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Gan To Kagaku Ryoho. Cancer &... Dec 2023The patient underwent sigmoidectomy with D3 lymph node dissection and partial bladder resection for sigmoid colon cancer(cT4bN1M0, cStage Ⅲa), after preoperative...
The patient underwent sigmoidectomy with D3 lymph node dissection and partial bladder resection for sigmoid colon cancer(cT4bN1M0, cStage Ⅲa), after preoperative chemotherapy with mFOLFOX plus panitumumab, and FOLFOXIRI plus bevacizumab. Postoperative adjuvant chemotherapy was performed by 8 courses of CAPOX. He relapsed hilar lymph nodes and peritoneal dissemination after 13 months after surgery, he underwent resection of the recurrent lesions. Four months after, he developed recurrence in liver and peritoneum. Although he was treated with FOLFIRI plus ramucirumab or aflibercept, resulted in progression of disease, then he received trifluridine tipiracil hydrochloride plus bevacizumab. At this point, the Japanese health insulance had started to cover pembrolizumab, this therapy was started as the fourth chemotherapy after the diagnosis of high frequency microsatellite instability(MSI), and then tumor markers rapidly declined. He underwent 38 courses of pembrolizumab, the recurrent lesions both liver and peritoneum disappeared. He had stoma closure, peritoneal dissemination disappeared not only intraoperatively but also in histologically from the peritoneal scar. He has received pembrolizumab for 4 years without another recurrence. Here, we report a case of MSI-high sigmoid colon cancer in which long-term survival was achieved by pembrolizumab for recurrent lesions resistant to conventional chemotherapy.
Topics: Humans; Male; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Sigmoid Neoplasms
PubMed: 38303192
DOI: No ID Found -
BMC Gastroenterology Feb 2024To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of clinical plans.
METHODS
As of October 1, 2022, the randomized controlled clinical trials of bevacizumab in combination with metastatic colorectal cancer published in PubMed, Cochrane Library and Medline databases were searched. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the short-term disease control effect and long-term survival of the treatment strategy.
RESULTS
21 RCTs (6665 patients; 3356 patients in the experimental group and 3309 patients in the control group; average age, 55-75 years) were treated with bevacizumab as the experimental group for metastatic colorectal cancer. BEV has stronger anti-tumor activity than the single treatment scheme (OR = 1.30, 95% CI: 1.11-1.52). And Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. The disease control of BEV combined therapy was better (OR = 1.36, 95% CI: 1.04-1.78). The same as compared with cediranib (OR = 1.94, 95% CI: 1.06-3.55). However, the long-term prognosis of BEV, including the overall survival (HRs = 0.98, 95% CI: 0.84-1.15) and progression-free survival (HRs = 1.05,95% CI: 0.97-1.13) were not prolonged. The survival benefits of cetuximab and panitumumab were not reflected.
CONCLUSION
The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability. However, it did not effectively improve the survival of patients. A more reasonable and effective treatment plan needs more clinical experimental support.
Topics: Humans; Middle Aged; Aged; Bevacizumab; Cetuximab; Panitumumab; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38302922
DOI: 10.1186/s12876-024-03134-w -
Clinical Cancer Research : An Official... Apr 2024We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab...
PURPOSE
We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial.
PATIENTS AND METHODS
Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI).
RESULTS
202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52-1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36-0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47-0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61-1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009).
CONCLUSIONS
Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.
Topics: Humans; Panitumumab; Antibodies, Monoclonal; Colorectal Neoplasms; Treatment Outcome; Colonic Neoplasms; Rectal Neoplasms; Fluorouracil; Leucovorin; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38289994
DOI: 10.1158/1078-0432.CCR-23-3023 -
BMC Medical Research Methodology Jan 2024Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective...
BACKGROUND
Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82-1.22) for all patients, and 0.99 (95% CI 0.75-1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus).
METHODS
We tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76-0.77 (95% CI 0.60-0.98) for all patients, and 0.55-0.73 (95% CI 0.41-0.93) for patients with wild-type KRAS.
RESULTS
Some applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals.
CONCLUSIONS
Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.
Topics: Humans; Panitumumab; Proto-Oncogene Proteins p21(ras); Treatment Switching; Computer Simulation; Probability; Randomized Controlled Trials as Topic
PubMed: 38253996
DOI: 10.1186/s12874-024-02140-6 -
Cancer Treatment Reviews Mar 2024Despite recent molecular and immunological advancements, prognosis of metastatic colorectal cancer (mCRC) patients remains poor. In this context, several retrospective... (Review)
Review
Despite recent molecular and immunological advancements, prognosis of metastatic colorectal cancer (mCRC) patients remains poor. In this context, several retrospective and phase II studies suggested that after failure of an upfront anti-EGFR based regimen, a subset of patients can still benefit from further anti-EGFR blockade. Several translational studies involving circulating tumor DNA (ctDNA) analysis demonstrated that cancer clones harboring mutations driving anti-EGFR resistance, which can arise under anti-EGFR agents selective pressure, often decay after anti-EGFR discontinuation potentially restoring sensitivity to this therapeutic strategy. Accordingly, several retrospective analyses and a recent prospective trial demonstrated that ctDNA RAS and BRAF wild-type mCRC patients are those benefitting the most from anti-EGFR rechallenge. Indeed, in molecularly selected patients, anti-EGFR rechallenge strategy achieved up to 30 % response rate, with a progression free survival longer than 4 months and an overall survival longer than 1 year, which favorably compared with other standard therapeutic options available for heavily pretreated patients. Anti-EGFR is also well tolerated with no unexpected toxicities compared to the upfront setting. However, several open questions remain to be addressed towards a broader applicability of anti-EGFR strategy in the everyday clinical practice such as the identification of the best rechallenge regimen, the right placement in mCRC therapeutic algorithm, the best ctDNA screening panel. In our systematic review, we revised available data from clinical trials assessing anti-EGFR rechallenge activity in chemo-refractory mCRC patients, discussing as well potential future scenarios and development to implement this therapeutic approach. Particularly, we discussed the role of ctDNA as a safe, timely and comprehensive tool to refine patient's selection and the therapeutic index of anti-EGFR rechallenge.
