Fluoropyrimidine-based Chemotherapy Research Articles

Nineteen-year, real-world experience of first-line combination chemotherapy in patients with metastatic colorectal cancer: a propensity score analysis from southern Thailand.

Combination fluoropyrimidine-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (CRC). We performed a propensity score (PS)-based analysis to report our real-world experience with long-term follow-up of this regimen for metastatic CRC. In this retrospective study, 170 patients with newly diagnosed metastatic CRC treated with first-line combination chemotherapy between January 2003 and March 2021 were identified. Cox proportional hazards regression analysis and PS-based approaches with the logistic regression model were adopted, and the results were compared. The hazard ratio for overall survival (OS) in the oxaliplatin- and irinotecan-based groups was 0.79 (95% confidence interval = 0.56-1.11), and the median OS times in these groups were 16.8 and 13.0 months, respectively. The median time to progression (TTP) for these regimens were 9.0 and 8.9 months, respectively. The objective response rates for the oxaliplatin- and irinotecan-based groups were 42.7% and 34.6%, respectively. OS and TTP did not differ between these regimens in all PS matching models. First-line treatment using fluoropyrimidine-based chemotherapy regimens in combination with oxaliplatin or irinotecan in patients with metastatic CRC provided comparable efficacy and tolerable toxicity profiles in a real-world setting with long-term follow-up.

Changes in Prescribing Patterns in Stage III Colon Cancer.

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Budget impact and transferability of cost-effectiveness of DPYD testing in metastatic breast cancer in three health systems.

The cost-effectiveness andbudget impact of introducing extended DPYD testing prior to fluoropyrimidine-based chemotherapy in metastatic breast cancer patients in the UK, The Netherlands and Hungary were examined. DPYD testing with ToxNav© was cost-effective in all three countries. In the UK and The Netherlands, the ToxNavstrategy led to more quality-adjusted life yearsand fewer costs to the health systems compared with no genetic testing and standard dosing of capecitabine/5-fluorouracil. In Hungary, the ToxNavstrategy produced more quality-adjusted life years at a higher costcompared with no testing and standard dose. The ToxNavstrategy was found to offer budget savings in the UK and in The Netherlands, while in Hungary it resulted in additional budget costs.

Circulating tumor DNA (ctDNA) to assess response in patients with anal cancer treated with definitive chemoradiation.

3524 Background: We hypothesize that circulating tumor DNA (ctDNA) dynamics can provide an early response indicator in patients with anal squamous cell carcinoma (ASCC) undergoing definitive chemoradiotherapy (CRT). Methods: Since 2021, patients with ASCC undergoing CRT at 2 institutions were offered ctDNA monitoring with the Natera Signatera assay, a commercial tumor-bespoke, multiplex PCR assay. All patients provided written informed consent for ctDNA testing. Patients were clinically restaged 3-4 months after CRT by clinical exam, endoscopy, and/or MRI, as well as annually with a chest, abdomen, and pelvis CT. Complete clinical response (cCR) was defined as having no tumor observed by digital exam, endoscopy, and/or MRI. Molecular ctDNA response was described according to cCR, tumor recurrence, and survival. Results: From January 2021 to October 2022, 41 patients with ASCC treated with CRT underwent ctDNA response assessment. Most patients (66%) had stage III disease. Patients were treated to a median radiation dose of 54 Gy in 27 fractions — with combinatorial mitomycin and fluoropyrimidine-based chemotherapy in 88% of patients, and fluoropyrimidine-based chemotherapy alone in 12%. The median follow-up was 22 weeks (range 0-89 weeks). ctDNA testing was performed in 36 patients at baseline, 31 patients during CRT, 27 patients within 40 days after CRT, 23 patients 3-6 months post-CRT, 23 patients 6-12 months post CRT, and 10 patients &gt; 12 months post CRT. At baseline, 89% of patients had detectable ctDNA. Patients with stage III, as compared to stage I-II, disease had numerically higher baseline ctDNA levels (29 vs. 2.9 mean tumor molecules per milliliter (MTM/mL), p = 0.04). ctDNA levels decreased with treatment (24 vs. 2.1 MTM/mL, p = 0.005) among the 24 patients with detectable baseline ctDNA and ctDNA tested during CRT. Fifty eight percent of patients converted from ctDNA positive to ctDNA negative during CRT. Similarly, post-CRT ctDNA levels decreased (23 vs. 0.01 MTM/mL, p = 0.01), with 95% of patients converting from ctDNA positive to ctDNA negative. The time to ctDNA clearance was significantly shorter than the time to cCR (median 31 vs. 131 days, p &lt; 0.0001). In follow up 2 patients reverted from ctDNA negative to ctDNA positive at 113 -155 days post-CRT. Currently all patients are clinically and radiographically without evidence of disease. Conclusions: Surveillance ctDNA monitoring provides an earlier response assessment for patients with ASCC undergoing CRT. However, longer term follow-up is required to determine if ctDNA response correlates with long-term recurrence free survival. Prospective trials are needed to assess the clinical utility of integrating molecular ctDNA response into therapeutic response surveillance.

