Adjuvant Treatment Of Colon Cancer Research Articles

Changes in clinical guidelines for the treatment of colorectal cancer in 2024

Aim. The ensuring that changes to clinical guidelines can be discussed more widely before they are formally introduced into clinical practice.Materials and methods. A brief review of the literature and rationale for each proposed major change in the treatment section is presented. The refusal to carry out preoperative radiation therapy for cancer of the upper ampullary rectum, the narrowing of indications for preoperative radiation therapy for cancer of the mid-ampullary rectum, as well as the expansion of indications for total non-adjuvant chemotherapy for rectal cancer with damage to the circular resection margin are discussed. Changes to the drug treatment section are discussed.Results. This article presents planned changes to clinical guidelines for the treatment of non-metastatic colorectal cancer in 2024. The most significant alterations concerned neoadjuvant treatment of rectal cancer and adjuvant treatment of colon cancer. A new algorithm was proposed for choosing rectal cancer neoadjuvant therapy, considering individual treatment decisions.Conclusion. A consensus was achieved concerning the necessity to expand indications for neoadjuvant rectal cancer chemotherapy, but only in patients with good functional status. The most benefit can be achieved in patients, for whom complete clinical response is the aim of the treatment and in patients with positive circumferential resection margin.

Effects of Viable and Heat-Inactivated Bifidobacterium longum D42 on Proliferation and Apoptosis of HT-29 Human Colon Cancer Cells.

Bifidobacterium longum is a common probiotic; both viable and heat-inactivated Bifidobacterium longum have many probiotic effects, such as anticancer effects. But some mechanisms of anticancer effects are still unclear, especially for heat-inactivated probiotics. In this study, we analyzed the effects of viable and heat-inactivated Bifidobacterium longum D42 on human colon cancer cells (HT-29). Cell proliferation, membrane permeability and apoptosis were detected by using the CCK-8 method, LDH method and Annexin V-FITC/PI kits. The ROS level and mitochondrial membrane potential were examined using the fluorescent probes DCFH-DA and JC-1. Real-time fluorescence quantitative PCR (RT-qPCR) and Western blot were used to detect the expression of mitochondrial apoptosis pathway genes and proteins. The results showed that viable and heat-inactivated Bifidobacterium longum D42 at concentrations of 1 × 106 CFU/mL significantly inhibited the proliferation of and increased the level of LDH release of HT-29 colon cancer cells. We found that they could increase the apoptosis rate of HT-29 cells. Moreover, they could also induce apoptosis by inducing cells to produce ROS and destroying the mitochondrial membrane potential of cells. Further studies found that they could increase the mRNA transcription and protein expression levels of the Caspase-3, Caspase-9 and Bax genes in cells, and reduce the mRNA transcription and protein expression levels of the Bcl-2 gene. In summary, our findings revealed that viable and heat-inactivated Bifidobacterium longum D42 have inhibitory effects on proliferation and promote the apoptosis of human colon cancer cells, and also have certain adjuvant drug therapeutic effects and have potential application value in the adjuvant treatment of colon cancer.

Attitudes of physicians and patients toward immediate and intraoperative chemotherapy treatment in colon cancer

IntroductionWe have shown in a Phase I trial that immediate adjuvant chemotherapy (IAC) during surgical resection and immediately postoperative is safe and feasible in patients with colon cancer (CC). IAC avoids delays in adjuvant treatment and has the potential to improve survival and quality of life. We aim to determine patients and providers attitudes toward this novel multidisciplinary treatment approach. MethodsTwo web-based surveys were administered to newly diagnosed CC patients, survivors, surgeons and oncologists. Surveys assessed treatment preferences and perceived barriers to IAC. Chi-square tests were conducted to compare differences between patients’ and providers’ responses. ResultsResponses were collected from 35 patients and 40 providers. Patients were more willing to: (1) proceed with IAC to finish treatment earlier thus possibly improving quality of life (p = 0.001); (2) proceed with IAC despite potential side effects (p < 0.001); and (3) proceed with a dose of intraoperative chemotherapy even if on final pathology, may not have been needed (p = 0.002). Patients were more likely to indicate no barriers to collaborative care (p = 0.001) while providers were more likely to cite that it is time consuming, thus a barrier to participation (p = 0.001), has scheduling challenges (p = 0.001), and physicians are not available to participate (p = 0.003). ConclusionsWe observed a discordance between what providers and patients value in perioperative and adjuvant CC treatment. Patients are willing to accept IAC despite potential side effects and without survival benefit, highlighting the importance of understanding patient preference.

