Circulating Tumor DNA Detection in the Management of Anti-EGFR Therapy for Advanced Colorectal Cancer

Background: Anti-EGFR antibodies are a standard care for advanced KRAS-wild type colorectal cancers. Circulating tumor DNA (ctDNA) monitoring during therapy can detect emergence of KRAS mutant clones and early resistance to therapy.Case Presentation: We describe a 61-years-old man presenting a metastatic and recurrent rectal cancer treated with different chemotherapy regimens. His tumor was KRAS wild-type based on tissue analysis and he was treated sequentially with cetuximab-based chemotherapy, chemotherapy alone and panitumumab-based chemotherapy. We performed sequential analysis of ctDNA using droplet digital PCR (ddPCR) and a commercial assay designed for the detection of frequent KRAS mutations during his clinical follow-up. Prior to the first cetuximab-based chemotherapy ctDNA analysis demonstrated an absence of KRAS mutations. Emergence of KRAS mutations in ctDNA occurred ~3 months after treatment initiation and preceded clinical and imaging progression in about 2 months. Fractional abundance of KRAS mutation rapidly increased to 70.7% immediately before a chemotherapy alone regimen was initiated. Interestingly, KRAS mutation abundance decreased significantly during the first two months of chemotherapy, reaching a fractional abundance of 3.0%, despite minimal clinical benefit with this therapy. Re-challenge with a different anti-EGFR antibody was attempted as later line, but high levels of KRAS mutations in ctDNA before therapy correlated with an absence of clinical benefit.Conclusions: The monitoring of resistance mutations in KRAS using ctDNA during the treatment of KRAS wild-type advanced colorectal cancers can detect the emergence of resistant clones prior to clinical progression. Dynamics of resistant clones may alter during periods on and off anti-EGFR antibodies, detecting window of opportunities for a re-challenge with these therapies

Efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma

OBJECTIVES: To evaluate the efficacy and safety of sorafenib in elderly patients with advanced hepatocellular carcinoma (HCC). METHODS: We analyzed data from a cohort of patients with advanced HCC treated using systemic treatment according to the local institutional protocol. Patients were divided into two groups, Group A, individuals o70 years of age, and Group B, individuals 70 years of age or older at the time of treatment initiation. Efficacy, measured based on overall survival (OS) and time to treatment failure (TTF), and toxicity were compared between groups. RESULTS: A total of 238 patients with advanced HCC who received sorafenib between 2007 and 2018 were evaluated. The median age for Group A was 59.1 years and that for Group B 73.6 years. The major prognostic characteristics were balanced between the groups. There were no significant differences in OS between Group A (8.0 months, 95%CI 6.34–9.3) and Group B (9.0 months, 95%CI 5.38–12.62), p=0.433, or in TTF between Group A (3.0 months, 95%CI 2.39–3.60) and Group B (3.0 months, 95%CI 1.68–4.32), p=0.936. There were no significant differences between Groups A and B with respect to the incidence of adverse events or treatment discontinuation because of toxicity. CONCLUSION: Efficacy and safety of sorafenib did not differ significantly between younger and older patients with HCC. Our data suggest that age alone should not restrict clinical decision-making for patients with advanced HCC

Increasing the Rates of Complete Response to Neoadjuvant Chemoradiotherapy for Distal Rectal Cancer: Results of a Prospective Study Using Additional Chemotherapy During the Resting Period

OBJECTIVES: Addition of chemotherapy in the resting period between radiotherapy completion and response assessment during neoadjuvant treatment for distal rectal cancer could potentially increase rates of complete tumor regression. The purpose of this study was to evaluate toxicity rates and the impact of an extended neoadjuvant chemoradiation regimen on complete response rates. METHODS: Thirty-four consecutive patients with nonmetastatic distal rectal cancer were prospectively included. Patients were managed by 5,400 Gy of radiation and 5-fluorouracil/leucovorin-based chemotherapy given for three consecutive days every 21 days for six cycles (three cycles concomitant with radiotherapy). Tumor response assessment was performed at ten weeks from radiation completion. Patients with complete clinical response were strictly monitored and were not immediately operated on. Patients with incomplete clinical response were referred to surgery. RESULTS: Twenty-nine patients had completed 12 months of follow-up and were included in this preliminary analysis. Twenty-eight (97%) successfully completed treatment. Fifteen of 16 patients had Grade III toxicities that were skin-related (93%). Median follow-up was 23 months. Fourteen patients (48%) were considered as complete clinical responders sustained for at least 12 months (median, 24 months) after chemoradiation completion by clinical assessment alone. An additional five patients (17%) were considered as complete responders with ypT0 results after full-thickness local excision. Overall, the complete response rate was 65%. CONCLUSIONS: The addition of chemotherapy during the resting period after neoadjuvant chemoradiation is associated with acceptable toxicity and high tolerability rates. The considerably high rates of complete response in this preliminary series requires further follow-up, but they may provide valuable information for future prospective, randomized trials

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib

Abstract Background Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. Methods A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model. Results Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 – 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3–4 in 44.4% of the patients. Conclusion In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression