Effects Of Concomitant Chemotherapy On Radiotherapy-Related Severe Late Toxicities In Cervical Cancer: A 20-Year Inter-Era Analysis

Purpose/Objective(s)To assess the effects of concomitant chemotherapy on radiotherapy-related severe late toxicities (SLT) after curative treatment of cervical cancer.Materials/MethodsFrom 1989 to 2009, 480 consecutive patients with cervical cancer treated at a single institution with radiotherapy (RT) or chemoradiotherapy (CRT) for curative intent were retrospectively analyzed. Severe late toxicity (SLT) was defined as grade ≥3 vaginal, urologic or gastrointestinal (GI) toxicity or any pelvic fracture, using CTCAE v. 4.0 criteria, occurring ≥6 months from treatment completion, and predating any salvage abdomino-pelvic re-irradiation/surgery. Covariates included age; race; body-mass index; history of hypertension, diabetes, intestinal disorder, abdominal surgery, or cigarette smoking; FIGO stage; histology; pre-treatment nodal dissection; brachytherapy dose-rate; dilator compliance; and pelvic EBRT, para-aortic nodal EBRT, and combined pelvic EBRT/brachytherapy doses assessed by late effects EQD2 model (assuming α/β = 3). Chi-squared analysis of these covariates was used to compare RT and CRT cohorts. Follow-up time comparison used Westenberg-Mood median test. Time to SLT was estimated with Kaplan-Meier analysis; comparisons used log-rank statistic. Multivariate analysis used the Cox proportional hazards model.ResultsThree hundred seventy-four patients (RT n = 195; CRT n = 179) were assessable with median follow-up of 35.5 mos (RT 45.7 mos; CRT 29.3 mos, p = 0.178). At 4 years, probability of freedom from vaginal SLT was 55.4% for RT (95% CI, 44.8-66.0%) and 30.8% for CRT (95% CI, 19.6-42.0%) (p < 0.001). At 30 mos, probability of freedom from skeletal SLT was 99.3% for RT (95% CI, 97.9-100%) and 92.5% for CRT (95% CI, 87.8-97.2%) (p = 0.010). At 3 years, probability of freedom from any SLT was 70.7% for RT (95% CI, 63.3-78.2%) and 55.8% for CRT (95% CI, 47.4-64.2%) (p = 0.025). After adjustment for case mix differences, the following factors were significantly associated with SLT on both univariate and multivariate analyses: vaginal SLT: CRT vs. RT (RR 3.8, p < 0.001) and dilator compliance (RR 0.43 for highly vs. moderately compliant, p = 0.004; RR 0.28 for highly vs. poorly compliant, p < 0.001); skeletal SLT: CRT vs. RT (RR 5.4, p = 0.030); GI SLT: none; urologic SLT: smoking history (RR 13.3, p = 0.012); any SLT: CRT vs. RT (RR 2.1, p = 0.001), age (RR 1.6, p = 0.022), histology (RR 2.1, p = 0.012), and dilator compliance (p < 0.001).ConclusionsIndependent of other predictive factors, the administration of concomitant chemotherapy may augment the development of radiotherapy-related severe vaginal, skeletal, and any late toxicities. Other predictive factors include dilator compliance for severe vaginal late toxicity and smoking history for severe urologic late toxicity. Purpose/Objective(s)To assess the effects of concomitant chemotherapy on radiotherapy-related severe late toxicities (SLT) after curative treatment of cervical cancer. To assess the effects of concomitant chemotherapy on radiotherapy-related severe late toxicities (SLT) after curative treatment of cervical cancer. Materials/MethodsFrom 1989 to 2009, 480 consecutive patients with cervical cancer treated at a single institution with radiotherapy (RT) or chemoradiotherapy (CRT) for curative intent were retrospectively analyzed. Severe late toxicity (SLT) was defined as grade ≥3 vaginal, urologic or gastrointestinal (GI) toxicity or any pelvic fracture, using CTCAE v. 4.0 criteria, occurring ≥6 months from treatment completion, and predating any salvage abdomino-pelvic re-irradiation/surgery. Covariates included age; race; body-mass index; history of hypertension, diabetes, intestinal disorder, abdominal surgery, or cigarette smoking; FIGO stage; histology; pre-treatment nodal dissection; brachytherapy dose-rate; dilator compliance; and pelvic EBRT, para-aortic nodal EBRT, and combined pelvic EBRT/brachytherapy doses assessed by late effects EQD2 model (assuming α/β = 3). Chi-squared analysis of these covariates was used to compare RT and CRT cohorts. Follow-up time comparison used Westenberg-Mood median