Topics: Humans; Colorectal Neoplasms; Retrospective Studies; Antibodies, Monoclonal; Cetuximab; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins B-raf
PubMed: 38237253
DOI: 10.1016/j.ctrv.2024.102683 -
Cancer Discovery May 2024KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical...
UNLABELLED
KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was five-fold more potent against NRASG12C compared with KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.
SIGNIFICANCE
These studies demonstrate that certain KRASG12C inhibitors effectively target all RASG12C mutations and that sotorasib specifically is a potent NRASG12C inhibitor capable of driving clinical responses. These findings have important implications for the treatment of patients with NRASG12C or HRASG12C cancers and could guide design of NRAS or HRAS inhibitors. See related commentary by Seale and Misale, p. 698. This article is featured in Selected Articles from This Issue, p. 695.
Topics: Humans; Membrane Proteins; Proto-Oncogene Proteins p21(ras); GTP Phosphohydrolases; Mutation; Cell Line, Tumor; Colorectal Neoplasms; Antineoplastic Agents; Pyrimidines; Piperazines; Pyridines
PubMed: 38236605
DOI: 10.1158/2159-8290.CD-23-1138 -
Surgical Case Reports Jan 2024The gold standard treatment for locally advanced colon cancer is curative surgery followed by adjuvant chemotherapy, although this approach is associated with serious...
Curative resection after percutaneous drainage followed by preoperative panitumumab monotherapy for locally advanced sigmoid colon cancer with intra-abdominal abscess: a case report.
BACKGROUND
The gold standard treatment for locally advanced colon cancer is curative surgery followed by adjuvant chemotherapy, although this approach is associated with serious concerns, such as high recurrence rates and occasionally unnecessary oversurgery. Neoadjuvant chemotherapy may be a promising strategy for overcoming these issues. This study reports a case of a recurrence-free patient who underwent curative resection without significant organ dysfunction after preoperative chemotherapy for locally advanced sigmoid colon cancer. The tumor coexisted with a large intra-abdominal abscess, and the patient was quite frail at the first visit. We performed percutaneous drainage followed by preoperative panitumumab monotherapy, which yielded favorable outcomes.
CASE PRESENTATION
A 78-year-old frail woman was emergently transferred to our hospital with fever and abdominal pain. The diagnosis was locally advanced sigmoid colon cancer stage IIIC (T4bN2aM0) with a large intra-abdominal abscess. Immediate curative surgery was inappropriate, considering both tumor progression and the patient's frailty. We performed percutaneous drainage and colostomy construction, which was followed by seven cycles of preoperative panitumumab monotherapy without significant adverse events. After these treatments, inflammation was well controlled, and the tumor shrank remarkably. Furthermore, the patient recovered well from frailty; therefore, curative sigmoidectomy combined with resection of the left ovary and stoma closure was possible without any postoperative complications. The final pathological finding was T3N0M0, stage IIA disease. The patient was recurrence-free and had no significant organ dysfunction 21 months after the curative surgery.
CONCLUSIONS
The management of intra-abdominal abscesses and tailor-made preoperative chemotherapy based on the patient's frailty may have been the key factors responsible for the favorable course of this patient. Although further research is needed on the appropriateness of percutaneous drainage for malignancies related to intra-abdominal abscesses and preoperative panitumumab use for locally advanced colon cancer, the study findings can serve as reference for managing similar cases in an aging society.
PubMed: 38233703
DOI: 10.1186/s40792-023-01800-x -
Surgical Case Reports Jan 2024Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a...
BACKGROUND
Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT.
CASE PRESENTATION
A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion.
CONCLUSIONS
The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.
PubMed: 38196031
DOI: 10.1186/s40792-024-01811-2 -
Translational Oncology Feb 2024The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the...
BACKGROUND
The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways.
METHODS
Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used. Anti-EGF VacAbs were obtained by immunizing rabbits with a fusion protein containing a synthetic, highly mutated variant of human EGF. Cell viability was determined by MTT, total and phosphorylated proteins by Western blotting, cell cycle distribution and cell death by flow cytometry and emergence of resistance by microscopic examination in low density cultures.
RESULTS
Anti-EGF VacAbs potentiated the antiproliferative effects of MEK, KRAS G12C, BRAF, PI3K and Akt inhibitors in KRAS, NRAS, BRAF and PIK3CA mutant cells and delayed the appearance of resistant clones in vitro. The effects of anti-EGF VacAbs were comparable or superior to those of panitumumab and cetuximab. The combination of anti-EGF VacAbs with the targeted inhibitors effectively suppressed EGFR downstream pathways and sera from patients immunized with an anti-EGF vaccine also blocked activation of EGFR effectors.
CONCLUSIONS
Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile.
PubMed: 38183801
DOI: 10.1016/j.tranon.2024.101878 -
Nature Medicine Jan 2024The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the...
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
Topics: Humans; Panitumumab; Proto-Oncogene Proteins p21(ras); Antibodies, Monoclonal; Colorectal Neoplasms; ErbB Receptors; Mutation; Antineoplastic Combined Chemotherapy Protocols; Piperazines; Pyridines; Pyrimidines
PubMed: 38177853
DOI: 10.1038/s41591-023-02717-6