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1.
Eur J Cancer ; 49(16): 3507-16, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23953030

ABSTRACT

BACKGROUND: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. METHODS: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation. RESULTS: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference. INTERPRETATION: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC. FUNDING: The trial was funded by Cancer Research UK and supported by Amgen Pharma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Aged , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Biological Availability , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cyclosporine/administration & dosage , Diarrhea/chemically induced , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Irinotecan , Kaplan-Meier Estimate , Male , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/metabolism , Odds Ratio , Time Factors , Treatment Outcome , United Kingdom
2.
Gut ; 59(11): 1501-10, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20947885

ABSTRACT

OBJECTIVE: There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis. METHODS: HSP27 levels were determined using combined two-dimensional gel electrophoresis and tandem mass spectrometry (12 cases) and by immunohistochemistry using tissue microarrays of colorectal cancers sampled at surgery and 80 diagnostic rectal biopsies. RESULTS: HSP27 overexpression was strongly associated with poor cancer-specific survival in rectal cancer (n=205, p=0.0063) but not colon cancer (n=199, p=0.7385) in the cohort with a poor prognosis. Multivariate Cox regression confirmed nodal metastases (p=0.0001) and HSP27 expression (p=0.0233) as independent markers of survival in rectal cancer. HSP27 levels remained unchanged in the majority of cases (65/80, 81%) between diagnostic biopsies and matched surgical samples, regardless of whether patients had undergone preoperative radiotherapy. In the cohort with a good prognosis the association between HSP27 and survival was not observed in patients with either rectal (n=115; p=0.308) or colon cancer (n=200; p=0.713). CONCLUSION: In a large cohort of patients with a poor prognosis, HSP27 is an independent marker of poor outcome in rectal cancer; its expression is not altered by neoadjuvant radiotherapy. This finding requires validation in an independent similar cohort of patients with rectal cancer. HSP27 levels merit evaluation as a stratification factor for treatment of rectal cancer.


Subject(s)
Biomarkers, Tumor/metabolism , Colonic Neoplasms/metabolism , HSP27 Heat-Shock Proteins/metabolism , Rectal Neoplasms/metabolism , Aged , Cohort Studies , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Female , Humans , Male , Middle Aged , Molecular Weight , Neoadjuvant Therapy , Neoplasm Proteins/metabolism , Prognosis , Proteomics/methods , Radiotherapy, Adjuvant , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Survival Analysis , Treatment Outcome
3.
Int J Radiat Oncol Biol Phys ; 72(1): 119-26, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18472366

ABSTRACT

PURPOSE: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. METHODS AND MATERIALS: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m2) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m2 b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. RESULTS: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. CONCLUSIONS: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Anus Neoplasms/drug therapy , Anus Neoplasms/radiotherapy , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Administration, Oral , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Diarrhea/etiology , Drug Administration Schedule , Feasibility Studies , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Infusions, Intravenous , Male , Middle Aged , Mitomycin/administration & dosage , Mitomycin/adverse effects , Neoplasm Recurrence, Local , Neutropenia/etiology , Radiotherapy Dosage , Remission Induction , United Kingdom
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