Real-world treatment trends and outcomes in elderly patients with metastatic colorectal cancer in the United States.

3591 Background: Prospective data to guide management of elderly patients with metastatic colorectal cancer (mCRC) is limited. Whether elderly patients derive the same degree of benefit from doublet chemotherapy as younger patients is not well understood. In this study we utilized real-world data from patients in the United States (US) to evaluate treatment trends and compare overall survival (OS) in younger versus older patients with mCRC who receive first-line (1L) chemotherapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to select patients ≥50 years old (yo) with mCRC treated with 1L fluoropyrimidine-based chemotherapy with or without the addition of targeted therapy. Overall survival from the initiation of 1L therapy, stratified by receipt of a doublet or single agent cytotoxic chemotherapy regimen was assessed independently within three age cohorts (50-69; 70-74, ≥75) using both a cox proportional hazard model and a propensity score weighted analysis to control for potential confounding variables. A subgroup analysis was performed in patients receiving bevacizumab as part of 1L therapy. Results: Of 14,440 patients who received 1L chemotherapy, 5,874 (40.7%) were ≥70 yo, including 3,656 (25.4%) who were 75 or older. Doublet chemotherapy was received by 7,505 (87.6%) patients age 50-64 yo, 1892 (85.3%) patients age 70-74 yo, and 2297 (62.2%) patients age 75 and above. In all three groups, multivariate analysis of single agent chemotherapy vs doublet chemotherapy showed a benefit to doublet chemotherapy with a hazard ratio of 1.14, (95% CI 1.04-1.24, p = 0.006), 1.22 (95% CI 1.05-1.42, p = 0.011) and 1.19 (95% CI 1.10-1.29, p &lt; 0.001), respectively. Similar results were noted when comparing doublet to single agent chemotherapy in the age 70-74 and ≥75 groups using a propensity score weighted analysis. In the subgroup of patients age ≥70 who received 1L bevacizumab, 2,604 received doublet chemotherapy and 441 received single agent chemotherapy. Median OS was 19 mos (95% CI: 18-20) vs 13 (95% CI: 11-15) vs with a propensity score weighted HR of 1.35 (95% CI 1.12-1.63, p = 0.001). Conclusions: A smaller percentage of patients over age 75 receive 1L doublet chemotherapy for mCRC in the US compared to patients age 50-69 or 70-74. Regardless of age, patients who receive doublet fluoropyrimidine-based chemotherapy appear to have improved overall survival compared to single agent chemotherapy. This retrospective US data is in contrast with recently presented data from a prospective phase III trial in Japan (JCOG1018). Elderly patients in the US should not be excluded from receiving doublet chemotherapy for mCRC without further prospective data.

Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma

Appendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease. To prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma. This open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low-grade mucinous appendiceal adenocarcinoma, with radiographic imaging demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered candidates for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of bowel obstruction, and use of total parenteral nutrition. Data were analyzed from November 2021 to May 2022. Patients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation. The primary end point was the percentage difference in tumor growth in treatment and observation groups. Key secondary end points included patient-reported outcomes in the chemotherapy and observation periods, objective response rate, rate of bowel complications, and differences in overall survival (OS). A total of 24 patients were enrolled, with median (range) age of 63 (38 to 82) years, and equal proportion of men and women (eg, 12 men [50%]); all patients had ECOG performance status of 0 or 1. A total of 11 patients were randomized to receive chemotherapy first, and 13 patients were randomized to receive observation first. Most patients (15 patients [63%]) were treated with either fluorouracil or capecitabine as single agent; 3 patients (13%) received doublet chemotherapy (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin or folinic acid, fluorouracil, and irinotecan hydrochloride), and bevacizumab was added to cytotoxic chemotherapy for 5 patients (21%). Fifteen patients were available to evaluate the primary end point of difference in tumor growth during treatment and observation periods. Tumor growth while receiving chemotherapy increased 8.4% (95% CI, 1.5% to 15.3%) from baseline but was not significantly different than tumor growth during observation (4.0%; 95% CI, -0.1% to 8.0%; P = .26). Of 18 patients who received any chemotherapy, none had an objective response (14 patients [77.8%] had stable disease; 4 patients [22.2%] had progressive disease). Median (range) OS was 53.2 (8.1 to 95.5) months, and there was no significant difference in OS between the observation-first group (76.0 [8.6 to 95.5] months) and the treatment-first group (53.2 [8.1 to 64.1] months; hazard ratio, 0.64; 95% CI, 0.16-2.55; P = .48). Patient-reported quality-of-life metrics identified that during treatment, patients experienced significantly worse fatigue (mean [SD] score, 18.5 [18.6] vs 28.9 [21.3]; P = .02), peripheral neuropathy (mean [SD] score, 6.67 [12.28] vs 38.89 [34.88]; P = .01), and financial difficulty (mean [SD] score, 8.9 [15.2] vs 28.9 [33.0]; P = .001) compared with during observation. In this prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma, patients did not derive clinical benefit from fluorouracil-based chemotherapy, given there were no objective responses, no difference in OS when treatment was delayed 6 months, and no difference in the rate of tumor growth while receiving chemotherapy. ClinicalTrials.gov Identifier: NCT01946854.

Frequency of fluoropyrimidine-related toxicity in patients with colon cancer from a Mexican oncology center.

e15616 Background: Fluoropyrimidines are chemotherapeutic agents used in various types of cancer such as colorectal, breast, gastric, etc. Approximately 30% of patients treated with fluoropyrimidines present severe toxicity, which can lead to death in around 1% of them. Reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD) can cause severe fluoropyrimidine-related toxicity. The objective of this study was to identify the frequency of fluoropyrimidine-related toxicity in patients treated at an oncology center from Northeast Mexico. Methods: Retrospective and observational study of patients treated at the Centro Universitario contra el Cáncer (CUCC) in Monterrey, Mexico. Patients older than 18 years with a diagnosis of colon cancer who were treated during 2021 with the diagnosis of colon and considered candidates for fluoropyrimidine-based chemotherapy (5-FU, capecitabine) were included. Pregnant patients were excluded. None of them had a DPYD testing performed. Results: We analyzed 88 patients, of whom 51 (58%) were men, 6 (7%) in stage I, 16 (18%) in stage II, 31 (35%) in stage III, and 35 (40%) in stage IV. The mean age was 59 years, 15 (17%) of them had a PS&gt;2, overall, 94% of patients received fluoropyrimidine-based CT, presenting up to 47 (57%) of toxicities, 26 (32%) in G1, 11 (13%) in G2, and 10 (12%) in G3; no G &gt; 4 toxicities were documented. There were 7 patients (9%) that required CT discontinuation due to toxicity at some point during their treatment (see Table 1). In the subgroup of patients in stage IV, 8 (24%) had PS&gt;2, and 6 (18%) of them had some mutational panel. Conclusions: This is one of the few descriptive studies of toxicities in a population from northeastern Mexico undergoing treatment with fluoropyrimidine-based CT, in which up to 9% of the patients discontinue treatment due to toxicity. Our findings evidence a high percentage of patients with fluoropyrimidine-related toxicity. DPYD testing has not been widely adopted in most oncology centers in Mexico, mostly because of the limited access to genome sequencing. Genetic studies in this population could identify poor metabolizers patients with a high risk of toxicity before starting treatment. [Table: see text]

Upfront palliative resection of primary tumor versus no resection in patients with synchronous metastatic colorectal cancer: The randomized phase 3 CAIRO4 study of the Dutch Colorectal Cancer Group (DCCG).

