Search

Background Olaparib is an orally available inhibitor of PARP-1. In pre-clinical studies, olaparib was shown to potentiate anti-tumor effects of irinotecan in colon cancer cell lines. This phase I study was conducted to evaluate the safety and tolerability of olaparib in combination with irinotecan. Patients and Methods Patients with advanced colorectal cancer whose disease progressed after at least one systemic therapy regimen were enrolled. Dose escalation and de-escalation were based on toxicity assessment. Pharmacokinetic samples were collected in Cycle 1 for olaparib, irinotecan and SN-38. Results Twenty-five patients were enrolled, 11 patients on a schedule of continuous olaparib and irinotecan every 3 weeks (Part A) and 14 patients on a schedule of intermittent olaparib and irinotecan every 2 weeks (Part B). Continuous olaparib administration was associated with higher than expected toxicities and was not considered to be tolerable. Intermittent olaparib administration was better tolerated, and the recommended phase 2 doses were olaparib 50 mg p.o twice daily days 1-5 and irinotecan 125 mg/m(2) i.v. every 2 weeks. Common toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia and abdominal pain. Nine patients had stable disease as the best response, 2 from Part A (3 and 9 months respectively), and 7 from Part B (median duration: 7.4 months; range: 4 to 13 months). There was no pharmacokinetic interaction between olaparib and irinotecan. Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353.

Background: Tissue factor pathway inhibitor (TFPI) is an anticoagulant with antimetastatic properties. The homozygous CC polymorphism of TFPI (-33T → C) is associated with higher TFPI levels and lower venous thromboembolism risk. This study was the first to evaluate the impact of this polymorphism on disease-free survival (DFS) in cancer patients after curative resection., Methods: A prospectively maintained tumor bank with clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin-fixed, paraffin-embedded normal colonic mucosa. Single nucleotide polymorphisms for TFPI (-33T → C), factor V Leiden (G1691A), and prothrombin (G20210A) were determined by polymerase chain reaction. Survival analysis was described using the Kaplan-Meier method. Multivariable regression analysis was performed using the Cox proportional hazard model., Results: Of the 127 patients identified, the CC genotype was found in 11 %. Venous thromboembolism incidence was 18 % in the TT/TC (wild type/heterozygous) genotypes and 7 % in the CC genotype (p = 0.46). The CC genotype was associated with superior DFS (hazard ratio 0.34, 95 % confidence interval 0.14-0.84; p = 0.02) with 5-year DFS of 63 vs. 24 % for CC vs. TT/TC, respectively. In multivariate analysis, CC polymorphism (hazard ratio 0.28, p = 0.008) was independently associated with improved DFS. The prevalence of factor V Leiden (0.8 %) and prothrombin (1.6 %) polymorphisms was too low to detect interaction with TFPI polymorphism or DFS., Conclusions: These findings indicate that the inherited anticoagulant homozygous -33T → C TFPI polymorphism may protect against colon cancer recurrence and suggests a mediating role for the coagulation system in cancer outcomes.

Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.

Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283., Patients and Methods: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D)., Results: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months)., Conclusion: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.

Objectives: The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies., Methods: In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400-500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated., Results: Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand-foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83%) and leukopenia (83%). Pharmacokinetic data revealed no clinically significant drug-drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60%)., Conclusions: With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.

Purpose: To determine antitumor activity of cetuximab monotherapy in patients with refractory metastatic colorectal carcinoma (mCRC) with lack of specific membrane immunostaining for the epidermal growth factor receptor (EGFR)., Patients and Methods: Patients had immunohistochemical (IHC)-determined mCRC with absent EGFR immunostaining that progressed after receiving at least one standard, fluoropyrimidine-containing chemotherapeutic regimen. Absent EGFR immunostaining was defined as the IHC absence of specific membrane staining in ≥500 cancer cells examined in well-preserved tissue. The study was performed prior to results of studies linking cetuximab sensitivity to K-ras mutation status. Patients received 400 mg/m(2) of intravenous (i.v.) cetuximab followed by once-weekly i.v. cetuximab 250 mg/m(2) until disease progression or unacceptable toxicity. Patients were evaluated for objective response at least every 6 weeks. Kaplan-Meier estimates were calculated for duration of response, time to progression (TTP), and overall survival (OS)., Results: Seven (8.2%) of 85 mCRC patients whose tumors lacked EGFR immunostaining had major responses following cetuximab treatment. The median duration of response was 5.1 months. Median TTP and OS were 2.5 months and 10.0 months, respectively; the 1-year survival rate was 39.6%. The most frequently reported cetuximab-related adverse events were acneiform dermatitis, fatigue, headache, and dry skin., Conclusion: Cetuximab monotherapy produces objective antitumor activity in patients with mCRC that does not express EGFR as determined by IHC. The activity and safety profiles of cetuximab monotherapy in mCRC lacking EGFR immunostaining are similar to previous observations in EGFR IHC-positive disease that was not selected based on K-ras mutation status.

