Line Treatment Of Colorectal Cancer Research Articles

Current status of palliative care for patients with unresectable metastatic colorectal cancer in China: a questionnaire-based survey

Objective: To analyze the current adoption of palliative care by patients with unresectable metastatic colorectal cancer (mCRC) in China. Methods: From 1 March 2023 to 30 June 2023, a questionnaire survey was conducted by random sampling. An exclusive research platform for the Blue Book on Clinical Diagnosis and Treatment of Metastatic Colorectal Cancer. An online questionnaire was sent to medical oncologists (including chief physicians, associate chief physicians, attending physicians and residents) in general hospitals and oncology hospitals in four major regions of East, Central, South and Northeast China. The questionnaire contained 28 questions requesting basic information about doctors, the number of patients with mCRC, the status of treatment from first to fourth line and beyond, points concerning treatment of pain in patients with mCRC, and expectations for the future. A medical team was responsible for the quality control of data collected, whereas statisticians performed the data cleaning and sorting and statistical analysis. Results: A total of 300 clinical questionnaires were collected, including 217 (72%) from doctors in general hospitals and 83 (28%) from doctors in oncology hospitals. Senior physicians (including associate chief physicians and chief physicians) accounted for 65% of the respondents, attending physicians 30%, and residents 5%. Within 3 months (average for each month), 46.4±26.6% patients were diagnosed with recurrent or unresectable mCRC by each physician, 51.6±26.8% of the patients being in cancer hospitals and 44.4±26.3% in general hospitals. One hundred percent of patients receiving first-line treatment received palliative care, as did 80.3% of those receiving second-line treatment, 58.2% of those receiving third-line treatment, and 35.1% of those receiving ≥fourth-line treatment. The primary factor governing selection of first-line treatment was guideline recommendations, whereas comorbidities and the patients' physical status dictated second line to fourth line treatment. Standard first-line treatment was administered to 93.8% of eligible patients, standard second-line treatment to 94.3%; and standard third-line treatment to 73.5%. First-line therapy included targeted therapy in 63.6% of patients and immunotherapy in 2.8%; second-line therapy included targeted therapy in 63.0% of patients and immunotherapy in 2.0%; third-line therapy included targeted therapy in 59.2% of patients and immunotherapy in 2.2%; and fourth-line therapy included targeted therapy in 48.7% of patients and immunotherapy in 3.1%. First-line treatment lasted an average of 9.6 months, second-line treatment 6.7 months, third-line treatment 4.9 months, and fourth-line treatment 3.7 months. More than 70% of the patients maintained a good quality of life after receiving first and second-line treatment and more than 60% of them had ECOG performance scores of 0-1. After receiving third- and fourth-line treatment, 50%-60% of patients maintained a good quality of life and 40%-50% of them maintained ECOG performance scores of 0-1. The survey also revealed that the main deficiencies in treatment were limited effectiveness of third-line treatment, insufficient availability and opportunity for clinical research, popularity of new drugs or new drug combination strategies, and limited channels for participation in multidisciplinary diagnosis and treatment. Clinicians reported looking forward to participating in more clinical research on new drugs, hearing about the experience of experts in the field, and discovery of new targets and new drugs that increased the options for posterior line treatment of colorectal cancer. Conclusions: This report objectively summarizes the current situation, treatment difficulties, and expectations of frontline physicians concerning management of mCRC, thus providing a basis for decision-making and future direction for the diagnosis and research on treatment of mCRC.

Isoflurane Suppresses Proliferation, Migration, and Invasion and Facilitates Apoptosis in Colorectal Cancer Cells Through Targeting miR-216

Objective: Surgery is the first line treatment of colorectal cancer (CRC). Anesthetic isoflurane may improve outcomes of cancer surgery. Herein, we investigated the effects of isoflurane on malignant behaviors of CRC cells and its underlying therapeutic target.Methods: SW620 and HCT116 CRC cells were exposed to a series of concentrations of isoflurane. CCK-8 assay was utilized for determination of the optimal concentration of isoflurane. Under treatment with isoflurane, proliferation, migration, and invasion were separately assessed via clone formation and transwell assays. Apoptotic levels were observed via flow cytometry and expression of Bax, Bcl-2, and Caspase3 proteins was quantified through western blot. MiR-216 expression was detected in isoflurane-induced SW620 and HCT116 cells by RT-qPCR. Following transfection with miR-216 mimic, malignant biological behaviors were examined in isoflurane-treated SW620 and HCT116 cells.Results: 40 μM isoflurane distinctly restrained proliferative, migrated, and invasive capacities and elevated apoptotic levels in SW620 and HCT116 cells. Up-regulation of miR-216 was found in CRC cells. Its expression was suppressed by isoflurane. MiR-216 mimic ameliorated the reduction in proliferation, migration, and invasion and the increase in apoptosis for 40 μM isoflurane-induced SW620 and HCT116 cells.Conclusion: Isoflurane, a promising drug of CRC, may suppress malignant biological behaviors of tumor cells. Furthermore, miR-216 is an underlying target of isoflurane. Thus, isoflurane could be adopted for CRC treatment.

