Second–line chemotherapy for non—small–cell lung cancer

Most of the experience with second-line chemotherapy for non-small-cell lung cancer (NSCLC) comes from small phase II trials, which have shown disappointing or inconsistent results. The notable exception has been docetaxel, which has been extensively studied as a second-line therapy for NSCLC. On the basis of consistent phase II activity, two large randomized phase III trials were conducted for patients with advanced NSCLC that had progressed either on or after first-line platinum-based therapy. In one trial, docetaxel, at either 100 or 75 mg/m2, was compared with a regimen of either vinorelbine or ifosfamide. In the second trial, docetaxel 75 to 100 mg/m2 was compared with best supportive care. Both trials showed significant improvement in survival, time to progression, and quality of life in the patients receiving docetaxel versus the control therapy. Based on these two large trials, it appears that the use of second-line therapy with single-agent docetaxel at a dose of 75 mg/m2 every 3 weeks is a reasonable practice in patients who maintain a good performance status.     

Treatment and relapse of interstitial lung disease in nivolumab-treated patients with non–small cell lung cancer

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non–small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post–marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.     

Conformal radiotherapy of stage III non–small cell lung cancer: a class solution involving non–coplanar intensity-modulated beams

Purpose: We developed a semiautomatic class solution to irradiate centrally located Stage III non–small cell lung cancer (NSCLC), involving a beam intensity modulation technique and optimization using a biophysical cost function.Methods and Materials: Treatment for 10 patients with Stage III NSCLC was planned, using a conventional three- or four-beam three-dimensional (3D) technique and two techniques involving, respectively, seven (BIM1) and five (BIM2) noncoplanar beam incidences with intensity modulation. Two planning target volumes were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic disease. Beams were divided into beam parts (segments) and their outlines were defined during virtual simulation. Optimization using a biophysical cost function determined beam weights, segment weights, and wedge angles. Biological end points included tumor control probability of both target volumes (TCP1 and TCP2) and normal tissue complication probability (NTCP) of heart, lung, and spinal cord. The resulting uncomplicated local control probability (UCLP) was calculated. Physical end points included dose at PTV1 expressed as a dose minimum and dose maximum. Target-dose inhomogeneity was constrained in all plans.Results: Concerning tumor evaluation, TCP1 was 74% (range 54–89%) for the 3D plan, 78.0% (range 62–94%) for BIM1, and 86.0% (range 59–93%) for BIM2. TCP1 1 TCP2 was, respectively, 67.0% (range 39–81%), 73.0% (range 56–94%), and 81.0% (range 54–93%). Minimum doses to PTV1 were 85, 80, and 88 Gy with the three respective techniques, while dose maxima were 89, 101, and 100 Gy. NTCPs of lung were 45.0% (range 11–75%) for 3D, 19.5% (range 8–59%) for BIM1, and 24.5% (range 3–61%) for BIM2. NTCPs of heart and spinal cord were comparable for all techniques. ULCPs were 37.0% (range 9–73%), 52.5% (range 22–86%), and 60.0% (range 20–85%), respectively. Applying physical limits to ensure clinical safety, minimum doses at PTV1 were recalculated. These were 72, 71, and 74 Gy for 3D, BIM1, and BIM2, respectively.Conclusion: The BIM2 plan is a candidate class solution for dose escalation studies in centrally located Stage III NSCLC.     

Radiographic features and poor prognostic factors of interstitial lung disease with nivolumab for non–small cell lung cancer

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non–small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia–like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia–like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia–like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.     

Targeting the PD-1/PD-L1 axis in non–small cell lung cancer

The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non–small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting; however, nivolumab failed to show a survival benefit possibly relating to patient selection based on PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research focuses on the development of PD-1 and PD-L1 inhibitor monotherapy in neoadjuvant and adjuvant NSCLC. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities including cytotoxic chemotherapies in the first-line NSCLC, other immunotherapies such as cytotoxic T-lymphocyte–associated protein 4 antagonists, molecularly targeted agents including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest owing to the potential for the abscopal effect, using radiotherapy to facilitate systemic treatment.     

Should extrapulmonary small cell cancer be managed like small cell lung cancer?

BACKGROUND:

The aim of this study was to determine if extrapulmonary small cell carcinomas (EPSCC) should be managed using protocols similar to those for small cell lung cancer (SCLC).

METHODS:

Treatment strategies, survival, patterns of failure, and prognostic factors for patients with EPSCC were analyzed retrospectively at a large cancer center. SCLC was excluded by thoracic computed tomography (75%) or chest radiography (25%).

RESULTS:

Of 120 eligible patients, 70% had limited disease (LD). Treatment modalities included chemotherapy (n = 82; 68%), radiotherapy (RT) (n = 80; 67%), and surgery (n = 41, 34%). The median survival for patients with LD and extensive disease was 1.4 years and 0.7 years, respectively. Gynecologic (n = 31) and gastrointestinal (n = 28) were the most common primary tumor sites. Gynecologic and head and neck primary tumor sites had better 1‐year survival than other sites (P = .019 and 0.005, respectively). Brain metastasis was the site of first distant failure in 4.1% of patients versus 35% for soft tissue metastases. The lifetime risk of brain metastasis was 13%. Definitive RT (P = .004), LD (P = .028), and prophylactic cranial irradiation (PCI) (P = .022) were found to be positive prognostic factors and weight loss (P < .001) was a negative prognostic factor on multivariate analysis.

