Efficacy of dose-escalated chemoradiation on complete tumour response in patients with locally advanced rectal cancer (RECTAL-BOOST); a phase 2 randomised controlled trial

Purpose Pathological complete tumour response following chemoradiation in patients with locally advanced rectal cancer (LARC) is associated with favourable prognosis and allows organ-sparing treatment strategies. We aimed to investigate the effect of an external radiation boost to the tumour prior to chemoradiation on pathological or sustained clinical complete tumour response in LARC. Methods and materials This multicentre, non-blinded, phase 2, randomised controlled trial followed the trials within cohorts-design, which is a pragmatic trial design allowing cohort participants to be randomized for an experimental intervention. Patients in the intervention group are offered the intervention (and can accept or refuse this), whereas patients in the control group are not notified about the randomisation. Participants of a colorectal cancer cohort referred for chemoradiation of LARC to either of two radiotherapy centres were eligible. Patients were randomised to no boost or an external radiation boost (5 x 3 Gy) without concurrent chemotherapy directly followed by standard pelvic chemoradiation (25 x 2 Gy with concurrent capecitabine). The primary outcome was pathological complete response (pCR, i.e. ypT0N0) in patients with planned surgery at 12 weeks or, as surrogate for pCR, a 2-year sustained clinical complete response for patients treated with an organ preservation strategy. Analyses were intention to treat. The study was registered with ClinicalTrials.gov, number NCTXXXXXX. Results Between Sept 2014 and July 2018, 128 patients were randomised. Fifty-one of the 64 (79.7%) patients in the intervention group accepted and received a boost. Compared with the control group, fewer patients in the intervention group had a cT4-stage and a low rectal tumour (31.3% versus 17.2% and 56.3% versus 45.3% respectively), and more patients had a cN2-stage (59.4% versus 70.3% respectively). Rate of pathological or sustained clinical complete tumour response was similar between the groups: 23 of 64 (35.9%, 95%CI 24.3-48.9) in the intervention group versus 24 of 64 (37.5%, 95%CI 25.7-50.5) in the control group (OR=0.94 95%CI 0.46-1.92). Near-complete or complete tumour regression was more common in the intervention group: 34 of 49 (69.4%) versus 24 of 53 (45.3%) in the control group (OR=2.74, 95%CI 1.21-6.18). Grade >3 acute toxicity was comparable: 6 of 64 (9.4%) in the intervention group versus 5 of 64 (7.8%) in the control group (OR=1.22 95%CI 0.35-4.22). Conclusion Dose escalation with an external radiotherapy boost to the tumour prior to neoadjuvant chemoradiation did not increase the pathological or sustained clinical complete tumour response rate in LARC

Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review

Purpose: Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer. Methods and Materials: The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathologic complete response (pCR) was conducted. Results: We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I2 = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025). Conclusions: Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer

Feasibility of preference-driven radiotherapy dose treatment planning to support shared decision making in anal cancer

Purpose/Objective: Chemo-radiotherapy is an established primary curative treatment for anal cancer, but clinically equal rationale for different target doses exists. If joint preferences (physician and patient) are used to determine acceptable tradeoffs in radiotherapy treatment planning, multiple dose plans must be simultaneously explored. We quantified the degree to which different toxicity priorities might be incorporated into treatment plan selection, to elucidate the feasible decision space for shared decision making in anal cancer radiotherapy. Material and methods: Retrospective plans were generated for 22 anal cancer patients. Multi-criteria optimization handles dynamically changing priorities between clinical objectives while meeting fixed clinical constraints. Four unique dose distributions were designed to represent a wide span of clinically relevant objectives: high-dose preference (60.2 Gy tumor boost and 50.4 Gy to elective nodes with physician-defined order of priorities), low-dose preference (53.75 Gy tumor boost, 45 Gy to elective nodes, physician-defined priorities), bowel sparing preference (lower dose levels and priority for bowel avoidance) and bladder sparing preference (lower dose levels and priority for bladder avoidance). Results: Plans satisfied constraints for target coverage. A senior oncologist approved a random subset of plans for quality assurance. Compared to a high-dose preference, bowel sparing was clinically meaningful at the lower prescribed dose [median change in V45Gy: 234 cm3; inter-quartile range (66; 247); p < .01] and for a bowel sparing preference [median change in V45Gy: 281 cm3; (73; 488); p < .01]. Compared to a high-dose preference, bladder sparing was clinically meaningful at the lower prescribed dose [median change in V35Gy: 13.7%-points; (0.3; 30.6); p < .01] and for a bladder sparing preference [median change in V35Gy: 30.3%-points; (12.4; 43.1); p < .01]. Conclusions: There is decision space available in anal cancer radiotherapy to incorporate preferences, although tradeoffs are highly patient-dependent. This study demonstrates that preference-informed dose planning is feasible for clinical studies utilizing shared decision making

