P-247 Outcomes of randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma

Shen, Jiancheng; Yousef, Abdelrahman M.G.; Zeineddine, Fadl A.; Zeineddine, Mohammad; Tidwell, Rebecca S. Slack; Wolff, Robert A.; Taggart, M.; Uppal, Abhineet; Rafeeq, Safia; Mansfield, Paul F.; Raghav, Kanwal; Overman, Michael J.; Fournier, Keith F.

doi:10.1016/j.annonc.2022.04.337

Cited by 4 publications

(6 citation statements)

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“…This should be studied prospectively, but there could be a role for treatment deescalation in these patients, particularly considering recent prospective data showing 5-fluorouracil-based chemotherapy is ineffective in this patient population. 33 Conversely, for patients with highly elevated tumor markers, the poor prognoses seen with current treatments, which have historically been chemotherapy designed for CRC, suggests that these patients be prioritized for clinical studies testing appendiceal cancer-specific therapies. The association with KRAS and GNAS somatic mutations and elevated levels of both CEA and CA19-9 suggests that high TM expression tumors may have intrinsically distinct biology compared with nonexpressing tumors, which may be indicative of different therapeutic vulnerabilities and should be explored in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest a possible role for serial TM measurement while receiving chemotherapy to assess for therapeutic response, important in appendiceal cancer given the difficulty in quantitating response by traditional imaging methods. 33 Figure A, Stage IV metastatic disease patients with normal, elevated, and highly elevated levels of carcinoembryonic antigen (CEA). B, Stage IV metastatic disease patients with normal, elevated, and highly elevated levels of carbohydrate antigen 19-9 (CA19-9).…”

Section: Jama Network Open | Oncologymentioning

confidence: 99%

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Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Yousef,

Zeineddine

et al. 2024

JAMA Netw Open

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ImportanceSerum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma.ObjectiveTo assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma.Design, Setting, and ParticipantsThis is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023.Main Outcomes and MeasuresAssociation of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival).ResultsA total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P &lt; .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P &lt; .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P &lt; .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P &lt; .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P &lt; .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9.Conclusions and RelevanceIn this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Jama Network Open | Oncologymentioning

confidence: 99%

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Yousef,

Zeineddine

et al. 2024

JAMA Netw Open

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“…This observation could be explained by early diagnosis in these patients when the tumor volume is insufficient to cause elevation of the TMs, which would be associated with an especially favorable outcome. Perhaps there could be a role for treatment de-escalation in these patients, particularly considering recent prospective data showing 5-FU-based chemotherapy is ineffective in this patient population 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps there could be a role for treatment de-escalation in these patients, particularly considering recent prospective data showing 5-FU-based chemotherapy is ineffective in this patient population 40 .…”

Section: Discussionmentioning

confidence: 99%

The Clinical Significance of CEA, CA19-9, and CA125 in Management of Appendiceal Adenocarcinoma

