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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 -
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 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 -
Biological & Pharmaceutical Bulletin 2024Hypomagnesemia commonly occurs as a side effect of panitumumab treatment. In severe cases, temporary discontinuation or dose reduction of panitumumab may be necessary....
Hypomagnesemia commonly occurs as a side effect of panitumumab treatment. In severe cases, temporary discontinuation or dose reduction of panitumumab may be necessary. Proton pump inhibitors (PPIs) are reportedly potential risk factors for hypomagnesemia. We conducted a multicenter study to assess the impact of PPIs on the risk of grade 3-4 hypomagnesemia in patients with metastatic colorectal cancer (mCRC) receiving panitumumab. We adjusted for potential bias using a propensity score-matched analysis and retrospectively reviewed the medical records of patients. Hypomagnesemia severity was graded according to the Common Terminology Criteria for Adverse Events, version 5.0. A total of 165 patients were enrolled in this study. The incidence of grade 3-4 hypomagnesemia was significantly higher in the PPI group than in the non-PPI group, both before (20.0% [30/60] vs. 8.0% [8/105], p = 0.026) and after propensity score matching (16.2% [6/37] vs. 0% [0/37], p = 0.025). In the propensity score-matched cohort, the risk of grade 3-4 hypomagnesemia was significantly higher in the PPI group (odds ratio, 2.19; 95% confidence interval, 1.69-2.84; p = 0.025). These findings suggest that concomitant use of PPIs significantly increases the risk of grade 3-4 hypomagnesemia in patients with mCRC receiving panitumumab. Therefore, close monitoring of these patients is imperative.
Topics: Humans; Panitumumab; Proton Pump Inhibitors; Retrospective Studies; Magnesium; Colonic Neoplasms; Colorectal Neoplasms
PubMed: 38171783
DOI: 10.1248/bpb.b23-00641 -
The Oncologist May 2024The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of...
BACKGROUND
The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP).
METHODS
Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1.
RESULTS
Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed.
CONCLUSIONS
Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.
Topics: Humans; Panitumumab; Female; Glioblastoma; Male; Middle Aged; Aged; Adult; Brain Neoplasms; Antineoplastic Agents, Immunological; ras Proteins; raf Kinases
PubMed: 38109296
DOI: 10.1093/oncolo/oyad320 -
International Journal of Pharmaceutics Jan 2024The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type...
Prolonging the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®): An orthogonal assessment of physicochemical, biological and microbiological properties of original opened glass vials and diluted saline preparations.
The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type metastatic colorectal cancers. However, stability data of these mAbs are generally missing or incomplete. Here, we report for the first time an orthogonal analysis of the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®), either undiluted vial leftovers or saline dilutions in polyolefin/polyamide infusion bags. All samples were stored at 2-8 °C protected from light, according to their summary of product characteristics (SmPCs). Alternatively, opened vials and preparations were maintained at 25 °C for 15 h, and then stored again at 2-8 °C protected from light to mimic a temporary interruption of the cold chain. Vial leftovers proved stable up to 180 days when stored according to their SmPCs, while compounded preparations in infusion bags maintained their physiochemical, biological and microbiological stability up to 30 days. Additionally, no changes were detected up to 30 days for the same samples undergoing a thermal excursion. Our results provide additional rationale to the SmPCs, crucial especially in the case of reassignment and pre-preparation of bags. This information will allow hospitals to achieve significant cost savings, and better organization of the entire therapeutic process.
Topics: Humans; Panitumumab; Cetuximab; Colorectal Neoplasms; Antibodies, Monoclonal; Antineoplastic Agents; Saline Solution
PubMed: 38040395
DOI: 10.1016/j.ijpharm.2023.123643 -
Pharmaceutics Nov 2023Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It... (Review)
Review
Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university's online library. The keywords were "Colorectal Cancer" AND "disease process" OR "disease mechanisms" OR "Current Treatment" OR "Prospects". Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low-medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux) and panitumumab (Verbitix). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells.
PubMed: 38004598
DOI: 10.3390/pharmaceutics15112620