AIM:There is no consensus for the use of adjuvant chemotherapy (ACT) after radical resection in rectal cancer. We use real-world data from the Netherlands (NL), England and Scotland, from patients who underwent surgery without neoadjuvant chemotherapy, to explore the potential benefit of ACT. MATERIALS AND METHODS:Routine administrative healthcare data from the NL (2012-2017), England (2014-2019) and Scotland (2013-2017) were used to identify patients with a clinical or pathological T3, T4, or N+ rectal cancer; managed with radical resection ± neoadjuvant (chemo)radiotherapy. Data on patient, tumour, treatment demographics and survival were collected. Kaplan-Meier curves and Cox regression models were used to understand the association between ACT and 5-year survival. Models were estimated for the total population and different pre-defined subgroups within each cohort, unadjusted and adjusted for relevant confounding factors. RESULTS:33,211 patients were included, 12,649, 18,729 and 1833 patients from NL, English and Scottish cohorts, respectively. ACT use differed with administration rates of 3.6%, 34.4% and 33.1%, respectively. The use of neo-adjuvant (chemo)radiotherapy was higher in NL (75·7%, 36.2% and 42.3%, respectively). The Hazard Ratio for death at 5 years was in favour of ACT in all three cohorts, reaching statistical significance in the English and Scottish cohorts (adjusted HR 0.66, 95% CI 0.61-0.71) and (adjusted HR 0.50, 95% CI 0.37-0.68), respectively. CONCLUSIONS:Whilst this survival benefit must be interpreted with caution due to the limitations of real-world data, in the absence of high-level evidence, it offers further weight to contemporary rectal cancer literature that multimodality treatment including systemic therapy offers an OS in rectal cancer.

Squamous-cell cancer of the anus is a rare entity. Fifty years ago, understanding the natural history was limited by the lack of an agreed staging system and a largely irrelevant but complex histological categorisation. Retrospective reports described a small number of patients, generally with small tumours, treated by diverse methods with limited follow-up. The use of therapeutic radiation was limited by observed acute toxicity. Some centres gained substantial experience with interstitial radiation, but knowledge and expertise regarding the natural history and optimal methods of treatment were difficult to accumulate and hand on. Radiotherapy (RT) with or without interstitial radiation as the primary treatment, chemoradiotherapy (CRT) both definitive and preoperative, local excision for residual after CRT and small margin carcinomas and ‘prophylactic’ groin dissections after radical surgery all had advocates in different centres. The dogma in Europe at the time favoured split-course treatments. Early experiments combining fluoropyrimidines and RT were refined with Nigro et al.’s landmark study in 1974. Subsequent regimens are variations and today CRT with concurrent fluoropyrimidines and mitomycin C is accepted as the standard primary treatment. Early randomised phase III trials proved CRT to be more effective than external beam RT alone, but uncertainty remained over the optimal integration of chemotherapy, the type of chemotherapy, the ideal RT doses and potential late effects. These questions were imperfectly addressed and led to subsequent pragmatic phase III trials testing the impact of induction and consolidation chemotherapy and dose escalation. We describe the historical perspective and examine the opportunities we failed to grasp.

PURPOSE:The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27. METHODS AND MATERIALS:People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated. RESULTS:Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed. CONCLUSIONS:The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.

14 Background: Our phase II randomized study was conducted in patients with previously untreated unresectable mCRC not eligible to receive standard oxaliplatin- or irinotecan- based chemotherapy regimens. The results of the primary study analysis were reported earlier and demonstrated a promising efficacy in terms of progression-free survival (PFS) and an acceptable safety profile for the combination of trifluridine/tipiracil + bevacizumab (E. Van Cutsem et al. Ann. Oncol. 2020). Here we present the final end-of-study analysis on the overall survival (OS). Methods: Eligible patients were randomized in 1:1 ratio to receive either trifluridine/tipiracil administered orally at 35 mg/m²/dose bid from days 1-5 and days 8-12, and bevacizumab at 5 mg/kg on days 1 and 15 of a 28-day treatment cycle (TT-B), or capecitabine administered orally at 1250 or 1000 mg/m²/dose bid (according to the patient’s status) from days 1-14 and bevacizumab at 7.5 mg/kg on day 1 of a 21-day treatment cycle (C-B). Cycles were repeated until documented disease progression, unacceptable toxicity, or investigator’s/patient’s decision. Following the treatment discontinuation, all patients were followed for OS until the end-of-study, which was defined as the date of the withdrawal visit for the last patient. In the absence of death confirmation or for patients alive as of the end-of-study date, survival time was censored at the date of their last study follow-up. For the OS analysis the HR and the corresponding 2-sided 80% and 2-sided 95% CIs for TT-B versus C-B were estimated using a Cox proportional hazard model adjusting for the stratification factors based on IWRS data. OS was summarized using Kaplan-Meier curves and further characterized in terms of the median and survival probabilities at 6, 12, 18, and 24 months along with the corresponding 2-sided 80% and 2-sided 95% CI (Brookmeyer and Crowley CI for median and Kalbfleisch and Prentice CI for survival probabilities). Results: From April 2016 to March 2017, 153 patients were randomized and followed until end-of-study on September 1, 2020. Twenty-one patients, 11 from TT-B and 10 from C-B, were alive and censored for the analysis. Median OS was 22.31 months in TT-B and 17.67 months in C-B with HR 0.78 (95% CI, 0.55, 1.10). Survival probability at 18 months in TT-B was 0.62 (95% CI, 0.50, 0.72), and 0.47 (95% CI, 0.35, 0.57) in C-B. Conclusions: Our study demonstrated earlier a median PFS of 9.2 months for TT-B and 7.8 months for C-B when administered to patients with previously untreated unresectable mCRC ineligible for standard combination chemotherapy. The final study analysis performed on OS, the main secondary endpoint, provided further evidence for TT-B as a noteworthy valuable regimen in this population settings. Clinical trial information: NCT02743221.

