the 2 patients with exon 20 mutation, 25 intermediate responders (including 10 patients under ongoing treatment) and 15 long-term responders (2 of whom are under ongoing treatment), including the 2 patients with both exon 20 and 21 mutations. Of the specimens obtained from non-responders, 3 stained with the anti- MET antibody and 1 stained with the anti-HGF antibody. Therefore, NSCLC with exon 20 mutation may respond to gefitinib treatment in the presence of an additional EGFR mutation.

The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR). We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation. A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p < 0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p < 0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival. PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

Neutrophil-to-lymphocyte ratio predicts the survival in patients with post-operative recurrence of non-small cell lung cancer

To analyze the impact of neutrophil-to-lymphocyte ratio (NLR) on survival of patients with post-operative recurrence of non-small cell lung cancer (NSCLC). The clinicopathological characteristics and outcome data of 235 patients with post-operative recurrent NSCLC were collected and reviewed. The best cut-off value of NLR at recurrence was identified according to the receiver operating characteristic curve (ROC curve), and all 235 patients were therefore divided into two groups based on the NLR value. The prognostic impact of NLR on survival in patients with recurrent NSCLC was tested by univariate and multivariate analyses. The NLR of 2.97 was identified as the optimal cut-off value. There was no statistically significant difference in the clinicopathological characteristics between the low NLR (NLR ≤ 2.97) and high NLR (NLR>2.97) groups at recurrence. The median post-recurrence survival of 235 patients was 13 months (range, 1-81 months). The post-recurrence 1-, 2-year survival rates were 58.4% and 32.6%, respectively. Univariate analysis showed that age at the time of operation >65 years (P = 0.009), a histological type of large cell lung cancer or sarcoma (P < 0.001), TNM stage III of the primary tumor (P = 0.043) and NLR>2.97 at recurrence (P < 0.001) were prognostic risk factors for post-recurrence survival, while preoperative NLR>2.97 was not (P = 0.104). The post-recurrence 1- and 2-year survival rates of the low recurrence NLR group were 74.7% and 43.1%, respectively, significantly higher than that of the high recurrence NLR group (35.4% and 17.2%, respectively) (P < 0.001). Cox multivariate analysis showed that age >65 (HR = 1.707, P = 0.001), TNM stage III of primary tumor (HR = 1.654, P = 0.001) and NLR>2.97 (HR = 2.859, P < 0.001) at recurrence were independent prognostic factors (P < 0.05 for all). An elevated NLR at recurrence indicates poor prognosis of NSCLC patients. NLR at recurrence may be an important independent prognostic factor of patients with recurrent NSCLC after curative resection.

Prognosis of recurrent non-small cell lung cancer following complete resection.

Prognosis following recurrence subsequent to complete resection of non-small-cell lung cancer (NSCLC) is considered a multifactorial process dependent on clinicopathological, biological and treatment characteristics. Gefitinib was approved for lung cancer treatment in Japan in 2002. The aim of the current study was to quantify the prognostic effects of these characteristics on post-recurrence prognosis. In total, 127 NSCLC patients were analyzed who underwent complete resection and subsequently had recurrent cancer. The correlation between characteristics of the initial and recurrent disease with post-recurrence prognosis was investigated. The factors clearly associated with post-recurrence prognosis using Cox proportional hazards models were age at recurrence (those <65 years of age typically had better prognoses) and interval between initial resection and recurrence (intervals of <1 year accompanied a worse prognosis). Epidermal growth factor receptor (EGFR) mutant patients treated with EGFR tyrosine kinase inhibitors (TKIs), exhibited the longest median survival following recurrence (37.4 months) in the sample. Treatment, particularly EGFR TKIs for recurrent NSCLC, was observed to significantly prolong survival. The results of the study highlight that various treatment modalities according to the clinical background of the patient should be considered in patients with postoperative recurrent NSCLC.