test. Time to SLT was estimated with Kaplan-Meier analysis; comparisons used log-rank statistic. Multivariate analysis used the Cox proportional hazards model. From 1989 to 2009, 480 consecutive patients with cervical cancer treated at a single institution with radiotherapy (RT) or chemoradiotherapy (CRT) for curative intent were retrospectively analyzed. Severe late toxicity (SLT) was defined as grade ≥3 vaginal, urologic or gastrointestinal (GI) toxicity or any pelvic fracture, using CTCAE v. 4.0 criteria, occurring ≥6 months from treatment completion, and predating any salvage abdomino-pelvic re-irradiation/surgery. Covariates included age; race; body-mass index; history of hypertension, diabetes, intestinal disorder, abdominal surgery, or cigarette smoking; FIGO stage; histology; pre-treatment nodal dissection; brachytherapy dose-rate; dilator compliance; and pelvic EBRT, para-aortic nodal EBRT, and combined pelvic EBRT/brachytherapy doses assessed by late effects EQD2 model (assuming α/β = 3). Chi-squared analysis of these covariates was used to compare RT and CRT cohorts. Follow-up time comparison used Westenberg-Mood median test. Time to SLT was estimated with Kaplan-Meier analysis; comparisons used log-rank statistic. Multivariate analysis used the Cox proportional hazards model. ResultsThree hundred seventy-four patients (RT n = 195; CRT n = 179) were assessable with median follow-up of 35.5 mos (RT 45.7 mos; CRT 29.3 mos, p = 0.178). At 4 years, probability of freedom from vaginal SLT was 55.4% for RT (95% CI, 44.8-66.0%) and 30.8% for CRT (95% CI, 19.6-42.0%) (p < 0.001). At 30 mos, probability of freedom from skeletal SLT was 99.3% for RT (95% CI, 97.9-100%) and 92.5% for CRT (95% CI, 87.8-97.2%) (p = 0.010). At 3 years, probability of freedom from any SLT was 70.7% for RT (95% CI, 63.3-78.2%) and 55.8% for CRT (95% CI, 47.4-64.2%) (p = 0.025). After adjustment for case mix differences, the following factors were significantly associated with SLT on both univariate and multivariate analyses: vaginal SLT: CRT vs. RT (RR 3.8, p < 0.001) and dilator compliance (RR 0.43 for highly vs. moderately compliant, p = 0.004; RR 0.28 for highly vs. poorly compliant, p < 0.001); skeletal SLT: CRT vs. RT (RR 5.4, p = 0.030); GI SLT: none; urologic SLT: smoking history (RR 13.3, p = 0.012); any SLT: CRT vs. RT (RR 2.1, p = 0.001), age (RR 1.6, p = 0.022), histology (RR 2.1, p = 0.012), and dilator compliance (p < 0.001). Three hundred seventy-four patients (RT n = 195; CRT n = 179) were assessable with median follow-up of 35.5 mos (RT 45.7 mos; CRT 29.3 mos, p = 0.178). At 4 years, probability of freedom from vaginal SLT was 55.4% for RT (95% CI, 44.8-66.0%) and 30.8% for CRT (95% CI, 19.6-42.0%) (p < 0.001). At 30 mos, probability of freedom from skeletal SLT was 99.3% for RT (95% CI, 97.9-100%) and 92.5% for CRT (95% CI, 87.8-97.2%) (p = 0.010). At 3 years, probability of freedom from any SLT was 70.7% for RT (95% CI, 63.3-78.2%) and 55.8% for CRT (95% CI, 47.4-64.2%) (p = 0.025). After adjustment for case mix differences, the following factors were significantly associated with SLT on both univariate and multivariate analyses: vaginal SLT: CRT vs. RT (RR 3.8, p < 0.001) and dilator compliance (RR 0.43 for highly vs. moderately compliant, p = 0.004; RR 0.28 for highly vs. poorly compliant, p < 0.001); skeletal SLT: CRT vs. RT (RR 5.4, p = 0.030); GI SLT: none; urologic SLT: smoking history (RR 13.3, p = 0.012); any SLT: CRT vs. RT (RR 2.1, p = 0.001), age (RR 1.6, p = 0.022), histology (RR 2.1, p = 0.012), and dilator compliance (p < 0.001). ConclusionsIndependent of other predictive factors, the administration of concomitant chemotherapy may augment the development of radiotherapy-related severe vaginal, skeletal, and any late toxicities. Other predictive factors include dilator compliance for severe vaginal late toxicity and smoking history for severe urologic late toxicity. Independent of other predictive factors, the administration of concomitant chemotherapy may augment the development of radiotherapy-related severe vaginal, skeletal, and any late toxicities. Other predictive factors include dilator compliance for severe vaginal late toxicity and smoking history for severe urologic late toxicity.