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Critical Reviews in Oncology/hematology Nov 2023In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR... (Review)
Review
BACKGROUND
In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial.
METHODS
Phase II-III randomized trials were included. Maintenance strategies considered were: observation, anti-EGFR or FP monotherapy, FP + anti-EGFR, doublet CT + anti-EGFR.
RESULTS
Maintenance with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.89) showed the greatest PFS benefit compared to observation, ranking first on SUCRA analysis (96.4%). Considering OS, doublet CT+ anti-EGFR, FP + anti-EGFR and anti-EGFR monotherapy yielded similar results. For PFS, FP + anti-EGFR confirmed to be valuable in BRAF wt patients and left sided tumors. In left sided tumors, the OS benefit of adding CT was limited. FP plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR.
CONCLUSIONS
FP + anti-EGFR can be considered a valuable maintenance option in RAS wt mCRC. EGFR monotherapy can be considered, especially in left-sided tumors.
PubMed: 37659764
DOI: 10.1016/j.critrevonc.2023.104106 -
Surgical Case Reports Aug 2023Early-stage colorectal cancer (CRC) is often treated endoscopically, but additional surgical resection may be considered depending on pathological findings.
BACKGROUND
Early-stage colorectal cancer (CRC) is often treated endoscopically, but additional surgical resection may be considered depending on pathological findings.
CASE PRESENTATION
A 73-year-old man was found to have early-stage sigmoid colon cancer by colonoscopy during a medical examination, and endoscopic mucosal resection (EMR) was performed. The lesion was a 7-mm-sized sessile polyp, and the pathological diagnosis was well-differentiated tubular adenocarcinoma, pT1 (submucosal invasion of 400 μm), with no lymphovascular invasion, low budding grade, and negative horizontal and vertical margins. Therefore, the patient was observed without postoperative treatment. One year later, a computed tomography (CT) scan showed multiple liver metastases. After five courses of preoperative chemotherapy with folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX) and panitumumab, liver metastases were reduced. The patient underwent extended right hepatic lobectomy. The pathological finding was well-to-moderately differentiated tubular adenocarcinoma, and immunohistochemistry findings were consistent with liver metastases from sigmoid colon cancer. Postoperatively, the patient received five courses adjuvant chemotherapy with FOLFOX. Although the patient had been recurrence-free for 5 years after liver resection, a CT scan revealed a nodular lesion in the sigmoid mesentery. Positron emission tomography (PET) showed abnormal accumulation in the same lesion. Therefore, the mesenteric nodules diagnosed as lymph metastasis and recurrence of sigmoid colon cancer and performed laparoscopic sigmoid colon resection with lymph node dissection. The pathological findings showed that the recurrent lesion in the mesentery formed a nodular infiltrate with venous, lymphatic, and neural invasion, but lymph node structures were not found, and it was assumed to be metastasis or recurrence due to lymphovascular invasion. The pathologic specimen of the sigmoid colon had no neoplastic lesions, which are considered to be a local recurrence on the mucosal surface. After sigmoid colectomy, adjuvant chemotherapy with CapeOX was conducted, and the patient has been recurrence-free for 13 months at present.
CONCLUSION
Even early-stage CRCs that have no pathological indications for additional resection have risks of metastases and recurrences, and we may need to consider that the criteria for additional resection should not be limited to pathological findings alone.
PubMed: 37650976
DOI: 10.1186/s40792-023-01731-7 -
Frontiers in Oncology 2023Twenty percent of colorectal cancer liver metastases (CLMs) are initially resectable with a 5-year survival rate of 25%-40%. Perioperative folinic acid, 5-fluorouracil,...
LM02 trial Perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases-a phase II study.
BACKGROUND
Twenty percent of colorectal cancer liver metastases (CLMs) are initially resectable with a 5-year survival rate of 25%-40%. Perioperative folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) increases progression-free survival (PFS). In advanced disease, the addition of targeting therapies results in an overall survival (OS) advantage. The aim of this study was to evaluate panitumumab and FOLFIRI as perioperative therapy in resectable CLM.