Circulating tumor DNA (ctDNA) and disease recurrence in early stage pancreatic cancer.

e16313 Background: Surgical resection with neoadjuvant and/or adjuvant chemotherapy remains to be the cornerstone in treatment for early-stage pancreatic adenocarcinoma. Disease recurrence after curative intent treatment remains to be very common, and early detection of disease recurrence remains challenging. Recent studies explored the role of ctDNA in guiding adjuvant treatment in colon cancer, but its role in pancreatic cancer remains unknown. Methods: Through comprehensive chart review, we identified patients who: 1. Diagnosed with early-stage pancreatic adenocarcinoma; 2. Underwent curative intent surgery at our institution from 2019 to 2021; 3. Have postoperative tissue informed ctDNA results with commercially available assay (Signatera, by Natera Inc). Results: A total of 14 patients, including 7 males and 7 females, were included in the study. Depending on location of tumor, types of surgery included Whipple procedure (N = 13) and distal pancreatectomy (N = 1). The median age at time of surgery was 62 years (Range: 41-83 years). Two patients received neoadjuvant chemotherapy, and 13 patients received adjuvant chemotherapy. Two patients also received adjuvant radiation. A total of 41 ctDNA readings were obtained. The median time from surgery to first ctDNA assay was 2.4 months. First post-op ctDNA was positive in 6 patients, all of whom received adjuvant chemotherapy but still experienced clinical recurrence after a median of 3.7 months. The median overall survival of those ctDNA+ patients was 11.4 months. In the remaining 8 patients, the median progression free survival was 14 months, with clinical recurrence being observed in 4 patients. Median overall survival was not reached at median follow up of 30.5 months (one patient died at 6 months without disease recurrence, and another died at 14 months with progressive disease). In the 4 patients who had clinical recurrence despite initially negative ctDNA, ctDNA turned positive 1 month before clinical recurrence in 1 patient. However, in the other 3 patients, recurrence occurred 3.1, 1.9 and 3.5 months after the most recent negative ctDNA result. Conclusions: Our study demonstrated that positive ctDNA reliably predicts clinical recurrence in early-stage pancreatic cancer after surgery, with a positive predictive value of 100%. Negative result appears to be less reliable. This may be explained by different shedding pattern and test sensitivity. Larger scale study is underway to further evaluate its role in determining prognosis and guiding adjuvant treatment.

Combinational chemotherapy for the treatment of colon cancer

The second leading cause of cancer-related death is colon cancer. Combination chemotherapy can lessen the chance of re-occurrence and demise due to recurred or illness that has spread in patients who have had curative surgery. According to the findings of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trials, combination regimens that include fluoropyrimidine and oxaliplatin are the current standard of care. Targeted medicines for combination adjuvant treatment in the second and third stages of colon cancer are an assuring area, there is no proof to support its use in this situation at this stage. Postoperative therapy has a well-established role in the elderly population, though the most appropriate regimen is still to be established. Improved surgical and radiotherapy techniques may help the patients achieve better results. Further studies should be undertaken in order to determine patient subgroups prone to recurrence, predict response to therapy, and develop better treatment strategies for individuals with colon cancer

SY19-4 Precision oncology for adjuvant treatment of colon cancer

Accurate prediction of recurrence risk is extremely important for tailoring adjuvant chemotherapy for individual colon cancer patients. To date, some multi-gene assay systems have been developed to evaluate recurrence risk in patients with colon cancer. The 12-gene Recurrence Score assay (Oncotype DX) for colon cancer has been validated in stage II and III colon cancer as well as breast cancer. Another micro array based assay system, 55-gene classifier (55GC) for colon cancer has also been validated in resected stage II and stage III treated with adjuvant chemotherapy in Japan.

