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

Figures & data

Table I. Patient and treatment characteristics.

Clinical disease stage:
– T	T1–2: 17 (5) T3: 247 (72) T4: 81 (23)
– N	N0: 44 (13) N1: 138 (40) N2: 159 (46) ND: 4 (1)
– M	M0: 327 (95) M1: 17 (5) ND: 1 (0)
Gender	Female: 135 (39) Male: 210 (61)
Median age (range)	67 years (26–87 years)
Median tumor dose primary external treatment (range)	50.4 Gy (27.0–62.0 Gy)
Median lymph node dose (range)	50.4 Gy (27.0–50.4 Gy)
Sequential external boost dose (38 pts)	6.0 Gy: 29 (8) 10 Gy: 2 (1) 12 Gy: 7 (2)
Intracavitary brachytherapy boost dose (137 pts)	5 Gy: 91 (26) 10 Gy: 46 (13)
Treatment technique	3D-CRT: 229 (66) IMRT: 116 (34)
Treatment position	Prone: 88 (26) Supine: 257 (74)
Chemotherapy (285 pts)	UFT: 270 (78) Other: 15 (4)
Median bladder volume (range)	177 cm^2 (35–902 cm^2)
Median Dmean for the bladder (range)	41.4 Gy (14.1–61.9 Gy)
Median relative V35Gy for the bladder (range)	0.71 (0.00–1.00)
Acute urinary toxicity – Grade 0 – Grade 1 – Grade 2 – Grade 3	166 (48) 138 (40) 39 (11) 2 (1)

3D-CRT, 3D conformal radiotherapy; IMRT, intensity-modulated radiotherapy. Numbers are absolute number of patients, with percentages of entire cohort (345 patients) in brackets, where nothing else is indicated.

Figure 1. Relationship between relative volume of the bladder receiving at least 35 Gy (V_35Gy) and the risk of grade 1 or above (thin line, blue) or grade 2 and above (thick line, green) acute urinary toxicity. Data points represent observed toxicity (with 68% confidence intervals), fitted lines represent fit to the logistic model (Equation 1). A) Dose-response taking only the dose metric, and no additional risk factors, into account. B) Dose-response for patients with the highest risk (male patients receiving a brachy therapy boost, dashed line/triangles), and dose-response for patients with the lowest risk (female, no brachytherapy, full line/diamonds). The fit to the logistic model takes V_35Gy, gender and brachytherapy (as a binary variable) into account.

Table II. Model fit quality for different dose metrics.

Dose metric	ln(L)	k	AIC	Volume parameter
Mean dose, Dmean	− 319.9	9	657.7	–
EUD	− 319.9	10	659.7	a = 1.27 (− 8.49–4.12)
Dose cut-off, Vx	− 318.4	10	656.8	x = 35.4 Gy (30.2–41.5 Gy)

Results of ordinal logistic model fits relating dose metrics to the risk of acute urinary toxicity. All models included 6 clinical variables (brachytherapy dose, gender, age, chemotherapy, treatment technique, and treatment position).

AIC, Akaikes Information Criterion; EUD, equivalent uniform dose; k, total number of parameters in model; ln(L), the natural logarithm of the likelihood of the model fit. Numbers in brackets represent 95% confidence intervals for the volume parameters.

Table III. Ordinal logistic model fits for dose cut-off model.

Parameter	All clinical factors	Only significant clinical factors
b0,1	− 0.62 (− 2.47; 1.17)	− 1.55 (− 2.22; − 0.86)
b0,2	− 2.84 (− 4.67; − 1.02)	− 3.75 (− 4.48; − 2.99)
b1	1.30 (0.29; 2.25)	1.68 (0.80; 2.49)
bbrachy-dose	0.069 (0.008; 0.129)	0.061 (0.004; 0.118)
bmale	0.62 (0.16; 1.06)	0.60 (0.16; 1.03)
bage	− 0.005 (− 0.026; 0.018)	–
bchemo	− 0.27 (− 0.89; 0.39)	–
bIMRT	− 0.05 (− 0.56; 0.48)	–
bprone	− 0.49 (− 1.10; 0.08)	–

Ordinal logistic model fits for the dose cut-off (V_x) model. Optimal fit was found for ∼35 Gy cut-off (35.4 Gy, 95% CI 30.2–41.5, for model with all factors, and 35.1 Gy, 95% CI 28.6–41.5, for significant factors only). Numbers indicate parameter values (Equation 1), numbers in brackets represent 95% confidence intervals.

Figure 2. Plot of predicted versus observed toxicity, illustrating the model calibration. Patients have been grouped by increasing risk, as predicted by a logistic model including V_35Gy, gender and brachytherapy dose. Blue diamonds (upper 6 points): Grade 1 and above cystitis. Green diamonds (lower 6 points): Grade 2 and above cystitis. Lack of calibration is indicated by deviance from the identity line (dotted line). Error bars show 68% confidence intervals.

Figure 3. Model fit quality of V_x model for all dose levels (x), estimated by the log likelihood divided by the number of patients in the model fit. Higher values indicate better fit to the clinical data. Black line: All patients in cohort. Dashed, blue line: Patients treated with 3D conformal (3D-CRT) treatment plans. Dotted, green line: Patients treated with intensity-modulated radiotherapy (IMRT) treatment plans.

Figure 4. Optimal dose cut-off model for acute toxicity for patients treated with A) intensity-modulated radiotherapy (IMRT, V_18Gy), B) 3D conformal radiotherapy (3D-CRT, V_50Gy), and C) the total patient cohort (V_35Gy). Figure A) and B) additionally show the observed response for the other patient group [3D-CRT in A) and IMRT in B)]. Figure C) shows observed response for all patients (solid diamonds: 3D-CRT, empty diamonds: IMRT). Thin, blue lines and diamonds: Risk of grade 1 or above acute cystitis. Thick, green lines and diamonds: Risk of grade 2 and above acute cystitis. Uncertainty bars indicate 68% confidence levels.