mFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial.

BACKGROUND: High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. METHODS: This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. DISCUSSION: The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Organoid forming potential as complementary parameter for accurate evaluation of breast cancer neoadjuvant therapeutic efficacy.

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.

Rectal cancer - avoiding surgery?

Nonoperative treatment of rectal cancer is gaining popularity. Several trials recently demonstrated advantages in disease-free survival with total neoadjuvant treatment (TNT) with the addition of the watch and wait (WW) strategy for locally advanced rectal cancer. On longer follow-up, an unexpected increased risk in local recurrence in the TNT group at the RAPIDO trial suggested early surgery for nonresponding tumours. The WW option is globally accepted for a complete clinical response; however, a high rate of regrowth was found in a registry with an increased risk of distant metastases, questioning the deleterious effect of deferral of surgery in this group. The short- and long-term toxic effects of neoadjuvant treatment are costs to consider in the National Comprehensive Cancer Network guidelines compared with the European Society for Medical Oncology guidelines, which favour surgery alone if good mesorectal resection is assured with increasing surgical proficiency adjusted to the precise anatomical location.

Efficacy of Sunitinib in Patients With Favorable and Intermediate Risk Metastatic Renal Cell Carcinoma - Lithuanian National Cancer Institute Experience.

BACKGROUND/AIM: According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. PATIENTS AND METHODS: Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). RESULTS: Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. CONCLUSION: Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.

Prognostic nutritional index and serum lactate dehydrogenase predict the prognosis of nasopharyngeal carcinoma patients who received intensity-modulated radiation therapy.

PURPOSE: This research aimed to evaluate the prognostic significance of baseline prognostic nutritional index (PNI) and lactate dehydrogenase (LDH) for the outcome of individuals diagnosed with non-metastatic nasopharyngeal carcinoma (NPC). METHODS: A retrospective analysis was conducted on data from 810 patients with non-metastatic NPC who underwent intensity-modulated radiation therapy (IMRT) with or without chemotherapy. The best cut-offs for PNI and LDH were identified by X-tile software to be 48.5 and 150, respectively. To find the independent prognostic factors for survival outcomes, univariate and multivariate regression analyses were conducted, and AUCs were used to compare their prognostic values. RESULTS: Multivariate analysis revealed that patients with PNI > 48.5 had better overall survival (OS) (HR: 0.502, P < 0.001), progression-free survival (PFS) (HR: 0.618, P < 0.001), and distant metastasis-free survival (DMFS) (HR: 0.637, P = 0.005). Higher LDH was associated with poorer OS (HR: 1.798, P < 0.001), PFS (HR: 1.671, P < 0.001), and DMFS (HR: 1.756, P < 0.001). The combination of low PNI and high LDH in non-metastatic NPC patients was correlated with poor OS (P < 0.001), PFS (P < 0.001), and DMFS (P < 0.001). The combination of PNI and LDH had the highest AUCs for predicting OS, PFS, and DMFS. CONCLUSIONS: PNI and LDH might become valuable predictors of the prognosis of non-metastatic NPC patients undergoing IMRT with or without chemotherapy. Prognostic accuracy can be enhanced by combining PNI and LDH.

Comparison of adjuvant capecitabine plus oxaliplatin (CAPOX) versus S-1 after gastrectomy: a population-based cohort study using a nationwide claims database.

