Oncology

Optimizing chemotherapy for frail and/or elderly patient with advanced gastroesophageal cancer (AGOAC): the GO2 phase III trial (2019)

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Type of publication:
Conference abstract

Author(s):
Swinson D.E.; Hall P.; Seymour M.; Lord S.; Marshall H.; Ruddock S.; Cairns D.; Waters J.; Wadsley J.; Falk S.; Roy R.; Joseph M.; Nicoll J.; Vellios Kamposioras K.; Tillett T.; Cummins S.; Grumett S.; Stokes Z.; Waddell T.; *Chatterjee A.; Garcia A.; Allmark C.; Khan M.; Petty R.

Citation:
Journal of Geriatric Oncology; Nov 2019; vol. 10 (no. 6), Supplement 1, S8

Abstract:
Introduction: aGOAC patients are frequently elderly and/or frail.
Objective(s): (i) find the optimum dose of oxaliplatin capecitabine (OCap) for this population; (ii) explore the use of an objective geriatric assessment to individualize dose for maximum overall treatment utility (OTU), a composite of clinical benefit, tolerability, quality of life (QL) and patient value.
Method(s): Patients with aGOAC were eligible if there was uncertainty of the appropriate dose of chemotherapy. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m2 d1, Cap 625 mg/m2 bd d1-21, q21d), B (80% Level A) or C (60% Level A). At 9 weeks, patients were scored for OTU. Non-inferiority (vs A) was assessed using PFS, censored at 12 months, with upper boundary HR 1.34 (based on patients' and clinicians' discussions), needing 284 PFS events per two-way comparison. In a separate sub-study, when there was uncertainty regarding the use of chemotherapy, patients were randomized between level C and supportive care alone (SCA).
Results and Conclusion(s): 512 patients were randomized, 2014-2017, at 61 UK centers. Age, performance status and frailty were similar in all arms. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C patients had the least toxicity and best OTU outcomes. When analyzed by baseline age, frailty and PS no group was identified who benefit more from higher treatment doses. A further 46 patients were randomized between chemotherapy and SCA. A non-significant trend to improved survival was observed (HR=0.69, CI 0.32-1.48) and QL deteriorated less with chemotherapy. This is the largest RCT specifically investigating frail and/or elderly aGOAC patients, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS, produced less toxicity and better overall treatment utility.

Will Weekly Win for Taxol in the UK: Comparison of Outcomes in Metastatic and locally advanced breast cancer with weekly vs. 3 weekly administration of paclitaxel: A randomised two-arm, prospective, multi-centre, open-label phase III trial comparing the activity and safety of a weekly versus a three-weekly paclitaxel treatment schedule in patients with advanced or metastatic breast cancer (2019)

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Type of publication:
Randomised controlled trial

Author(s):
Cameron, D. and Verrill, M.

35 patients from Shrewsbury and Telford Hospital NHS Trust were involved in this trial.

Citation:
Unpublished final report

Abstract:
Background: Paclitaxel has significant anti-tumour activity in patients with metastatic breast cancer who either relapse after, or are resistant, to anthracycline based treatment. In this setting, paclitaxel was routinely given as a 3-hour IV infusion at a dose of 175 mg/m2 every 3 weeks. With the aim of optimising dose and schedule of paclitaxel for patients with metastatic breast cancer, a weekly, dose-dense regimen was developed and used in various settings.
Patients and Methods: A total of 569 patients were recruited into the trial – the first and last patients were randomised on 16 September 2002 and 31 July 2006 respectively. The 2 arms were well balanced for sites of metastases, extent of prior radiotherapy and chemotherapy. The median follow up at May 2012 (when the final analysis was performed) was 94 months = 7 years, 10 months.
Results: Response rates for the weekly regimen were significantly higher than the 3-weekly arm (chi-squared test of association: p = 0.002; responses were weekly CR 3.2%, PR 18.3% vs. 3-weekly CR 1.7% and PR 11.3%). There was no significant difference in either time to progression (log rank test: p = 0.127) or overall survival (log rank test: p = 0.193) between the 2 arms.
Conclusions: In this randomised controlled trial of best scheduling, weekly paclitaxel showed a statistically higher objective response activity compared to 3-weekly schedule but no survival benefit was seen.