Impact of EGFR tyrosine kinase inhibitors on skeletal-related events in EGFR mutation-positive non-small cell lung cancer patients with bone metastases.

e18054 Background: Clinical outcome of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with bone metastases is less well known. The purpose of this study was to evaluate the clinical outcome of EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR tyrosine kinase inhibitors (TKIs). Methods: From January 2008 to December 2010, 127 patients received first-line chemotherapy for advanced or postoperative recurrent NSCLC with bone metastasis at our institution. EGFR mutational status was analyzed using a PCR-based assay for EGFR exons 18 to 21. Clinical outcome including the incidence of skeletal-related events (SREs), time to the first SREs from first-line chemotherapy and overall survival (OS) was evaluated by the EGFR TKIs-sensitive mutations status (either exon 19 deletion or L858R in exon 21). SREs were defined as a pathologic fracture, spinal cord compression, surgery to bone, radiation therapy (RT) to bone, other radiological intervention, and hypercalcemia of malignancy. Results: Sixty-two (50%) of the 125 patients were sensitive EGFR mutations positive. 39 of 62 (63%) EGFR mutation-positive patients were treated with EGFR TKIs (gefitinib or erlotinib) as first-line chemotherapy, and most of negative patients received cytotoxic agents such as platinum-based chemotherapy. Zoledronic acid were administered in 50 % of EGFR mutation-positive patients, and in 57 % of negative patients, respectively (P= 0.59). With a median follow-up of 13 months, the incidence of SREs were 21% in EGFR mutation-positive patients, and 38% in negative patients, respectively (P&lt;0.05). Additionally, median time to first SREs from first-line chemotherapy in EGFR mutation-positive patients was significantly longer than negative patients (13 months versus 6 months, P&lt;0.05). Median OS in mutation-positive patients was 26 months, as opposed to 12 months in negative patients (P&lt;0.05). Conclusions: Our study indicated that EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR TKIs have favorable clinical outcome on SREs compared with mutation-negative patients.

Clinical Significance of Epidermal Growth Factor Receptor Gene Mutations on Treatment Outcome after First-line Cytotoxic Chemotherapy in Japanese Patients with Non-small Cell Lung Cancer

The relationship between the EGFR gene mutation status and clinical outcome has not fully been assessed in patients with non-small cell lung cancer (NSCLC) who received cytotoxic agents. The aim of this study was to clarify its association. We also examined whether this association could be affected by previous gefitinib treatment. Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy in their treatment course were included in this study. An EGFR mutation was determined in exons 19 and 21 by direct sequencing. Of 194 Japanese patients with advanced or relapsed NSCLC assessable for mutation analysis, 60 received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment courses. EGFR mutations significantly affected progression-free survival (PFS) in the first-line cytotoxic chemotherapy regimens in the multivariate analysis (hazard ratio for PFS = 0.422; p = 0.0422). In contrast, in 28 (47%) of the 60 patients who also received cytotoxic chemotherapy after the relapse to gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status, and its sensitivity was retained even in the second-line treatment setting in patients with EGFR mutations. EGFR mutations were therefore significantly associated with a better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, whereas gefitinib sensitivity was associated with an EGFR mutation even in the second-line or later treatment settings.

Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer (NSCLC)

7670 Background: The relationship between EGFR mutation status and clinical outcome has not fully been assessed in NSCLC patients receiving cytotoxic agents. The aim of this study was to clarify its association. We also examined if this association could be affected by the prior gefitinib treatment or not. Methods: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment course and whose tumors were assessable for EGFR mutation analysis were included in this study. EGFR mutation was determined in exons 19 and 21 by direct sequencing. Results: Sixty patients were included in the study, including 6 (10%) patients who received the first-line gefitinib monotherapy followed by cytotoxic chemotherapy in the second-line or later settings. Of the 54 (90%) patients, 22 also underwent subsequent cytotoxic chemotherapy after the relapse to gefitinib monotherapy. EGFR mutations were detected in 17 (28%) patients. In the first-line cytotoxic chemotherapy setting (n=54), EGFR mutations significantly affected progression-free survival (PFS) with 6-month PFS rates of 45.8 vs. 21.9% (p=0.05). This was also observed in the multivariate analysis (HR=0.42, p=0.04). EGFR mutation was also significantly correlated with overall survival (OS) in the multivariate analysis (HR=0.26, p &lt;0.01). Contrary, in the 28 (47%) of 60 patients who received cytotoxic chemotherapy after gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status and its sensitivity was retained even in the second-line setting in patients with EGFR mutations. Conclusion: EGFR mutation was significantly associated with better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, while the sensitivity to gefitinib was associated with EGFR mutation even in the second-line or later setting. No significant financial relationships to disclose.

