The importance of non-small cell lung cancer (NSCLC) histologic subtype has increased during the last few decades because of an unprecedented shift in epidemiology and an increasing number of ...target-specific chemotherapeutic agents. This review examined histology as a potential prognostic and/or predictive factor of clinical outcomes in advanced NSCLC.
Literature searches of articles from 1982 to 2007 were conducted. We identified publications detailing phase II or III studies, retrospective analyses, and meta-analyses that reported a statistically significant prognostic or predictive role for histology.
Of 408 publications identified, 11 reported a prognostic association between histology and clinical outcomes, and 7 suggested that histologic subtype was predictive of outcomes in patients with advanced NSCLC treated with specific cytotoxic chemotherapy regimens. Fourteen publications reported histology was prognostic and/or predictive in patients treated with epidermal growth factor receptor inhibitors. Inadequate data collection, test methodology, or study design—including insufficient sample size, misclassified samples, and grouping of histologic subtypes for analysis—may have obscured the interpretation of the role of histology in many of the studies.
Although differences in study design and analyses make definitive conclusions difficult, evidence suggests that histology may be prognostic or predictive of clinical efficacy outcomes. To determine which patients would benefit from specific treatments and to further understand the role of histology, future studies should focus on establishing a definitive histologic diagnosis, and should include an analysis of histologic subtypes and efficacy outcomes.
The patient‐reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE) complements capture of symptomatic adverse events (AEs) by clinicians. Previous trials have ...typically used a limited subset of relevant symptomatic AEs to reduce patient burden. We aimed to determine the feasibility of administering all 80 AEs included in the PRO‐CTCAE library by approaching consecutive patients enrolled in a large academic phase I program at three points in time. Here, we report a preplanned analysis after enrolling the first 20 patients. All items were answered on 51 of 56 potential visits (adherence 91%). Three (5%) additional PRO‐CTCAE assessments were partially completed, and two (4%) were missed because of conflicting appointments. No patient withdrew consent or chose not to complete the assessments once enrolled on study. Future trials of experimental drugs that incorporate the PRO‐CTCAE should consider using this unselected approach to identify adverse events more completely.
Evidence shows that subjective toxicities are underreported in patients with cancer and that collection of this information directly from patients can improve the reliability and precision of symptomatic adverse events detection. This study reported the feasibility of using the complete set of subjective symptoms from PRO‐CTCAE library developed by the National Cancer Institute in patients on phase I clinical trials.
Abstract Aim The aim is to evaluate the impact of cisplatin dose modification on outcomes of human papillomavirus (HPV)-related (HPV+) and HPV-unrelated (HPV−) locally advanced head and neck cancer ...(LAHNC) treated with chemoradiotherapy (CRT). Patients and methods A pooled analysis was conducted of stage III/IV oropharyngeal cancer (OPC), carcinoma of unknown primary (CUP) and laryngo-hypopharyngeal cancer (LHC) patients treated with single-agent cisplatin CRT in 2000–2012 from two tertiary academic cancer centres. HPV status was determined by p16 staining and/or in situ hybridisation. LHC was assumed to be HPV−. Unknown HPV status OPC/CUPs were excluded. Overall survival (OS) was calculated. Multivariable analysis (MVA) evaluated the impact of cisplatin dose intensity on survival for HPV+ and HPV− cohorts separately. Results A total of 404 HPV+ and 255 HPV− LAHNC (481 OPC, 18 CUP, 160 LHC) patients were included. Median follow-up was 4.3 (0.5–11.9) years. Three-year OS for cisplatin <200, =200, and >200 mg/m2 subgroups were 52%, 60%, and 72% ( P = 0.001) for the HPV− and 91%, 90%, and 91% ( P = 0.30) for the HPV+ patients. MVA confirmed a survival benefit with cisplatin >200 mg/m2 for the HPV− (hazard ratio HR 0.5, 95% confidence interval CI: 0.3–0.7, P < 0.001) but not for HPV+ (HR 0.6, 95% CI: 0.4–1.1, P = 0.104). There was a superior OS trend in the HPV+ T4 or N3 high-risk subset ( N = 107) with cisplatin >200 mg/m2 (HR 0.5, 95% CI: 0.2–1.1, P = 0.07). Conclusions A survival benefit of cisplatin dose >200 mg/m2 is evident for HPV− LAHNC patients, but not for HPV+ cohort overall, although the T4 or N3 subset may benefit from a higher cumulative cisplatin dose.
•Definitive RT/CRT for OSCC achieved acceptable rate of locoregional control.•Definitive RT is a reasonable alternative treatment strategy if surgery is not possible.•cN2-3 is associated with poor ...distant control, DFS, and OS.
To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT).
All OSCC patients treated radically with IMRT (without primary surgery) between 2005–2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed.
Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p < 0.02) on multivariable analysis. Grade ≥ 3 late toxicity was reported in 9% of patients (most common: grade 3 osteoradionecrosis in 6%).
Non-operative management of OSCC resulted in a meaningful rate of locoregional control, and could be an alternative curative approach when primary surgery would be declined, unsuitable or unacceptably delayed.
Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on ...conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.
Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non–small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related ...adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug–induced diarrhea, with implications for optimizing treatment with such agents.
BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors are treated with targeted therapies. Effective treatment has not been established for Class 2/3 ...or BRAF Fusions. We investigated whether BRAF mutation class differed according to clinical, genomic, and transcriptomic variables in cancer patients.