Evaluating the Trade-offs Men with Localised Prostate Cancer Make Between the Risks and Benefits of Treatments: The COMPARE Study (2020)

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Type of publication:
Journal article

Author(s):
Watson V, McCartan N, Krucien N, Abu V, Ikenwilo D, Emberton M, Ahmed HU

Study involved patients at Shrewsbury and Telford Hospital NHS Trust

Citation:
Journal of Urology. 2020 Aug;204(2):273-280

Abstract:
PURPOSE: COMPARE (COMparing treatment options for ProstAte cancer) aimed to evaluate and quantify the trade-offs patients make between different aspects of active surveillance and definitive therapy.
METHODS: A Discrete Choice Experiment (DCE) tool was used to elicit patients' preferences for different treatment characteristics in 34 urology departments. Patients with localised prostate cancer completed the DCE within one week of being diagnosed and before they made treatment decisions. The DCE was pre-tested (N=5) and piloted (n=106) with patients. Patients chose their preferred treatment profile based on six characteristics: treatment type (active surveillance, focal therapy, radical therapy), return to normal activities, erectile function, urinary function, not needing more cancer treatment and 10-15 year cancer-specific survival. Different tools were designed for low-intermediate (n=468) and high-risk (n=166) patients. An error-components conditional logit model was used to estimate preferences and trade-offs between treatment characteristics.
RESULTS:Low-intermediate risk patients were willing to trade 6.99% absolute decrease in survival to have active surveillance over definitive therapy. They were willing to trade 0.75%, 0.46% and 0.19% absolute decrease in survival for a one-month reduction in time-to-return to normal activities, and 1% absolute improvements in urinary and sexual function, respectively. High-risk patients were willing to trade 3.10%, 1.04% and 0.41% absolute decrease in survival for a one-month reduction in time-to-return to normal activities and 1% absolute improvements in urinary and sexual function, respectively.
CONCLUSIONS: Patients with low-intermediate risk prostate cancer preferred active surveillance to definitive therapy. Patients of all risks were willing to trade-off cancer-specific survival for improved quality-of-life.Registration:clinicaltrials.gov Registration Identifier NCT01177865Funding:Medical Research Council (UK) (grant reference: G1002509)

Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial (2020)

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Type of publication:
Randomised controlled trial

Author(s):
Fernando I.N.; Spooner D.; Latief T.N.; Stevens A.; Bowden S.J.; Herring K.; Ahmed I.; Rea D.W.; Brookes C.L.; Marshall A.; Dunn J.; Grieve R.; Poole C.J.; Churn M.; *Agrawal R.K.; Brunt A.M.; Goodman A.; Canney P.; Ritchie D.; Bishop J.

Citation:
Radiotherapy and Oncology; 2020; Vol 24; p. 52-61

Abstract:
Background: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity.
Method(s): SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893.
Finding(s): Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). Interpretation(s): Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF.

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Human immunodeficiency disease in new diagnoses of head and neck squamous cell cancer: are we testing? (2019)

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Type of publication:
Journal article

Author(s):
*McNamara K.J.; Saunders T.F.C.; *Ahsan F.; *Fernandez C.

Citation:
Journal of Laryngology and Otology; Vol. 133(12) p. 1038-1040

Abstract:
BACKGROUND: Human immunodeficiency virus infected patients have a three-fold increased risk of head and neck squamous cell carcinoma. The British HIV Association recommends human immunodeficiency virus testing in all new diagnoses of head and neck squamous cell carcinoma.
OBJECTIVE(S): This observational study aimed to examine the current routine practice of human immunodeficiency virus testing in patients with newly diagnosed head and neck squamous cell carcinoma, and to address the importance of this test in promoting the early diagnosis and treatment of human immunodeficiency virus.
METHOD(S): All head and neck cancer multidisciplinary teams in England were questioned on their protocol for human immunodeficiency virus testing in new diagnoses of head and neck squamous cell carcinoma.
RESULT(S): Only 1 out of 30 hospitals leading head and neck multidisciplinary teams (3.3 per cent) routinely offered human immunodeficiency virus testing in this high-risk patient group.
CONCLUSION(S): This observational study highlights that head and neck specialists are not aware of, and are consequently not complying with, routine human immunodeficiency virus testing as recommended by the British HIV Association guidelines.