Attitudes of physicians and patients toward the timing of adjuvant treatment in colon cancer.

e15596 Background: We have previously shown in a Phase I trial that administration of immediate adjuvant chemotherapy (IAC) at the time of surgical resection and immediately postoperatively is safe and feasible in colon cancer (CC) patients. IAC avoids delays in adjuvant treatment and has the potential to improve survival and quality of life. However, two fundamental questions must be answered: will patients be willing to accept the possibility of more severe side effects in exchange for earlier treatment (Tx) completion and theoretically better survival? And will physicians depart from established CC treatment practices?. Methods: A web-based survey was administered to newly diagnosed CC patients (within 1 year of surgery) and survivors (&gt; 1 year post op). A similar web-based survey was administered to surgeons and medical oncologists in academic and community settings across the country. Surveys assessed patients’ and providers’ treatment preferences, attitudes towards care, and perceived barriers to IAC. Descriptive statistics were conducted including chi-square tests to compare differences between patients’ and providers’ responses. Results: Responses were collected from 35 patients and 40 providers. Patient respondents were 48% survivors and 52% newly diagnosed CC patients. Among the providers, 60% of the medical oncologists and 75% of the surgeons worked at academic medical centers. Compared to providers, patients were more willing to: 1) proceed with IAC to finish treatment earlier thereby improving quality of life (p = 0.002); 2) proceed with IAC to finish treatment earlier, despite potential side effects (p &lt; 0.001); and 3) proceed with a single dose of intraoperative chemotherapy that, based on final pathologic stage, may not be needed (p = 0.002). Patients were also more likely than providers to indicate that there are no barriers to collaborative care (p = 0.001) while providers were more likely to cite that collaborative care is time consuming (p = 0.001), comes with scheduling challenges (p = 0.001), and that physicians are not readily available to participate in it (p = 0.003). Conclusions: We observed a disconnect between what providers and patients value in the perioperative and adjuvant colon cancer treatment course. Colon cancer patients are willing to accept intraoperative chemotherapy and early adjuvant chemotherapy via this novel multidisciplinary approach even if this treatment were associated with additional side effects, and without promise of a survival benefit.[Table: see text]

Current Perspectives on the Importance of Pathological Features in Prognostication and Guidance of Adjuvant Chemotherapy in Colon Cancer.

There is not a clear consensus on which pathological features and biomarkers are important in guiding prognosis and adjuvant therapy in colon cancer. The Pathology in Colon Cancer, Prognosis and Uptake of Adjuvant Therapy (PiCC UP) Australia and New Zealand questionnaire was distributed to colorectal surgeons, medical oncologists and pathologists after institutional board approval. The aim of this study was to understand current specialist attitudes towards pathological features in the prognostication of colon cancer and adjuvant therapy in stage II disease. A 5-scale Likert score was used to assess attitudes towards 23 pathological features for prognosis and 18 features for adjuvant therapy. Data were analysed using a rating scale and graded response model in item response theory (IRT) on STATA (Stata MP, version 15; StataCorp LP). One hundred and sixty-four specialists (45 oncologists, 86 surgeons and 33 pathologists) participated. Based on IRT modelling, the most important pathological features for prognosis in colon cancer were distant metastases, lymph node metastases and liver metastases. Other features seen as important were tumour rupture, involved margin, radial margin, CRM, lymphovascular invasion and grade of differentiation. Size of tumour, location, lymph node ratio and EGFR status were considered less important. The most important features in decision making for adjuvant therapy in stage II colon cancer were tumour rupture, lymphovascular invasion and microsatellite instability. BRAF status, size of tumour, location, tumour budding and tumour infiltrating lymphocytes were factored as lesser importance. Biomarkers such as CDX2, EGFR, KRAS and BRAF status present areas for further research to improve precision oncology. This study provides the most current status on the importance of pathological features in prognostication and recommendations for adjuvant therapy in Australia and New Zealand. Results of this nationwide study may be useful to help in guiding prognosis and adjuvant treatment in colon cancer.