Using the AACR GENIE (v.12) cancer database, the distribution of BRAF mutation class in adult cancer patients was analyzed according to sex, age, primary race, and tumor type. Genomic alteration data and transcriptomic analysis was performed using The Cancer Genome Atlas.
BRAF mutations were identified in 9515 (6.2%) samples among 153,834, with melanoma (31%), CRC (20.7%), and NSCLC (13.9%) being the most frequent cancer types. Class 1 harbored co-mutations outside of the MAPK pathway (TERT, RFN43) vs. Class 2/3 mutations (RAS, NF1). Across all tumor types, Class 2/3 were enriched for alterations in genes involved in UV response and WNT/β-catenin. Pathway analysis revealed enrichment of WNT/β-catenin and Hedgehog signaling in non-V600 mutated CRC. Males had a higher proportion of Class 3 mutations vs. females (17.4% vs. 12.3% q = 0.003). Non-V600 mutations were generally more common in older patients (aged 60+) vs. younger (38% vs. 15%
< 0.0001), except in CRC (15% vs. 30% q = 0.0001). Black race was associated with non-V600 BRAF alterations (OR: 1.58;
< 0.0001).
Class 2/3 BRAFs are more present in Black male patients with co-mutations outside of the MAPK pathway, likely requiring additional oncogenic input for tumorigenesis. Improving access to NGS and trial enrollment will help the development of targeted therapies for non-V600 BRAF mutations.
We aimed to investigate the impact of lymph node ratio (LNR, number of positive nodes/total number of excised nodes) on regional-only-failure, distant-only-failure and overall survival (OS) in oral ...squamous cell carcinoma (OSCC).
Retrospective review of pN0-2 OSCC-patients (1994–2012) treated with curative-surgery with neck dissection±postoperative radiotherapy (PORT)±concurrent chemotherapy. LNR was subjected to multivariable analysis (MVA) of regional-only-failure, distant-only-failure and OS.
Overall 914 patients were identified; median follow-up: 51months (1–189); pN0: 482 (52.7%), pN1: 128 (14%), pN2a: 6 (0.7%); pN2b: 225 (24.6%); pN2c: 73 (8%); median number of dissected nodes: 36 (6–125); median number of pN+: 2 (1–49); median LNR for pN+ patients: 6%; extranodal extension: 187 (20.5%). Bilateral neck dissection: 368 (40.3%); PORT: 452 (49.5%); and concurrent chemotherapy: 80 (8.8%). High grade, lymphovascular invasion perineural invasion and pT3–4 were associated with high LNR. On MVA, LNR was associated with regional-only-failure (HR=1.06; 95%CI: 1.04–1.08; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.02–1.05; p=0.004) and lower OS (HR=1.03; 95%CI: 1.02–1.05; p<0.001). Similarly, in pN2-subgroup: LNR was associated with regional-only-failure (HR=1.04; 95%CI: 1.02–1.06; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.01–1.06; p=0.045) and lower OS (HR=1.03; 95%CI: 1.02–1.04; p<0.001).
High LNR is associated with higher regional-only-failure/distant-only-failure and lower OS. LNR should be assessed in future prospective trials for selection of adjuvant therapy.
Immune checkpoint inhibitors have revolutionized cancer treatment. They can induce cutaneous immune-related adverse events. One patient with immune-related eczema and two with immune-related bullous ...pemphigoid were successfully treated with dupilumab. Guidelines recommend the use of systemic steroids to manage moderate-to-severe cutaneous immune-related adverse events. They could potentially interfere with immunotherapy. There is a need to find alternative treatments that are safe in a cancer setting.
Despite more than 2 years having elapsed since the onset of SARS-CoV-2 pandemic, a level of hesitation around increased SARS-CoV-2 vaccine toxicity in cancer patients receiving immunotherapy (IO) ...remains. This hesitation stems from the idea that IO agents could elicit an overwhelming immune stimulation post vaccination and therefore increase the risk of vaccine-related toxicity. The aim of our study was to explore serological responses to SARS-CoV-2 vaccination in patients treated with IO and describe the level of immune stimulation using parameters such as blood cytokines, autoantibody levels and immune related adverse events (irAEs) post vaccination. Fifty-one evaluable patients were enrolled in this longitudinal study. Absolute levels and neutralization potential of anti-SARS-CoV-2 antibodies were not significantly different in the IO group compared to non-IO. Chemotherapy adversely affected seroconversion when compared to IO and/or targeted treatment. Following vaccination, the prevalence of grade ≥2 irAEs in patients treated with IO was not higher than the usual reported IO toxicity. We report, for the first time, that anti-SARS-CoV-2 vaccination, elicited the generation of five autoantibodies. The significantly increased autoantibodies were IgM autoantibodies against beta-2 glycoprotein (p = 0.02), myeloperoxidase (p = 0.03), nucleosome (p = 0.041), SPLUNC2 (p < 0.001) and IgG autoantibody against Myosin Heavy Chain 6 (MYH6) (p < 0.001). Overall, comprehensive analysis of a small cohort showed that co-administration of SARS-CoV-2 vaccine and IO is not associated with increased irAEs. Nevertheless, the detection of autoantibodies post anti-SARS-CoV-2 vaccination warrants further investigation (NCT03702309).
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