Addition of AAP to ADT is standard of care for APC (metastatic, M1 and high-risk non-metastatic, M0). We tested transcriptome signatures as prognostic and predictive biomarkers for patients (pt) starting ADT +/- AAP. Whole transcriptome profiling was performed using a clinical test (Decipher, Veracyte, San Diego) on tumor index core mRNA from pt randomised 1:1 ADT:ADT+AAP in STAMPEDE. A pre-specified statistical analysis plan was approved by the trial oversight groups. Cox models were fit with mRNA signature, AAP (+/-), age, WHO PS, pre-ADT PSA, NSAIDs/aspirin use, Gleason score, and disease burden (M0N0 vs M0N1 vs M1 low volume vs M1 high volume) as covariates. Primary analyses included Decipher genomic classifier (GC, continuous) for prognosis and AR-activity (AR-A, average vs low) for prediction. AAP trial closed to follow up Nov 2021. Of 1917 pt (full trial cohort, FTC) enrolled Nov 2011 - Jan 2014, 1824 consented to tumor analysis; 1298 (71%) reviewed centrally, 974 (75%) gave transcriptomes; 781 (80%) passed QC. Of 781, 50% vs 52% in FTC were M1; other clinical variables, well balanced. Median follow-up = 94 months (IQR: 84 - 97). GC was strongly prognostic in APC (per 0.1 increment, M1 OS (HR [95% CI] 1.17 [1.09 - 1.26], p < 0.001), M0 MFS (HR 1.20 [1.09 - 1.31], p < 0.001), Table. AR-A showed no interaction with AAP (interaction HR 0.86 [0.56 - 1.33], p = 0.5). Secondary analyses showed consistent effect of AAP across PAM50, PSC and GC and worse outcome for low AR-A (M1, OS HR: 1.30 [0.99 - 1.70], p = 0.06; M0, MFS HR: 1.56 [1.08 - 2.27], p = 0.02).Table: 1358OBaseline met statusTreatmentDecipher GCEnd-pointFree of an event at 72 monthsM1ADT>medianOS17%ADT + AAP>medianOS43%ADT≤medianOS51%ADT + AAP≤medianOS64%M0ADT>medianMFS53%ADT + AAP>medianMFS66%ADT≤medianMFS81%ADT + AAP≤medianMFS85% Open table in a new tab Decipher GC is strongly prognostic in APC treated with ADT +/- AAP. AAP effect is consistent across AR-A, PAM50, PSC and GC categories but absolute benefit varied. We clinically qualify mRNA signatures for potential use in treatment intensification/de-intensification of pt treated with ADT + AAP.

RAPIDO (Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation) has become a pivotal trial in the management of locally advanced rectal cancer (LARC). The trial investigates a policy of short-course pre-operative radiotherapy (SCPRT) followed by chemotherapy at meaningful systemic doses before defined surgery compared against standard pre-operative long-course chemoradiotherapy (LCCRT)—considered to be a global standard of care (SOC). Is short-course radiotherapy and total neoadjuvant therapy the new standard of care in locally advanced rectal cancer? A sensitivity analysis of the RAPIDO clinical trialAnnals of OncologyVol. 33Issue 8PreviewThe results of the RAPIDO trial have been accepted as evidence in favour of short-course radiotherapy (SC-RT) followed by chemotherapy before total mesorectal excision in high-risk locally advanced rectal cancer. A noteworthy concern is that the RAPIDO trial did not ensure that all patients in the control arm received adjuvant chemotherapy. This may bias statistical estimates in favour of the experimental arm if adjuvant chemotherapy is active in rectal cancer. Moreover, the 5-year update revealed an increase in the risk of local relapse in the experimental arm. Full-Text PDF

AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72; PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346; de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6; in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8); AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2); most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52); RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10-9. ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr.