METHODS
Patients with previously untreated, wild-type Rat sarcoma virus (RAS), and resectable CLM were included. Preoperative four and postoperative eight cycles of panitumumab and folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) were administered. Primary objectives were efficacy and safety. Secondary endpoints included PFS and OS.
RESULTS
We enrolled 36 patients in seven centers in Austria (intention-to-treat analyses, 35 patients). There were 28 men and seven women, and the median age was 66 years. About 91.4% completed preoperative therapy and 82.9% underwent liver resection. The R0 resection rate was 82.7%. Twenty patients started and 12 patients completed postoperative chemotherapy. The objective radiological response rate after preoperative therapy was 65.7%. About 20% and 5.7% of patients had stable disease and progressive disease, respectively. The most common grade 3 adverse events were diarrhea, rash, and leukopenia during preoperative therapy. One patient died because of sepsis, and one had a pulmonary embolism grade 4. After surgery, two patients died because of hepatic failure. Most common grade 3 adverse events during postoperative therapy were skin toxicities/rash and leukopenia/neutropenia, and the two grade 4 adverse events were stroke and intestinal obstruction. Median PFS was 13.2 months. The OS rate at 12 and 24 months were 85.6% and 73.3%, respectively.
CONCLUSIONS
Panitumumab and FOLFIRI as perioperative therapy for resectable CLM result in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Median PFS was 13.2 months, and the 24-month OS rate was 73.3%. These data are insufficient to widen the indication of panitumumab from the unresectable setting to the setting of resectable CLM.
PubMed: 37621684
DOI: 10.3389/fonc.2023.1231600 -
Oncology Letters Sep 2023Drug-induced thrombocytopenia is an adverse reaction characterized by accelerated platelet destruction. The present study described a case of thrombocytopenia that...
Drug-induced thrombocytopenia is an adverse reaction characterized by accelerated platelet destruction. The present study described a case of thrombocytopenia that occurred during treatment with panitumumab. A female patient aged 49 years with metastatic rectal adenocarcinoma was treated with 9 out of 12 cycles of therapy with the standard of care, 5-fluorouacil (5-FU), oxaliplatin and folic acid, in association with panitumumab. During cycle 10, the patient developed severe thrombocytopenia, so the therapy was adjusted to a lower dosage; however, during cycle 11, after administration of panitumumab and before administration of 5-FU or oxaliplatin, the patient again presented with severe thrombocytopenia, with a platelet count <2×10/l. Immunology test results were negative apart from anti-nucleus antibodies (titration, 1:160). Naranjo's algorithm was used to establish the relationship between the use of panitumumab and thrombocytopenia onset and a score of 6 ('probable') was found. The temporal link between the onset of symptoms and administration of therapy, the relapse of thrombocytopenia after re-administration of the drug during cycle 11 (positive rechallenge) and Naranjo score of 6 ('probable') are crucial elements for establishing the causal relationship and the probability that thrombocytopenia was related to the administration of panitumumab. The patient then underwent two cycles of therapy with 5-FU, folic acid and irinotecan, in association with bevacizumab, experiencing again the same adverse event. Treatment with monoclonal antibodies was suspended altogether in favor of a switch to trifluridine/tipiracil. No other serious adverse events were reported.
PubMed: 37600345
DOI: 10.3892/ol.2023.13984 -
The Oncologist Dec 2023Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to...
INTRODUCTION
Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC.
METHODS
Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status.
RESULTS
No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment.
CONCLUSIONS
The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).
Topics: Humans; Panitumumab; Colorectal Neoplasms; Benzimidazoles; Colonic Neoplasms; Rectal Neoplasms; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 37597246
DOI: 10.1093/oncolo/oyad210 -
The Annals of Applied Statistics Dec 2022Late-stage clinical trials have been conducted primarily to establish the efficacy of a new treatment in an intended population. A corollary of population heterogeneity...