Although both capecitabine plus oxaliplatin (CAPOX) and S-1 are accepted as adjuvant chemotherapy following gastrectomy for gastric cancer, the better option between the two is still controversial. We conducted a retrospective nationwide cohort study using data from the National Health Insurance Service of Korea. We included patients who underwent gastrectomy for a primary diagnosis of gastric cancer between January 1, 2013, and December 31, 2018. The study compared the survival outcomes of patients who received postoperative chemotherapy based on S-1 (Arm S) vs. CAPOX (Arm C), as well as other relevant clinical variables such as comorbidity and completion of planned treatment. A total of 6602 patients were included in the analysis, with 4199 in Arm S and 2403 in Arm C. After propensity score matching, the final study population consisted of 2067 patients in each arm. Arm C showed statistically inferior 5-year overall survival (OS) and disease-free survival (DFS) rates compared to Arm S (84.0% vs. 90.0%; p < 0.0001; and 78.4% vs. 86.1%; p < 0.0001). Age (65 ≥ vs. < 65) and the incomplete planned treatment also had a significant negative effect on both OS and DFS. In the multivariable analysis, Arm C still showed worse OS (hazard ratio [HR], 1.609; 95% confidence intervals [CI], 1.339-1.934; p < 0.0001) and DFS (HR, 1.552; 95% CI 1.333-1.807; p < 0.0001) than Arm S. Both S-1 and CAPOX showed excellent efficacy, but this nationwide cohort study suggests that S-1 may be a better option in certain clinical situations.

Changes in Prescribing Patterns in Stage III Colon Cancer.

BACKGROUND: For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. PATIENTS AND METHODS: To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. RESULTS: A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). CONCLUSIONS: Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

The Association of Oxaliplatin-Containing Adjuvant Chemotherapy Duration with Overall and Cancer-Specific Mortality in Individuals with Stage III Colon Cancer: A Population-Based Retrospective Cohort Study.

PURPOSE: Few studies have examined the relationship between duration of oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer and mortality in routine practice. We examined the association between treatment with 50% versus >85% of a maximal course of adjuvant therapy (eight cycles of CAPOX, twelve cycles of FOLFOX) and mortality in stage III colon cancer. METHODS: Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019. In the primary comparison, we compared patients who received 50% or >85% of a maximal course of adjuvant therapy; in a secondary comparison, we evaluated a dose effect across patients who received FOLFOX in one-cycle increments from six to ten cycles against >85% (more than ten cycles) of a maximal course of FOLFOX. The main outcomes were overall and cancer-specific mortality. Follow-up began 270 days after adjuvant treatment initiation and terminated at the first of the outcome of interest, loss of eligibility for Ontario's Health Insurance Program, or study end. Overlap propensity score weights accounted for baseline between-group differences. We determined the hazard ratio, estimating the association between mortality and treatment. Non-inferiority was concluded in the primary comparison for either outcome if the upper limit of the two-sided 95% CI was ≤1.11, which is the margin used in the International Duration Evaluation of Adjuvant Chemotherapy Collaboration. RESULTS: We included 3546 patients in the analysis of overall mortality; 486 (13.7%) received 50% and 3060 (86.3%) received >85% of a maximal course of therapy. Median follow-up was 5.4 years, and total follow-up was 20,510 person-years. There were 833 deaths. Treatment with 50% of a maximal course of adjuvant therapy was associated with a hazard ratio of 1.13 (95% CI 0.88 to 1.47) for overall mortality and a subdistribution hazard ratio of 1.31 (95% CI 0.91 to 1.87) for cancer-specific mortality versus >85% of a maximal course of therapy. In the secondary comparison, there was a trend toward higher overall mortality in patients treated with shorter durations of therapy, though confidence intervals overlapped considerably. CONCLUSION: We could not conclude that treatment with 50% of a maximal course is non-inferior to >85% of a maximal course of adjuvant therapy for mortality in stage III colon cancer. Clinicians and patients engaging in decision-making around treatment duration in this context should carefully consider the trade-off between treatment effectiveness and adverse effects of treatment.

Influence of Prognostic Nutritional Index on the Surveillance After Surgery-Based Systematic Therapy for Breast Cancer.

