First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study.

BACKGROUND: Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. METHODS: TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1-5 and 8-12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1-14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. RESULTS: At 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. CONCLUSIONS: TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. CLINICAL TRIAL INFORMATION: NCT02743221 (clinicaltrials.gov).

Prevalence of nodal involvement in rectal cancer after chemoradiotherapy.

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.

When patients are diagnosed with rectal cancer and the tumour grows beyond the rectal wall there is a high risk that the tumour has spread to nearby lymph nodes. This study showed that this relationship between tumour invasion depth and lymph node involvement is similar after treatment with (chemo)radiotherapy. Patients who have tumour cells remaining in the lymph nodes after (chemo) radiotherapy have a worse prognosis than patients who do not have cancer cells remaining in the lymph nodes. When an organ-preserving treatment is considered as an alternative therapy, this should be kept in mind during patient counselling.

Body Composition and Dose-limiting Toxicity in Colorectal Cancer Chemotherapy Treatment; a Systematic Review of the Literature. Could Muscle Mass be the New Body Surface Area in Chemotherapy Dosing?

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.

The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

BACKGROUND: The improved overall survival (OS) after short course preoperative radiotherapy (SCPRT) using 5 × 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 immunological 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 × 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.

Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus: results of a post hoc analysis from the randomised phase III ACT II trial.

BACKGROUND: Concurrent chemoradiation is standard-of-care for patients with squamous cell carcinoma of the anus. Poor compliance to chemotherapy, radiotherapy treatment interruptions and unplanned breaks may impact adversely on long-term outcomes. METHODS: The ACT II trial recruited 940 patients with localised squamous cell carcinoma of the anus, and assigned patients to mitomycin (week 1) or cisplatin (weeks 1 and 5), with fluorouracil (weeks 1 and 5) and radiotherapy (50.4 Gy in 28 fractions over 38 days). This post hoc analysis examined the association between baseline factors (age, gender, site, T stage and N stage), and compliance to treatment (radiotherapy and chemotherapy), and their effects on locoregional failure-free survival, progression-free survival (PFS) and overall survival (OS). Compliance was categorised into groups. Radiotherapy: six groups according to total dose and overall treatment time (OTT). Chemotherapy: three groups (A = per-protocol; B = dose reduction or delay; C = omitted). RESULTS: A total of 931/940 patients were assessable for radiotherapy and 936 for chemotherapy compliance. Baseline glomerular filtration rate <60 ml/min and cisplatin were significantly associated with poor week 5 compliance to chemotherapy (P = 0.003 and 0.02, respectively). Omission of week 5 chemotherapy was associated with significantly worse locoregional failure-free survival [hazard ratio (HR) 2.53 (1.33-4.82) P = 0.005]. Dose reductions/delays or omission of week 5 chemotherapy were associated with significantly worse PFS {HR: 1.56 [95% confidence interval (CI): 1.18-2.06], P = 0.002 and HR: 2.39 (95% CI: 1.44-3.98), P = 0.001, respectively} and OS [HR: 1.92 (95% CI: 1.41-2.63), P < 0.001 and HR: 2.88 (95% CI: 1.63-5.08), P < 0.001, respectively]. Receiving the target radiotherapy dose in >42 days is associated with worse PFS and OS [HR: 1.72 (95% CI: 1.17-2.54), P =0.006]. CONCLUSION: Poor compliance to chemotherapy and radiotherapy were associated with worse locoregional failure-free survival, PFS and OS. Treatment interruptions should be minimised, and OTT and total dose maintained. CLINICAL TRIAL NUMBER: ISRCTN 26715889.

Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study.

BACKGROUND: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies. PATIENTS AND METHODS: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety. RESULTS: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents. CONCLUSION: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL. CLINICAL TRIAL INFORMATION: NCT02743221 (ClinicalTrials.gov).

UK national cohort of anal cancer treated with intensity-modulated radiotherapy: One-year oncological and patient-reported outcomes.

