Optimizing treatment sequencing of chemotherapy for patients with rectal cancer: The KIR randomized phase II trial.

BACKGROUND: Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. METHODS: Between 2010-2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). RESULTS: Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33-72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). CONCLUSION: We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.

A Phase I, Dose Escalation, Single Dose Trial of Oral Attenuated Salmonella typhimurium Containing Human IL-2 in Patients With Metastatic Gastrointestinal Cancers.

Salmonella has been shown to preferentially colonize solid tumors. It is known that toxicity limits the systemic administration of immunomodulatory cytokines that have a significant anticancer effect. Therefore, we tested a unique cancer treatment strategy comprised of oral delivery of Saltikva, an attenuated strain of Salmonella typhimurium that contain the human gene for interleukin-2. In preclinical experimentation, a significant antitumor effect without toxicity was observed. A dose escalation, single dose, Phase I trial was conducted. Dose escalation (10 to 10) while monitoring for dose limiting toxicity and response was performed. Flow cytometry was conducted to determine the immunologic effect. In total 22 patients were administered Saltikva. Eight patients did not complete the trial. No toxicity or adverse events were observed. There was no survival advantage. Flow cytometry demonstrated an increase in circulating natural killer (NK) cells and NK-T cells when comparing the prestudy period. The results of this phase I dose escalation study show that oral attenuated S. typhimurium containing the human interleukin-2 gene caused no significant toxicities up to doses of 10 colony forming unit. There was no evidence of partial or complete response. All patients had progressive disease and eventually succumbed to their illness. Although no survival advantage was seen in this single dose study, the statistically significant increase in circulating NK and NK-T cell demonstrates an immunologic effect from this treatment regimen and suggest that a multiple dose study should be undertaken.

Elaeagnus angustifolia Plant Extract Inhibits Angiogenesis and Downgrades Cell Invasion of Human Oral Cancer Cells via Erk1/Erk2 Inactivation.

Oral cancer is a common malignancy in both men and women worldwide; this cancer is characterized by a marked propensity for invasion and spreading to local lymph nodes. On the other hand, Elaeagnus angustifolia (EA) is a medicinal plant that has been used for centuries for treating many human diseases in the Middle East. However, the effect of EA plant extract on human cancers especially oral has not been investigated yet. Thus, first we examined the outcome of EA flower extract on angiogenesis, using the chorioallantoic membrane (CAM) of the chicken embryo; we found that EA extract reduces blood vessel development of the CAM. Then, we investigated the effect of EA flower extract on selected parameters in FaDu and SCC25 oral cancer cell lines. Our results show that EA extract inhibits cell proliferation and colony formation, in addition to the initiation of S cell cycle arrest and reduction of G1/G2 phase. In parallel, EA extract provokes differentiation to an epithelial phenotype "mesenchymal-to-epithelial transition: MET" which is the opposite of "epithelial-to-mesenchymal transition, EMT": an important event in cell invasion and metastasis. Thus, EA plant extract causes a dramatic decrease in cell invasion and motility abilities of FaDu and SCC25 cancer cells in comparison with their controls. These changes are accompanied by an upregulation of E-cadherin expression. The molecular pathway analysis of the EA flower extract reveals that it can inhibit the phosphorylation of Erk1/Erk2, which could be behind the inhibition of angiogenesis, the initiation of MET event, and the overexpression of E-cadherin. Our findings indicate that EA plant extract can reduce human oral cancer progression by the inhibition of angiogenesis and cell invasion via Erk1/Erk2 signaling pathways.

Comparing Clinical Characteristics and Outcomes of Young-onset and Late-onset Colorectal Cancer: An International Collaborative Study.

BACKGROUND: Compared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients. MATERIALS AND METHODS: Six international tertiary cancer centers conducted a retrospective study. Patients with YO CRC (aged 18-44 years) and LO CRC (aged > 44 years) diagnosed with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were enrolled. Patients were randomly chosen from each center's database, and the patient demographics and treatment information were collected. The data were then centralized, and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival and mortality, and YO was compared with LO. Site-specific HRs were pooled using a random-effects meta-analysis. RESULTS: Overall, 498 patients, including 224 with YO (129 men; mean age, 37 ± 5.5 years) and 274 with LO (167 men; mean age, 64.8 ± 9.5 years) CRC, were included. At the diagnosis, 137 patients (61.2%) and 122 patients (44.5%) with YO and LO CRC had metastatic disease, respectively. For both cohorts, the 3 most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was performed in 141 YO (63.0%) and 219 LO (79.9%) patients. The longitudinal noncurative treatment patterns were similar, but more biologic therapy was used for these YO patients. The pooled progression-free survival analysis results for first-line noncurative treatment favored LO (HR, 1.96; 95% CI, 1.04-3.68). The mortality analysis showed no significant differences between the 2 groups (YO: HR, 1.53; 95% CI, 0.91-2.58). CONCLUSION: Despite similar treatment patterns and survival outcomes, YO disease might be clinically more aggressive.

