Bladder carcinoma definitive EBRT with or without chemotherapy

Bladder preservation with salvage surgery as part of protocol 

• Muscle-invasive urothelial carcinoma.
• T2a–T4a, N0-2, M0.

• Patients with increased perioperative mortality and morbidity risk.
• Patients medically or technically unsuitable for cystectomy, but suitable for curative intent chemoradiation (optimal approach) or radiation therapy alone.
• Patients suitable for cystectomy, but with a preference for bladder preservation.

• Ideally haemoglobin level >100g/l, preferably >120 g/l.
• Renal function satisfactory for concurrent chemotherapy.

• ECOG 0-2.

Cautions

• Previous high dose radiation to the pelvis.

• Poor urinary and bowel function.

• Widespread carcinoma in situ (CIS), multifocal tumours, or gross macroscopic disease following a transurethral resection of bladder tumour (TURBT).

• When primary cystectomy is possible, consider these factors which increase the risk of local failure following EBRT: ^rrrr
  • Large tumour diameter (>5 cm).
  • Multifocal bladder tumours.
  • Hydronephrosis.
  • Incomplete TURBT.
  • Widespread Carcinoma in situ (CIS) component.

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Non-rheumatoid collagen vascular disorders.

• Cardiac implantable electronic devices (CIEDs).

• Maximal transurethral resection of bladder tumour (TURBT) recommended prior to commencing radiation therapy - complete is not always possible. Consider proceeding directly to bladder preservation, if macroscopic clearance is not anticipated. 

• Suitable patients should be considered for salvage surgery in the event of a recurrence or incomplete response.
• When attempting bladder conservation, long term surveillance is recommended.
• Consider stenting for hydronephrosis prior to radiation treatment.

Timing of chemotherapy

• Chemotherapy is to be given at the beginning of each week (Monday/Tuesday), or within the first 2 days of radiation treatment.
• On the days chemotherapy is administered, radiation treatment should be given after chemotherapy (preferable).

*Currently there is no high level evidence, however in certain patients these lymph node dose prescriptions may be considered.

Prescription notes

• There is currently no high level evidence for treating patients with nodal disease with hypofractionation. The RCM considers conventional fractionation (2 Gy/fx) to be the preferred regimen.
• Treatment delays could impact on local control and should be avoided.^r
• If using a two phase technique, consider:
  • planning phase 2 with the bladder full to assist with reducing the small bowel dose
  • removing some of the bladder wall (distant from the primary tumour) from the phase 2 volume.^r
• Dose escalation remains investigational and should only be performed in the setting of prospective data collection or a clinical study.

• Consider adaptive radiation therapy (ART), particularly in the setting of higher prescription  doses.^r

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume notes

• Due to variable bladder filling and the potential for geographical miss, lesions positioned in the dome of the bladder should be treated using a single phased approach. The two-phased approach may be particularly suitable in cases where the tumour is well-lateralised or situated over the trigone, with good evidence of absence of CIS away from the index lesion.

Target volume guides

• FROGG consensus guidelines for muscle invasive bladder cancer.^r​

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Target verification notes

• Patients should have a daily CBCT with online soft tissue matching prior to radiation treatment.

Efficacy

The key evidence supporting this protocol is from a phase III trial by James et al. (n = 360).^r Patients with muscle-invasive bladder cancer, cT2-T4a, N0, M0, were randomised to receive chemoradiation or radiation therapy alone. Chemotherapy involved fluorouracil infusion and mitomycin, with one-third of patients in each arm receiving discretionary neoadjuvant chemotherapy. Radiation therapy was 64 Gy in 32 fractions or or 55 Gy in 20 fractions. At a median follow-up of 70 months, the 2-year recurrence-free rate was 67% in the chemoradiation arm versus 54% in the radiation therapy alone arm (HR = 0.68, 95% CI:0.48-0.96, p = 0.03). Five-year overall survival rates were 48% with chemoradiation arm versus 35% with radiation alone (HR = 0.82, 95% CI:0.63-1.09, p = 0.16). A trend towards reduced cystectomy rates of 11.4% versus 16.8% (p = 0.07) at 2 years was observed in the chemotherapy arm. The findings suggest this chemoradiation schedule is an alternative option to cisplatin.

Fig 1. Kaplan-Meier analysis of survival over 72 months of follow-up

(A) locoregional disease-free survival; (B) invasive locoregional disease-free survival; (C) overall survival p-values were calculated by log-rank test stratified according to the randomisation group. 

© N Engl J Med 2012^r

No randomised trials comparing radical cystectomy versus trimodality bladder preservation have been completed. Several non-randomised prospective and retrospective studies of combined modality treatment have confirmed survival outcomes comparable to cystectomy alone.^rrr Most studies of combined modality treatment report 5-year survival rates of 50-60%.^rrr

Gogna et al. 2006 reported the combined analysis of two successive phase II trials of chemoradiation utilising weekly cisplatin (TROG 97.01 and TROG 99.06).^r In TROG 99.06, 43 patients received 64 Gy in 32 fractions with weekly cisplatin 35 mg/m². Completion of the TROG 99.06 was 80%. The complete response rate at 6 months post-radiation therapy completion was 70%. The local control  rate (free of both superficial and invasive recurrence) at 5 years was 45%. At 5 years, 61% had retained a functional bladder. Within 12 months, 13% of patients had salvage surgery, of which 8% was for progressive/persistent or recurrent disease.