Effects of Lactobacillus acidophilus KLDS1.0901 on Proliferation and Apoptosis of Colon Cancer Cells.

Colon cancer is the most common type of malignant tumor. The cytotoxicity effect of lactic acid bacteria may be active by inhibiting cancer cell proliferation, producing anticancer compounds, and inducing apoptosis in cancer cells, but the mechanism is unclear. Our previous study revealed that Lactobacillus acidophilus KLDS1.0901 has good probiotic properties. In this study, We screened out the highest inhibition rate of L. acidophilus KLDS1.0901 and assessed the effects on the proliferation of HT-29, Caco-2, and IEC-6 cells. Then, the apoptosis mechanism of HT-29 cells was studied when treated with L. acidophilus KLDS1.0901. Results showed that L. acidophilus KLDS1.0901 inhibited the proliferation of HT-29 and Caco-2 cells in a dose-dependent manner and reached the maximum under the condition of multiplicity of infection (MOI) = 100 (rate of Lactobacillus to cells) at 48 h. With the increase in time and MOI, reactive oxygen species in HT-29 cells, the apoptosis rates of HT-29 cells were increased, and the amount of blue fluorescence of the cells was also increased after Hoechst 33258 staining. Furthermore, L. acidophilus KLDS1.0901 reduced the mitochondrial membrane potential of HT-29 cells. Notably, 1,133 differentially expressed genes were screened by transcriptomics research, including 531 up-regulated genes and 602 down-regulated genes. These genes were involved in the nuclear factor κB and PI3K-AKT signaling pathways related to the apoptosis of HT-29 cells. These findings suggested that L. acidophilus KLDS1.0901 has the potential to be used in the development of a new type of functional foods for adjuvant treatment of colon cancer.

Adjuvant treatment of colon cancer with microsatellite instability - the state of the art.

Adjuvant chemotherapy with fluoropyrimidine (FP) plus oxaliplatin in stage III resected colorecatal cancer (RCRC) resulted in a 30% relative reduction of disease recurrence risk and mortality. The presence of altered mismatch repair genes identify tumors with microsatellite instability (MSI) that have a better prognosis than stable tumors, but data about adjuvant chemotherapy benefit in this subgroup are compelling. We investigate the role of adjuvant therapy in resected MSI RCRC. The standard treatment is the association of FP plus oxaliplatin, while it can avoided in low risk stage II, thanks to its good prognosis. We propose a practice strategy to approach MSI RCRC in line with the current knowledge. In consideration of the dramatic results in chemorefractory MSI metastatic CRC, there are assumptions that immunotherapy can become a potential alternative to classical systemic therapies also in the adjuvant setting. We await the results of ongoing studies to draw further conclusions."

The Influence of Adjuvant Chemotherapy Dose Intensity on Five-Year Outcomes in Resected Colon Cancer: A Single Centre Retrospective Analysis.

There is evidence that achieving a dose intensity > 80% in adjuvant colon cancer treatment improves survival. In total, 192 consecutive patients with resected stage III and high-risk stage II colon cancer that received adjuvant chemotherapy were retrospectively analyzed. Patients who received at least 6 weeks of adjuvant therapy were included. The primary objective was to assess the influence of dose index (DI) and relative dose intensity (RDI) on DFS and OS at 3 and 5 years in patients receiving fluorouracil-based doublet therapy with oxaliplatin (FOLFOX) (5-FU and oxaliplatin assessed separately), or capecitabine monotherapy. In the capecitabine group, DFS rates for 3 and 5 years were 66.7% and 57.6%, respectively, while OS rates were 80.3% and 66.7%, respectively. Those who received FOLFOX had DFS rates of 76.9% and 71.2% at 3 and 5 years, respectively. OS rates were 86.4% and 76.7% at 3 and 5 years, respectively. Median RDI was 73.8% for capecitabine and 76.3% and 85.6% for the oxaliplatin and 5-FU components respectively. Based on a multivariate analysis in patients receiving FOLFOX, those with an oxaliplatin DI > 80% had improvements in DFS and OS compared to those with an oxaliplatin DI of ≤80%. Otherwise, there was no significant difference in DFS or OS when comparing patients who achieved an RDI or a DI of above versus below 80% in the patients receiving adjuvant chemotherapy for resected colon cancer.