Patient and work flow and costs associated with staff time and facility usage at a comprehensive cancer centre in Quebec, Canada--a time and motion study.

BACKGROUND: Mapping patient and work flow and cost analysis studies can help determine the most efficient and cost effective way of providing health services while still maintaining the best standards of care. This study used both time and motion methodology and hospital data to assess the contribution of staff time and facility usage to the overall cost of cancer care during patient visits to a comprehensive cancer centre in Quebec, using metastatic colorectal cancer as a model. METHODS: A workflow diagram was created mapping direct and indirect steps involved during a patient's physician or treatment (FOLFOX/bevacizumab or XELOX/bevacizumab) visit. Staff were timed as they performed each task and this data together with compensation amounts were used to calculate personnel costs. Mean work times and 95% confidence intervals (CI) were calculated. Operation and maintenance (O&M) costs for the Centre were calculated using information from hospital databases. All costs were presented in constant Canadian dollars for the 2010-2011 fiscal year period. RESULTS: For physician visits, direct and indirect personnel costs were $9.25 (95%CI:$7.00-$11.51) and O&M costs were $60.21, for a total of $69.46 (95%CI:$67.21-$71.72). For treatment visits, personnel and O&M costs were $71.91 (95%CI:$45.53-$98.29) and $62.00 respectively for a total of $133.91 (95%CI:$107.53-$160.29). When calculated for treatment alone, the total cost was $136.06 (95%CI:$109.16-$162.95) for FOLFOX/bevacizumab and $119.94 (95%CI:$96.89-$142.99) for XELOX/bevacizumab. The highest cumulative personnel costs were for the pharmacists and nurses ($38.87 and $34.82 respectively). Regarding patient flow, total time in between steps was 77.6 and 49.5 minutes for a physician or treatment visit respectively. CONCLUSIONS: This study from a health care provider's perspective, demonstrated that in the context of increasingly expensive therapies, costs associated with staff time and facility usage do not contribute greatly to the overall cost of treating cancer at this cancer centre. It also illustrated the need for improvements in patient and work flow to reduce wait times in the clinic.

Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies.

Nrf2 is a key transcription factor, which induces a cytoprotective gene array. Nrf2 is regulated at the posttranslational level through proteasomal degradation through an interaction with the adapter protein Keap1. High levels of Nrf2, resulting from a loss of function mutation in Keap1, were reported in chemoresistant non-small cell lung cancer. We observed very low levels of Nrf2 and of Nrf2-regulated detoxification proteins as a frequent phenotype in the more chemosensitive breast cancer, and when engineering increased Nrf2 levels, we found resistance to both doxorubicin and paclitaxel. We here show that basal Nrf2 levels in different cell lines correlate with their respective sensitivity to a common cytotoxic chemotherapy. Nrf2 and its regulated genes and proteins are the targets of a major strategy in cancer prevention. Molecules that interfere with the Nrf2-Keap1-Cul3 protein-protein interactions result in higher levels of Nrf2. Both naturally occurring and synthetic molecules with this effect have been suggested as clinical chemopreventive agents, including molecules derived from cruciferous vegetables such as the isothiocyanate sulforaphane and even green tea polyphenols. Here, we determine the impact of these putative chemopreventive agents on the sensitivity of established cancer cell lines to chemotherapy. We confirmed that these molecules do increase Nrf2 and detoxification enzyme levels in breast cancer cell lines with very low basal Nrf2 levels, and this is associated with significant chemoresistance to cytotoxic drugs. Both effects are less in another breast cancer cell line with intermediate Nrf2, and in lung cancer cells with high Nrf2, these same molecules have no effect on Nrf2 but do actually enhance chemoresistance. While the details of dose and schedule of these agents require further study in in vivo models, these data sound a cautionary note for the use of these agents in patients with established cancers who are undergoing chemotherapy treatment.

The flavonoid Casticin has multiple mechanisms of tumor cytotoxicity action.

We studied the mechanism of anti-tumor activity of the flavonoid Casticin, derived from Achillea millefolium. Casticin anti-tumor activity results in cell growth arrest in G2/M and in apoptotic death. As a tubulin-binding agent (TBA), Casticin induces p21, which in turn inhibits Cdk1. Moreover, Casticin appears to down regulate cyclin A. These observations could explain Casticin-induced G2/M arrest. Following Casticin exposure, Bcl-2 depletion occurs in cancer cells, and a sub-G1 accumulation occurs in the cell cycle. Moreover, following a transient transfection with Bcl-2, MN1 cells are resistant to Casticin. A number of features suggest that Casticin could be important in cancer therapy. Indeed, Pgp over expressing cells are not resistant to Casticin, and its cell killing effect is observed even in p53 mutant or null cell lines.