EMBRACE
Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer

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Abstract

Background and purpose

The EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO).

Material and methods

A total of 1176 patients were analysed. Median follow up (FU) was 27 (1–83) months. Morbidity (CTCAE v.3) and PRO (EORTC QLQ-C30&CX24) was prospectively assessed at baseline (BL), and during FU.

Results

The most frequent symptoms were frequency/urgency, incontinence, and cystitis with grade 2–4 prevalence rates of 4.3%, 5.0% and 1.7% and grade 1–4 prevalence rates of 24.5%, 16.1% and 5.8% at 3-years. The most frequent PRO endpoints were “urinary frequency” and “leaking of urine”. Prevalence of “Quite a bit” or “very much” bother fluctuated from 14.0% to 21.5% for “frequency”, while “leaking of urine” increased from 4.6% at BL to 9.3% at 3-years.

Actuarial 3-year incidence of grade 3–4 urinary morbidity was 5.3% with most events being urinary frequency, incontinence and ureteral strictures. Grade 3–4 fistula, bleeding, spasm and cystitis were all <1.0% at 3/5-years. No grade 5 toxicity occurred.

Conclusion

Urinary grade 3–4 morbidity with IGABT was limited. Urinary morbidity grade 2–4 comprises mainly frequency/urgency, incontinence and cystitis and has considerable prevalence in PRO. Various urinary morbidity endpoints have different patterns of manifestation and time course.

Section snippets

Patients

The EMBRACE study opened in July 2008 and finalised accrual in December 2015 with 1416 patients from 24 centres. Patients eligible for inclusion in the EMBRACE study were previously untreated, biopsy proven cervical cancer, FIGO stage IB-IVA (and stage IVB with metastatic nodes below L1 only) treated with curative definitive radio (chemo)therapy and IGABT.

For this urinary morbidity analysis, patients were excluded when: not meeting the selection criteria or not receiving treatment as planned (n

Results

In the 1176 patients analysed in this study, the median FU was 27 (1–83) months. The patient, disease and treatment characteristics are reported in Table 1.

Baseline urinary symptoms

Prevalence of individual urinary symptoms at BL included mainly urinary frequency or incontinence. For other endpoints, few patients had symptoms at BL (Appendix 1).

Incidence of urinary symptoms during follow up (FU)

Crude maximum incidence of individual urinary symptoms showed mainly mild (grade 1) to moderate (grade 2) symptoms (Table 2). Urinary frequency, incontinence and cystitis were the endpoints most commonly reported (Table 2). The actuarial probability that a patient had any bladder morbidity (≥grade 1) within 3/5-years was 69.8%

Baseline incidence of PRO

Prevalence of PRO before treatment included mainly “urine frequency”, while “leaking of urine”, “pain/burning feeling when passing urine” or “difficulty emptying the bladder” was reported by a smaller proportion of the patients (Appendix 2).

Patient reported outcome (PRO) versus physician assessed morbidity

Associations between physician assessed and PRO urinary frequency as well as PRO and incontinence were found. In consultations where the physician scored the patient as having CTCAE grade 2 frequency or incontinence, 70.9% and 62.3% reported themselves ≥“quite a bit” or “very much” bother, respectively. For CTCAE grade 1, this was 35.0% and 19.3%, and for CTCAE score 0, this was 8.9% and 2.0%, respectively (Fig. 4).

Discussion

This EMBRACE report includes 1176 patients with LACC treated with definitive (chemo)radiotherapy including IGABT. The EMBRACE study provides systematically recorded prospective longitudinal information on physician assessed morbidity and PRO; and this report adds to previously published EMBRACE reports on vaginal and rectal toxicity [19], [20], [21].

The risk of severe to life-threatening grade 3–4 urinary morbidity was 5.3%/6.3% at 3/5-years and included all individual bladder endpoints and

Conclusion

This large prospective study with longitudinal data collection provides a detailed and comprehensive overview of urinary morbidity. The study will serve as benchmark in future IGABT for LACC. It demonstrates that severe bladder morbidity after IGABT is limited and compares favourably to 2D brachytherapy. Mild to moderate morbidity is still relatively pronounced especially with a high level of urinary frequency and progressively increasing incontinence according to both physician and patient

Conflict of interest

None.

Acknowledgements

Inclusion of patients in the EMBRACE 1 study was done by centres in the EMBRACE collaborative group (Appendix 4).

EMBRACE was supported by Nucletron, an Elekta company and Varian Medical System through grants and study sponsoring through Vienna Medical University and research grants from The Danish Cancer Society (grant number R125-A7753-15-S37).

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