3517 Background: Primary tumor resection (PTR) in patients with synchronous metastatic colorectal cancer (CRC) has been associated with a survival benefit in comparative cohort studies. In the CAIRO4 phase III randomized trial, the potential benefit of upfront PTR followed by systemic therapy versus systemic therapy alone was investigated. Methods: Main eligibility criteria included histologically confirmed CRC, unresectable metastases, resectable primary tumor in situ without related severe symptoms, and WHO performance status (PS) 0-2. Eligible patients were randomized to first-line fluoropyrimidine-based chemotherapy plus bevacizumab with or without upfront PTR strategy. Randomization was stratified for number of metastatic sites (1 versus more), institution, WHO PS (0-1 versus 2), serum LDH (normal versus &gt; ULN), and location of the primary tumor (left versus right-sided). The primary endpoint was overall survival (OS), which was analyzed by intention-to-treat (ITT) using the MaxCombo test. The original sample size of 306 patients was amended to 206 participants due to slow accrual. With final primary analysis based on 181 events, the study had 71% power to detect the OS difference of 19 versus 13 months deemed clinically relevant in the original sample size calculation. The trial is registered as NCT01606098. Results: Between August 2012 and February 2021, 206 patients were randomized: 103 patients to each arm. Two patients in the upfront PTR arm were excluded due to ineligibility. A total of 204 patients (57% male, median age 65 [IQR 59 -71] years, 50% right-sided CRC and 98% WHO PS 0-1) were included with a median follow-up of 63.6 months. In the upfront PTR arm 5% of patients did not undergo PTR and 13% did not receive subsequent systemic therapy. In the arm without upfront PTR, 1% of patients did not receive systemic therapy. The median number of cycles was 9 [IQR 4-15] in the upfront PTR arm versus 11 [6-16] in the arm without upfront PTR. Median OS was 20.5 (95% CI 17.0 – 25.1) months in the upfront PTR arm and 18.3 (95% CI 16.0 – 22.2) months in the arm without upfront PTR (p = 0.345). Median PFS was 10.1 (95% CI 8.7-11.7) months in the upfront PTR arm and 10.1 (95% CI 8.6-11.8) months in the arm without upfront PTR (p = 0.805). At a later point in their disease course, 1.9% of patients in the arm without upfront PTR underwent a colostomy and 16.5% required PTR for symptom palliation. Conclusions: In patients with synchronous metastatic CRC amenable to palliative systemic therapy without severe symptoms related to the primary tumor, upfront PTR did not result in a significant median OS difference compared to immediate start with systemic treatment. Funding: This work was funded by the Dutch Cancer Society (grant KUN 2012-5697) and Hoffmann-La Roche Ltd. Clinical trial information: NCT01606098 .

Differential Efficacy of Targeted Monoclonal Antibodies in Left-Sided Colon and Rectal Metastatic Cancers

