Prognostic factors in patients with stage Ⅳ non-small cell lung cancer

Objective： To investigate the prognostic factors for stage Ⅳ non-small cell lung cancer （NSCLC） with distant metastasis and establish a reliable model of clinical prognostic index. Methods： From January 1990 to April 2005, 313 primary NSCLC patients with metastasis, who had been treated in Shanghai Chest Hospital, were reviewed. Survival time was estimated according to the Kaplan-Meier method. Cox proportional hazard regression model was used for multivariate analysis. Results：Among the 313 cases of non-small cell lung cancer （NSCLC） at stage Ⅳ, there were 218 and 95 patients with metastasis to single and different organs, respectively. The overall median survival time for all 313 cases of NSCLC patients was 10.8 （9.00, 12.30） months and the overall 1-, 2-, 3-, 4- and 5-year survival rate was 45%, 18%, 12%, 4% and 0%. There were 63, 174, 127, 36, 18, 11 and 5 patients with metastasis to brain （20.13%）, bone （55.59%）, lung （40.58%）, liver （11.50%）, adrenal gland （5.75%）, subcutaneous （3.51%） and others, respectively. The survival time was shortest in subcutaneous metastasis （4.6 months）, and liver 7.0 months, brain 8.0 months, adrenal gland 8.6 months, bone 10.6 months, lung 11.8 months. Kaplan-Meier estimation showed that patients anatomic typing, KPS, numbers of organ with metastasis, appetite, liver, adrenal gland and subcutaneous metastasis, body weight loss, smoking, index of smoking, chemotherapy, cycles of chemotherapy were the predictors of survival. Multivariate analysis showed survival statistically significant correlation with anatomic typing, KPS, appetite, liver and subcutaneous metastasis, body weight loss, cycles of chemotherapy. The relative risk （RR） was 1.51, 1.97, 1.55, 1.67, 2.56, and 2.56 respectively. Conclusion： Survival time decreases distinctly in patients who had distant metastasis to more than two different organs （P〈0.01）. Bone is the commonest organ for distant metastasis in lung cancer. The prognosis is poor when lung cancer appears subcutaneous metastasis and liver metastasis. Independent prognostic factors in patient with stage Ⅳ non-small cell lung cancer were liver and subcutaneous metastasis, anatomic typing, KPS, appetite, body weight loss, cycles of chemotherapy.     

Prognostic factors in patients with stage IV non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths among both men and women over the world. In 2002, lung can- cer accounted for more deaths than breast cancer, prostate cancer, and colon cancer combined[1]. Non-small cell lung cancer (NSCLC) represents 75%–85% of all lung cancers. Lung cancer is hard to discovered until it’s at an advanced stage and the outlook for recovery is poor. Approximately two-thirds of NSCLC patients have advanced-stage at di- agnosis. Stage IV NSCLC denotes …     

Which patients with stage III non-small cell lung cancer should undergo surgical resection?

The treatment of patients with stage III NSCLC remains controversial. Stage III NSCLC comprises a fairly heterogeneous group of tumors, and furthermore only sparse data from randomized clinical trials exist to guide therapy decisions. This review article proposes a management algorithm for patients with stage III NSCLC that is based upon the currently available data on surgical therapy, chemotherapy, and radiation therapy. By necessity, given the paucity of strong data, a good deal of opinion is offered. The choice to proceed with aggressive, combined modality treatment is presented in light of extent of local disease as well as patient performance status.     

Does smoking or family history influence the prognosis of patients with non-small cell lung cancer?

The prognostic significance of pack-years smoked (PY) and family history of cancer (FH) was studied using the Cox proportional hazard model in 970 patients with non-small cell lung cancer. PY influenced survival only in women after other variables were adjusted [Hazard ratio (HR): 1.75 (1.45-2.11)]. FH also influenced survival with marginal significance in women with stage I disease [HR: 2.17 (0.89-5.29), p=0.088]. Furthermore, these two factors operated additively in women [HR for patients with both smoking and family histories over those without either: 2.25 (1.18-4.26)], but not in men.     

Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer?