Cancer due to its heterogeneous nature and large prevalence has tremendous socioeconomic impacts on populations across the world. Therefore, it is crucial to discover effective panels of biomarkers for diagnosing cancer at an early stage. Cancer leads to alterations in cell growth and differentiation at the molecular level, some of which are very unique. Therefore, comprehending these alterations can aid in a better understanding of the disease pathology and identification of the biomolecules that can serve as effective biomarkers for cancer diagnosis. Metabolites, among other biomolecules of interest, play a key role in the pathophysiology of cancer whose levels are significantly altered while 'reprogramming the energy metabolism', a cellular condition favored in cancer cells which is one of the hallmarks of cancer. Metabolomics, an emerging omics technology has tremendous potential to contribute towards the goal of investigating cancer metabolites or the metabolic alterations during the development of cancer. Diverse metabolites can be screened in a variety of biofluids, and tumor tissues sampled from cancer patients against healthy controls to capture the altered metabolism. In this review, we provide an overview of different metabolomics approaches employed in cancer research and the potential of metabolites as biomarkers for cancer diagnosis. In addition, we discuss the challenges associated with metabolomics-driven cancer research and gaze upon the prospects of this emerging field., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest regarding the content of this article., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To address the issue that most microsatellite-stable (MSS) and proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) patients have minimal response to immunotherapy, this meta-analysis evaluated the efficacy and safety of durvalumab and tremelimumab with concomitant treatment in treating MSS/pMMR metastatic colorectal cancer., Methods: All included trials were prospective studies with a median patient age of 63 years, of which 94.2% were MSS/pMMR mCRC patients, with a male to female ratio of 1.5:1. Based on durvalumab and tremelimumab treatment, one study performed surgical resection on resectable cases, while the other four studies performed radiotherapy or chemotherapy on unresectable cases. Analyses include objective response rate (ORR).etc. for drug activity, overall survival (OS) and progression-free survival (PFS) for therapeutic efficacy, and adverse events (AEs) for safety. The risk of bias was assessed by sensitivity analysis., Results: 5 studies involving 228 patients were included in this meta-analysis. The pooled estimates showed a median OS of 9.26 months, median PFS of 2.53 months, partial response (PR) of 13.6%, stable disease (SD) of 32.8%, ORR of 12.5% and disease control rate (DCR) of 65.4%. AEs were generally low, with pruritus (27.5%), diarrhea (28.8%), and fatigue (53.9%) being the most common, while other AEs occurred at less frequencies., Conclusions: Durvalumab and tremelimumab with concomitant treatment for MSS/pMMR mCRC patients is relatively effective and safe, which is helpful in addressing the problem of mCRC with MSS/pMMR that has minimal response to immunotherapy., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Human Ethics: Not applicable. Consent to Participate Declarations: Not applicable. Standards of Reporting: Systematic reviews and meta-analyses (PRISMA) and protocols (Prisma-P). Clinical Trial Number: Not applicable. Reviewer Disclosure: Peer reviewers on this manuscript have no relevant financial or other relationships to disclose., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pancreatic cancer has a poor prognosis despite ongoing advances in systemic and multimodal therapies. This review analyzes recent progress and future directions in pancreatic cancer clinical trials, emphasizing the evolution from traditional approaches to a more personalized and biologically-driven treatment paradigm. While improvements in overall survival have been achieved through perioperative therapies, gaps remain in our understanding of optimal treatment strategies. Key questions include selection of specific chemotherapeutic agents, duration of preoperative therapy, the role of radiotherapy, and accurate and real-time assessment of response to therapy. Historically, pancreatic cancer clinical trials have been designed based on anatomic criteria, failing to account for the inherent biologic heterogeneity of this disease. The field is now moving towards a precision oncology approach, leveraging genomic and transcriptomic data to identify predictive biomarkers and personalize treatment selection. Novel clinical trial designs, such as platform and basket trials, are accelerating the evaluation of new therapeutic strategies and facilitating efficient patient selection, particularly in the context of new emerging targeted therapies such as KRAS inhibitors. Furthermore, implementation of dynamic response assessment techniques, such as circulating tumor DNA and radiomics, may inform treatment decision-making and improve prediction of long-term outcomes. By integrating these evolving strategies, the emerging clinical trial landscape has the potential to transform the treatment of pancreatic cancer and yield meaningful improvements in patient outcomes., (© 2025. Society of Surgical Oncology.)