BackgroundThe recommended first-line chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is bevacizumab (BEV)-containing therapy for right-sided colon cancer (R) and antiepidermal growth factor receptor antibody (anti-EGFR)-containing therapy for left-sided colon cancer (L) or rectal cancer (RE). However, anatomical or biological heterogeneity reportedly exists between L and RE. Therefore, we aimed to compare the efficacies of anti-EGFR and BEV therapies for L and RE, respectively. MethodsWe retrospectively reviewed 265 patients with KRAS (RAS)/BRAF wild-type mCRC treated with fluoropyrimidine-based doublet chemotherapy plus anti-EGFR or BEV as the first-line treatment at a single institution. They were divided into 3 groups: R, L, and RE. Overall survival (OS), progression-free survival (PFS), objective response rate, and conversion surgery rate were analyzed. ResultsForty-five patients had R (anti-EGFR/BEV: 6/39), 137 patients had L (45/92), and 83 patients had RE (25/58). In patients with R, both median (m) PFS and OS were superior with BEV therapy (mPFS, anti-EGFR vs. BEV: 8.7 vs. 13.0 months, hazard ratio [HR]: 3.90, P = .01; mOS, 17.1 vs. 33.9 months, HR: 1.54, P = .38). In patients with L, better mPFS and comparable mOS with anti-EGFR therapy were observed (mPFS, 20.0 vs. 13.4 months, HR: 0.68, P = .08; mOS, 44.8 vs. 36.0 months, HR: 0.87, P = .53), whereas, in patients with RE, comparable mPFS and worse mOS with anti-EGFR therapy were observed (mPFS, 17.2 vs. 17.8 months, HR: 1.08, P = .81; mOS, 29.1 vs. 42.2 months, HR: 1.53, P = .17). ConclusionsEfficacies of anti-EGFR and BEV therapies may differ between patients with L and RE.

Advanced statistics identification of participant and treatment predictors associated with severe adverse effects induced by fluoropyrimidine-based chemotherapy

PurposeAdverse effects following fluoropyrimidine-based chemotherapy regimens are common. However, there are no current accepted diagnostic markers for prediction prior to treatment, and the underlying mechanisms remain unclear. This study aimed to determine genetic and non-genetic predictors of adverse effects.MethodsGenomic DNA was analyzed for 25 single nucleotide polymorphisms (SNPs). Demographics, comorbidities, cancer and fluoropyrimidine-based chemotherapy regimen types, and adverse effect data were obtained from clinical records for 155 Australian White participants. Associations were determined by bivariate analysis, logistic regression modeling and Bayesian network analysis.ResultsTwelve different adverse effects were observed in the participants, the most common severe adverse effect was diarrhea (12.9%). Bivariate analysis revealed associations between all adverse effects except neutropenia, between genetic and non-genetic predictors, and between 8 genetic and 12 non-genetic predictors with more than 1 adverse effect. Logistic regression modeling of adverse effects revealed a greater/sole role for six genetic predictors in overall gastrointestinal toxicity, nausea and/or vomiting, constipation, and neutropenia, and for nine non-genetic predictors in diarrhea, mucositis, neuropathy, generalized pain, hand–foot syndrome, skin toxicity, cardiotoxicity and fatigue. The Bayesian network analysis revealed less directly associated predictors (one genetic and six non-genetic) with adverse effects and confirmed associations between six adverse effects, eight genetic predictors and nine non-genetic predictors.ConclusionThis study is the first to link both genetic and non-genetic predictors with adverse effects following fluoropyrimidine-based chemotherapy. Collectively, we report a wealth of information that warrants further investigation to elucidate the clinical significance, especially associations with genetic predictors and adverse effects.

Lessons learned in adjuvant colorectal cancer

SummaryColorectal cancer (CRC) is one of the most frequent malignancies. While adjuvant fluoropyrimidine-based chemotherapy has been established as standard of care for patients with stage III disease, its value and role are still uncertain for stage II disease. This review discusses the usefulness of adjuvant therapy in both stages and highlights the use of liquid biopsy via circulating tumor DNA (ctDNA) for the assessment of minimal residual disease which will shape the therapy decision for adjuvant treatment in future.

Chemotherapy and targeted therapy for advanced biliary tract cancers: an umbrella review

BackgroundMalignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs).MethodsAn umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools.ResultsA total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13–63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2–5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43–36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59–19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39–4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04–10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27–4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7–0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3–10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18–8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients’ OS (HR = 0.91, 95% CI 0.74–1.12, GRADE: Moderate) when compared with best supportive care.ConclusionsThis study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with “Moderate” or “High” levels; however, most of the outcomes were still at “low” or “very low” levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

Ginseng-containing traditional medicine preparations in combination with fluoropyrimidine-based chemotherapy for advanced gastric cancer: A systematic review and meta-analysis.