OBJECTIVE: Prognostic nutritional index (PNI) is a comprehensive reflection of the nutritional and immune status of the patient, which is closely related to the ability of the organism to clear tumor cells and reduce local recurrence. Several findings suggested that PNI was a prognostic indicator for breast cancer, but the conclusions were conflicting. We aimed to comprehensively elucidate the prognostic value of PNI in breast cancer patients. METHODS: Relevant studies in PubMed, Embase, Cochrane Library, and Web of Science databases were searched through March 2023. Data extraction and literature quality assessment of the screened studies were performed. The associations between PNI and overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in breast cancer patients who received clinical treatment were assessed by hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: A total of 7 studies involving 2212 patients met the inclusion criteria. High PNI was a favorable independent predictor of prolonged OS and PFS after clinical treatment in breast cancer patients compared to low PNI (for OS: HR = .38, 95% CIs .31 ∼ .46, P < .001; for DFS: HR = .32, 95% CIs .19 ∼ .51, P < .001). In subgroup analysis, high PNI was a prognostic factor for extended DFS in the context of a study sample size ≥300 (HR = .39, 95% CIs .28 ∼ .54, P < .001) and patients not receiving neoadjuvant chemotherapy (HR = .51, 95% CIs .37 ∼ .70, P < .001). CONCLUSION: The PNI has a significant correlation with the prognosis of breast cancer patients. We suggest that individualized targeted treatment and long-term surveillance should be implemented for patients with different levels of PNI.

Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial.

INTRODUCTION: Colon cancer remains one of the most prevalent cancers worldwide. Unfortunately, there are no recognized and effective therapeutic strategies to prevent tumor recurrence after radical resection and chemotherapy, and the disease-free survival (DFS) in patients with stage IIIB or IIIC disease remains unsatisfactory. Xian-Lian-Jie-Du optimization decoction (XLJDOD) is a Chinese herbal medicine (CHM) empirical prescription, which has been validated experimentally and clinically that could inhibit the progression of colorectal cancer and ameliorate the symptoms. The purpose of this study is to evaluate the efficacy and safety of XLJDOD in prevention of recurrence of colon cancer. METHODS: This study is a multi-center, double-blind, randomized, placebo-controlled trial conducted at 13 hospitals of China. Following the completion of surgery and adjuvant 5- fluorouracil-based chemotherapy, a total of 730 subjects with stage IIIB or IIIC colon cancer will be randomized in a 1:1 ratio to an intervention group (n = 365; XLJDOD compound granule) and a control group (n = 365; Placebo). Patients will receive 6-month treatments and be followed up with 3 monthly assessments for 2 years. The primary outcome is 2-year DFS rate and the secondary outcomes are 1, 2-year relapse rate (RR), overall survival (OS) and quality of life (QoL). Safety outcomes such as adverse events will be also assessed. A small number of subgroup analysis will be carried out to explore the heterogeneity of effects of XLJDOD. DISCUSSION: The outcomes from this randomized controlled trial will provide objective evidences to evaluate XLJDOD's role as an adjuvant treatment in colon cancer. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT05709249. Registered on 31 Jan 2023.

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance).

PURPOSE: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. EXPERIMENTAL DESIGN: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). RESULTS: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases.

BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

DNA Repair Pathway in Ovarian Cancer Patients Treated with HIPEC.

DNA repair pathways are essential for maintaining genome stability, and understanding the regulation of these mechanisms may help in the design of new strategies for treatments, the prevention of platinum-based chemoresistance, and the prolongation of overall patient survival not only with respect to ovarian cancer. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) together with cytoreductive surgery (CRS) and adjuvant systemic chemotherapy is receiving more interest in ovarian cancer (OC) treatment because of the typical peritoneal spread of the disease. The aim of our study was to compare the expression level of 84 genes involved in the DNA repair pathway in tumors and the paired peritoneal metastasis tissue of patients treated with CRS/platinum-based HIPEC with respect to overall patient survival, presence of peritoneal carcinomatosis, treatment response, and alterations in the BRCA1 and BRCA2 genes. Tumors and metastatic tissue from 28 ovarian cancer patients collected during cytoreductive surgery before HIPEC with cisplatin were used for RNA isolation and subsequent cDNA synthesis. Quantitative real-time PCR followed. The most interesting findings of our study are undoubtedly the gene interactions among the genes CCNH, XPA, SLK, RAD51C, XPA, NEIL1, and ATR for primary tumor tissue and ATM, ATR, BRCA2, CDK7, MSH2, MUTYH, POLB, and XRCC4 for metastases. Another interesting finding is the correlation between gene expression and overall survival (OS), where a low expression correlates with a worse OS.

