6 research outputs found
Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: The pilot phase of a randomised controlled trial
Summary:
Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more eff ective than similar postoperative
treatment for oesophageal, gastric, and rectal cancers, perhaps because of more eff ective micrometastasis eradication
and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to
investigate the feasibility, safety, and effi cacy of preoperative chemotherapy for colon cancer.
Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced
(T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly
assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m², l-folinic acid 175 mg, fl uorouracil
400 mg/m² bolus, then 2400 mg/m² by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a
further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS
wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the fi rst
6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a
minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of
defunctioning colostomy as stratifi cation variables. Primary outcome measures of the pilot phase were feasibility,
safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat.
This trial is registered, number ISRCTN 87163246.
Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3–4
gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with
no signifi cant diff erences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99)
versus 12% (six of 51) had complications prolonging hospital stay (p=0·81). 98% (50 of 51) of postoperative
chemotherapy patients had T3 or more advanced tumours confi rmed at post-resection pathology compared with 91%
(90 of 99) of patients following preoperative chemotherapy (p=0·10). Preoperative therapy resulted in signifi cant
downstaging of TNM5 compared with the postoperative group (p=0·04), including two pathological complete
responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p<0·0001), resection margin involvement (4%
[ four of 99] vs 20% [ten of 50], p=0·002), and blinded centrally scored tumour regression grading: 31% (29 of 94) vs 2%
(one of 46) moderate or greater regression (p=0·0001).
Interpretation Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is
feasible with acceptable toxicity and perioperative morbidity. Proceeding to the phase 3 trial, to establish whether the
encouraging pathological responses seen with preoperative therapy translates into improved long-term oncological
outcome, is appropriate
CD200 Expression Suppresses Natural Killer Cell Function and Directly Inhibits Patient Anti-tumor Response in Acute Myeloid Leukemia
Upregulation of the immunosuppressive cell surface glycoprotein, CD200, is a common feature of acute myeloid leukemia (AML) and is associated with poor patient outcome. We investigated whether CD200 overexpression on AML cells could specifically compromise patient natural killer (NK) cell anti-tumor responses. We found that CD200hi patients showed a 50% reduction in the frequency of activated NK cells (CD56dimCD16+) compared with CD200lo patients. Additionally, NK receptor expression (NKp44 and NKp46) on these cells was also significantly downregulated in CD200hi patients. To assess whether NK cell activity was directly influenced by CD200 expression, we examined the effect of ectopic expression of CD200. These assays revealed that both NK cell cytolytic activity and interferon-γ response were significantly reduced toward CD200+ leukemic targets and that these targets showed increased survival compared with CD200− cells. Similarly, NK cells isolated from AML patients were less functionally active toward CD200hi autologous blasts from both cytolytic and immunoregulatory perspectives. Finally, blocking CD200 alone was sufficient to recover a significant proportion of NK cell cytolytic activity. Together, these findings provide the first evidence that CD200 has a direct and significant suppressive influence on NK cell activity in AML patients and may contribute to the increased relapse rate in CD200+ patients