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Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer.

ABSTRACT: To test, in a single-arm, prospective, phase 2 trial, whether adding the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to concurrent chemoradiotherapy for previously untreated, locally advanced, inoperable non-small cell lung cancer would improve survival and disease control without increasing toxicity.Forty-eight patients with previously untreated non-small cell lung cancer received intensity modulated radiation therapy (63 Gy/35 fractions) on Monday through Friday, with chemotherapy (paclitaxel 45 mg/m², carboplatin area under the curve [AUC] = 2) on Mondays, for 7 weeks. All patients also received the EGFR tyrosine kinase inhibitor erlotinib (150 mg orally 1/d) on Tuesday-Sunday for 7 weeks, followed by consolidation paclitaxel-carboplatin. The primary endpoint was time to progression; secondary endpoints were overall survival (OS), toxicity, response, and disease control and whether any endpoint differed by EGFR mutation status.Of 46 patients evaluable for response, 40 were former or never-smokers, and 41 were evaluable for EGFR mutations (37 wild-type [WT] and 4 mutated [all adenocarcinoma]). Median time to progression was 14.0 months and did not differ by EGFR status. Toxicity was acceptable (no grade 5, 1 grade 4, 11 grade 3). Twelve patients (26%) had complete responses (10 WT, 2 mutated), 27 (59%) partial (21 WT, 2 mutated, 4 unknown), and 7 (15%) none (6 WT, 2 mutated, 1 unknown) (P=.610). At 37.0 months' follow-up (range, 3.6-76.5 months) for all patients, median OS time was 36.5 months, and 1-, 2-, and 5-year OS rates were 82.6%, 67.4%, and 35.9%, respectively; none differed by mutation status. Twelve patients had no progression, and 34 had local and/or distant failure. Eleven of 27 distant failures were in the brain (7 WT, 3 mutated, 1 unknown).Toxicity and OS were promising, but time to progression did not meet expectations. The prevalence of distant failures underscores the need for effective systemic therapy.

SUBMITTER: Komaki R

PROVIDER: S-EPMC4432249 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer.

Komaki Ritsuko R Allen Pamela K PK Wei Xiong X Blumenschein George R GR Tang Ximing X Lee J Jack JJ Welsh James W JW Wistuba Ignacio I II Liu Diane D DD Hong Waun Ki WK

International journal of radiation oncology, biology, physics 20150601 2

<h4>Purpose</h4>To test, in a single-arm, prospective, phase 2 trial, whether adding the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to concurrent chemoradiotherapy for previously untreated, locally advanced, inoperable non-small cell lung cancer would improve survival and disease control without increasing toxicity.<h4>Methods and materials</h4>Forty-eight patients with previously untreated non-small cell lung cancer received intensity modulated radiation therapy ...[more]

PMID: 25968826

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Project description:BACKGROUND:We evaluated the impact of thoracic radiation in patients with non-small cell lung cancer (NSCLC), considering the depletion of total lymphocytes, use or not of chemotherapy, and radiation doses in healthy lung tissue. METHODS:Patients with stage III NSCLC, ECOG 0 to 2, receiving radiotherapy with or without chemotherapy were prospectively evaluated. All patients should be treated with three-dimensional radiotherapy and received biologically effective doses (BED10?/? 10) of 48 to 80 Gy. Peripheral blood lymphocyte total counts were measured at the start of radiotherapy and at 2, 6 and 12 months after radiotherapy. Along with lymphocytes, PTV and doses of 5 Gy and 20 Gy in healthy lung tissue were also evaluated as potential factors influencing overall survival (OS) and progression-free survival (PFS). RESULTS:A total of 46 patients were prospectively evaluated from April 2016 to August 2019, with a median follow-up of 13 months (interquartile range, 1-39 months). The median of OS of all cohort was 22,8 months (IC 95% 17,6-28,1) and the median PFS was 19,5 months (IC 95%: 14,7-24,2). Most patients received concurrent or neoadjuvant chemotherapy (43; 93.4%). No patient received adjuvant immunotherapy. The lower the lymphocyte loss at 6 months after radiotherapy (every 100 lymphocytes/mcL), the greater the chance of PFS (HR, 0.44; 95%CI, 0.25-0.77; P?=?0.004) and OS (HR, 0.83; 95%CI, 0.70-0.98; P?=?0.025; P?=?0.025). BED was a protective factor for both PFS (HR, 0.52; 95%CI 0.33-0.83; P?=?0.0006) and OS (HR, 0.73; 95%CI 0.54-0.97; P?=?0.029). CONCLUSIONS:Our results suggest that lymphocyte depletion after radiotherapy reduces tumor control and survival in patients with stage III lung cancer. Radiation doses equal or higher than 60?Gy (BED10 72 Gy) improve PFS and OS, but they negatively affect lymphocyte counts for months, which reduces survival and the potential of immunotherapy. KEY POINTS:SIGNIFICANT FINDINGS OF THE STUDY: Thoracic irradiation for locally advanced lung cancer depletes T lymphocytes for months. Patients whose lymphocyte loss is lower have better overall survival and progression-free survival. WHAT THIS STUDY ADDS:It is necessary to protect the lymphocyte population, as well as other organs at risk. New forms of irradiation for large fields are needed. Furthermore, could immunotherapy before chemo-radiotherapy, with a greater number of lymphocytes, bring an even better result?

Project description:the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. in the training cohort, 100 Stage II-III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95-1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32-0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28-0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18-0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10-0.56, p < 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09-0.86, p = 0.025). our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II-III melanoma patients.

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Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer.

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Adding Erlotinib to Chemoradiation Improves Overall Survival but Not Progression-Free Survival in Stage III Non-Small Cell Lung Cancer.

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