Mak et al. 2014 published a combined analysis of six successive multimodality RTOG trials 468 patients in total; one phase III trial and five phase II trials.^r In principle, these studies offered induction chemoradiation followed by re-staging cystoscopy, and then proceeded to immediate cystectomy if a complete response was not achieved, or onto completion of chemoradiation if a complete response was achieved (total dose of approximately 64 Gy). However, a diverse range of radiation therapy and chemotherapy schedules were used. The complete response rate to induction chemoradiation was 69%. At a median follow-up of 4.3 years, 5-year overall survival was 57%, disease-specific survival was 71%, local failure rate was 43%, and intact bladder rate was 80%. The 10-year outcomes are presented in table 2. Of the 100 patients who underwent cystectomy, 62% were for incomplete response to induction, and 36% for salvage after delayed recurrence (5-year survival for this group was 45%).

Table 2. Pooled Long-Term Outcomes

© J Clin Oncol 2014^r

Fig 2. Kaplan-Meier analysis of overall and disease-specific survival

(A) Overall survival in all patients; (E) Disease-specific survival in patients with a complete response after combined-modality therapy compared with patients who were non-responders.

© J of Clin Oncol 2014^r

Pelvic nodal irradiation

Conformal radiation therapy techniques are allowing re-evaluation of tolerance, toxicity and efficacy of pelvic nodal irradiation. This is in the context of treating elective pelvic nodes or node positive disease at diagnosis, and of newer chemotherapy regimens. Pathological nodal involvement is reported in approximately 25% of patients who undergo cystectomy and lymph node dissection.^r In studies of bladder only chemoradiation trials, pelvic nodal relapse rates of 5.5% have been reported.^rr A randomised single institution trial which compared chemoradiation to the bladder alone versus whole pelvis plus bladder boost, showed no significant difference in rates of bladder preservation, locoregional recurrence, disease-free survival, or overall survival, and a rate of nodal recurrence of 15% in both arms.^r For clinically node negative patients, elective nodal irradiation increases toxicity and there is no evidence that elective nodal irradiation improves outcomes.^r

Intrafraction bladder filling

A study by Mangar et al. identified that in the 20 minute period it takes to set-up and deliver a radiation fraction, the bladder filling was 0.16ml/min in a linear fashion for the first 150 ml, indicating that a CTV to PTV expansion of 1.5 cm would account for approximately 95% of bladder expansion and location.^r

Bladder IMRT / VMAT

For IMRT/VMAT techniques, toxicity and outcome data (series data) utilising various fractionation schedules, simultaneous integrated boosts, and with or without nodal volumes has been published.^rrr While data remains limited, this is a field of continued interest.

Adaptive Radiation Therapy

The principle of bladder adaptive radiation therapy (ART) is to account for daily variation in bladder volume. Immediately following pre-treatment imaging and assessment, a 'plan of the day' is selected from a library of plans and used for treatment. Review of ART practices by Kibrom et al. indicates a number of techniques being trialled including online/off-line imaging, 'plan of the day', or daily re-planned/optimised techniques.^r While ART has merit, it is yet to be determined how to apply ART in a sustainable and safe process, that is applicable to all radiation oncology centres and taking into account varying resources, staffing and skill sets. These challenges have been evaluated in the TROG 10.01 BOLART feasibility study, which demonstrated both the applicability and challenges in the execution of a bladder ART program.^r

Toxicity

A summary of the most clinically significant toxicities associated with this protocol are included in the table below:

* Data from Huddart et al. for all patients combined.^r
§ In all cases of grade 3 or 4 genitourinary toxicity, the patient was later found to have persistent/recurrent superficial or invasive disease and subsequently underwent salvage cystectomy. 
^# Incidence of late-toxicity reported at any time during follow-up

In the James trial, there was a small increase in acute grade 3 or greater 3 toxicity for those receiving chemoradiation, compared to radiation alone (36.0% versus 27.5%, p=0.07).^r This difference was primarily due to a significant increase in gastrointestinal toxicity in the chemoradiation group (9.6% versus 2.7%, p=0.007). There was no significant difference in late toxicity or bladder volume between the two groups.

To date, there is no evidence that using a reduced high dose volume reduces toxicity. The combined analysis of both phase II TROG studies found no difference in acute toxicity for those who received the full dose to the bladder, compared with the cone down boost.^r The larger randomised trial by Huddart et al. also found no difference in acute or late toxicity when comparing a reduced volume high dose boost compared to a single phase whole bladder technique.^r