Neoadjuvant Osimertinib Followed by Sequential Definitive Radiation Therapy and/or Surgery in Stage III Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer: An Open-Label, Single-Arm, Phase 2 Study.

PURPOSE: The treatment for unresectable, locally advanced stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiation therapy (CRT) followed by consolidation durvalumab. This study aimed to evaluate the benefit of neoadjuvant osimertinib as an alternative therapy to this approach with the aim of reducing the radiation field. METHODS AND MATERIALS: This investigation was a nonrandomized, open-label, single-arm, phase 2, prospective, proof-of-concept study. Eligible patients were classified as having treatment-naïve, nonoperable, stage III epidermal growth factor receptor-mutant NSCLC. Patients received 80 mg of oral osimertinib daily for 12 weeks before definitive radiation therapy (RT) and/or surgery. The response was assessed at weeks 6 and 12. For responders, sequential definitive RT and/or surgery were planned. Nonresponders were started on standard CRT. After RT ± surgery or CRT, patients were followed for 2 years without adjuvant therapy. The primary endpoint was the objective response rate (ORR), with September 20, 2022, set as the cut-off for data collection. Secondary endpoints were safety and the gross tumor volume (GTV), planned tumor volume (PTV), and the percentage of total lung volume minus GTV exceeding 20 Gy (V20%) before versus after osimertinib. Exploratory analyses included assessments of the presence of plasma circulating tumor-free DNA (ctDNA) before osimertinib treatment, at weeks 6 and 12, at the end of RT, and 6 weeks post-RT. RESULTS: Twenty-four patients were included (19 women; median age, 73 years; range, 51-82 years). Nineteen of 24 had never smoked, 20 of 24 had adenocarcinoma, 16 of 24 had exon 19 deletions, and 8 of 24 had exon 21 mutations. Participants had stage IIIA (10), IIIB (9), or IIIC (5) disease. Three patients were excluded from the analysis (1 dropped out and 2 were still undergoing osimertinib treatment at the cut-off date). The ORR to induction osimertinib was 95.2% (17 partial response, 3 complete response, and 1 progressive disease). After induction osimertinib, 13 of 20 patients were definitively radiated, 3 of 20 underwent surgery, and 5 of 20 were excluded. Four patients were restaged as stage IV (contralateral ground-glass opacities responded to osimertinib), and 1 patient withdrew informed consent. Three patients underwent surgery, one of whom was treated with RT. Two patients achieved pT1aN0, and one achieved pathologic complete response. The median GTV, PTV, and V20% before osimertinib treatment were 47.4 ± 76.9 cm3 (13.5-234.9), 227.0 ± 258.8 cm3 (77.8-929.2), and 27.1 ± 16.4% (6.2-60.3), respectively. The values after osimertinib treatment were 27.5 ± 42.3 cm3 (2.99-137.7; -48 ± 20%; P = .02), 181.9 ±198.4 cm3 (54-718.1; -31 ± 20%; P = .01), and 21.8 ± 11.7% (9.1-44.15; -24 ± 40%; P = .04), respectively. PTV/GTV/V20% reduction was associated with tumor size and central location. The median follow-up time was 28.71 months (range, 0.4-45.1 months), and median disease-free survival was not reached (mean, 30.59; standard error, 3.94; 95% confidence interval, 22.86-38.31). ctDNA was detected in 5 patients; 4 of 5 were positive for ctDNA at baseline and became negative during osimertinib induction but were again positive after osimertinib treatment was terminated. Interestingly, 3 patients who were ctDNA negative at baseline became weakly positive after RT and then were negative at follow-up. No significant adverse events were reported during the osimertinib or radiation phases. CONCLUSIONS: Neoadjuvant osimertinib therapy is feasible in patients with stage III lung cancer NSCLC, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile. Osimertinib induction for 12 weeks before definitive radiation (chemo-free) significantly reduced the radiation field by nearly 50% with a linear association with tumor size. Further studies are needed to test this chemo-free approach for long-term outcomes before practices are changed.

[FDG PET/CT FOR TREATMENT RESPONSE ASSESSMENT IN CANCER].

INTRODUCTION: FDG PET/CT (fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT)) imaging reflects functional-metabolic changes occurring within the malignant process in response to therapy. Since these changes usually precede anatomic alterations, this imaging technique is highly valuable in assessing response during and after therapy and is superior to CT. FDG PET/CT following initiation of cancer therapy has a prognostic value, predicting progression free survival and overall survival. In some malignancies FDG PET/CT can guide personalized medicine by tailoring therapy in accordance with the metabolic cancer response in the individual patient. In lymphoma patients, including Hodgkin's disease (HD) and diffuse large B-cell lymphoma (DLBCL), FDG PET/CT is useful for monitoring response and guiding therapy, both after and early during therapy. Various quantitative and visual criteria systems are used for assessing cancer response to therapy by FDG PET/CT. Acquaintance with these interpretation methods and their adjustment to new anti-cancerous mechanisms such as in immunotherapy, is important for accurate imaging and meaningful interpretation. Large prospective meticulously performed studies, using standardized methodology, are required to further establish and expand the use of FDG PET/CT for the assessment of response to therapy in various malignancies.

Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P<0.001) in the dexrazoxane group, but no significant difference in the incidence of treatment delays or cancellations. The incidence of cardiac events was the same in both treatment groups with and without dexrazoxane. There was a nonsignificantly lower mortality rate in the dexrazoxane group (9.6%) compared with the nondexrazoxane group (15.0%) at data lock. Adding dexrazoxane to doxorubicin in adjuvant therapy patients leads to higher rates of bone marrow suppression in all blood components, as well as more febrile neutropenia events, and dose reductions. No differences in events defined as cardiac toxicities were detected. Dexrazoxane had no detrimental effect on survival, despite the higher hematological toxicity, the older median age, and the higher prevalence of HER2-positive disease in the dexrazoxane group.

The diagnostic and prognostic value of ProGRP in lung cancer.

AIM: To investigate the diagnostic and prognostic significance of pro-gastrin-releasing peptide (ProGRP) in non-small cell (NSCLC) and small cell lung cancer (SCLC) and compare this marker with other known serum markers in lung cancer. PATIENTS AND METHODS: Serum levels of ProGRP, neuron-specific enolase (NSE), CYFRA 21-1 and carcinoembryonic antigen (CEA) were measured in 37 patients with benign pulmonary disease (BPD), 88 with advanced NSCLC and 37 with SCLC. RESULTS: The ProGRP assay showed a better clinical performance than that of NSE in discriminating between SCLC and BPD or NSCLC, especially at specificity higher than 90%. ProGRP and NSE sensitivity in SCLC at 95% specificity versus the BPD group was 78.4% and 48.6%, (p=0.001) and at 97.7% specificity versus NSCLC, 75.7% and 37.8%, respectively (p=0.001). A significant association of low ProGRP levels with high-grade NSCLC tumors was found (p=0.002). A univariate analysis showed a significant association of ProGRP with survival both in NSCLC and SCLC (p=0.03 and p=0.04, respectively). In multivariate analysis, performance status (PS) and CYFRA 21-1 in NSCLC, and PS, CYFRA 21-1 and serum lactic dehydrogenase in SCLC were found as significant variables with an independent impact on survival. CONCLUSION: ProGRP is a useful marker in SCLC, with diagnostic performance better than that of NSE and demonstrating association with survival in NSCLC and SCLC limited to univariate analysis.

Computed tomography screening for lung cancer: applicability of an international protocol in a single-institution environment.

BACKGROUND: The purpose of this study was to assess the applicability of an annual low-dose computed tomography (CT) screening program for lung cancer in a single institution in Israel, which has a relatively lower prevalence of lung cancer compared with other Western countries, and to examine stage distribution of detected lung cancers. PATIENTS AND METHODS: A cohort of 842 former and current smokers underwent baseline low-dose CT screening and a total of 942 annual repeat screenings over a period of 68 months. The definition of positive results on baseline and repeat screening and their diagnostic workup were guided by the common International Early Lung Cancer Action Program protocol. Recommendations for biopsy of suspicious nodules were based on nodule size, nodule growth, non-resolution following antibiotic therapy, and positron emission tomography scan. RESULTS: The test result was positive in 102 of the 842 baseline screenings (12%) and in 45 of the 942 annual repeat screenings (5%), and biopsy was recommended in 12 baseline and 2 annual screenings. Twelve of the 14 cancers diagnosed (86%) were stage I tumors. CONCLUSION: Our study indicates that the adoption of a common international protocol is feasible, even in a very different clinical setting, yielding a high proportion of early-stage lung cancers.

The prognostic significance of circulating neuroendocrine markers chromogranin a, pro-gastrin-releasing peptide and neuron-specific enolase in patients with advanced non-small-cell lung cancer.

BACKGROUND: Chromogranin A (CGA), Pro-gastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE) are known as immunohistochemical tissue markers closely associated with neuroendocrine differentiation in non-small-cell lung carcinoma (NSCLC). The aim of the present study was to assess the value of serum levels of these markers in predicting response to chemotherapy and survival of patients with unresectable NSCLC. METHODS: The study included 67 patients with advanced NSCLC treated with chemotherapy. Before treatment, serum levels of CGA, ProGRP and NSE were measured with commercial kits. RESULTS: No association was found between serum NSE and age, gender, histology, performance status or extent of the disease. Distribution of serum CGA differed significantly according to gender and histology, with higher levels being found in men (p = 0.01) and in squamous cell carcinoma (p = 0.01). Serum ProGRP levels correlated with disease extent, being higher in patients with metastatic disease (M1) than in those with locoregional disease (M0; p = 0.02). The association of NSE, CGA and ProGRP levels with response to chemotherapy was not significant. While NSE had no impact on survival, the median survival was shorter for patients with elevated serum CGA and longer for patients with high ProGRP levels. Association with survival was significant when the Classification and Regression Tree (CART)-derived or median cutoff points were explored. On inclusion in multivariate Cox models, both CGA and ProGRP retained significance with high levels showing an opposite effect on survival [CART-derived cutoff points: CGA, relative risk (RR) -4.0; p < 0.001, and ProGRP, RR -0.4; p = 0.006, and median cutoff points: CGA, RR -1.8; p = 0.04, and ProGRP, RR -0.5; p = 0.03]. The combined use of CGA, ProGRP and NSE allowed for definition of two sets of patients with significantly different median survival times (25.2 vs. 8.8 months, p = 0.0001). CONCLUSIONS: In the circulation, CGA and Pro-GRP appear to bear important information related to the prognosis for NSCLC patients before chemotherapy. While a high CGA before treatment was found as an unfavorable prognostic determinant, a high ProGRP conferred a survival advantage. The combined use of serum CGA, ProGRP and NSE may supply additional information to prognosis.