The combined effect of dichloroacetate and 3-bromopyruvate on glucose metabolism in colorectal cancer cell line, HT-29; the mitochondrial pathway apoptosis

Background5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells.MethodsMTT (3–4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines.ResultsTreatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax.ConclusionMitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.

6. Functional impact of neuropathy in patients receiving oxaliplatin chemotherapy

The development of a generalised sensory neuropathy is the dose-limiting side-effect of the chemotherapeutic drug, oxaliplatin, the first line treatment in colorectal cancer. However, the functional impact of oxaliplatin-induced neuropathy has not been investigated. The present study was undertaken to investigate the potential relationship between neurophysiological parameters and functional outcomes in colorectal cancer patients treated with oxaliplatin chemotherapy. Nerve conduction studies and clinical examinations were conducted in 10 colorectal cancer patients receiving oxaliplatin chemotherapy (mean age 58.3 years; 7 male, 3 female). Symptoms of chemotherapy-induced peripheral neuropathy (CIPN) were assessed using the FACT-GOG NTX 13 questionnaire. The 9-hole peg test was undertaken by all patients as a measure of upper limb dexterity. All assessments were conducted at baseline, at the final cycle of treatment and 3 months following treatment completion. Three months following treatment completion there was a reduction in median and sural sensory amplitudes following oxaliplatin treatment (median; 67.8 ± 7.2%, sural; 62.4 ± 8%). This was accompanied by an increase in 9-hole peg test time (right hand; 4.9 ± 4.2%, left hand; 5.1 ± 3%). Assessment of neuropathy-related quality of life demonstrated an increase in neuropathic impairments which continued to progress following cessation of treatment, a phenomenon known as ‘coasting’ (FACT-GOG NXT-13 questionnaire; 27.4 ± 5.7%). Importantly, a significant correlation was noted between reductions in sural sensory amplitude, a marker of neuropathy severity, and prolongation in 9-hole peg test time (left hand r = 0.8, right hand r = 0.6). This study demonstrates prominent functional alterations in oxaliplatin treated patients that correlate with nerve conduction markers of neuropathy severity. This study emphasises the functional impact of oxaliplatin-induced neuropathy and underscores the importance of developing neuroprotective strategies for patients receiving oxaliplatin treatment.

Incidence and significance of K-RAS mutation in first line treatment of colorectal cancer (cc): Experience of a single institution (Hospital Universitario Central de Asturias (HUCA))

e15081 Background: Although the significance of K-RAS mutation and cetuximab/panitumumab has been established in first line (ASCO 08 abstract 2# and 4000#) and in previously treated patients (pts) (NEJM 2008; 359: 1757. JCO 2008; 26: 374. JCO 2008; 26: 1626), data of the significance of this mutation in relation to bevacizumab is scarcer (JNCI 2005; 97: 981). Methods: Sample tissue of alive patients diagnosed of stage IV colorectal cancer were analyzed for the presence of K-RAS mutation by PCR amplification and direct sequencing. Data regarding presence of K-RAS mutation were retrospectively analyzed in relation to clinical data. Results: From IV to XII 08 122 paraffin embedded samples were analyzed. The percentage of mutant cases were 41% (95% CI 32–51%). The most frequent mutant type was Gly12Asp (37%) followed by Gly12Val (25%) and Gly13Asp (19%). We have clinical data of 94 pts. 62 were men and 32 female. 25 pts had received previous complementary treatment; in 80 pts primary tumor was previously resected (85%); median number of affected organs was 1 (1–4); in first line 76 pts received bevacizumab and 18 did not received any biological agent. Response Rate (RR) between mutant and no mutant pts was 48% (95% CI 37–59%) vs 47.8% (95% CI 32–63%) (p=0.92). Median follow up was 15.4 months. Progression free survival was 15 months for mutant and native K-RAS. There were no differences in response or PFS in any subgroup studied. Multivariable Cox analysis did not find any significant difference between sex (p=0.78), primary resected organ (p=0.28), liver metastases (p=0.37), LDH value at diagnosis (p=0.0.43), employ of biological agents in first line (p=0.37) or mutation in K-RAS gene (p=0.68). Conclusions: The percentage of K-RAS mutants is coherent with the results of the literature; mutations Gly12Asp, Gly12Val, and Gly13Asp represents the majority of the cases (81%); no significant relation was found between responses or DFS and mutations in the gene. No significant financial relationships to disclose.

