Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary ...cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail.
We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement.
Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials.
ClinicalTrials.gov NCT01050621.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic.
The target population was divided into three cohorts: ...pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021).
The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort.
The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.
Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We ...hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients.
This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS
EGFR v2 qPCR (Roche) test.
Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (
= 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (
= 0.001).
Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.
The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard ...first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62-13.44) months for first-line treatment, and 4.4 (95% CI: 1.47-7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9-30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5-27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.
The effect of COVID-19 on treatment outcomes in the literature remains limited and is mostly reported either as predictive survival using prioritization and modeling techniques. We aimed to quantify ...the effect of COVID-19 on lung cancer survival using real-world data collected at the Jewish General Hospital, Montreal.
This is a retrospective chart review study of patients diagnosed between March 2019 and March 2022. We compared three cohorts: pre-COVID-19, and 1st and 2nd year of the pandemic.
417 patients were diagnosed and treated with lung cancer at our centre: 130 in 2019, 103 in 2020 and 184 in 2021. Although the proportion of advanced/metastatic-stage lung cancer remained the same, there was a significant increase in the late-stage presentation during the pandemic. The proportion of M1c (multiple extrathoracic sites) cases in 2020 and 2021 was 57% and 51%, respectively, compared to 31% in 2019 (
< 0.05). Median survival for early stages of lung cancer was similar in the three cohorts. However, patients diagnosed in the M1c stage had a significantly increased risk of death. The 6-month mortality rate was 53% in 2021 compared to 47% in 2020 and 29% in 2019 (
= 0.004). The median survival in this subgroup of patients decreased significantly from 13 months in 2019 to 6 months in 2020 and 5 months in 2021 (
< 0.001).
This study is, to our knowledge, the largest single-institution study in Canada looking at lung cancer survival during the COVID-19 pandemic. Our study looks at overall survival in the advanced/metastatic setting of NSCLC during the COVID-19 pandemic. We have previously reported on treatment pattern changes and increased wait times for NSCLC patients during the pandemic. In this study, we report that the advanced/metastatic subgroup had both an increase in the 6-month mortality rate and worsening overall survival during this same time period. Although there was no statistical difference in the proportion of patients with advanced disease, there was a concerning trend of increased M1c disease in cohorts 2 and 3. The higher M1c disease during the COVID-19 pandemic (cohorts 2 and 3) likely played a crucial role in increasing the 6-month mortality rate and leading to a reduced overall survival of lung cancer patients during the pandemic. These findings are more likely to be better identified with longer follow-up.
The risk of symptomatic deep vein thrombosis (DVT) among patients with non-small cell lung cancer (NSCLC) has not been well studied. We conducted a retrospective cohort study of patients with NSCLC ...to determine the incidence of DVT and to characterize predictors of DVT in patients with NSCLC.
The pulmonary oncology database of the Sir Mortimer B. Davis–Jewish General Hospital contains prospectively collected clinical data on lung cancer patients since January 1, 1997. We identified all consecutive patients with histologically confirmed new diagnoses of NSCLC between January 1, 1997 and December 31, 2004, and we determined the occurrence of an objectively defined DVT. Data on clinical and tumor characteristics were collected and compared among patients with DVT and patients without DVT.
Of the 493 NSCLC patients included in the cohort for a total of 634 person-years, 67 (13.6%) patients developed objectively confirmed DVTs, with an incidence of 110 cases (95% confidence interval CI 80, 130) per 1000 person-years. An adjusted multivariable regression analysis showed that advanced stage (rate ratio RR 2.63, 95% CI 1.38, 5.00) and male sex (RR 1.75, 95% CI 1.03–2.94) were independent predictors of DVT.
Our results show a high incidence of DVT in NSCLC patients. Advanced stage and, to a lesser extent, male sex, are important predictors of DVT. Trials to evaluate the use of prophylactic anticoagulant treatments in patients with NSCLC should be conducted.
Background:
Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer ...(NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system.
Methods:
A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model.
Results:
Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195–3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01–0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations.
Conclusion:
The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy.
Abstract Background Multiple studies have demonstrated an increased risk of lung cancer in the presence of emphysema detected visually on computed tomography (CT) independent of smoking history and ...airflow obstruction. The relationship between emphysema and specific histologic subtypes of lung cancer remains uncertain. Objective To determine the extent to which emphysema on chest CT is associated with lung cancer histology. Methods Cross-sectional analysis of consecutive lung cancer patients referred to the Jewish General Hospital was performed (2001–2009). All those with demographic data, smoking history (pack-years), documented histology and chest CT were included. Emphysema was graded on CT by three readers, using a standardized rubric. Odds of each lung cancer subtype were compared between patients with and without emphysema, and adjusted for age, sex, physician diagnosed COPD and smoking history by multiple logistic regression. Results Complete data were available for 498 lung cancer patients (mean age 68 years; 44% female; 16% never smokers; 53% without emphysema on CT). The most common histologies were adenocarcinoma (242 49%), squamous (71 14%), undifferentiated (48 10%) and small cell carcinoma (42 8%). The presence of emphysema was associated with increased odds of squamous (OR 3.1; 95% CI 1.8–5.3) and small cell (OR 2.1; 95% CI 1.1–4.1) carcinoma. After adjustment for age, sex, COPD and smoking history, emphysema was associated with squamous (adjusted OR 2.6; 95% CI 1.4–4.8) but not small cell (adjusted OR 1.5; 95% CI 0.76–3.1) carcinoma. Sensitivity analysis was performed by sequential censoring of each histologic subtype yielding similar results. Adenocarcinoma was less common in the presence of emphysema relative to squamous and small cell carcinoma (adjusted OR 0.62; 95% CI 0.41–0.92). When these latter histologies were censored, no significant association between adenocarcinoma and emphysema was observed (adjusted OR 1.0; 95% CI 0.49–2.1). Conclusions Relative to other histologic subtypes, the odds of squamous carcinoma were significantly increased among lung cancer patients with emphysema after adjustment for age, sex, COPD and smoking history. Other common subtypes were not independently associated with emphysema.
Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with nonsmall cell lung cancer ...(NSCLC).
The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high-performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening.
These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR-TKI. Among 251 patients with advanced disease, 100 individuals received EGFR-TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR-TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR-TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation.
Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types.
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