Patients’ and partners’ views of care and treatment provided for metastatic castrate‐resistant prostate cancer in the UK (2019)

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Type of publication:
Journal article

Author(s):
Catt S, Matthews L, May S, Payne H, Mason M, Jenkins V.

Citation:
European Journal of Cancer Care. 2019 Nov;28(6):e13140.

Note:
14 of the 37 participants were recruited from the Royal Shrewsbury Hospital

Abstract:
OBJECTIVE: Documentations of the experiences of patients with advanced prostate cancer and their partners are sparse. Views of care and treatment received for metastatic castrate-resistant prostate cancer (mCRPC) are presented here.
METHODS: Structured interviews conducted within 14 days of a systemic therapy for mCRPC starting and 3 months later explored the following: treatment decisions, information provision, perceived benefits and harms of treatment, and effects of these on patients' and partners' lives.
RESULTS: Thirty-seven patients and 33 partners recruited from UK cancer centres participated. The majority of patients (46%) reported pain was their worst symptom and many wanted to discuss its management (baseline-50%; 3 months-33%). Patients and partners believed treatment would delay progression (>75%), improve wellbeing (33%), alleviate pain (≈12%) and extend life (15% patients, 36% partners). At 3 months, most men (42%) said fatigue was the worst treatment-related side effect (SE), 27% experienced unexpected SEs and 54% needed help with SEs. Most patients received SE information (85% written; 75% verbally); many additionally searched the Internet (33% patients; 55% partners). Only 54% of patients said nurse support was accessible.
CONCLUSION: Pain and other symptom management are not optimal. Increased specialist nurse provision and earlier palliative care links are needed. Dedicated clinics may be justified.

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6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial (2019)

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Type of publication:
Randomised controlled trial

Author(s):
Helena M Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Karen McAdam, Luke Hughes-Davies, Adrian N Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel Rea, Sanjay Raj, Pamela Woodings, Mark Harries, Donna Howe, Kerry Raynes, Helen B Higgins, Maggie Wilcox, Chris Plummer, Janine Mansi, Ioannis Gounaris, Betania Mahler–Araujo, Elena Provenzano, Anita Chhabra, Jean E Abraham, Carlos Caldas, Peter S Hall, Christopher McCabe, Claire Hulme, David Miles, Andrew M Wardley, David A Cameron, Janet A Dunn on behalf of PERSEPHONE Steering Committee and Trial Investigators.

Randomising consultants at the Royal Shrewsbury Hospital were: *Huzeifa Gadir, *Laura Pettit, *Rajiv Agrawal, and *Sheena Khanduri. Principal investigator at the Royal Shrewsbury Hospital was: *Laura Pettit.

Citation:
Lancet 2019; 393: p. 2599–612

Abstract:
Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is noninferior to the standard 12-month treatment regarding disease-free survival.
Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).
Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001).
Interpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.

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Breast Screening Age Extension; High Cancer Pick up Rate of Small Breast Cancers Amenable to Breast and Axillary Conservation (2019)

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Type of publication:
Conference abstract

Author(s):
*Cielecki L. ; *Burley S.; *Lake B.; *Williams S.; *Appleton D.