Bevacizumab plus XELOX as first-line therapy for patients with metastatic colorectal cancer

15114 Background: Bevacizumab (BEV) is a monoclonal antibody that inhibits tumour angiogenesis by targeting VEGF. In a phase III trial, BEV significantly improved overall (OS) and progression-free survival (PFS) when combined with first-line irinotecan plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (IFL) in patients with metastatic colorectal cancer (mCRC). Methods: Patients had to have: mCRC; no surgery within 28 days; no prior CT for metastatic disease; ECOG PS 0/1, adequate organ function. CT consisted in Xelox (oxaliplatine 130 mg/m2 plus capecitabine 1000 mg/m2 bid 14 days) plus BEV 7,5 mg/kg was given on day 1 with every 3 weeks. Tumour assessments were performed every 3 cycles. The primary objective was PFS and overall response; secondary objectives included safety, and OS. Results: By July, 2006, 35 pts had been enrolled. Male 71%; median age 64 years; PS 0–1 (88,6%). The most common site of metastases was liver (100%). Among the 35p. Related grade 3–4 AEs were reported in 10 (28,6%) pts. GI perforation 3%, diarrhea 8,6%, hypertension 3%; neuropathy 6%. Overal response was observed in 63% pts (CR 3%; PR 60%). Conclusions: The scarce toxicity, the efffectiveness and the non requirement of central venous access, make it an interesting alternative to the first line treatment of colorectal cancer. No significant financial relationships to disclose.

5,10-methylenetetrahydrofolic acid with 5-fluorouracil as first line treatment in metastatic colorectal cancer: Phase II study results

3599 Background: 5-Fluorouracil (FU) plus Leucovorin (LV) has historically been the standard first line treatment of colorectal cancer. Although LV modestly enhances FU activity, it can increase systemic toxicity and also must be intracellularly converted in multiple steps to its active metabolite, 5,10-methylenetetrahydrofolate (CoFactor [CO]). Unlike LV, CO directly modulates FU inhibition of thymidylate synthase without the need for metabolic conversion. Preclinical models show reduced hematologic toxicity of CO+FU with enhanced efficacy compared to FU+LV. We evaluated CO+FU chemotherapy in patients with previously untreated mCRC. Methods: Patients (pts) had performance status ECOG 0–2 and objectively measurable mCRC. Prior adjuvant therapy was allowed including FU+LV. Fifty pts were enrolled and treated with CO 60mg/m2 and FU 450mg/m2 (weekly IV bolus) for 6 weeks, followed by 14 day rest. Response was measured at 16 wks (WHO criteria). Results: As of January 2006, 50 pts received at least 1 dose of drug and are no longer on treatment. Patient demographics: median age = 65 (range 42–86), M/F = 60%/40%. Mean number of doses was 18.0 (range 2–41). Overall incidence of grade 3/4 AEs was 14 (28%). No grade 3/4 drug-related hematologic toxicity was observed. There was no significant effect on HCT, Bili, WBC, ALT, and AST during the course of the study. Objective response rate (CR + PR) to first line treatment with CO+FU based on independent blinded review was 35% (2 CR, 14 PR, 23 SD, 7 PD; 95% CI: 21.4–50.2) based on 46 pts evaluable for response. Median time to tumor progression was 163 days (95% CI: 105 -189). Twenty pts are deceased and median survival has not been reached. Conclusions: The results suggest thatCO+FU is safe, well tolerated, and has activity in mCRC. In the optimum treatment strategy afforded by the availability of numerous drugs, the high level of activity and low toxicity of CO+FU suggests that this combination may be a good initial treatment in a sequential strategy of mCRC management, especially among pts who would benefit by minimizing initial toxicity. [Table: see text]

