Objective
Appendiceal mucinous neoplasms (AMNs) are a rare and heterogeneous disease for which clinical management is challenging. We aim to review the literature regarding modalities of treatment to ...guide the management of AMNs.
Methods and Review Criteria
We conducted a PubMed search in February 2016 for English‐language publications, using the terms “appendiceal,” “appendix,” “carcinoma,” “cancer,” “mucinous,” “treatment,” “genes,” “target,” “genomic,” and terms listed in the articles' subheadings. Published reports and s from the American Society of Clinical Oncology meetings were also searched.
Results
In this review, we summarize current data and controversies in AMN classification, clinical presentation, molecular alterations, treatment outcomes with regard to cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and the role of systemic chemotherapy.
Conclusion
Appendiceal mucinous neoplasms are a heterogeneous group of tumors with a rising incidence. Treatment is based on stage and histology. Low‐grade tumors are treated surgically with resection of the primary site in early stage disease, or peritoneal debulking and HIPEC in patients with advanced stage disease. Treatment of high‐grade tumors requires further prospective trials, and options include debulking surgery and HIPEC with or without preoperative chemotherapy. Trials evaluating novel therapies based on the molecular profiling of AMN tumors are needed to evaluate therapeutic options in patients who are not surgical candidates.
Implications for Practice
This review provides a reference to guide gastroenterologists, pathologists, surgeons, and oncologists in the management of appendiceal mucinous neoplasms (AMNs), a rare and heterogeneous disease with no consensus on histologic classification or guidelines for treatment algorithms. This review summarizes all AMN classifications and proposes a treatment algorithm based on stage and histology of disease.
Appendiceal mucinous neoplasms are rare and challenging to manage. This review summarizes the current literature and controversies in classification, clinical presentation, molecular alterations, and treatment outcomes in this heterogeneous group of tumors and provides guidelines for treatment.
SummaryBackgroundRegorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. ...Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. MethodsIn this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. FindingsBetween June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98–1·57). The primary endpoint was met: 23 (43%, 95% CI 29–56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15–37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3–4 adverse events were fatigue (seven 13% patients in the dose-escalation group vs 11 18% in the standard-dose group), hand-foot skin reaction (eight 15% patients vs ten 16% patients), abdominal pain (nine 17% patients vs four 6% patients), and hypertension (four 7% patients vs nine 15% patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). InterpretationThe dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. FundingBayer HealthCare Pharmaceuticals.
Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug ...resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it's associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy.
The emergence of targeted therapies for the treatment of metastatic colorectal cancer (mCRC) has considerably improved survival, but has also resulted in a dilemma of identifying the optimal sequence ...and combination of various agents in the mCRC treatment landscape. A number of cytotoxic agents, including irinotecan, oxaliplatin, 5‐fluorouracil, capecitabine, and TAS‐102, are available for treatment of mCRC. Additionally, whereas patients harboring rat sarcoma viral oncogene homolog (RAS)–wild type mCRC can be treated with the anti‐epidermal growth factor receptor antibodies cetuximab and panitumumab or antiangiogenic agents (bevacizumab, ziv‐aflibercept, and ramucirumab), patients with RAS‐mutant mCRC are limited to antiangiogenic agents as biologic options. Regorafenib, a multikinase inhibitor, can be used in both RAS subgroups. As such, the recommended sequence of therapies that should be received by each subgroup must also be considered separately. This review provides an overview of recent clinical data for approved and investigational targeted therapies that have been studied across different mCRC treatment lines and patient subgroups. It also examines emerging trends in the treatment landscape for mCRC, including treatment with immune checkpoint inhibitors and the utilization of genomic profiling.
Implications for Practice
Currently, there are no established guidelines for optimal sequencing of cytotoxic or targeted agents in metastatic colorectal cancer (mCRC). This review provides a snapshot of the current mCRC treatment paradigm and examines the latest clinical data that support the utilization of several targeted agents alone or in combination with backbone chemotherapy across different lines of treatment and patient populations, highlighting recommendations for their usage. Recent advances in the treatment landscape are also summarized, including genomic profiling and preliminary results with immune checkpoint inhibitors.
摘要
靶向治疗的出现大大提高了转移性结直肠癌（mCRC）的生存率, 但同时也导致难以识别多种mCRC治疗药物的最佳顺序和组合的困境。包括伊立替康、奥沙利铂、5‐氟尿嘧啶、卡培他滨和TAS‐102在内的多种细胞毒性药物可以用于治疗mCRC。此外, 尽管罹患大鼠肉瘤病毒癌基因同源物（RAS）‐野生型mCRC的患者可以接受抗表皮生长因子受体抗体西妥昔单抗和帕尼单抗或抗血管生成药物（贝伐单抗、阿柏西普和雷莫芦单抗）治疗, 但RAS突变mCRC患者只能接受抗血管生成药物作为生物学治疗。两个RAS亚组中均可使用瑞戈非尼（一种多激酶抑制剂）。因此, 也必须单独考虑每个亚组应接受的治疗的推荐顺序。本次回顾提供了已获批准疗法和研究性靶向治疗（已在不同mCRC治疗线和患者亚组中进行过研究）的最新临床研究数据的概览。本次回顾还考察了mCRC治疗领域的新趋势, 包括使用免疫检查点抑制剂治疗和基因组分析。
对临床实践的启示：目前仍然没有关于细胞毒性或靶向药物治疗转移性结直肠癌（mCRC）的最佳顺序的既定指南。本回顾简要介绍了当前mCRC的治疗方法。我们回顾了支持在不同的治疗线和患者人群中单独使用几种靶向药物或靶向药物与核心化疗药物联合给药的最新临床研究数据, 并重点回顾了关于这些药物的使用建议。此外, 我们还总结了治疗领域的最新进展, 包含基因组分析和使用免疫检查点抑制剂的初步结果。
This article summarizes the current treatment landscape for metastatic colorectal cancer, reviews the clinical data supporting the roles for targeted therapies in treatment sequencing, examines investigational treatments for third‐line metastatic colorectal cancer, and reviews emerging trends in therapeutic strategies and molecular testing.
In heavily pretreated patients with mutant KRAS G12C colorectal cancer, adagrasib induced a response in 19% as single agent and in 46% in combination with cetuximab, an epidermal growth factor ...receptor antibody.
Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the ...treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov , number NCT02314169. Results We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% 95% CI 15–33) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.
-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications.
alterations in colorectal cancer are ...classified into three functional categories on the basis of signaling mechanisms, with the class I
mutation occurring most frequently in colorectal cancer. Functional categorization of
mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with
mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in
-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in
-mutated advanced colorectal cancer.
Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely ...in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation.PURPOSEAdagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation.In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety.METHODSIn this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety.As of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients.RESULTSAs of October 1, 2022, 64 patients with KRASG12C-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients.Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.CONCLUSIONAdagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRASG12C-mutated solid tumors.
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