Chemotherapy dosing is traditionally based on body surface area calculations; however, these calculations ignore separate tissue compartments, such as the lean body mass (LBM), which is considered a big pool of drug distribution. In our era, colorectal cancer patients undergo a plethora of computed tomography scans as part of their diagnosis, staging and monitoring, which could easily be used for body composition analysis and LBM calculation, allowing for personalised chemotherapy dosing. This systematic review aims to evaluate the effect of muscle mass on dose-limiting toxicity (DLT), among different chemotherapy regimens used in colorectal cancer patients. This review was carried out according to the PRISMA guidelines. MEDLINE and EMBASE databases were searched from 1946 to August 2019. The primary search terms were 'sarcopenia', 'myopenia', 'chemotherapy toxicity', 'chemotherapy dosing', 'dose limiting toxicity', 'colorectal cancer', 'primary colorectal cancer' and 'metastatic colorectal cancer'. Outcomes of interest were – DLT and chemotoxicity related to body composition, and chemotherapy dosing on LBM. In total, 363 studies were identified, with 10 studies fulfilling the selection criteria. Seven studies were retrospective and three were prospective. Most studies used the same body composition analysis software but the chemotherapy regimens used varied. Due to marked study heterogeneity, quantitative data synthesis was not possible. Two studies described a toxicity cut-off value for 5-fluorouracil and one for oxaliplatin based on LBM. The rest of the studies showed an association between different body composition metrics and DLTs. Prospective studies are required with a larger colorectal cancer cohort, longitudinal monitoring of body composition changes during treatment, similar body composition analysis techniques, agreed cut-off values and standardised chemotherapy regimens. Incorporation of body composition analysis in the clinical setting will allow early identification of sarcopenic patients, personalised dosing based on their LBM and early optimisation of these patients undergoing chemotherapy.

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-smallcell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50mg vistusertib bd 3/7 days for 6/ 7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.

After curative surgery for colorectal cancer (CRC), some studies indicate poorer survival in obese patients. Adjuvant chemotherapy (ACT) for CRC is commonly capped at a body surface area (BSA) ≥2.2m2, potentially reducing chemotherapy average cumulative relative dose (ACRD) and average relative dose intensity (ARDI) in obese patients. Individual participant-level data from MOSAIC, SCOT, PROCTORSCRIPT, and CHRONICLE (CRC-ACT) randomised-trials, with derivable BMI, BSA, and chemotherapy doses, were included from the OCTOPUS consortium. ARDI and ACRD were calculated as percentages of actual to expected (full BSA-based) dose intensity (cumulative dose/treatment duration in weeks) or cumulative dose, respectively, averaged across the drugs in the regimen. Two-stage random-effects meta-analyses of linear or Cox proportional hazards regression models were performed to explore BMI-ARDI/-ACRD and ARDI-/ACRD-survival relationships, respectively. The primary outcome was disease-free survival (DFS), and secondary outcomes were overall (OS) and cancer-specific (CSS) survival, in addition to ARDI and ACRD. All models where adjusted for age, sex, performance status, t-stage and n-stage (in addition to BMI in the survival models). 7269 patients were eligible. BMI 5kg/m2 increments were associated with a 2.04% reduction in cycle 1 dose (95% CI:-2.45,-1.64; p ACRD 5% increments were associated with improved DFS (HR 0.953 (0.926, 0.980); p=0.001), OS (HR 0.931(0.908, 0.955); p < 0.001) and CSS (HR 0.941(0.924, 0.959); p < 0.001) survival. However, no significant relationship was demonstrated for ARDI (DFS HR 1.015 (0.967, 1.065); p=0.552; OS HR 1.035 (0.990, 1.081); p 0.134; CSS HR 1.022 (0.982, 1.064); p =0.282), nor for sex-interactions for both ACRD and ARDI. ACRD is more important than ARDI in determining survival. Elevated BMI is associated with a reduced cycle 1 dose and a modest ACRD reduction. These indirect effects through under-treatment might explain poorer survival in obese patients, rather than direct effects of obesity resulting from, for example, tumour biology.