Ginseng-containing traditional medicine preparations (G-TMPs) in combination with fluoropyrimidine-based chemotherapy (FBC) are well-known treatments for advanced gastric cancer (AGC), with a superior efficacy to FBC alone. However, evidence regarding their efficacy remains limited. The purpose of this meta-analysis is to evaluate the efficacy and safety of G-TMPs in combination with FBC for the treatment of AGC. Eight electronic databases were searched for randomized controlled trials (RCTs) using G-TMPs with FBC for the treatment of AGC. The primary outcome included the tumor response, while the secondary outcomes included the quality of life (QoL), proportions of peripheral blood lymphocytes, adverse drug reactions (ADRs), and levels of cancer biomarkers. The quality of evidence for each outcome was assessed using GRADE profilers. A total of 1,960 participants were involved in the 26 RCTs included. Patients treated with FBC plus G-TMPs had better objective response (risk ratio [RR] = 1.23, 95% confidence interval [CI]: 1.13 to 1.35, p < 0.00001) and disease control (RR = 1.13, 95% CI: 1.08 to 1.19, p < 0.00001) rates than those treated with FBC alone. Additionally, the combination group had a better QoL, higher proportions of CD3+ T cells, CD4+ T cells, and natural killer cells, as well as a higher CD4+/CD8+ T-cell ratio. Furthermore, lower levels of CA19-9, CA72-4, and CEA were confirmed in the combination treatment group. In addition, G-TMPs reduced the incidence of ADRs during chemotherapy. In combination with FBC, G-TMPs can potentially enhance efficacy, reduce ADRs, and improve prognosis for patients with AGC. However, high-quality randomized studies remain warranted. PROSPERO Number: CRD42021264938.

Screening for dihydropyrimidine dehydrogenase deficiency by measuring uracilemia in chronic kidney disease patients is associated with a high rate of false positives

BackgroundPretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on the measurement of plasma uracil ([U]) is recommended prior to the administration of fluoropyrimidine-based chemotherapy. Cancer patients frequently have impaired kidney function, but the extent to which kidney function decline impacts [U] levels has not been comprehensively investigated. MethodsWe assessed the relationship between DPD phenotypes and estimated glomerular filtration rate (eGFR) in 1751 patients who benefited on the same day from a screening for DPD deficiency by measuring [U] and [UH2]:[U], and an evaluation of eGFR. The impact of a kidney function decline on [U] levels and [UH2]:[U] ratio was evaluated. ResultsWe observed that [U] was negatively correlated with eGFR, indicating that [U] levels increase as eGFR declines. For each ml/min of eGFR decrease, [U] value increased in average by 0.035 ng/ml. Using the KDIGO classification of chronic kidney disease (CKD), we observed that [U] values >16 ng/ml (DPD deficiency) were measured in 3.6 % and 4.4 % of stage 1 and 2 CKD (normal-high eGFR, >60 ml/min/1.73 m2) patients, but in 6.7 % of stage 3A CKD patients (45 to 59 ml/min/1.73 m2), 25% of stage 3B CKD patients (30 to 44 ml/min/1.73 m2), 22.7% of stage 4 CKD patients (15 to 29 ml/min/1.73 m2 and 26.7% of stage 5 CKD patients (<15 ml/min/1.73 m2). [UH2]:[U] ratios were not impacted by kidney function. ConclusionDPD phenotyping based on the measurement of plasma [U] in patients with decreased eGFR is associated with an exceedingly high rate of false positives when kidney function decline reaches 45 ml/minute/1.73 m2 of eGFR or lower. In this population, an alternative strategy that remain to be evaluated would be to measure the [UH2]:[U] ratio in addition to [U].