Assessing the representativeness of trial populations for contemporary real-world cancer patients: A case study of adjuvant chemotherapy for colon cancer.

306 Background: Randomized controlled trials are the gold standard for assessing the efficacy of new cancer therapies and are required for marketing approval. However, participants enrolled into trials are often not representative of the more diverse populations in whom treatment will ultimately be delivered. Real-world data can be used to potentially bridge this gap by evaluating the effectiveness and safety of therapies in more generalizable populations. In this study, we describe differences in demographic and clinical characteristics between participants enrolled in a phase III trial of adjuvant chemotherapy for colon cancer and a contemporary comparator cohort using structured oncology electronic medical records (EMR) data. Methods: We drew upon publications from the Multicenter International Study of Oxaliplatin/5 Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) recruiting patients primarily from Western Europe with stage II or III colon cancer from October 1998-January 2001. This trial established FOLFOX (oxaliplatin + 5-FU) as the standard of care over 5FU alone in treating stage III colon cancer and led to US marketing approval. For comparison, we identified patients diagnosed with stage II or III colon cancer (September 2014-2020) who received FOLFOX in the IQVIA US Oncology EMR database via E360, IQVIA’s Real World Discovery and Analytics platform. In the two populations, we described distributions of prognostic factors including age, sex, stage of disease, body mass index (BMI), and Eastern Cooperative Group (ECOG) performance status. Results: The MOSAIC trial included 2,246 participants; we identified 4,566 patients starting FOLFOX in the EMR comparator. Median age was similar: 61 versus 62 years, but the range differed (19-75 years versus 18-85 years) in the trial and EMR comparator, respectively. Female sex was similar at 44% and 48%, while the proportion of patients with stage III disease differed considerably at 60% and 84% for trial and EMR comparator, respectively. Half (51%) of all EMR patients were missing ECOG status; among those with a reported ECOG status, 96% had a score of 0-1, while 87% of trial participants had an ECOG of 0-1. BMI was missing in 34% of patients in the EMR comparator; among those with a reported BMI, 28% had a BMI &lt; 25, while 54% of trial participants had a BMI &lt; 25. Conclusions: Colon cancer patients receiving FOLFOX in an EMR comparator had a similar age and sex distribution as MOSAIC trial participants, but were more likely to have stage III disease. Missing ECOG and BMI data were common in the EMR comparator, which limited comparisons. Structured oncology EMR data represent an important resource for generating real-world evidence; future data enrichment efforts focused on critical patient-level variables via unstructured EMR extraction may improve data completeness and quality.