Background: Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours., Patients and Methods: Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy., Results: In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response., Conclusions: A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment., (© 2021. Society of Surgical Oncology.)

Background: The relative success of cisplatin-based chemotherapy regimens for PDAC in clinical trials warrants a review of the literature to assess the cumulative results. This study aims to assess the efficacy of cisplatin-containing regimens for PDAC in terms of survival and response outcomes using a systematic review and proportional meta-analysis., Methods: In this study, an electronic search was conducted on PubMed, Cochrane Library, Scopus, and Google Scholar to find relevant literature. The random effects model was used to assess pooled overall response rate, stable disease rate, progressive disease rate, 1-year overall survival rate, and their 95% CIs. Publication bias was assessed using funnel plot symmetry and the one-tailed Eggers' test. In all cases, p-value < 0.05 was indicative of significant results. The review is registered with PROSPERO: CRD42023459243., Results: A total of 34 studies consisting of 1599 patients were included in this review. All the included studies were of good quality. In total, 906 patients were male, and the median age of the patients was 58-69 years. Overall, 599 patients had cancer of the pancreatic head, 139 had cancer of the pancreatic body, and 102 patients had cancer of the pancreatic tail. The pooled risk ratios (RRs) revealed an overall response rate of 19.2% (95% CI, 14.6-24.2%), a stable disease rate of 42.3% (95% CI, 36.6-48.8), a 1-year overall survival rate of 40% (95% CI, 34.3-45.8), and progressive disease rate of 24.7% (95% CI, 18.8-31.2). Commonly reported adverse events were anemia, thrombocytopenia, abdominal adverse events, neutropenia, fatigue, leukopenia, alopecia, anorexia, mucositis, stomatitis, and hepatobiliary adverse events., Conclusion: Cisplatin-containing regimens have shown moderate efficacy with significant improvement in overall survival at 1 year, stable disease rate, and progressive disease rate; however, only a small percentage of patients achieved an overall response rate., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab., Methods: A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS., Results: The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81)., Conclusion: Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pancreatic adenocarcinoma is an aggressive disease marked by high rates of both local and distant failure. In the minority of patients with potentially resectable disease, multimodal treatment paradigms have allowed for prolonged survival in an increasingly larger pool of well-selected patients. Therefore, it is critical for surgical oncologists to be abreast of current guideline recommendations for both surgical management and multimodal therapy for pancreas cancer. We discuss these guidelines, as well as the underlying data supporting these positions, to offer surgical oncologists a framework for managing patients with pancreatic adenocarcinoma., (© 2023. Society of Surgical Oncology.)