CONCLUSIONS:

Patients with EPSCC usually experienced short survival, often with early distant metastasis. Although PCI was associated with improved overall survival, brain metastasis was less frequent than in patients with SCLC, and therefore the potential benefit of PCI was less than in patients with SCLC. Definitive chemoradiotherapy was associated with better outcomes and should be delivered whenever feasible. Cancer 2010. © 2010 American Cancer Society.     

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non–small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non-small cell lung cancer （NSCLC） patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age 〉 65 years （P = 0.011）, smoking status （P = 0.009）, intracranial symptoms （P = 0.022）, clinical T category （P = 0.010）, clinical N category （P = 0.003）, increased partial thromboplastin time （P 〈 0,001）, and platelet count （P 〈 0.001）. Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration （median, 17.3 months versus 11.1 months; P 〈 0.001）. A similar result was observed for platelet counts （median, 16.3 months versus 11.4 months; P = 0.004）. Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases （R2 = 1.698, P 〈 0.001 and R2 = 1.699, P 〈 0.001, respectively）. Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.     

The role of new agents in advanced non—small–cell lung carcinoma

Over the past 5 to 7 years, new and promising systemic agents have entered the therapeutic armamentarium in the treatment of advanced non-small-cell lung cancer. In particular, the taxanes, irinotecan, vinorelbine, and gemcitabine, have each been shown to perturb the natural history of this disease. In combination with cisplatin, these agents have yielded improvements in response rates and in survival, compared with either cisplatin alone or with older platinum combinations, with consistent 1-year survival rates of 30% to 40% or more and response rates exceeding 25%. Other factors may also be responsible for improved survival rates, including patient selection, improved supportive care, and more extensive screening procedures, such as CT and positron emission tomography, which have resulted in stage migration. Future directions will focus on the role of nonplatinum combinations, particularly in the elderly and in patients with compromised performance status; salvage therapy in patients with intact performance status; quality of life and quality adjusted survival; and the role of new biologic agents, which alter the tumor milieu and may be readily integrated into standard cytotoxic regimens. Except for unfit or unwilling patients, there is no room for therapeutic nihilism.     

TNF-α enhancement of CD62E mediates adhesion of non–small cell lung cancer cells to brain endothelium via CD15 in lung-brain metastasis

BackgroundCD15, which is overexpressed on various cancers, has been reported as a cell adhesion molecule that plays a key role in non-CNS metastasis. However, the role of CD15 in brain metastasis is largely unexplored. This study provides a better understanding of CD15/CD62E interaction, enhanced by tumor necrosis factor-α (TNF-α), and its correlation with brain metastasis in non–small cell lung cancer (NSCLC).MethodsCD15 and E-selectin (CD62E) expression was demonstrated in both human primary and metastatic NSCLC cells using flow cytometry, immunofluorescence, and Western blotting. The role of CD15 was investigated using an adhesion assay under static and physiological flow live-cell conditions. Human tissue sections were examined using immunohistochemistry.ResultsCD15, which was weakly expressed on hCMEC/D3 human brain endothelial cells, was expressed at high levels on metastatic NSCLC cells (NCI-H1299, SEBTA-001, and SEBTA-005) and at lower levels on primary NSCLC (COR-L105 and A549) cells (P < .001). The highest expression of CD62E was observed on hCMEC/D3 cells activated with TNF-α, with lower levels on metastatic NSCLC cells followed by primary NSCLC cells. Metastatic NSCLC cells adhered most strongly to hCMEC/D3 compared with primary NSCLC cells. CD15 immunoblocking decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (P < .0001), confirming a correlation between CD15 and cerebral metastasis. Both CD15 and CD62E expression were detected in lung metastatic brain biopsies.ConclusionThis study enhances the understanding of cancer cell-brain endothelial adhesion and confirms that CD15 plays a crucial role in adhesion in concert with TNF-α activation of its binding partner, CD62E.     

Immune checkpoint inhibitors in advanced non–small cell lung cancer: A metacentric experience from India

BackgroundImmune check point inhibitors (ICIs) have changed the treatment paradigm of driver mutation negative non–small cell lung cancer (NSCLC) and they are increasingly incorporated in first-line treatment. Real-world experience of use of these drugs is limited. We aim to evaluate the real-world experience of use of ICIs in patients with advanced NSCLC.Patients and methodsMedical records of patients with NSCLC treated with ICIs at 4 major academic cancer centers in India between January 2016 and December 2018 were analyzed. The type of ICI taken, response rates, survival, and toxicity profiles were analyzed.ResultsThe median age at presentation was 60 years (range: 27-79 years). Nivolumab was the most commonly used ICI drug [80%, n = 70] followed by pembrolizumab [10%, n = 9], and atezolizumab [10%, n = 9]. The median number of ICIs cycles received were 4 (range 2-65). Among the evaluable responses in 74 patients, the objective response rates was 25.6% and clinical benefit rate was 46%. Immune related toxicity occurred in 39.9% of patients but, severe toxicity of Grade III and Grade IV occurred in 5 (5.6%) patients. After a median follow-up time of 8.86 months (95%CI 5.2-11.1) the progression-free survival was 4.73 months (95%CI 3.7-8.9), and overall survival was 11.6 months (95%CI 7.33-NR). ECOG PS at the time of start of ICIs was found to be significant determinant of Progression-free survival and overall survival.ConclusionOur study demonstrates the feasibility of usage of ICIs in advanced NSCLC in Indian setting with acceptable safety profile and comparable responses with the published studies.     

Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non–small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified.

Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations.

Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.