Impact of Geriatric Assessment on the Tolerability of Combination Chemotherapy in Older Patients with Advanced Cancer: A Matched-Pair Analysis

Because of their individual vulnerabilities, treatment decisions for older patients can be difficult. Geriatric assessment (GA) may help to select patients for systemic treatment, but its value is still unproven. Older cancer patients (≥65 years of age) with and without complex GA followed by discussion in the geriatric-oncologic conference, who had been treated in palliative intention with standard combination chemotherapy at the Evang. Kliniken Essen-Mitte, were retrospectively evaluated. All patients had been orally informed about the treatment options and had chosen chemotherapy beside supportive care. To reduce selection bias, the method of propensity-score matching was performed. Patient groups treated in the years 2011–2013 (without GA, group 1) and in the years 2014–2015 (with GA, group 2) were compared regarding different toxicity endpoints. The primary endpoint of the study was defined as numbers of patients with unplanned admission to the hospital or death during first-line chemotherapy and GA should reduce these events by 15%. Overall, 114 patients were evaluated in both groups. The median age was 74 years. Patients suffered from gastrointestinal carcinomas (47%), lung cancer (28%), breast cancer (12%), and other cancer types (3%). Consequently, most patients were treated with platinum-based (41%), fluoropyrimidine-based (35%), or anthracycline-based (13%) combination chemotherapy. In group 2, the events were numerically lower for all toxicity endpoints. The need for a premature stop of treatment was 54.4% in group 1 compared to 29.8% in group 2 (p < 0.01) and also the treatment-related mortality was significantly lower in group 2 (17.5% vs. 5.3%; p = 0.04). The primary endpoint, the rate of unplanned hospital admission, and death was 49.1% versus 35.1% (difference 14.0%), which did not reach the predefined border of 15%. There was a nonsignificant overall survival benefit in the group with GA (22.6 vs. 18.4 months). GA appears useful to better select older patients with advanced cancer for combination chemotherapy. The significant reduction of mortality during chemotherapy justifies the efforts and costs which need to be expended. To evaluate the effect of GA on overall survival, prospective trials are required.

Circulating tumor DNA (ctDNA) for response assessment in patients with anal cancer treated with definitive chemoradiation.

1 Background: We hypothesized that circulating tumor DNA (ctDNA) clearance could provide an early signal for clinical complete response (cCR) and/ or long-term recurrence compared to standard clinical exam modalities in patients with anal squamous cell carcinoma (ASCC) undergoing definitive chemoradiation (CRT). Methods: Since early 2021 patients with ASCC undergoing CRT at 2 institutions were offered ctDNA monitoring with a commercially available tumor-bespoke multiplex PCR assay. All patients provided written informed consent for ctDNA testing. Patients were clinically restaged, 3-4 months post-CRT, by clinical exam, endoscopy, and/ or MRI and annually with CT chest, abdomen, and pelvis. cCR was defined as no tumor by digital exam, endoscopy and/or MRI. Molecular ctDNA response is described according to cCR, tumor recurrence, and survival. Results: From January 2021 to September 2022, 31 patients with ASCC treated with definitive CRT underwent ctDNA response assessment. The majority (68%) of patients had stage III disease. Patients were treated to a median radiation dose of 54Gy in 27 fractions with combinatorial mitomycin and fluoropyrimidine-based chemotherapy in 94%, and fluoropyrimidine-based chemotherapy alone in 6%. The median follow up was 22 weeks. ctDNA testing was performed in 25 of these patients at baseline, 26 patients during CRT, and 20 patients 30-days post-CRT. At baseline 88% of patients had detectable ctDNA. Patients with stage III, as compared to stage I-II, disease had numerically higher baseline ctDNA levels (26 vs 4 mean tumor molecules per milliliter (MTM/mL), p=0.08). ctDNA levels decreased with treatment (19 vs 0.9 MTM/mL, p=0.05) among the 18 patients with detectable ctDNA and ctDNA tested during CRT, with 50% of patients entering molecular remission. Similarly, ctDNA levels decreased (21 vs 0.2 MTM/mL, p=0.05) among the 16 patients with detectable ctDNA and ctDNA tested post-CRT, with 94% entering molecular remission. All patients in molecular remission were confirmed to have a cCR. Time to molecular ctDNA remission was significantly shorter than time to cCR (median 30 vs 135 days, p &lt;0.01). There were no molecular recurrences among the 16, 14, and 7 patients with ctDNA testing at 2-4 months, 4-8 months, and 8-12 months post-CRT. All patients are alive and without clinical/ radiographic evidence of disease. Conclusions: Surveillance ctDNA monitoring may provide an earlier response assessment for patients with ASCC undergoing CRT compared to standard clinical measures. Longer term follow-up is required to determine if ctDNA response correlates with long term recurrence free survival. Larger trials are needed to assess the clinical utility of integrating molecular ctDNA response in therapeutic response surveillance.