Background: The prognostic relevance of laterality, microsatellite instability (MSI), and KRAS status in colon cancer has been established. However, their effect on conditional overall survival (COS) remains unknown., Methods: COS is the probability of surviving additional years after a time from diagnosis. The National Cancer Database (2010-2017) was queried for adults with non-metastatic colon cancer and known mutation status undergoing curative resection. COS was investigated at 2 years., Results: Of 4838 patients, 3716 survived at least 2 years: 15% had stage I, 38% stage II, and 46% stage III disease. Fifty-nine percent had a right-sided tumor, 16% were MSI-high, and 37% were mutated KRAS (mKRAS). The proportion of patients alive at 2 years was higher for stage I compared with stage II and III (65 vs. 61 vs. 54%). The 5-year overall survival for stage I-III was 80, 76, and 67% for the initial cohort, and 90, 88, and 86% for those alive at 2 years. After adjustment, higher pathologic T and N stage, tumor deposits, and no chemotherapy were associated with worse COS (p < 0.01). While laterality and MSI status were not associated with COS, mKRAS was independently associated with decreased COS (HR 1.35, 95% CI 1.12-1.62)., Conclusion: Patients with mKRAS had worse COS, suggesting that these mutations confer an aggressive biologic behavior, with patients remaining at higher risk of death 2 years after diagnosis. Routine evaluation of KRAS status should be considered in patients with non-metastatic disease for prognostication and to identify those who might benefit from modified surveillance protocols., (© 2023. Society of Surgical Oncology.)

Background: Immune checkpoint inhibitors have recently replaced over chemotherapy as the first-line treatment for microsatellite instability-high or mismatch repair deficient (dMMR/MSI-H) stage 4 colorectal cancers. Considering this success, many studies have tried to replicate the use of immune checkpoint inhibitors, either as a single agent or in combination with other therapeutic agents, in the treatment of proficient mismatch repair (pMMR/MSS) stage 4 colorectal cancers. This review summarizes the seminal clinical data about the immune checkpoint inhibitors used in pMMR/MSS colorectal cancers and some future directions., Results: Studies concerning the use of immune checkpoint inhibitors as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy have proven inefficient in the treatment of pMMR/MSS colorectal cancer. However, a small subset of patients with pMMR/MSS colorectal cancer who has a mutation in POLE and POLD1 enzymes may respond to immunotherapy. Moreover, patients without liver metastasis appear to have a better chance of response. New immune checkpoint targets are being identified, such as VISTA, TIGIT, LAG3, STING signal pathway, and BTLA, and studies are ongoing to determine their efficiency in this disease type., Conclusion: Immune checkpoint inhibitor-based regimens have not yet shown any meaningful positive outcomes for most pMMR/MSS colorectal cancers. A beneficial effect among a minority of these patients has been observed, but concrete biomarkers of response are lacking. Understanding the underlying mechanisms of immune resistance should guide further research for overcoming these obstacles., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Conventional chemotherapy has significant limitations for colorectal cancer (CRC) treatment, especially those who have developed metastatic recurrence CRC. A growing number of studies have investigated the potential use of monoclonal antibodies (mAbs) for CRC therapy. mAbs showing clinical benefits for CRC, making the treatment more selective with lower side effects without significant immunogenicity. In addition, recent advancements in antibody engineering strategies and the development of bifunctional or even trifunctional drugs have helped to overcome heterogeneity as the main challenge in cancer treatment. The current review discusses advances in applying mAbs for CRC therapy alone, combined, or with small molecules., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Colorectal cancers are among the most commonly found cancers over the world. In spite of the recent advancements in diagnosis and prognosis, the management of this metastatic condition remains a challenge. The utility of monoclonal antibodies in the healing of patients with colorectal cancer has opened a new chapter in the quest for newer therapies. The resistance to the standard treatment regimen made it mandatory to search for newer targets. Mutagenic alterations in the gene engaged in cellular differentiation and growth pathway have been the reason for resistance to treatment. The newer therapies target the various proteins and receptors involved in the signal transduction and down streaming pathways leading to cell proliferation. This review presents an insight into the newer targeted therapies for colorectal cancer involving tyrosine kinase blockers, epidermal growth factor receptors, vascular endothelial growth factor, immune checkpoint therapy, and BRAF inhibitors., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer is the most challenging disease for medical professionals to treat. The factors underlying the complicated situation include anticancer drug-associated toxicity, non-specific response, low therapeutic window, variable treatment outcomes, development of drug resistance, treatment complications, and cancer recurrence. The remarkable advancement in biomedical sciences and genetics, over the past few decades, however, is changing the dire situation. The discovery of gene polymorphism, gene expression, biomarkers, particular molecular targets and pathways, and drug-metabolizing enzymes have paved the way for the development and provision of targeted and individualized anticancer treatment. Pharmacogenetics is the study of genetic factors having the potential to affect clinical responses and pharmacokinetic and pharmacodynamic behaviors of drugs. This chapter emphasizes pharmacogenetics of anticancer drugs and its applications in improving treatment outcomes, selectivity, toxicity of the drugs, and discovering and developing personalized anticancer drugs and genetic methods for prediction of drug response and toxicity., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: The aim of this study is to determine the optimal indications for preoperative pelvic radiotherapy (RT) in patients with metastatic rectal cancer who underwent curative-intent surgical resection and/or ablation., Methods: Between January 2000 and October 2019, 246 patients who met our inclusion criteria were enrolled. Preoperative RT was performed in 22 patients (8.9%). Lower margin below the peritoneal reflection (p < 0.001), mesorectal fascia (MRF) invasion (p = 0.02), and lateral pelvic lymph node (LPLN) involvement (p = 0.005) were more frequent in the preoperative RT group., Results: During the median follow-up period of 13.3 months (interquartile range [IQR]: 6.0-36.3 months), local recurrence (LR) was identified in 60 patients (24.4%). It was the first site of recurrence in 45 of them (18.3%). Among them, three patients were in the preoperative RT group. On multivariable analysis, lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, carcinoembryonic antigen (CEA) level ≥ 10 ng/mL before treatment, and preoperative RT were significant prognostic factors for LR-free survival (LRFS). In the patient group without any risk factors, the 2-year LRFS rate was 94.9% without preoperative RT. In the patient group with one or more risk factors, the 2-year LRFS was 64.4% without and 95.2% with preoperative RT., Conclusion: LR developed in about 25% of patients within 2 years. Preoperative RT should be considered, especially in patients with a risk factor for LR, including lower margin below the peritoneal reflection, MRF invasion, LPLN involvement, or CEA ≥ 10 ng/mL before treatment., (© 2022. Society of Surgical Oncology.)