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) might be new therapeutic strategies for advanced non-small cell lung cancer (NSCLC). Here a total of 12,520 patients from 23 randomized controlled trials (RCTs) were enrolled to evaluate the efficacy and safety of VEGFR-TKIs quantitatively in advanced NSCLC. Compared with non-VEGFR-TKIs, VEGFR-TKIs regimen significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.805-0.874, P < 0.001], objective response rates (ORR) [relative risk (RR): 1.374, 95% CI: 1.193-1.583, P < 0.001] and disease control rates (DCR) (RR: 1.113, 95% CI: 1.027-1.206, P = 0.009), but not overall survival (OS) (HR: 0.960, 95% CI: 0.921-1.002, P = 0.060) for NSCLC patients. The RR of all-grade neutropenia, thrombocytopenia, hypertension, hemorrhage, fatigue, anorexia, stomatitis, diarrhea, rash, hand-foot skin reaction (HFSR) were increased in patients received VEGFR-TKIs. As for high-grade (≥ 3) adverse events (AEs), VEGFR-TKIs were associated with higher RR of neutropenia, thrombocytopenia, hypertension, fatigue, stomatitis, diarrhea, rash and HFSR. This study demonstrates VEGFR-TKIs improve PFS, ORR and DCR, but not OS in advanced NSCLC patients. VEGFR-TKIs induce more frequent and serious AEs compared with control therapies.     

Impact of dendritic cell vaccines pulsed with Wilms’ tumour-1 peptide antigen on the survival of patients with advanced non-small cell lung cancers

PurposeDendritic cell (DC)-based vaccines have been expected to serve as new therapeutic approaches for advanced non-small cell lung cancers (NSCLCs); however, their clinical outcomes have not been fully elucidated. We report a single-centre clinical study analysing factors affecting the survival of patients with advanced NSCLCs who received DC vaccines pulsed with or without Wilms’ tumour protein-1 (WT1) peptide.MethodsAmong 62 patients with previously treated inoperable or postoperatively relapsed NSCLCs who met the inclusion criteria, DCs from 47 (76%) patients who showed HLA-A2402/0201/0206 were pulsed with one or more corresponding WT1 peptide antigens. DC vaccines were intradermally injected biweekly.ResultsClinical responses based on response evaluation criteria in solid tumours (RECIST) were found in 31 (50%) patients at 3 months after the first DC vaccine (complete response: 1 (1.6%), partial response: 4 (6.5%), stable disease: 26 (41.9%)). Median survival time was 27 months (82% in 1 year and 54% in 2 years) from initial diagnosis, and that was 12 months (48% in 1 year and 22% in 2 years) from the first DC vaccination. Importantly, multivariate analyses revealed that only two factors, blood haemoglobin and the use of WT1 peptides, significantly affected the overall survival of patients from both initial diagnosis and first vaccination.ConclusionsThis study is the first to suggest that DC vaccines pulsed with WT1 may hold a significant impact to prolong the overall survival of patients with advanced NSCLCs.     

Targeted therapy in non-small cell lung cancer

Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes, giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human     

The influence of intraoperative pleural perfusion with matrine–cisplatin or cisplatin on stromal cell-derived factor-1 in non-small cell lung cancer patients with subclinical pleural metastasis

The early diagnosis and treatment of non-small cell lung cancer (NSCLC) in patients with subclinical pleural metastasis is currently a challenge. In an effort to establish a method for the diagnosis and treatment of these patients, we conducted a single-blind study during which intraoperative pleural lavage cytology (PLC) was performed in 164 patients with NSCLC without obvious pleural effusion. Stromal cell-derived factor-1 (SDF-1) serum concentrations were analyzed using enzyme-linked immunoassay on day 1 prior to tumor resection and on day 7 postoperatively. Western blot analysis was used for the detection of CXCR4 protein expression in resected tumors. Intraoperative pleural perfusion chemotherapy, with either cisplatin or cisplatin plus matrine, was given to patients with positive PLC. A group of 30 patients with NSCLC that did not undergo intraoperative PLC were used as a control group. Of the 164 study patients, 41 (25%) patients had positive PLC. Serum SDF-1 concentrations were higher in PLC-positive patients compared with patients negative for PLC and control patients. Serum SDF-1 concentrations were also lower at postoperative day 7 in patients treated with cisplatin plus matrine compared with control patients and those perfused with cisplatin alone. A lower incidence of chemotherapy-related adverse events was observed in patients treated with cisplatin plus matrine versus those treated with cisplatin alone during the first postoperative month. Patients with positive PLC showed a higher CXCR4 protein expression than patients with negative PLC. Based on the results of this study, PLC combined with serum SDF-1 concentration measurements may be considered as an effective index to determine the risk of subclinical pleural metastasis in patients with lung cancer. In addition, cisplatin plus matrine was confirmed as an initial approach for pleural perfusion and was superior to cisplatin alone.     