BACKGROUND: Concurrent chemoradiotherapy is the standard treatment for anal cancer. Following national UK implementation of intensity-modulated radiotherapy (IMRT), this prospective, national cohort evaluates the one-year oncological outcomes and patient-reported toxicity outcomes (PRO) after treatment. MATERIALS AND METHODS: A national cohort of UK cancer centers implementing IMRT was carried out between February to July 2015. Cancer centers provided data on oncological outcomes, including survival, and disease and colostomy status at one-year. EORTC-QLQ core (C30) and colorectal (CR29) questionnaires were completed at baseline and one-year followup. The PRO scores at baseline and one year were compared. RESULTS: 40 UK Cancer Centers returned data with a total of 187 patients included in the analysis. 92% received mitomycin with 5-fluorouracil or capecitabine. One-year overall survival was 94%; 84% were disease-free and 86% colostomy-free at one-year followup. At one year, PRO results found significant improvements in buttock pain, blood and mucus in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. No significant deteriorations were reported in diarrhea, bowel frequency, and flatulence. Urinary symptom scores were low at one year. Moderate impotence symptoms at baseline remained at one year, and a moderate deterioration in dyspareunia reported. CONCLUSIONS: With national anal cancer IMRT implementation, at this early pre-defined time point, one-year oncological outcomes were reassuring and resulted in good disease-related symptom control. one-year symptomatic complications following CRT for anal cancer using IMRT techniques appear to be relatively mild. These PRO results provide a basis to benchmark future studies.

BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC).

BACKGROUND: Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). METHODS/DESIGN: This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on "T" and "N" downstaging were calculated. FINDINGS: Twenty patients aged 18-75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%-85%). INTERPRETATION: The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.

Ablative stereotactic radiotherapy for oligometastatic colorectal cancer: Systematic review.

BACKGROUND: SBRT is a novel modality in treatment for oligometastatic colorectal cancer. We aimed to perform a systematic review of results of SBRT in maintaining LC (local control) for CRC liver and lung oligometastases. MATERIALS AND METHODS: The review was performed according to PRISMA and PICO guidelines. Database search using keywords: stereotactic, colon, colorectal, cancer, sbrt, sabr returned 457 results. 15 were included in the study. Only cohorts with CRC histology and reported LC were included. RESULTS: For liver LC rates ranged from 50% to 100% after 1 year and 32% to 91% after 2 years. BED range 40.5-262.5 Gy (Gray). For lung LC rates ranged from 62% to 92% after 1 one year and from 53% to 92% after 2 years. BED range 51.3-262.5 Gy. CONCLUSIONS: SBRT of oligometastatic CRC offers high LC with low morbidity and toxicity. It requires more observational studies and randomized trials but available data on clinical efficacy is promising, however not yet matured.

Session 4: What should we do for poor responders after chemoradiotherapy: bad biology or should the fight go on?

Just over 50% of patients with advanced rectal cancer have a poor response to chemoradiotherapy with resultant poor outcomes. Professor Glimelius reviews the evidence base for defining such patients and the potential role, if any, of further treatment.

Genital marginal failures after intensity-modulated radiation therapy (IMRT) in squamous cell anal cancer: no higher risk with IMRT when compared to 3DCRT.

Intensity-modulated radiotherapy (IMRT) is considered the preferred option in squamous cell canal cancer (SCAC), delivering high doses to tumor volumes while minimizing dose to surrounding normal tissues. IMRT has steep dose gradients, but the technique is more demanding as deep understanding of target structures is required. To evaluate genital marginal failure in a cohort of patients with non-metastatic SCAC treated either with IMRT or 3DCRT and concurrent chemotherapy, 117 patients with SCAC were evaluated: 64 and 53 patients were treated with IMRT and 3DCRT techniques, respectively. All patients underwent clinical and radiological examination during their follow-up. Tumor response was evaluated with response evaluation criteria in solid tumors v1.1 guideline on regular basis. All patients' data were analyzed, and patients with marginal failure were identified. Concomitant chemotherapy was administered in 97 and 77.4% of patients in the IMRT and 3DCRT groups, respectively. In the IMRT group, the median follow-up was 25 months (range 6-78). Progressive disease was registered in 15.6% of patients; infield recurrence, distant recurrence and both infield recurrence and distant recurrence were identified in 5, 4 and 1 patient, respectively. Two out of 64 patients (3.1%) had marginal failures, localized at vagina/recto-vaginal septum and left perineal region. In the 3DCRT group, the median follow-up was 71.3 months (range 6-194 months). Two out of 53 patients (3.8%) had marginal failures, localized at recto-vaginal septum and perigenital structures. The rate of marginal failures was comparable in IMRT and 3DCRT groups (χ2 test p = 0.85). In this series, the use of IMRT for the treatment of SCAC did not increase the rate of marginal failures offering improved dose conformity to the target. Dose constraints should be applied with caution-particularly in females with involvement of the vagina or the vaginal septum.