Effect of Preoperative Chemotherapy on the Isolation Outcome of Primary Human Hepatocytes.

Primary human hepatocytes isolated from surgically resected liver tissue are an essential resource for pharmaceutical and toxicological studies. Patients undergoing partial liver resections have often received preoperative chemotherapy. The aim of our study was to investigate whether preoperative chemotherapy has effects on the outcome of cell isolation or the metabolic function of cultured hepatocytes. Liver specimens from 48 patients were used for hepatocyte isolation. Out of these, 21 patients had prior chemotherapy, with fluoropyrimidine-based regimen in 14 patients. Viability and cell yield as parameter for the outcome of isolation, as well as transaminase levels, urea or albumin secretion to the culture medium were not different between hepatocytes from pretreated and untreated donor. Furthermore, the transcription levels of cytochrome P450 (CYP) 1A2, CYP 2B6, and CYP 3A4 of cultured hepatocytes were not affected by prior chemotherapy of the tissue donors. In conclusion, hepatocytes from tissue donors that underwent fluoropyrimidine-based chemotherapy regimens before isolation seem to perform as well as hepatocytes without preoperative chemotherapy exposure. Our results suggest that hepatocytes from patients who received combination chemotherapy before liver resection are an uncompromised resource for pharmacological and toxicological studies. Impact statement Isolated primary human hepatocytes are an essential resource for pharmacological and toxicological studies. Our results present further evidence that isolated hepatocytes from patients who received combination chemotherapy before liver resection are an uncompromised resource for pharmacological and toxicological studies-especially when fluoropyrimidine-based regimens are used.

Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.

Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective.

Pembrolizumab plus cisplatin and fluorouracil demonstrated superior efficacy and comparable safety compared with fluorouracil and cisplatin (FP) as first-line treatment for locally advanced unresectable or metastatic carcinoma of the esophagus and gastroesophageal junction adenocarcinoma in a phase III trial (KEYNOTE-590). This study evaluated the cost effectiveness of pembrolizumab plus FP versus FP and versus a blended chemotherapy comparator including FP, carboplatin plus paclitaxel, FOLFOX, FOLFIRI, docetaxel plus FP, trastuzumab plus FP, and trastuzumab plus FOLFOX from a US healthcare payer's perspective. A partitioned survival model was developed with three health states (progression-free, progressive disease, and death). Overall survival, progression-free survival, time on treatment, and adverse events were informed by patient-level data from KEYNOTE-590. The blended chemotherapy comparator reflected the current US treatment landscape and was assumed to have similar efficacy and safety as FP. Health utilities were estimated using linear mixed-effects models based on EQ-5D-5L data from the trial. Resource use and cost inputs (2020 US dollars) were based on US standard sources and literature. Costs, life-years, and quality-adjusted life-years (QALYs) discounted at 3.0% per year and incremental cost-effectiveness ratio were outcomes in the model. Sensitivity and scenario analyses were conducted to assess the robustness of base-case results. Compared with FP, pembrolizumab plus FP produced a mean gain of 0.86 life-year and 0.77 QALY with additional costs of $112,630 over 37.6 years, yielding an incremental cost-effectiveness ratio of $147,097 per QALY. Results were similar when the intervention was pembrolizumab plus alternative chemotherapies or when blended chemotherapy became the comparator. Results were most sensitive to different overall survival extrapolation approaches. Our analysis suggests that pembrolizumab plus chemotherapy extended life-years and QALYs and is cost effective compared with chemotherapy alone as a first-line treatment for advanced esophageal cancer in the USA given a willingness-to-pay threshold of $150,000 per QALY.

The Role of Systemic Therapy in Resectable Colorectal Liver Metastases: Systematic Review and Network Meta-Analysis.

Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.