A RARE CASE OF OXALIPLATIN-INDUCED PULMONARY FIBROSIS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Oxaliplatin is a third generation platinum derivative alkylating agent. The platinum compound binds to the DNA forming crosslink which inhibits DNA replication and transcription, resulting in cell death. It is a nonspecific cell cycle cytotoxic agent. Common side effects are peripheral neuropathy, and induced hypersensitivity [1]. CASE PRESENTATION: 65-year-old Caucasian male with past medical history of chronic obstructive pulmonary disease not on home oxygen, former tobacco smoker and alcohol user presents to the emergency department for worsening dyspnea for three weeks. He recently completed 6 cycles of 5 Fluorouracil and Oxaliplatin for Stage IIIA Sigmoid Adenocarcinoma. Patient denies use of recreational drugs. Earlier that day he was at the pulmonary clinic and ambulatory oxygen measurement showed saturation of 60% on room air. High dose steriods were initiated, the patient continued to require high flow nasal cannula and then was on noninvasive positive pressure ventilation. He was subsequently intubated and his course was complicated by a left pneumothorax requiring a chest tube. He was not a candidate for a lung transplant and was placed on comfort care and expired shortly thereafter. Review of system: positive for cough, white phlegm, chills for three days. Physical Exam: afebrile, heart rate 108, respiration 30-34, blood pressure 142/91, oxygen saturation 89% on high flow nasal cannula of 40 liters per minute, and fraction of inspired oxygen of 100%. He appeared acutely ill, unable to complete full sentences, alert and oriented x4. Lungs had bilateral crackles and expiratory wheezes. Diagnostic: Leukocytosis 14.7, Hgb/Hct:11.0/ 34.6. platelet 143. ALT 59, AST 78, AlkPhos 164, LDH 1,333. CRP 4.79, negative troponin, TSH 0.2446, Procalcitonin 0.2. Negative Mycoplasma, and Covid PCR times two. ABG shows respiratory alkalosis. Sputum and blood cultures are negative. CT chest with contrast at another hospital showed subpleural fibrotic changes within lungs bilaterally. CT Angiogram 8 days later showed extensive bullous disease throughout both lungs with areas of emphysematous changes, moderate to severe interstitial changes along the periphery of both lungs suggestive of pulmonary fibrosis. Chest x-ray reveals diffuse bilateral interstitial and alveolar airspace disease. Bronchoscopy washout pathology is unremarkable for malignant cells. DISCUSSION: Fluorouracil, Leucovorin with Oxaliplatin (FOLFOX) and Capecitabine with Oxaliplatin (CAPOX) are the two common therapies for stage III colon cancer [2]. Porcine model in vivo lung perfusion studies concluded dose dependent lung toxicity of fibrin deposits and white blood cell infiltrated at 72 hours with 80mg/L dose of Oxaliplatin, and evidence was proven by severe impaired P/F ratio [3]. CONCLUSIONS: This case presents a rare side effect of oxaliplatin causing Pulmonary Fibrosis. REFERENCE #1: Sohn, K.-H., et al., Incidence and Risk of Oxaliplatin-Induced Hypersensitivity in Patients with Asymptomatic Prior Exposure: A Prospective Observational Study. The Journal of Allergy and Clinical Immunology: In Practice, 2018. 6(5): p. 1642-1648.e2. REFERENCE #2: André, T., et al., Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. New England Journal of Medicine, 2004. 350(23): p. 2343-2351. REFERENCE #3: Ramadan, K., et al., A model to assess acute and delayed lung toxicity of oxaliplatin during in†vivo lung perfusion. The Journal of thoracic and cardiovascular surgery, 2020 DISCLOSURES: No relevant relationships by ASMA HAJI DATOO, source=Web Response No relevant relationships by Ajith puthillath, source=Web Response No relevant relationships by Jennifer Williams, source=Web Response

The Early Impact of the IDEA Collaboration Results: How the Results Changed Prescribing Practice.

BackgroundTraditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined.MethodsIn an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer.ResultsThe survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease.ConclusionThis survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.