Characterization of outcomes in patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors past RECIST version 1.1–defined disease progression in clinical trials

Based on anecdotal cases of clinically important decreases in tumor size following initial evidence of disease progression when treating patients with anti-PD-1 therapies, investigators have conducted clinical trials in patients with metastatic non-small lung cancer (mNSCLC) receiving anti–PD-1 therapy allowing for treatment past RECIST-defined disease progression (TPP). We describe the findings of a pooled analysis of three clinical trials submitted to the US Food and Drug administration (FDA) where treatment of patients with mNSCLC permitted TPP in terms of reduction in the sum of target lesions following initial RECIST-defined progression. We identified patients who received TPP and the characteristics and post-TPP change in tumor burden. All patients had advanced or mNSCLC and had previously received a platinum-based doublet regimen. In total, 535 patients were treated with anti–PD-1 therapy in three clinical trials of which 121 patients (23%) received TPP. Among all 535 patients treated with anti–PD-1 therapy, the partial response (PR) rate (≥30% reduction in the size of target lesions compared to baseline) following TPP was 1.9% (10 of 535) or 8.3% (10 of 121) in the TPP subgroup. Patients who responded to TPP were more likely to have responded to the initial course of anti–PD-1 therapy, prior to progression. The subgroup of patients who received TPP appeared to have similar baseline characteristics and response to initial treatment compared to the overall population. This suggests that a treatment strategy that includes TPP may not benefit the overall population. The risks of TPP should be weighed against the low likelihood of a PR and the potential for changing to a different therapy with a higher likelihood of benefit.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar^®), vinorelbine (Navelbine^®) and irinotecan (Campto^®), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20–30% and 1-year survival rates of 30–40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-α. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Efficacy of plasma TGF-β1 level in predicting therapeutic efficacy and prognosis in patients with advanced non-small cell lung cancer

We hypothesized that serial assessment of TGF-β1 during chemotherapy might predict therapeutic response and prognosis in non-small cell lung cancer (NSCLC) patients. Plasma TGF-β1 levels were quantified before first, second, and third cycles of chemotherapy in 42 advanced NSCLC patients and correlated with therapeutic response. Plasma TGF-β1 levels measured before first and second cycles of chemotherapy failed to predict response to therapy. The increased presence of TGF-β1 measured before second and third cycles of chemotherapy was associated with poor survival. Estimation of plasma TGF-β1 during the course of chemotherapy might not be a reliable biomarker for predicting therapeutic efficacy in NSCLC.     

Relationship of serum levels of VEGF and TGF-β1 with radiosensitivity of elderly patients with unresectable non-small cell lung cancer