Purpose: The study aimed to evaluate the relationship between intra-tumor metabolic heterogeneity parameters of 18 F-FDG and KRAS mutation status in colorectal cancer (CRC) patients and which threshold heterogeneity parameters could better reflect the heterogeneity characteristics of colorectal cancer., Methods: Medical data of 101 CRC patients who underwent 18 F-FDG PET/CT and KRAS mutation analysis were selected. On PET scans, 18 F-FDG traditional indices maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity parameters coefficient of variation with a threshold of 2.5 (CV 2.5 ), CV 40% , heterogeneity index-1 (HI-1), and HI-2 of the primary lesions were obtained. We inferred correlations between these 18 F-FDG parameters and KRAS mutation status., Results: 41 patients (40.6%) had KRAS gene mutation. Assessment of FDG parameters showed that SUVmax (19.00 vs. 13.16, p < 0.001), MTV (11.64 vs. 8.83, p = 0.001), and TLG (102.85 vs. 69.76, p < 0.001), CV 2.5 (0.55 vs. 0.46, p = 0.006), and HI-2 (14.03 vs. 7.59, p < 0.001) of KRAS mutation were higher compared to wild-type (WT) KRAS. CV 40% (0.22 vs. 0.24, p = 0.001) was lower in the KRAS mutation group, while HI-1 had no significant difference between the two groups. Multivariate analysis showed that MTV (OR = 4.97, 1.04-23.83, p = 0.045) was the only significant predictor in KRAS mutation, using a cut-off of 7.62 (AUC = 0.695), and MTV showed a sensitivity of 90.2% and specificity of 45.0%. However, the PET parameters were not independent predictors in KRAS mutation., Conclusion: KRAS gene mutant CRC patients had more 18 F-FDG uptake (SUVmax, MTV, TLG) and heterogeneity (CV 2.5 , HI-2) than WT KRAS. MTV was the only independent predictor of KRAS gene mutation in colorectal cancer patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population., Methods: Consecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regression was used to determine whether laterality was an independent prognostic factor., Results: From 1993 to 2012, 487 patients [182 with right colon cancer (RCC), 305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5 years. Fifty-seven percent (n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%, P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%; P < 0.01) and LCC (73% vs. 55%; P < 0.01). On multivariable analysis, HAI remained associated with improved OS (HR 0.52; 95% CI 0.39-0.70; P < 0.01) but primary tumor site did not (HR 0.83; 95% CI 0.63-1.11; P = 0.21). Additional significant prognostic factors on multivariable analysis included age, number of tumors, node-positive primary, positive margins, RAS mutation, two-stage hepatectomy, and extrahepatic disease. Cox proportional hazard regression determined no significant interaction between HAI and laterality on OS [parameter estimate (SEM), 0.12 (0.28); P = 0.67]., Conclusions: Our data show an association of adjuvant HAI and increased OS in patients who underwent curative hepatectomy, irrespective of primary tumor location. Laterality should therefore not impact decision-making when offering adjuvant HAI.

