Expert Consensus Document on Pulmonary Metastasectomy Handy, John R.; Bremner, Ross M.; Crocenzi, Todd S. ...
The Annals of thoracic surgery,
February 2019, 2019-02-00, 20190201, Letnik:
107, Številka:
2
Journal Article
A key challenge in the treatment of advanced non-small-cell lung cancer (NSCLC) is improving outcomes for patients who have achieved at least stable disease after standard first-line therapy. ...Although current guidelines recommend a maximum of six cycles of first-line therapy, even in responding patients, recent trials have shown benefit with maintenance therapy.
We reviewed the English literature for randomized controlled trials on prolonged therapy for NSCLC conducted between January 1999 and January 2010. The search was supplemented by a review of abstracts presented at the American Society of Clinical Oncology annual meetings (2004 to 2010), the World Lung Cancer Conference (2007 to 2009), and the 2009 Joint European CanCer Organisation-European Society for Medical Oncology conference.
Several alternative strategies for prolongation of chemotherapy have been tested: these can be broadly categorized as continuation (prolongation of the first-line regimen until disease progression, unacceptable toxicity, or administration of a predefined greater number of treatment cycles), switch-maintenance (administration of an active agent immediately after completion of the initial course of chemotherapy), and continuation-maintenance (ongoing administration of a lower intensity version of the first-line chemotherapy regimen). These approaches differ from traditional second line, which is defined as treatment administered after documented clinical progression subsequent to first-line therapy.
There are no data to support continuation chemotherapy in advanced NSCLC. Switch-maintenance trials with erlotinib and pemetrexed have demonstrated an improvement in overall survival. Thus far, continuation-maintenance has shown an improvement in progression-free survival, without an overall survival advantage.
Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non-small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum ...clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression.
The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m(2)) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m(2) on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL).
Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups.
We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.
Objective To determine the response rate, toxicity, and rate of complete resection after induction chemoradiotherapy for locally advanced thymic tumors, which were defined by specific radiographic ...criteria. Methods A single-arm, pilot trial was conducted at 4 institutions. Patients with thymoma or thymic carcinoma who met specific criteria on computed tomography were accrued. Induction therapy consisted of 2 cycles of cisplatin and etoposide combined with 45 Gy of thoracic radiotherapy. Patients underwent computed tomography and positron emission tomography before and after induction therapy and then resection was attempted. Postoperative chemoradiotherapy was administered in selected patients. The primary endpoint was the pathologic response to induction therapy. The secondary endpoints were toxicity, surgical complications, radiographic response, and the rate of R0 resection. Results A total of 22 patients were accrued during a 5-year period (1 patient withdrew before starting induction therapy). Of the 22 patients, 21 completed induction therapy, and 9 (41%) experienced grade 3 or 4 toxicity. A total of 10 patients had a partial radiographic response and 11 had stable disease. Of the 21 patients, 17 (77%) underwent an R0 resection, 3 (14%) an R1 resection, and 1 (5%) underwent debulking. Eight patients sustained surgical complications (36%), and two patients (9%) died postoperatively. Of the 21 patients, 13 (62%) had either thymic carcinoma or B3 thymoma and 15 (71%) had either Masaoka stage III or IV disease. No patient had a complete pathologic response, but 5 specimens (24%) had <10% viable tumor. Conclusions The present induction chemoradiotherapy protocol, which used specific computed tomography inclusion criteria to successfully select locally advanced thymic tumors, appeared to be tolerable and resulted in a high rate of complete surgical resection.
Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired ...drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
Mutations in BRAF are present in 4% of non-small cell lung cancer (NSCLC), of which half are well-characterized activating variants affecting codon 600 (classified as class I). These mutations, most ...commonly BRAF V600E, have been associated with response to BRAF/MEK-directed small molecule kinase inhibitors. NSCLC with kinase-activating BRAF mutations occurring at other codons (class II variants) represent a substantial portion of BRAF-mutated NSCLC, but use of targeted therapy in these tumors is still under investigation. Class II mutations have been described in other tumor types and have been associated with response to BRAF/MEK-targeted agents, although optimal treatment strategies for these patients are lacking. This report presents a case of a woman with metastatic NSCLC harboring a class II BRAF p.N486_P490del variant who had a sustained clinical response to combination therapy with dabrafenib and trametinib. This first report of the use of BRAF/MEK-targeted therapy for this variant in NSCLC supports consideration of such treatment for tumors with class II BRAF variants.
Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor ...cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.
Significance A better mechanistic understanding of the survival benefits and identification of biomarkers of response would greatly enhance the optimal utilization of antiangiogenic agents such as ...bevacizumab in combination with chemotherapy in the treatment of cancer. This study indicates that the benefits of bevacizumab with chemotherapy in non–small cell lung cancer (NSCLC) patients may depend on tumor vascular function during treatment. These correlative studies also provide new insights into the selection of NSCLC patients most likely to benefit from the addition of bevacizumab treatment to chemotherapy. The imaging and circulating biomarker candidates should be further evaluated in larger studies.
Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non–small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population—may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.
The mechanisms of acquired resistance to the irreversible EGFR inhibitor afatinib are not well documented. We performed this prospective clinical trial to determine the prevalence of the mutation ...T790M in afatinib-resistant patients.
Eligible patients had EGFR mutations; they were tyrosine kinase inhibitor–naive and were treated with afatinib, 40 mg daily. At enrollment, patients consented to a future repeat biopsy at the time of acquired resistance.
A total of 24 patients were enrolled. The objective response rate was 58% (95% confidence interval CI: 37–78) with a median progression-free survival of 11.4 months (95% CI: 5.9–13.7) and median overall survival of 20.8 months (95% CI: 15.1–40.5). Of the 24 patients enrolled, 23 progressed and only 14 completed repeat biopsy at time of progression, with 11 samples sufficient for molecular analysis. Of those 11 patients, four (36% 95% CI: 10.9–69.2) harbored T790M.
T790M is likely a common resistance mechanism in patients treated with first-line afatinib. Although repeat biopsies at progression are crucial in elucidating resistance mechanisms, this study suggests that clinical and technical issues often limit their feasibility, highlighting the importance of developing noninvasive tumor-genotyping strategies.
This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced ...non–small-cell lung cancer.
Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.
Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.
HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.
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