Citation:
European Journal of Surgical Oncology; Nov 2019; vol. 45 (no. 11); p. 2212-2213

Abstract:
Background: In 2012, Public Health England (PHE) extended the age range for breast screening up to 73. For screening to be an effective tool, one of the Wilson criteria is to detect disease that could be treated at an early stage. This audit aimed to measure the effectiveness of the upper age screening extension in Shropshire by comparing the cancer diagnosis rate to general screening population, size of cancer, and the ability to perform breast conservation.
Method(s): Retrospective analysis of Breast Screening age extension of women invited to be screened aged 71 to 73 years old in Shropshire. Data included number of women invited, uptake rate, recall rate, cancer diagnosis and surgical treatment.
Result(s): 5517 older women were invited into Shropshire Breast Screening Programme as part of the AgeX trial by PHE since September 2014. 4801 women attended and were screened; 87% uptake rate, which exceeds BSP attendance rate of >80%. 104 women were recalled to assessment (2.1%) which is below BSP standard of <5% recall rate for incident screens. 46.1% (48) of women recalled to assessment were given a cancer diagnosis, this is compared to 30.5% in general screening population. 41.6% of the invasive cancer was <15mm. 95.8% of patients had surgery, with 70.8% of patients having breast and axillary conservation surgery.
Conclusion(s): BSP Standards uptake rate and recall rate have been exceeded by upper age extension. Our experience shows high cancer pick up rate of small cancers with the majority patients able to have breast conserving surgery.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial (2019)

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Type of publication:
Journal article

Author(s):
Clarke, N W; Ali, A; Ingleby, F C; Hoyle, A; Amos, C L; Attard, G; Brawley, C D; Calvert, J; Chowdhury, S; Cook, A; Cross, W; Dearnaley, D P; Douis, H; Gilbert, D; Gillessen, S; Jones, R J; Langley, R E; MacNair, A; Malik, Z; Mason, M D; Matheson, D; Millman, R; Parker, C C; Ritchie, A W S; Rush, H; Russell, J M; Brown, J; Beesley, S; Birtle, A; Capaldi, L; Gale, J; Gibbs, S; Lydon, A; Nikapota, A; Omlin, A; O'Sullivan, J M; Parikh, O; Protheroe, A; Rudman, S; *Srihari, N N; Simms, M; Tanguay, J S; Tolan, S; Wagstaff, J; Wallace, J; Wylie, J; Zarkar, A; Sydes, M R; Parmar, M K B; James, N D

Citation:
Annals of Oncology; Dec 2019 30(12) p. 1992-2003

Abstract:
BACKGROUND STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients.
METHODS We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional.
RESULTS Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression).
CONCLUSIONS The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

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See Erratum - The authors regret that Fig.2F has been incorrectly titled. The correct title is “Failure-free survival high burden M1”.

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Best supportive care (BSC) with or without lowdose chemotherapy (chemo) in frail elderly patients with advanced gastroesophageal cancer (aGOAC): The uncertain randomization of the GO2 phase III trial (2019)

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Type of publication:
Conference abstract

Author(s):
Swinson D.; Hingorani M.; Stokes Z.; Dent J.; Guptal K.; *Chatterjee A.; Kamposioras K.; Grumett S.A.; Khan M.; Marshall H.; Ruddock S.; Allmark C.; Katona E.; Howard H.C.; Velikova G.; Lord S.; Hall P.S.; Seymour M.T.

Citation:
Journal of Clinical Oncology; May 2019; vol. 37

Abstract:
Background: Before 2000, trials comparing BSC +/chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using lowdose chemo in a frail population, with comprehensive baseline health and frailty assessment.
Method(s): In the GO2 trial, elderly and/or frail aGOAC pts with a ?certain? indication for chemo were randomised between 3 chemo doses. In this GO2 sub-study, pts with an ?uncertain? indication for chemo were instead randomised to BSC +/- the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR >=30 and bili < 2xULN were required. Baseline assessment included global QL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d121 (modified if eGFR 3050 ml/min or bili 1.52.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not preset, but around 60 pts were anticipated.
Result(s): 558 pts entered GO2 at 61 centres 201417, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p<0.01) or distant mets (p<0.05). OS was not significantly improved with chemo; however we cannot exclude HR >0.32. QL deteriorated less with BSC+chemo than with BSC alone.
Conclusion(s): In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty.

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