Yousef,

Zeineddine

et al. 2023

Preprint

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ImportanceSerum tumor markers CEA, CA19-9, & CA125 have been useful in the management of gastrointestinal and gynecological cancers, however there is limited information regarding their utility in patients with appendiceal adenocarcinoma.ObjectiveAssessing the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes, pathologic, and molecular features in patients with appendiceal adenocarcinoma.DesignThis is a retrospective study with results reported in 2023. The median follow-up time was 43 months.SettingSingle tertiary care comprehensive cancer center.ParticipantsUnder an approved Institutional Review Board protocol, the Palantir Foundry software system was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least one tumor marker measured at MD Anderson between 2016 and 2023.ResultsA total of 1,338 patients with appendiceal adenocarcinoma were included, with a median age of 56.5 years. The majority of the patients had metastatic disease (80.7%). CEA was elevated in more than half of the patients tested (56%), while CA19-9 and CA125 were elevated in 34% and 27%, respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; 82% vs 95%, 84% vs 92%, and 69% vs 93% elevated vs normal for CEA, CA19-9, and CA125 respectively (all p<0.0001). Quantitative evaluation of tumor markers increased prognostic ability. Patients with highly elevated (top 10thpercentile) CEA, CA19-9 or CA125 had markedly worse survival with 5-year survival rates of 59%, 64%, and 57%, respectively (HR vs. normal : 9.8, 6.0, 7.6, all p<0.0001). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease elevated CEA, CA19-9 or CA125 were all still associated worse survival (HR vs. normal : 3.4, 1.8, 3.9, p<0.0001 for CEA and CA125, p=0.0019 for CA19-9). Interestingly tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high relative to low-grade tumors (18.3 vs. 15.0, p=0.0009). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with a 11-fold increased risk of death in patients with all three tumor markers elevated relative to those with none elevated. Mutation inKRASandGNASwere associated with significantly higher levels of CEA and CA19-9.ConclusionsThese findings demonstrate the utility of measuring CEA, CA19-9, and CA125 in the management of appendiceal adenocarcinoma. Given their prognostic value, all three biomarkers should be included in the initial workup of patients diagnosed with appendiceal adenocarcinoma.Key PointsQuestionCan serum tumor markers CEA, CA19-9, or CA125 be useful in management of patients with appendiceal adenocarcinoma?FindingsIn this single institution retrospective cohort study, elevation of CEA, CA19-9, or CA125 were associated with significantly worse 5-year survival; 82% vs 95%, 84% vs 92%, and 69% vs 93% elevated vs normal respectively. Moreover, quantitative evaluation of tumor markers increased prognostic ability. Further analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with a 11-fold increased risk of death in patients with all three tumor markers elevated relative to those with none elevated.MeaningGiven their prognostic value, all three biomarkers should be included in the initial workup of patients diagnosed with appendiceal adenocarcinoma.

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“…4 Although capecitabine ameliorates 5-Fu-induced adverse effects, recent clinical reports have revealed that capecitabine, both in monotherapy and combined therapy, could induce severe peripheral neuropathy, manifested as numbness, paresthesia, hypoesthesia and even somatization disorders. 5 Based on various clinical trials, the peripheral neuropathy rates caused by capecitabine range from 36% to 73%, 4,6,7 greatly lowering the patients' quality of life. To date, investigations of capecitabineinduced peripheral neurotoxicity have only focused on clinical symptoms without further mechanistic studies.…”

Section: Introductionmentioning

confidence: 99%

Dihydromyricetin reverses capecitabine‐induced peripheral myelin dysfunction through modulation of oxidative stress

Fang,

Lou,

Zhou

et al. 2024

Clin Exp Pharma Physio

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Previous clinical reports have shown that capecitabine, an oral prodrug of 5‐fluorouracil (5‐Fu), can induce peripheral neuropathy, resulting in numbness, paresthesia and hypoesthesia. However, the mechanism through which capecitabine causes peripheral nerve injury remains unclear. Here, we demonstrate that systemic administration of capecitabine leads to myelin abnormalities in the peripheral nerves of mice, which are possibly attributed to the death of Schwann cells, the myelinating cells in the peripheral nervous system. Furthermore, our results show that 5‐Fu induces significant oxidative stress in Schwann cells by inhibiting the expression of the anti‐oxidative protein DJ‐1, leading to a decrease in Schwann cell markers. We found that the anti‐oxidant dihydromyricetin (DMY) reverses 5‐Fu‐induced Schwann cell death and oxidative stress and alleviates capecitabine‐induced myelin abnormalities. Taken together, our data indicate that capecitabine induces peripheral myelin dysfunction by regulating DJ‐1‐mediated oxidative stress in Schwann cells and reveal DMY as a potential therapeutic strategy for capecitabine‐induced peripheral neuropathy.

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P-247 Outcomes of randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma

Cited by 4 publications

References 0 publications

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

The Clinical Significance of CEA, CA19-9, and CA125 in Management of Appendiceal Adenocarcinoma

Dihydromyricetin reverses capecitabine‐induced peripheral myelin dysfunction through modulation of oxidative stress

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