Sleep and cancer recurrence and survival in patients with resected Stage III colon cancer: findings from CALGB/SWOG 80702 (Alliance).

BACKGROUND: We sought to assess the influences of sleep duration, sleep adequacy, and daytime sleepiness on survival outcomes among Stage III colon cancer patients. METHODS: We conducted a prospective observational study of 1175 Stage III colon cancer patients enrolled in the CALGB/SWOG 80702 randomised adjuvant chemotherapy trial who completed a self-reported questionnaire on dietary and lifestyle habits 14-16 months post-randomisation. The primary endpoint was disease-free survival (DFS), and secondary was overall survival (OS). Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary and lifestyle factors. RESULTS: Patients sleeping ≥9 h-relative to 7 h-experienced a worse hazard ratio (HR) of 1.62 (95% confidence interval (CI), 1.01-2.58) for DFS. In addition, those sleeping the least (≤5 h) or the most (≥ 9 h) experienced worse HRs for OS of 2.14 (95% CI, 1.14-4.03) and 2.34 (95% CI, 1.26-4.33), respectively. Self-reported sleep adequacy and daytime sleepiness showed no significant correlations with outcomes. CONCLUSIONS: Among resected Stage III colon cancer patients who received uniform treatment and follow-up within a nationwide randomised clinical trial, very long and very short sleep durations were significantly associated with increased mortality. Interventions targeting optimising sleep health among indicated colon cancer patients may be an important method by which more comprehensive care can be delivered. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.

The clinical impacts of postoperative complications after colon cancer surgery for the clinical course of adjuvant treatment and survival.

AIM: We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan PATIENTS AND METHODS: The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group). RESULTS: A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively). CONCLUSION: POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Vitamin D supplementation increases objective response rate and prolongs progression-free time in patients with advanced melanoma undergoing anti-PD-1 therapy.

BACKGROUND: Vitamin D3 is a prohormone with pleiotropic effects, including modulating the functions of the immune system and may affect the effectiveness of anti-PD-1 treatment in patients with cancer. According to the literature, the potential mechanism of vitamin D's influence on the effectiveness of therapy is most likely related to the amount and activity of tumor-infiltrating lymphocytes. There are data showing the effect of vitamin D on cells regulating the activity of CD8 lymphocytes. METHODS: A total of 200 patients with advanced melanoma were included in the study. All patients received anti-PD-1 immunotherapy (nivolumab or pembrolizumab) as first-line treatment. Serum vitamin D levels were measured in patients both before and every 12 weeks during treatment. Part of the group had vitamin D measured retrospectively from the preserved serum. The other part of the supplementation group was tested prospectively. RESULTS: The response rate in the group with low vitamin D levels and not supplemented was 36.2%, whereas in the group with normal baseline levels or a normal level obtained with supplementation was 56.0% (p = .01). Moreover, progression-free survival in these groups was 5.75 and 11.25 months, respectively (p = .03). In terms of overall survival, there was also a difference in favor of the group with normal vitamin D levels (27 vs. 31.5 months, respectively; p = .39). CONCLUSIONS: In our opinion, maintaining the vitamin D level within the normal range during anti-PD-1 immunotherapy in advanced melanoma patients should be a standard procedure allowing the improvement of treatment outcomes.

A novel prognostic index for diffuse large B-cell lymphoma combined baseline metabolic tumour volume with clinical and pathological risk factors.