This study aimed to evaluate the relationship of serum levels of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) with radiosensitivity of elderly patients with unresectable non-small cell lung cancer (NSCLC) receiving three-dimensional conformal radiation therapy (3D-CRT). Fifty-eight elderly patients with unresectable NSCLC and 40 healthy controls were enrolled in this study. Serum levels of VEGF and TGF-β1 were detected by the enzyme-linked immunosorbent assay (ELISA) method before and after 3D-CRT. Clinical performances of serum VEGF and TGF-β1 levels in predicting radiosensitivity of NSCLC patients with 3D-CRT were evaluated. Serum VEGF and TGF-β1 levels of NSCLC patients were higher than those of health controls (all p?<?0.05). After 3D-CRT treatment, 41 patients achieved effective clinical response (complete response (CR)?+?partial response (PR)) and 17 patients were ineffective clinical response (stable disease (SD)?+?progressive disease (PD)). There was no significant difference in the VEGF and TGF-β1 levels between the effective and ineffective groups before 3D-CRT (all p?>?0.05). Serum levels of VEGF and TGF-β1 after 3D-CRT in the effective group were lower compared with the levels before 3D-CRT treatment (p?<?0.001 and 0.027, respectively). However, no significant differences in serum VEGF and TGF-β1 levels between before and after 3D-CRT in the ineffective group were observed (p?=?0.196 and 0.517, respectively). We observed significant differences in serum VEGF and TGF-β1 levels between the effective and ineffective groups after 3D-CRT (p?<?0.001 and 0.013, respectively). Sensitivity and specificity of VEGF combined with TGF-β1 in predicting radiosensitivity of NSCLC patients with 3D-CRT were 87.8 and 94.1 %, respectively. In conclusion, our results indicate that serum VEGF and TGF-β1 levels may accurately predict radiosensitivity of elderly patients with unresectable NSCLC receiving 3D-CRT.     

The role of βIII-tubulin in non-small cell lung cancer patients treated by taxane-based chemotherapy

Background

The aim of this study is to evaluate whether class III β-tubulin (TUBB3) expression could predict progression-free survival or overall survival in relapsed non-small cell lung cancer (NSCLC) patients treated with taxene-based chemotherapy.

Methods

Immunohistochemistal staining was used to examine the expression of TUBB3 in resected lung tumor specimens obtained from 56 patients treated with platinum-based chemotherapy against recurrent tumors after curative resections. Excision repair cross-complementation group 1, breast cancer susceptibility gene 1, vascular endothelial growth factor, Ki-67, CD34, and p53 were also correlated with clinical features and outcome after treatment.

Results

Of the 56 patients enrolled in the study, 29 were treated by carboplatin plus paclitaxel as first-line treatment, and 24 patients received docetaxel monotherapy as second- or third-line treatment. A positive TUBB3 expression is closely associated with a poor response to taxane-based chemotherapy. TUBB3 expression was an independent prognostic factor for predicting poor progression-free survival after docetaxel administration. However, TUBB3 expression could not predict outcome after carboplatin plus paclitaxel treatment. The other biomarkers tested were not independent prognostic factors for predicting outcome after taxane-based chemotherapy.

Conclusion

TUBB3 expression is associated with resistance to taxane-based chemotherapy and is an independent prognostic factor for predicting poor progression-free survival after docetaxel treatment alone. TUBB3 expression may be a predictive marker for chemoresistance to docetaxel in NSCLC with postoperative recurrent disease.     

ASAP3 expression in non-small cell lung cancer: association with cancer development and patients’ clinical outcome

ASAP3 belongs to Arf-specific GTPase-activating proteins which regulate Arfs by stimulating their intrinsic GTP hydrolysis. ASAP3 expression and the clinical significance in malignant tumors are largely unknown. In this study, we examined ASAP3 expression in non-small cell lung cancer (NSCLC) to find out its clinicopathological significance. Immunohistochemistry shows elevated expression of ASAP3 in cancer tissues (54.8 % (57/104)) compared to normal lung tissues (18.0 % (9/50)) (p?<?0.05). Increased ASAP3 expression was associated with poor differentiation, lymph node metastasis, and advanced TNM stages in NSCLC (p?<?0.05). Survival analysis reveals that ASAP3 expression contributes to patients’ poor clinical outcome (p?<?0.05). We also examined ASAP3 expression in several lung cancer cell lines using Western blotting. We downregulated ASAP3 expression in LTE cell which has a relative high level of ASAP3 expression using siRNA and found that reduced ASAP3 leads to significant inhibition of cancer cell invasion (p?<?0.05). These data indicate that ASAP3 is elevated in NSCLC and may contribute to cancer development and patients’ poor clinical outcome, which is possibly due to its critical roles in regulating cancer invasion.