Towards individualized dose constraints: Adjusting the QUANTEC radiation pneumonitis model for clinical risk factors

<div><p></p><p><i>Background.</i> Understanding the dose-response of the lung in order to minimize the risk of radiation pneumonitis (RP) is critical for optimization of lung cancer radiotherapy. We propose a method to combine the dose-response relationship for RP in the landmark QUANTEC paper with known clinical risk factors, in order to enable individual risk prediction. The approach is validated in an independent dataset. <i>Material and methods.</i> The prevalence of risk factors in the patient populations underlying the QUANTEC analysis was estimated, and a previously published method to adjust dose-response relationships for clinical risk factors was employed. Effect size estimates (odds ratios) for risk factors were drawn from a recently published meta-analysis. Baseline values for <i>D</i>₅₀ and γ₅₀ were found. The method was tested in an independent dataset (103 patients), comparing the predictive power of the dose-only QUANTEC model and the model including risk factors. Subdistribution cumulative incidence functions were compared for patients with high/low-risk predictions from the two models, and concordance indices (c-indices) for the prediction of RP were calculated. <i>Results.</i> The reference dose- response relationship for a patient without pulmonary co-morbidities, caudally located tumor, no history of smoking, < 63 years old, and receiving no sequential chemotherapy was estimated as <i>D</i>₅₀⁰ = 34.4 Gy (95% CI 30.7, 38.9), <i>γ</i>₅₀⁰ = 1.19 (95% CI 1.00, 1.43). Individual patient risk estimates were calculated. The cumulative incidences of RP in the validation dataset were not significantly different in high/low-risk patients when doing risk allocation with the QUANTEC model (p = 0.11), but were significantly different using the individualized model (p = 0.006). C-indices were significantly different between the dose-only and the individualized model. <i>Conclusion.</i> This study presents a method to combine a published dose-response function with known clinical risk factors and demonstrates the increased predictive power of the combined model. The method allows for individualization of dose constraints and individual patient risk estimates.</p></div

Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer

<div><p></p><p><b>Background.</b> Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity based on a large, single-institution series.</p><p><b>Material and methods.</b> In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0–5). Clinical variables and radiation dose to the bladder were related to graded toxicity using multivariate ordinal logistic regression. Three models were optimized, each containing all available clinical variables and one of three dose metrics: Mean dose (<i>D_mean</i>), equivalent uniform dose (<i>EUD</i>), or relative volume given <i>x</i> Gy or above (dose cut-off model, <i>V_x</i>). The optimal dose metric was chosen using the Akaike Information Criterion (AIC).</p><p><b>Results.</b> Grade 1 cystitis was experienced by 138 (40%), grade 2 by 39 (11%) and grade 3 by two (1%) patients, respectively. Dose metrics were significantly correlated with toxicity in all models, but the dose cut-off model provided the best AIC value. The only significant clinical risk factors in the <i>V_x</i> model were male gender (p = 0.006) and brachytherapy boost (p = 0.02). Reducing the model to include gender, brachytherapy boost and <i>V_x</i> yielded odds ratios OR_male = 1.82 (1.17–2.80), OR_brachy = 1.36 (1.02–1.80 for each 5 Gy), <i>x = </i>35.1 Gy (28.6–41.5 Gy). The predicted risk of grade 2 and above cystitis ranged from 2% to 26%.</p><p><b>Conclusion.</b> Acute cystitis correlated significantly with radiation dose to the bladder; the dose-cut-off model (<i>V_35Gy</i>) was superior to <i>D_mean</i> and <i>EUD</i> models. Male gender and brachytherapy boost increased the risk of toxicity. Wide variation in predicted risks suggests room for treatment optimization using individual dose constraints.</p></div