Survival After Recurrent Nonsmall-Cell Lung Cancer After Complete Pulmonary Resection

Survival characteristics of patients who have recurrent nonsmall-cell lung cancer after surgical resection are not well understood. Little objective evidence exists to justify treatment for these patients. We prospectively followed 1,361 consecutive patients with nonsmall-cell lung cancer who underwent complete surgical resection at our institution from January 1997 to December 2001. Only patients having recurrent cancer were included in the analysis. Multivariable Cox proportional hazards models were used to evaluate the effect of prognostic factors on postrecurrence survival. Follow-up was achieved in 1,073 patients, and recurrent cancer developed in 445. Complete information was available on 390 patients for analysis. There were 262 men and 128 women. Median age at time of recurrence was 69 years. Median time from surgical resection to recurrence was 11.5 months, and median postrecurrence survival was 8.1 months. Recurrence was intrathoracic in 171 patients, extrathoracic in 172, and a combination of both in 47. Treatments after recurrence included surgery in 43 patients, chemotherapy in 59, radiation in 73, and a combination in 96. All patients who received treatment survived longer than those who received no treatment. Preoperative chemotherapy and postoperative radiotherapy for the primary lung cancer, poor Eastern Cooperative Oncology Group Performance Status, decreased disease-free interval from initial resection to recurrence, symptoms at recurrence, and certain location of recurrence significantly decreased postrecurrence survival. In our experience, treatment for recurrent nonsmall-cell lung cancer significantly prolongs survival. Various treatment modalities including surgery should be considered in patients with postoperative recurrent nonsmall-cell lung cancer.

Phase II Study of Carboplatin Combined with Biweekly Docetaxel for Advanced Non-small Cell Lung Cancer

The combination of carboplatin and docetaxel has been considered one of the standard treatments for advanced non-small cell lung cancer (NSCLC). To investigate a safer and more convenient schedule for outpatient, we conducted a phase II study to evaluate the efficacy and the safety of carboplatin plus biweekly docetaxel for advanced NSCLC. Patients with stage IIIB, IV, or postoperative recurrent NSCLC with good performance status were administered docetaxel at a dose of 35 mg/m on days 1 and 15 and carboplatin at an area under the curve (AUC) of 6 on day 1 every 4 weeks for at least three cycles. Fifty patients were treated with median of three cycles (range 1-6). Grade 3/4 toxicities included neutropenia in 18 patients (36%), thrombocytopenia in 4 patients (8%), and anemia in 10 patients (20%). No patient experienced febrile neutropenia. Nonhematological toxicities were also mild to moderate, and there were no treatment-related deaths. The overall response rate was 30%, and the disease control rate was 70%. Among the elderly population, 54% of patients achieved partial response. Median progression-free survival was 4.8 months, and median overall survival was 11.8 months. Biweekly docetaxel plus carboplatin has a similar efficacy and lower toxicity compared with a standard triweekly regimen of docetaxel plus carboplatin, which is a suitable regimen for outpatients, including elderly patients.

Never-smoking history predicts long-term survival in patients with non-small cell lung cancer with postoperative recurrence

20047 Background: Factors affecting long-term survival after postoperative recurrence in non-small cell lung cancer (NSCLC) patients have not been fully understood. Furthermore, molecular features of them also have remained undetermined. The aim of this study was to identify these possible factors and to investigate their association with epidermal growth factor receptor (EGFR) mutation. Methods: Fifty-eight patients with postoperative recurrent NSCLC treated at Okayama University Hospital between January 1999 and December 2003 were retrospectively analyzed. We defined those surviving for 2 years or longer after postoperative recurrence as long-term survivors. Tumor samples for EGFR mutation analysis were available in 32 (55%) patients and were examined in exons 18 to 21 of EGFR using direct sequence method. Results: Demographics of 58 patients were as follows: median age 65 years (range, 33–85 years), male/female, 69%/31%; adenocarcinoma/others, 69%/31%; ever/never-smokers, 66%/34% and local/local and distant/distant recurrence; 29%/10%/61%. Median survival time and 1-year survival rate for 58 patients were 22.7 months and 79%, respectively, with a minimum follow-up time of 2 years. Half of 28 long-term survivors did not have any smoking history, whereas only 6 never-smokers were included in the remaining 30 patients who died within 2 years, indicating that never-smoking history is significantly associated with long-term survival (p=0.016). In multivariate analysis, never-smoking history was a significant predictive factor for long-term survival (Odds ratio 4.90, 95% confidence interval: 1.26–19.00, p=0.022). Among 32 patients analyzed for EGFR mutation, patients harboring EGFR mutation in ever-smokers and in never-smokers were 10% and 82%, respectively. Seven (47%) of 15 long-term survivors analyzed had EGFR mutation; however, only 4 (24%) of 17 patients who died within 2 years did (p = 0.169). Conclusions: Our data suggest that never-smoking history might have a favorable effect on long-term survival in postoperative recurrent NSCLC patients, and long-term survivors tend to have EGFR mutation. No significant financial relationships to disclose.

Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan

7077 Background: Previous clinical trials have revealed that gefitinib is more likely to be effective in non-small cell lung cancer (NSCLC) with activating somatic mutations of epidermal growth factor receptor (EGFR). Most of those reports evaluated NSCLC patients who had post-operative recurrence and then received gefitinib retrospectively using their surgical specimens. However, many NSCLC patients are inoperable at diagnosis. Thus we conducted this study to examine EGFR mutation status by diagnostic tumor samples before gefitinib treatment and investigate the correlation between EGFR mutation and the efficacy of gefitinib. Methods: We prospectively evaluated various tumor samples obtained from NSCLC patients who had never received gefitinib for EGFR mutations in exon 18–23. For patients treated with gefitinib after the examination of EGFR mutations, the response to gefitinib was also evaluated. Results: From June 2004 to November 2005, 91 patients with advanced or post-operative recurrent NSCLC enrolled onto this study and 104 tumor samples were obtained from transbronchial biopsies, effusions, as well as surgical specimens. Thirty-two mutations including deletions in exon 19 in 23 patients and L858R in 9 patients were detected among those 91 patients; 30 in 81 adenocaricinoma, 1 in 2 adenosquamous cell carcinoma, and 1 in 5 large cell carcinoma. The mutations were found more frequently in female (51.9%) than male (12.8%), in never smoker (52.0%) than smoker (14.6%). Response rate of gefitinib in patients with EGFR mutations was 65.0% (13 of 20) compared to 37.5% (3 of 8) in patients without mutations. Among 7 patients with EGFR mutations who were examined multiple tumor samples, 3 had the discrepancy of EGFR gene status between different samples obtained at different time points, suggesting genetic heterogeneity of their tumors. The EGFR status of the most recent samples is likely to be correlated to the response to gefitinib. Conclusions: The EGFR mutation analysis was possible not only from surgical specimens but also from daily available diagnostic samples. For patients with EGFR mutations, gefitinib could achieve a promising high response rate. We propose to examine the most recent tumor samples to predict the sensitivity to gefitinib reliably. No significant financial relationships to disclose.

A phase II trial of weekly paclitaxel and carboplatin for elderly patients with advanced non-small cell lung cancer (NSCLC)

7248 Background: Paclitaxel combined with carboplatin (PC) is a commonly used regimen in advanced NSCLC. Although some studies suggested that PC is also effective for elderly patients, weekly paclitaxel combined with carboplatin for those patients has not been reported. We conducted this phase II trial to evaluate the safety and the efficacy of weekly paclitaxel and carboplatin for elderly patients with advanced NSCLC. Methods: Patients with stage IIIB, IV or postoperative recurrent NSCLC, PS ≤ 1, ≥ 70 years old received weekly paclitaxel (70mg/m2/wk) on d1, 8, 15, and carboplatin (AUC 6) on d1. Treatment was repeated every 4 weeks. Results: From May 2002 to Aug 2004, 42 patients were enrolled: median age (range), 75 (70–81); male/female, 32/10; stage IIIB/IV/postoperative recurrence, 13/25/4. Two patients never received study drug and 40 patients were evaluable for the safety and the efficacy. ≥Grade 3 toxicities included neutropenia (70%); thrombocytopenia (15%); anemia (13%); infection (10%); fatigue and febrile neutropenia (5%). No ≥grade 3 neurotoxicity was observed. One treatment related death (infection) was observed. Overall response rate was 45%; CR=0, PR=18, SD=11, PD=7, NE=4. To date, median survival time was 13 months and the 1-year survival rate was 58%. Conclusion: These results suggest that weekly paclitaxel and carboplatin is comparable to standard PC in efficacy and seems to be safer than standard PC. We are now conducting a randomized trial that compare weekly paclitaxel and carboplatin to standard PC. No significant financial relationships to disclose.