BACKGROUND The purpose of this study was to investigate the prevalence of ypN+ status according to ypT category in patients with locally advanced rectal cancer treated with chemoradiotherapy and total mesorectal excision, and to assess the impact of ypN+ on disease recurrence and survival by pooled analysis of individual-patient data. METHODS Individual-patient data from 10 studies of chemoradiotherapy for rectal cancer were included. Pooled rates of ypN+ disease were calculated with 95 per cent confidence interval for each ypT category. Kaplan-Meier and Cox regression analyses were undertaken to assess influence of ypN status on 5-year disease-free survival (DFS) and overall survival (OS). RESULTS Data on 1898 patients were included in the study. Median follow-up was 50 (range 0-219) months. The pooled rate of ypN+ disease was 7 per cent for ypT0, 12 per cent for ypT1, 17 per cent for ypT2, 40 per cent for ypT3, and 46 per cent for ypT4 tumours. Patients with ypN+ disease had lower 5-year DFS and OS (46.2 and 63.4 per cent respectively) than patients with ypN0 tumours (74.5 and 83.2 per cent) (P < 0.001). Cox regression analyses showed ypN+ status to be an independent predictor of recurrence and death. CONCLUSION Risk of nodal metastases (ypN+) after chemoradiotherapy increases with advancing ypT category and needs to be considered if an organ-preserving strategy is contemplated.

Background: The improved overall survival (OS) after short course preoperative radiotherapy (SCPRT) using 5 x 5 Gy reported in the early rectal cancer trials could not be replicated in subsequent phase III trials. This original survival advantage is attributed to poor quality of surgery and the large differential in local recurrence rates, with and without SCPRT. Immuno-modulation during and after SCPRT and its clinical implications have been poorly investigated. We propose an alternative explanation for this survival benefit in terms of im-munological mechanisms induced by SCPRT and the timing of surgery, which may validate the concept of consolidation chemotherapy. Material and methods: We reviewed randomized controlled trials (RCTs) and studies of SCPRT from 1985 to 2019. We aimed to examine the precise timing of surgery in days following SCPRT and identify evidence for immune modulation, neo-antigens and memory cell induction by radiation. Results: Considerable variability is reported in randomised trials for median overall treatment time (OTT) from start of SCPRT to surgery (8-14 days). Only three early trials showed a benefit in terms of OS from SCPRT, although the level of benefit in preventing local recurrence was consistent across all trials. Different patterns of immune effects are observed within days after SCPRT depending on the OTT, but human leukocyte antigen (HLA)-1 expression was not upregulated. Conclusions: SCPRT has a substantial immune-stimulatory potential. The importance of the timing of surgery after SCPRT may have been underestimated. An optimal interval for surgery after 5 x 5 Gy may lead to better outcomes, which is possibly exploited in total neoadjuvant therapy schedules using consolidation chemotherapy. Individual patient meta-analyses from appropriate SCPRT trials examining outcomes for each day and prospective trials are needed to clarify the validity of this hypothesis. The interaction of SCPRT with tumour adaptive immunology, in particular the kinetics and timing, should be examined further.

Abiraterone acetate plus prednisolone previously showed a clear survival advantage in men starting long-term hormone therapy for prostate cancer in STAMPEDE, a randomized controlled trial using a multi-arm multi-stage platform design. STAMPEDE included a wide range of men with M1 or M0 disease. The LATITUDE trial, in patients with high-burden M1 disease only, reported a similar magnitude of effect to the comparable subset of STAMPEDE pts. We report long-term outcomes in the M1 subset of pts in STAMPEDE. All patients received androgen deprivation therapy (ADT). Stratified randomization allocated pts 1:1 to ADT alone or adding daily abiraterone acetate 1000mg + prednisolone 5mg (SOC+AAP) continued until PSA, radiological & clinical progression. The primary outcome measure was death from any cause. The data freeze for this long-term analysis was planned for 3yr after the primary survival results when a meaningful increase in data was anticipated. Analyses used Cox proportional hazards & flexible parametric models, adjusted for baseline stratification factors. Of 1,917 pts contemporaneously randomized to these groups (Nov-2011 to Jan-2014), 1,003 (52%) had M1 disease. The M1 groups were balanced: median age 67yr; 48% high-burden, 44% low-burden, 8% burden not assessable; 94% newly-diagnosed; median PSA 97ng/ml. Median follow-up had increased from 3.5yr to 6.1yr & number of ADT-only deaths increased by 50%, from 218 previously to 329. With 244 ADT+AAP deaths, the adjusted HR=0·60 (95%CI 0·50—0·71; p=0.31x10-9) favouring ADT+AAP, with 5-yr survival improved from 41% ADT-only to 60% ADT+AAP. The relative effect of abiraterone was similar in low-burden (HR=0·55; 95%CI 0·41—0·76) and high-burden (HR=0·54; 95%CI 0·43—0·69) patients. Median time on ADT+AAP was 2.4yr, with a current maximum of 8.1yr. Toxicity at 4yr post-randomisation was similar, with 16% of patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of M1 prostate cancer patients was achieved with ADT + abiraterone acetate + prednisolone, irrespective of burden of disease.