OBJECTIVES: This study aimed to develop a novel prognostic index integrating baseline metabolic tumour volume (MTV) along with clinical and pathological parameters for diffuse large B-cell lymphoma (DLBCL). METHODS: This prospective trial enrolled 289 patients with newly diagnosed DLBCL. The predictive value of novel prognostic index was compared with Ann Arbor staging and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI). We used the concordance index (C-index) and a calibration curve to determine its predictive capacity. RESULTS: Multivariate analysis revealed high MTV (>191 cm 3 ), Ann Arbor stage (III-IV) and MYC/BCL2 double expression lymphoma (DEL) to be independently associated with inferior progression-free survival (PFS) and overall survival (OS). Ann Arbor stage and DEL could be stratified by MTV. Our index, combining MTV with Ann Arbor stage and DEL status, identified four prognostic groups: group 1 (no risk factors,), group 2 (one risk factor), group 3 (two risk factors), and group 4 (three risk factors). The 2-year PFS rates were 85.5, 73.9, 53.6, and 13.9%; 2-year OS rates were 94.6, 87.0, 67.5, and 24.2%, respectively. The C-index values of the novel index were 0.697 and 0.753 for PFS and OS prediction, which was superior to Ann Arbor stage and NCCN-IPI. CONCLUSION: The novel index including tumour burden and clinicopathological features may help predict outcome of DLBCL (clinicaltrials.gov identifier: NCT02928861).

Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.

PURPOSE: Preventing metastases by using perioperative interventions has not been adequately explored. Local anesthesia blocks voltage-gated sodium channels and thereby prevents activation of prometastatic pathways. We conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral infiltration of local anesthesia on disease-free survival (DFS). METHODS: Women with early breast cancer planned for upfront surgery without prior neoadjuvant treatment were randomly assigned to receive peritumoral injection of 0.5% lidocaine, 7-10 minutes before surgery (local anesthetics [LA] arm) or surgery without lidocaine (no LA arm). Random assignment was stratified by menopausal status, tumor size, and center. Participants received standard postoperative adjuvant treatment. Primary and secondary end points were DFS and overall survival (OS), respectively. RESULTS: Excluding eligibility violations, 1,583 of 1,600 randomly assigned patients were included in this analysis (LA, 796; no LA, 804). At a median follow-up of 68 months, there were 255 DFS events (LA, 109; no LA, 146) and 189 deaths (LA, 79; no LA, 110). In LA and no LA arms, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95; P = .017) and 5-year OS rates were 90.1% and 86.4%, respectively (HR, 0.71; 95% CI, 0.53 to 0.94; P = .019). The impact of LA was similar in subgroups defined by menopausal status, tumor size, nodal metastases, and hormone receptor and human epidermal growth factor receptor 2 status. Using competing risk analyses, in LA and no LA arms, 5-year cumulative incidence rates of locoregional recurrence were 3.4% and 4.5% (HR, 0.68; 95% CI, 0.41 to 1.11), and distant recurrence rates were 8.5% and 11.6%, respectively (HR, 0.73; 95% CI, 0.53 to 0.99). There were no adverse events because of lidocaine injection. CONCLUSION: Peritumoral injection of lidocaine before breast cancer surgery significantly increases DFS and OS. Altering events at the time of surgery can prevent metastases in early breast cancer (CTRI/2014/11/005228).[Media: see text].

A prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged ≥ 80 years after curative resection of colorectal cancer, the HiSCO-03 study.

PURPOSE: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥ 80 years. We conducted a prospective multi-institutional phase II study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. PATIENTS AND METHODS: Patients with stage III CRC aged ≥ 80 years who underwent curative resection were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1-28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. RESULTS: Sixty-nine patients were enrolled between 2013 and 2021. Of the 69 patients, 65 were included in the analysis. There were 32 males and 33 females with a median age of 82 years (range 80-88 years). In the primary endpoint, administration completion rate was 67.3% (95% confidence interval 54.9-77.6%), and the lower limit of the 95% confidence interval was below the threshold of 60%. 21 patients discontinued treatment because of adverse events (AEs) and refused treatment. The median relative dose intensities were 84% (range 4-100%) for UFT, and 100% (range 4-100%) for LV. Incidence of grade three or higher AEs were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). CONCLUSIONS: The indications for adjuvant UFT/LV therapy for elderly CRC aged ≥ 80 years were considered limited. It is necessary to clarify the background of patients in whom drug administration is discontinued and investigate their impact on long-term prognosis.