Effect of PRM1201 Combined With Adjuvant Chemotherapy on Preventing Recurrence and Metastasis of Stage III Colon Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BackgroundChemotherapy is the standard adjuvant treatment for colon cancer. Chinese herbal formula PRM1201 improves the efficacy of chemotherapy when used in combination with Cetuximab or Bevacizumab in patients with metastatic colorectal cancer. This study aims to explore the benefits of treatment with chemotherapy plus PRM1201 in the postoperative adjuvant setting.MethodsIn this parallel-group study, patients who had undergone curative resection for stage III colon cancer were randomly assigned to receive adjuvant chemotherapy (FOLFOX q2w for 6 months, or CapeOx q3w for 6 months) plus PRM1201 (chemo+PRM1201 group) or adjuvant chemotherapy plus placebo (chemo+placebo group). The primary endpoint was disease-free survival (DFS), and the secondary endpoints were quality of life (QOL) and toxicity.ResultsA total of 370 patients were randomly assigned to chemotherapy plus PRM1201 group (n = 184) and chemotherapy plus placebo group (n = 186). Up to October 30, 2019, 96 events of recurrence, metastasis, or death had been reported, of which 38 events were in the group of chemotherapy plus PRM1201 and 58 events in the chemo+placebo group. The 3-year DFS rate was 77.1 and 68.6% in the chemo+PRM1201 and chemo+placebo group, respectively (hazard ratio [HR], 0.63; 95% CI, 0.42 to 0.94). The QOL of patients in the chemo+PRM1201 group were significantly improved in terms of global quality of life, physical functioning, role functioning, emotional functioning, fatigue, and appetite loss. The incidence of grade 3 or 4 treatment-related adverse event (TRAEs) were similar between the two arms.ConclusionsChemotherapy in combination with PRM1201 improved the adjuvant treatment of colon cancer. PRM1201 can be recommended as an effective option in clinical practice.Clinical Trial RegistrationChinese Clinical Trials Registry, identifier ChiCTR-IOR-16007719.

Benefit of Oxaliplatin in Stage III Colon Cancer According to IDEA Risk Groups: Findings from the ACCENT Database of 4934 Patients

BackgroundThe International Duration Evaluation of Adjuvant Chemotherapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. Patients were classified into low risk and high risk, suggesting low-risk patients may be offered only 3 months of treatment. In this study, we aimed to assess the benefit of oxaliplatin in the adjuvant setting per IDEA risk groups, using data from 3 large adjuvant phase III studies, namely Multicenter International Study of Oxaliplatin/Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), C-07, and XELOXA. MethodsUsing the MOSAIC, C-07, and XELOXA previously published studies, we identified 2810 low-risk and 2124 high-risk patients with stage III colon cancer. We used Cox regression model to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. Based on design similarity and equivalent follow-up data, MOSAIC and C-07 were pooled, whereas XELOXA was analyzed separately. Subgroup analyses were also performed for T4 and/or N2 patients. ResultsIndividuals with IDEA low and high risk derived overall survival benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios of 0.79 (0.66-0.95) and 0.84 (0.71-0.99), respectively. Among individuals with IDEA high risk, those with T4 disease did not gain overall survival benefit from addition of oxaliplatin with hazard ratio of 0.95 (0.71-1.27). Similar results were demonstrated using data from the XELOXA study. ConclusionIDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer. T4 disease may predict lack of benefit from oxaliplatin addition.

Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Effectiveness of adjuvant FOLFOX vs 5FU/LV in adults over age 65 with stage II and III colon cancer using a novel hybrid approach.

Estimates of cancer therapy effects can differ in clinical trials and clinical practice, partly due to underrepresentation of certain patient subgroups in trials. We utilize a hybrid approach, combining clinical trial and real-world data, to estimate the comparative effectiveness of two adjuvant chemotherapy regimens for colon cancer. We identified patients aged 66 and older enrolled in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer. Similar patients were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, initiating adjuvant chemotherapy with either 5-fluorouracil (5FU) alone or in combination with oxaliplatin (FOLFOX). We used logistic regression to estimate the likelihood of trial enrollment as a function of age, sex, and substage. Using inverse odds of sampling weights (IOSW), we compared 5-year mortality in patients randomized to FOLFOX vs 5FU using weighted Cox proportional hazards regression, the Nelson-Aalen estimator for cumulative hazards, and bootstrapping for 95% confidence intervals (CIs). There were 690 trial participants and 3834 SEER-Medicare patients. The SEER-Medicare population was older and had a higher proportion of stage IIIB and IIIC patients than the trial. After controlling for differences between populations, the IOSW 5-year HR was 1.21 (0.89, 1.65), slightly farther from the null than the trial estimate (HR = 1.14, 95%CI: 0.87, 1.49). This study supports mounting evidence of little to no incremental reduction in 5-year mortality for FOLFOX vs 5FU in older adults with stage II-III colon cancer, emphasizing the importance of combining clinical trial and real-world data to support such conclusions.