Background: The aim of this study was to analyze risk factors of local recurrence (LR) after exclusive laparoscopic thermo-ablation (TA) with or without associated liver resection., Methods: Between 2012 and 2017, among 385 patients who underwent 820 TA in our department, 65 (17%) patients (HCC = 11, LM = 54) had exclusive laparoscopic TA representing 112 lesions (HCC = 17, LM = 95). TA was associated with other procedures in 57% of cases (liver resection 81%). All TA were done without liver clamping. Median tumor size was 1.8 cm [ranges from 0.3 to 4.5], 18% of the lesions were larger than 3 cm in size and 11% close to major liver vessels. Tumors locations were 77.5% in right liver, 36% in S7&S8, and 46% in S7&S8&S4a., Results: Mortality was nil and morbidity rate 15.4% including Dindo-Clavien > II grade 3%. The median follow-up was 24 months [0.77-75]. Per lesion LR rate after TA was 18% (n = 19 patients) with a mean time of 7.6 months. Among patients with LR, 18 (95%) could have been re-treated successfully (new resection = 11, re-TA = 7). Multivariate analyses revealed that tumor location in S7 alone, S7&S8 and/or S7, S8, or S4a were independent risk factors of LR after TA., Conclusions: Exclusive laparoscopic TA is a safe and an effective tool to treat liver malignancies with or without liver resection. Other than classical risk factors, tumor location in upper segments of the liver, are independent risk factors for LR.

Esophageal cancer has a poor prognosis despite the fact that surgical techniques have been advanced and optimized, and systemic multimodality approaches have progressed recently. Adding chemotherapy, radiotherapy, and immunotherapy to the basic surgical approach have been shown to have therapeutic benefit for esophageal cancer. This review describes the latest development of chemoradiotherapy, chemotherapy, and immunotherapy, which have contributed to the reduction in esophageal cancer growth and improved the survival of patients. Chemoradiation is a treatment option for resectable esophageal cancer to preserve the esophagus for patients who cannot tolerate surgery. Moreover, a combination of chemoradiotherapy and salvage surgery could extend the survival of patients. The effects of a triplet chemotherapy regimen are currently being verified in some Phase III studies for unresectable advanced/recurrent esophageal cancer. In addition, with the great promise of immune checkpoint inhibitors, strategies that incorporate the use of immunotherapy may shift from the metastatic setting to the neoadjuvant/adjuvant setting as a result of clinical trials. More precise comprehension of the molecular biology of esophageal cancer is expected to further control disease progression using multimodality treatments in the future.

Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

Background: Tumor location and KRAS mutational status have emerged as prognostic factors of colorectal cancer. We aimed to define the prognostic impact of primary tumor location and KRAS mutational status among synchronous colorectal liver metastases (CRLM) patients who underwent simultaneous curative-intent surgery (SCIS)., Methods: We compared the clinicopathologic characteristics and long-term outcomes of 227 patients who underwent SCIS for synchronous CRLM, according to tumor location and KRAS mutational status. We cross-classified tumor location and KRAS mutational status and compared survival outcomes between the four resulting patient groups., Results: Forty-one patients (18.1%) had right-sided (RS) tumors and 186 (81.9%) had left-sided (LS) tumors. One-third of tumors (78/227) harbored KRAS mutations. The KRAS mutant-type (KRAS-mt) was more commonly observed among RS tumors than among LS tumors [21/41 (51.2%) vs. 57/186 (30.6%), p = 0.012]. Median follow-up time was 43.4 months. Patients with RS tumors had shorter survival times than those with LS tumors [median disease-free survival (DFS): RS, 9.9 months vs. LS, 12.1 months, p = 0.003; median overall survival (OS): RS, 49.7 months vs. LS, 88.8 months, p = 0.039]. RS tumors were a negative prognostic factor for DFS [hazard ratio (HR) 1.878, p = 0.001] and OS (HR 1.660, p = 0.060). RS KRAS-mt and LS KRAS wild-type (KRAS-wt) tumors had the worst and best oncological outcomes, respectively., Conclusion: Tumor location has a prognostic impact in patients who underwent SCIS for CRLM, and RS KRAS-mt tumors yielded the worst oncological outcome. These results may allow for more tailored multimodality treatments.

Losatuxizumab vedotin (formerly ABBV-221) is a second-generation antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). In this multicenter phase 1 study, eligible patients with EGFR-dependent solid tumors received losatuxizumab vedotin (3 + 3 design) intravenously at starting dose of 0.3 mg/kg over 3 h per 21-day cycle, with alternate dosing schedules utilized (2 weeks on/1 week off or weekly) to mitigate infusion reactions. Forty-five patients received ≥1 doses of losatuxizumab vedotin (13 colon, 6 non-small cell lung cancer, 5 head and neck [HNC], 5 glioblastoma multiforme, 2 breast, 14 other). Tumor samples were evaluated for EGFR protein expression by immunohistochemistry, EGFR and EGFR ligand mRNA expression by RNAseq, and results compared with outcome. Most common adverse events were infusion-related reaction (22/45; 49%) and fatigue (20/45; 44%). While most infusion reactions were grade ≤ 2, four patients experienced grade ≥3 infusion reactions. Several infusion reaction mitigation strategies were explored. Because of the high incidence of infusion reactions, the trial was stopped and the maximum tolerated dose was not reached. The last cleared dose: 6 mg/kg/cycle. Nineteen patients (42%) had stable disease; 4 remained on study >6 months. One HNC patient with increased levels of EGFR and EGFR ligands (amphiregulin, epiregulin) achieved a confirmed partial response. Pharmacokinetic analysis of losatuxizumab vedotin showed exposures appeared to be approximately dose-proportional. The high frequency of infusion reactions necessitated early closure of this trial. The detailed mitigation strategies used in this protocol for infusion-related reactions may provide beneficial information for trial design of agents with high infusion reaction rates.

Background: Serum carcinoembryonic antigen (CEA) is a widely used tumor marker in colorectal cancer (CRC), but within normal range of preoperative CEA levels the clinical significance of CEA is unknown., Objective: The aim of this study was to evaluate the usefulness of CEA within the normal range as a prognosticator of non-metastatic CRC., Methods: This retrospective cohort study included 2021 CRC patients with normal preoperative CEA who underwent elective curative surgery (discovery group). We determined the optimal cut-off value for disease-free survival (DFS) discrimination using the Contal and O'Quigley method. We also assessed the prognostic significance of the cut-off value in a prospective cohort of 171 stage III colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (validation group)., Results: The optimal cut-off CEA value was 2.1 ng/mL in the discovery group. The DFS rates were significantly poorer in patients with high-normal preoperative CEA levels (2.1-5.0 ng/mL) than in those with low-normal CEA levels (< 2.1 ng/mL) in both groups. A high-normal CEA level was an independent risk factor for DFS in both groups, and was associated with inferior DFS in patients with stage II and III disease and in never or former smokers. The correlation between DFS and CEA levels was more distinct in left-sided colon and rectal cancer., Conclusions: A high-normal preoperative CEA level (≥ 2.1 ng/mL), even within the normal range, was an independent prognosticator for poor DFS in CRC. The usefulness of CEA was influenced by smoking status and tumor location in addition to tumor stage.