Late-stage clinical trials have been conducted primarily to establish the efficacy of a new treatment in an intended population. A corollary of population heterogeneity in clinical trials is that a treatment might be effective for one or more subgroups, rather than for the whole population of interest. As an example, the phase III clinical trial of panitumumab in metastatic colorectal cancer patients failed to demonstrate its efficacy in the overall population, but a subgroup associated with tumor KRAS status was found to be promising (Peeters et al. ( 28 (2010) 4706-4713)). As we search for such subgroups via data partitioning based on a large number of biomarkers, we need to guard against inflated type I error rates due to multiple testing. Commonly-used multiplicity adjustments tend to lose power for the detection of subgroup treatment effects. We develop an effective omnibus test to detect the existence of, at least, one subgroup treatment effect, allowing a large number of possible subgroups to be considered and possibly censored outcomes. Applied to the panitumumab trial data, the proposed test would confirm a significant subgroup treatment effect. Empirical studies also show that the proposed test is applicable to a variety of outcome variables and maintains robust statistical power.
PubMed: 37521002
DOI: 10.1214/21-AOAS1589 -
The Oncologist Oct 2023HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR... (Meta-Analysis)
Meta-Analysis
BACKGROUND
HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes.
METHODS
A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses.
RESULTS
Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates.
CONCLUSIONS
While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.
Topics: Humans; Antibodies, Monoclonal; Colorectal Neoplasms; Retrospective Studies; ErbB Receptors; Panitumumab; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols
PubMed: 37463037
DOI: 10.1093/oncolo/oyad200 -
ESMO Open Aug 2023Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the... (Randomized Controlled Trial)
Randomized Controlled Trial
Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212).
BACKGROUND
Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest.
METHODS
PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy.
RESULTS
In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis.
CONCLUSIONS
In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.
Topics: Humans; Male; Female; Panitumumab; Leucovorin; Colorectal Neoplasms; Treatment Outcome; Fluorouracil; Colonic Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37441876
DOI: 10.1016/j.esmoop.2023.101568 -
Clinical Cancer Research : An Official... Oct 2023High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in...
PURPOSE
High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.
EXPERIMENTAL DESIGN
Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).
RESULTS
A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.
CONCLUSIONS
High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.
Topics: Humans; Amphiregulin; Epiregulin; Cetuximab; Panitumumab; Retrospective Studies; Colorectal Neoplasms; Artificial Intelligence; Intercellular Signaling Peptides and Proteins; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors
PubMed: 37363997
DOI: 10.1158/1078-0432.CCR-23-0859 -
International Journal of Surgery Case... Jul 2023Perirectal abscesses are uncommon in colorectal cancer. Although abscess infection should be controlled before colorectal cancer treatment, abscess formation makes...
INTRODUCTION AND IMPORTANCE
Perirectal abscesses are uncommon in colorectal cancer. Although abscess infection should be controlled before colorectal cancer treatment, abscess formation makes surgical resection and preoperative treatment difficult. There is currently no established treatment for colorectal cancer with perirectal abscesses. Here, we present a case of rectal cancer with a perirectal abscess that was resected after systemic chemotherapy followed by chemoradiotherapy.
CASE PRESENTATION
A 73-year-old man presented to the outpatient clinic with complaints of weight loss and general malaise. Colonoscopy revealed a circumferential tumor 3 cm from the anal verge, and examination of the endoscopic biopsy specimen indicated a well-differentiated tubular adenocarcinoma. Pelvic magnetic resonance imaging revealed a perirectal abscess on the ventral aspect of the rectum. After sigmoid colostomy was performed to control the infection, 4 cycles of panitumumab and modified fluorouracil, leucovorin, and oxaliplatin were administered. After the perirectal abscess disappeared, chemoradiotherapy to the whole pelvis (radiotherapy 45Gy/25 fractions plus tegafur-gimeracil-oteracil) was administered. Total pelvic exenteration with an ileal conduit was performed via open surgery. The pathological diagnosis was well-differentiated tubular adenocarcinoma with complete resection and negative resection margins. No recurrence of cancer has been observed 26 months after surgery.
CLINICAL DISCUSSION
Treatment of colorectal cancer with perirectal abscess is difficult to define the extent of resection due to the spread of inflammation. We believe that treatment should address high risk of local recurrence.
CONCLUSION
After sigmoid colostomy, complete resection of colorectal cancer with perirectal abscess could be achieved by systemic chemotherapy followed by chemoradiotherapy.
PubMed: 37329610
DOI: 10.1016/j.ijscr.2023.108403