Practice Variation in the Adjuvant Treatment of Colon Cancer in the Netherlands: A Population-based Study.

Adjuvant chemotherapy is recommended for a subgroup of colon cancer patients based on patient and tumour characteristics. Population-based data on the adoption of the prevailing guideline recommendations including the assessment of tumour mismatch repair (MMR) status are limited, while variations in treatment strategies may influence patient outcomes. Therefore, the aim of the study was to assess practice variation in adjuvant chemotherapy administration in colon cancer patients. We examined the association between patient, demographic and tumour characteristics on the odds of being treated with adjuvant chemotherapy in a random sample of adult stage II-III colon cancer patients from the Dutch National Cancer Registry (2008-2015) and assessed its association with survival. The study population consisted of 2,044 patients of whom 18% (79 out of 450) were high-risk stage II and 65% (645 out of 997) were stage III colon cancer and received adjuvant chemotherapy. Chemotherapy administration differed between individual hospitals (high-risk stage II: 0-39%; p=0.01; stage III: 50-78%; p=0.06). Type of hospital (teaching versus academic) and the presence of a pT4 tumour were positively associated (high-risk stage II), and bowel perforation and examined regional lymph nodes (<10) were negatively associated (stage III) with adjuvant treatment. Higher age was associated with non-administration of adjuvant chemotherapy for both stages. Tumour MMR-status assessment increased from 9% to 23% (p<0.001), but 62% of high-risk stage II and 13% of stage III patients did not undergo guideline-recommended MMR-status testing. Adjuvant chemotherapy was correlated with survival for stage III (HR=0.4; 95%CI=0.3-0.5) but not for high-risk stage II patients (HR=1.2; 95%CI=0.7-2.2). Significant practice variation in the adjuvant treatment of colon cancer on hospital level was demonstrated, predominantly in high-risk stage II patients. The implementation of MMR testing was suboptimal. We recommend continuous monitoring of treatment patterns using population-based data, which should facilitate hospital auditing and improve guideline implementation and quality of care for colon cancer patients.

Effectiveness of adjuvant FOLFOX versus 5FU for colon cancer treatment in community oncology practice using a hybrid study approach.

7067 Background: Treatment effects may differ between trials and community settings, in part due to underrepresentation of certain patient subgroups in trials. We used a hybrid approach combining clinical trial and real-world data to compare the effectiveness of adjuvant FOLFOX vs 5FU for stage II-III colon cancer in community oncology practice. Methods: We used Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) combined with patients who met trial eligibility criteria within US Oncology from 1/1/2008-5/31/2019. In the combined data, we used logistic regression to estimate the probability of trial enrollment as a function of age, sex, substage, body mass index (BMI), and performance status. We estimated inverse odds of sampling weights and weighted MOSAIC participants to reflect three US Oncology populations: 1) patients meeting trial eligibility, 2) stage III patients, and 3) stage III patients initiating FOLFOX. Within the weighted trial populations, we estimated mortality hazard ratios (HRs) and bootstrapped 95% confidence intervals (CIs) comparing FOLFOX with 5FU. Results: There were 2246 MOSAIC participants and 9335 US Oncology patients. MOSAIC participants were younger, had more stage II cancer, lower BMI, and worse performance status compared with US Oncology patients. After weighting MOSAIC participants to reflect the US Oncology populations, the HRs were attenuated (Table) compared with the original MOSAIC estimate (HR = 0.84; 0.71,1.00). Conclusions: When differences between trial and clinical populations exist and response to therapy varies across subgroups, treatment efficacy can differ from clinical effectiveness. Compared with trial results, we found that effectiveness of FOLFOX versus 5FU was attenuated in community oncology practice. [Table: see text]