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Burnett B.,North Wales Cancer Treatment Center
European Journal of Oncology Pharmacy | Year: 2012

Study objectives: Protein-based medicines have specific storage requirements to ensure chemical stability and purity, but exposure to different environmental conditions can occur in normal use. The effect of extended unrefrigerated storage and thermal cycling on the stability of Hospira filgrastim (Nivestim) was examined. Methods: Three batches of two presentations of Hospira filgrastim prefilled syringes (30 MU and 48 MU) were kept refrigerated until 1-8 months after expiry. After this period, the samples were exposed to either three cycles of storage at 25 ± 2°C and 5 ± 3°C, seven days at 25 ± 2°C in light or dark conditions, three cycles at 25 ± 2°C and 5 ± 3°C, followed by seven days at room temperature (light and dark), or frozen for three days. Expired control samples were maintained at 5 ± 3°C. Samples were analysed for appearance, pH, particulate matter, protein concentration, impurities, biological activity and sterility. Results: All of the parameters measured for each sample of Hospira filgrastim were within the shelf life specification requirements, and there was no qualitative difference between parameters measured in samples that had undergone environmental stressing versus those maintained at 5 ± 3°C. Conclusion: Hospira filgrastim formulations are unaffected by cyclical changes in temperature between the fridge and 25 ± 2°C, and are also unaffected by exposure either to room temperature for seven days or to freezing for three days. Therefore, physicians, pharmacists and patients can be confident that Hospira filgrastim remains active and stable during environmental excursions commonly encountered in general use. Source

James R.D.,Kent Cancer Center | Glynne-Jones R.,Mount Vernon Hospital | Meadows H.M.,University College London | Cunningham D.,Royal Marsden Hospital | And 13 more authors.
The Lancet Oncology | Year: 2013

Background: Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. Methods: In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m2 on day 1) or cisplatin (60 mg/m2 on days 1 and 29), with fluorouracil (1000 mg/m2 per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. Findings: We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9-6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference -0·9%, 95% CI -4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0·95, 95% CI 0·75-1·21; p=0·70). Interpretation: The results of our trial-the largest in anal cancer to date-show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Funding: Cancer Research UK. © 2013 Elsevier Ltd. Source

Gollins S.,North Wales Cancer Treatment Center | Sebag-Montefiore D.,University of Leeds
Clinical Oncology | Year: 2016

Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5-10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management.The current standard is local pelvic treatment (surgery ± preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival. © 2015 The Royal College of Radiologists. Source

Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Sebag-Montefiore D.,University of Leeds | Adams R.,University of Cardiff | Gollins S.,North Wales Cancer Treatment Center | And 3 more authors.
Cancer | Year: 2013

Background: Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial 98-11 (RTOG 98-11). Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/ mitomycin C. METHODS: In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). RESULTS: Palpable, clinically positive lymph nodes were associated with LRF (P =.012), a greater risk of ACD (P =.031), and decreased OS (P =.006) in multivariable analyses. Men had worse outcomes than women for LRF (P =.036), ACD (P =.039), and OS (P =.008). On average, a lower hemoglobin level had an adverse effect on ACD (P =.008), and a higher white blood cell count had an adverse effect on OS (P =.001). However, external validation of the score was poor for LRF (area under the curve [AUC] = 54%) but was better for ACD (AUC = 67%) and OS (AUC = 63%). CONCLUSIONS: The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively. Cancer 2013. © 2012 American Cancer Society. This analysis of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I) complements 2 other studies, adding further evidence that palpable inguinal lymph node status and sex are independently prognostic of overall survival, locoregional failure, and anal cancer death. In addition, after adjusting for sex and lymph node status, presenting hemoglobin level is identified as another prognostic factor for anal cancer death. Copyright © 2012 American Cancer Society. Source

Glynne-Jones R.,Mount Vernon Cancer Center | Sebag-Montefiore D.,St Jamess Hospital | Adams R.,University of Cardiff | McDonald A.,Beatson West of Scotland Cancer Center | And 5 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. Methods and Materials: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. Results: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35-1.12; p = 0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48-1.68; p = 0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p = 0.51). OTT was longer by 6.1 days for EBRT (p = 0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p = 0.03). Conclusions: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control. © 2011 Elsevier Inc. Source

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