To perform a cost-effectiveness analysis of primary chemoradiation therapy (CRT) versus transoral robotic surgery (TORS) for clinical N2, human papillomavirus (HPV)-positive oropharyngeal carcinoma.
...We developed a Markov model to describe the health states after treatment with CRT or TORS, followed by adjuvant radiation therapy or CRT in the presence of high-risk pathology (positive margins or extracapsular extension). Outcomes, toxicities, and costs were extracted from the literature. One-way sensitivity analyses (SA) were performed over a wide range of parameters, as were 2-way SA between the key variables. Probabilistic SA and value of information studies were performed over key parameters.
The expected quality-adjusted life years (QALYs)/total costs for CRT and TORS were 7.31/$50,100 and 7.29/$62,200, respectively, so that CRT dominated TORS. In SA, primary CRT was almost always cost-effective up to a societal willingness-to-pay of $200,000/QALY, unless the locoregional recurrence risk after TORS was 30% to 50% lower, at which point it became cost effective at a willingness-to-pay of $50-100,000/QALY. Probabilistic SA confirmed the importance of locoregional recurrence risk, and the value of information in precisely knowing this parameter was more than $7M per year. If the long-term utility after TORS was 0.03 lower than CRT, CRT was cost-effective over nearly any assumption.
Under nearly all assumptions, primary CRT was the cost-effective therapy for HPV-associated, clinical N2 OPC. However, in the hypothetical event of a large relative improvement in LRR with surgery and equivalent long-term utilities, primary TORS would become the higher-value treatment, arguing for prospective, comparative study of the 2 paradigms.
The VeriStrat test is a serum proteomic signature originally discovered in non-responders to second line gefitinib treatment and subsequently used to predict differential benefit from erlotinib ...versus chemotherapy in previously treated advanced non-small cell lung cancer (NSCLC). Multiple studies highlight the clinical utility of the VeriStrat test, however, the mechanistic connection between VeriStrat-poor classification and poor prognosis in untreated and previously treated patients is still an active area of research. The aim of this study was to correlate VeriStrat status with other circulating biomarkers in advanced NSCLC patients - each with respect to clinical outcomes.
Serum samples were prospectively collected from 57 patients receiving salvage chemotherapy and 70 non-EGFR mutated patients receiving erlotinib. Patients were classified as either VeriStrat good or poor based on the VeriStrat test. Luminex immunoassays were used to measure circulating levels of 102 distinct biomarkers implicated in tumor aggressiveness and treatment resistance. A Cox PH model was used to evaluate associations between biomarker levels and clinical outcome, whereas the association of VeriStrat classifications with biomarker levels was assessed via the Mann-Whitney Rank Sum test.
VeriStrat was prognostic for outcome within the erlotinib treated patients (HR = 0.29, p < 0.0001) and predictive of differential treatment benefit between erlotinib and chemotherapy ((interaction HR = 0.25; interaction p = 0.0035). A total of 27 biomarkers out of 102 unique analytes were found to be significantly associated with OS (Cox PH p ≤ 0.05), whereas 16 biomarkers were found to be associated with PFS. Thrombospondin-2, C-reactive protein, TNF-receptor I, and placental growth factor were the analytes most highly associated with OS, all with Cox PH p-values ≤0.0001. VeriStrat status was found to be significantly associated with 23 circulating biomarkers (Mann-Whitney Rank Sum p ≤ 0.05), 6 of which had p < 0.001, including C-reactive protein, IL-6, serum amyloid A, CYFRA 21.1, IGF-II, osteopontin, and ferritin.
Strong associations were observed between survival and VeriStrat classifications as well as select circulating biomarkers associated with fibrosis, inflammation, and acute phase reactants as part of this study. The associations between these biomarkers and VeriStrat classification might have therapeutic implications for poor prognosis NSCLC patients, particularly with new immunotherapeutic treatment options.
Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape ...is changing rapidly as a result of the positive impact of effective inhibitors of tumor driver mutations, and the more recent discovery that immune modulation with anti-PD-1/PD-L1 monoclonal antibodies results in tumor regression and prolonged survival. While a relatively small subset of lung cancer patients are candidates for inhibitors of driver mutations, the majority of advanced lung cancer patients are candidates for an immunotherapy regimen. Many of these patients have cachexia, which is associated with increased cancer therapy toxicity and possibly reduced responsiveness to immunotherapy. Two ongoing cachexia trials, one testing a ghrelin analogue and the other testing a multimodal strategy, have endpoints which assess clinical benefit-weight gain and relief of anorexia/cachexia symptoms. Provided that the trial objectives are achieved, these treatment strategies will provide a way to relieve suffering and distress for cachectic cancer patients. While awaiting the results of these trials, it would be reasonable to consider designing studies testing cachexia treatments combined with first-line immunotherapy and chemotherapy-immunotherapy in stage IV lung cancer patients, with enhanced overall survival being one of the endpoints.
First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (
) mutation is a tyrosine kinase inhibitor (TKI). Despite higher ...response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients.
This study is a retrospective review of 137 patients with advanced
-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses.
On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282-7.029,
= 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063-1.425,
= 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS.
Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.
The optimal locoregional therapy for stage IIIA non-small cell lung cancer (NSCLC) is controversial, with definitive chemoradiation therapy (CRT) and neoadjuvant therapy followed by surgery (NT-S) ...serving as competing strategies. In this study, we used the National Cancer Database to determine the prevalence and predictors of NT in a large, modern cohort of patients.
Patients with stage IIIA NSCLC treated with CRT or NT-S between 2003 and 2010 at programs accredited by the Commission on Cancer were included. Predictors were categorized as clinical, time/geographic, socioeconomic, and institutional. In accord with the National Cancer Database, institutions were classified as academic/research program and as comprehensive and noncomprehensive community cancer centers. Logistic regression and random effects multilevel logistic regression were performed for univariable and multivariable analyses, respectively.
The cohort consisted of 18,581 patients, 3,087 (16.6%) of whom underwent NT-S (10.6% induction CRT, 6% induction chemotherapy). The prevalence of NT-S was constant over time, but there were significant relative 31% and 30% decreases in pneumonectomy and right-sided pneumonectomy, respectively, over time (P trend <.02). In addition to younger age, lower T stage, and favorable comorbidity score, indicators of higher socioeconomic status were strong independent predictors of NT-S, including white race, higher income, and private/managed insurance. The type of institution (academic/research program vs comprehensive or noncomprehensive community cancer centers, odds ratio 1.54 and 2.08, respectively) strongly predicted NT-S, but treatment volume did not.
Neoadjuvant therapy followed by surgery was an uncommon treatment approach in Commission on Cancer programs, and the prevalence of postinduction pneumonectomy decreased over time. Higher socioeconomic status and treatment at academic institutions were significant predictors of NT-S. Further research should be performed to enable a better understanding of these disparities.
The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine ...kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.
In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with ...cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring
mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic
mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval CI, 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the
-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the
-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the
hypothesis warrant consideration.
Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome ...differs by race and ethnicity is relatively understudied.
The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients.
Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408).
Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation.
Preoperative concurrent chemoradiotherapy (CRT) is an accepted treatment for potentially resectable, locally advanced, non-small-cell lung cancer (NSCLC). We reviewed a decade of single institution ...experience with preoperative split-course CRT followed by surgical resection to evaluate survival and identify factors that may be helpful in predicting outcome.
All patients treated with preoperative split-course CRT and resection at Rush University Medical Center (RUMC) between January 1999 and December 2008 were retrospectively analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), local-regional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS). Patient and treatment related variables were assessed for correlation with outcomes.
A total of 54 patients were analyzed, 76% Stage IIIA, 18% Stage IIIB, and 6% oligometastatic. The pathologic complete response (pCR) rate was 31.5%, and the absence of nodal metastases (pN0) was 64.8%. Median OS and 3-year actuarial survival were 44.6 months and 50%, respectively. Univariate analysis revealed initial stage (p < 0.01) and percent weight change during CRT (p < 0.01) significantly correlated with PFS/OS. On multivariate analysis initial stage (HR, 2.4; 95% CI, 1.18-4.90; p = 0.02) and percent weight change (HR, 0.79; 95% CI, 0.67-0.93; p < 0.01) maintained significance with respect to OS. There were no cases of Grade 3+ esophagitis, and there was a single case of Grade 3 febrile neutropenia.
The strong correlation between weight change during CRT and OS/PFS suggests that this clinical parameter may be useful as a complementary source of predictive information in addition to accepted factors such as pathological response.
The aim of this study was to assess the efficacy of maintenance pembrolizumab in patients with extensive-stage SCLC after treatment with platinum and etoposide.
Patients with extensive-stage SCLC ...with a response or stable disease after induction chemotherapy were eligible. Pembrolizumab at a dose of 200 mg administered intravenously every 3 weeks was initiated within 8 weeks of the last cycle of chemotherapy. The primary end point of the study was progression-free survival (PFS) from study registration, with overall survival (OS) as a key secondary end point. Available tumor tissue was assessed for expression of programmed death ligand 1 (PD-L1) both in the tumor cells and in the surrounding stroma. Blood for circulating tumor cells was collected before the first, second, and third cycles of pembrolizumab.
Of the 45 patients enrolled, 56% were male and 22% had treated brain metastases. The median PFS was 1.4 months (95% confidence interval CI: 1.3–2.8), with a 1-year PFS of 13%. The median OS was 9.6 months (95% CI: 7.0–12), with a 1-year OS of 37%. Of the 30 tumors that could be assessed, three had PD-L1 expression (≥1%) in the tumor cells. A total of 20 tumors could be assessed for PD-L1 expression in the stroma. The median PFS in the eight patients with tumors positive for expression of PD-L1 at the stromal interface was 6.5 months (95% CI: 1.1–12.8) compared with 1.3 months (95% CI: 0.6–2.5) in 12 patients with tumors negative for this marker. No unexpected toxicities were observed.
Maintenance pembrolizumab did not appear to improve median PFS compared with the historical data. However, the 1-year PFS rate of 13% and OS rate of 37% suggest that a subset of patients did benefit from pembrolizumab.
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