Anti-VEGF antibody bevacizumab (Avastin) with 5FU/LV as third line treatment for colorectal cancer

To evaluate the activity and safety of bevacizumab when given with standard 5FU/leukovorin (LV) regimens in patients with metastatic colorectal cancer who have failed irinotecan and oxaliplatin-based treatments. Bevacizumab was given at 5 mg/kg as an IV infusion every 2 weeks. Patients received 5FU according to Roswell Park or the de Gramont regimen. Nineteen patients enrolled, median age 60, median PS: 1. Most common toxicity attributable to bevacizumab was mild hypertension, epistaxis and mild proteinuria; 1 patient had a CNS haemorrhage. The median number of cycles was 1 (8 weeks). Clinical benefit as disease stabilisation lasting 2-6 months was noted in 9 patients, whereas 10 progressed (median f/u: 5 months). TTP was 16 weeks, and the overall survival has not been reached (24+ weeks). Bevacizumab may result in growth arrest and clinical benefit in a substantial proportion of patients with colorectal cancer and no alternative treatment.

Therapy of elderly patients with colorectal carcinoma

Treating elderly patients with colorectal cancer is a challenging task for which many aspects have to be taken into account. Almost 70% of patients with colorectal cancer are 65 years or older and the number of elderly patients is expected to increase. As elderly patients frequently exhibit adverse physical or socio-economic conditions, a thorough geriatric assessment of the patient's suitability for therapy is essential before making a decision. The first line treatment for colorectal cancer is surgery. Complete resection of the tumor should also be attempted in elderly patients, as there are little differences in cancer--specific survival in selected elderly patients compared to younger patients. Surgery with palliative intention can be attempted for symptom control or to prevent later local complications caused by the primary tumor. At present, adjuvant 5-FU based chemotherapy (in colon cancer) and adjuvant radio-chemotherapy (in rectal cancer) in the elderly is recommended for locally advanced or node positive tumor after tumor resection, since the benefit seems to be comparable to that achieved in younger patients. There is also enough data to support the use of 5-FU based chemotherapy in elderly patients in the palliative setting. New drugs have recently been added to the armentarium for the treatment of metastatic colorectal cancer. However, there is as yet not sufficient data to guide the use of these new drugs (such as oxaliplatin or irinotecan) in elderly patients. However, first clinical studies seem to indicate a comparable efficacy and toxicity in elderly patients to that observed in younger patients. Further clinical trials of chemotherapy in elderly patients with colorectal cancer are necessary to gain information about treatment recommendations. It is the aim of this manuscript to summarize the current knowledge about the management of colorectal cancer in elderly patients.

Irinotecan: a new treatment in metastatic colorectal cancer

Objective. Historically, outcomes of metastatic colorectal cancer therapy have been disappointing, with fluorouracil (5-FU) producing response rates of no more than 15%. The addition of leucovorin increases response rates; however, survival rates are largely unaffected. Recently, the topoisomerase I inhibitor, irinotecan, has proved active in metastatic colorectal cancer and is indicated as second-line therapy following disease recurrence or progression after 5-FU-based therapy. More recently, irinotecan plus 5-FU-LV was compared with 5-FU-LV as first line treatment of colorectal cancer, showing impressive results. This article discusses the role of irinotecan, as a single agent and in combination with 5-FU-LV, in the treatment of advanced colorectal cancer. Data sources. A MEDLINE search was conducted using 5-fluorouracil, irinotecan, leucovorin, and metastatic colorectal cancer as primary search terms. Reference lists, bibliographies of pertinent articles, and abstracts from the American Society of Clinical Oncology and the European Society for Medical Oncology annual meetings were also identified and reviewed. Clinical literature was reviewed and analyzed. Data synthesis. Results of studies comparing irinotecan with continuos infusion 5-FU or best supportive care suggest that irinotecan is superior to either treatment as second-line therapy of metastatic colorectal cancer. Based on these study results, along with irinotecan's lack of cross-resistance with other chemotherapy agents and mechanism of action that differs from 5-FU, phase III trials evaluating the use of irinotecan in combination with 5-FU-LV as first-line treatment for advanced colorectal cancer were conducted. The results of a pivotal trial evaluating irinotecan plus 5-FU-LV in this setting show superior response rates (RRs), time to tumor progression (TTP), and median survival times (MSTs) when compared with 5-FU-LV alone. This combination represents a major advance in the treatment of metastatic colorectal cancer and should be considered the first-line treatment standard.