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Treatment of Bladder Cancer

Chapter 16 – Bladder Cancer in the Elderly

Treatment of NMIBC

TURB always represents the first step of treatment of BC. It is performed under anaesthesia and consists of removal of all the papillary lesions as well as deep muscle below the papillary lesions and all lesions suspicious of Cis. Lack of muscle in the specimen is an imperative indication for repeat TURB. The use of fluorescence might be helpful, especially if Cis is suspected based on positive cytology. It is a surgical procedure that deserves surgical application. Relapse and progression are linked to the disease itself but also to the quality of the TURB.

An immediate post-operative instillation (IPOP) of chemotherapy is mandatory in the absence of bladder perforation.

This will allow for PT staging and grading, allowing risk-adapted treatment (Table below)

Risk groups

Risk groupCharacteristicsTreatment
Low riskPrimary solitary < 3 cm, PUNLMP, No CisIPOP. Nothing more
Intermediate riskAll lesions not defined in the 2 other groupsBladder instillations: chemotherapy (such as mitomycin C weekly for 8 weeks followed by maintenance) for up to 12 months or BCG (weekly for 6 weeks, followed by 3 weekly instillations at months 3, 6 and 12)
High riskT1 or high grade (or G3) or Cis or multiple and recurrent and large (> 3 cm) Ta G1-2

An early repeated TURB is mandatory.

BCG instillations for 3 years (weekly for 6 weeks, followed by 3 weekly instillations at months 3, 6 and every 6 months up to 3 years)

For the highest risks (T1G3 + Cis, micropapillary lesions, multiple large pT1G3): an immediate cystectomy must be discussed

PUNLMP, papillary urothelial neoplasia of low malignant potential; Cis, carcinoma in situ; IPOP, immediate post-operative instillation; BCG, Bacillus Calmette–Guérin; TURB, transurethral resection of the bladder.

These instillations might lead to severe toxicities and require strict follow up procedures and well-defined and sometimes urgent standardised treatment to optimise their tolerance and efficacy. Complications must be prevented with the implementation of strict rules: no instillations under pressure, sterile urine culture before each instillation, no macroscopic haematuria for BCG, no bladder perforation for chemotherapy.

After treatment, follow-up is based on repeated cytology and endoscopy, usually every 6 months, and upper tract exam (CT-based). Patients must be advised and helped to stop smoking.

Prognosis of NMIBC
Tumour recurrence and progression are the clinically relevant events associated with the diagnosis of NMIBC. Tumour recurrences and new occurrences are observed in approximately two-thirds of patients during follow-up, depending on several prognostic factors such as stage, grade, number, and size of initial lesions. The presence of recurrence at the first cystoscopy at three months is a strong predictor of prognosis. Progression from NMIBC to MIBC varies depending on stage, grade, number, and size of initial lesion/s from approximately 4% for low-grade Ta tumours to 50% for high-grade T1 tumours. Associated Cis is known to substantially increase the risk of progression.

Follow-Up
Patients with pTa, pT1, and low-grade tumours should receive UC and cystoscopy three to four times per year for the first two years and at six-monthly intervals for the following three years.

Patients with high-grade lesions or Cis should be followed at three-monthly intervals for the first three years and at six-monthly intervals thereafter.

Nothing special has to be considered for senior adults, except for an in-depth discussion regarding the benefits and drawbacks of instillations, especially for BCG. This is particularly important when side effects occur.

Treatment of Non-Metastatic MIBC

Real life data show that MIBC are undertreated worldwide, and especially in senior adults. The 5 and 10 year survival rates after radical cystectomy (RC) for MIBC are around 80% and 60% for organ confined disease, around 50% and 35% for non-organ confined disease (≥ pT3) and 35% and 30% in node positive disease. Systemic relapses are frequent, close to 20% for organ confined, 35% for non-organ confined and 50% for node positive disease.

The optimal way to manage T2-4 N0 M0 MIBC is neoadjuvant polychemotherapy containing cisplatin followed by RC and extended nodal dissection. This dissection comprises the bilateral obturator, internal and external iliac nodal region up to the primary iliac at the level of the crossing ureter. This is a minimum, and more extended templates have been suggested but are still under discussion. In men, this procedure includes “EN bloc” removal of the bladder, the prostate and the seminal vesicles. In women, usually part of the anterior vaginal wall is removed with the uterus and the ovaries. Every attempt must be made not to perforate the bladder during the procedure, and to obtain negative surgical margins, including at least frozen sections at the urethral level.

Following cystectomy, urinary diversion is necessary. It can be either through an ileal conduit, with a neobladder, or with a continent catheterisable reservoir implanted most frequently at the lower right abdomen. These latter procedures are more surgically demanding and are associated with more post-operative complications compared with the ileal conduit. Finally, the real quality of life improvement is still under debate, although they lead to a better self-image compared with the ileal conduit.

This treatment approach is associated with significant mortality and morbidity, especially the surgical part. Therefore, treating senior adults represents a major challenge and this is best done by a specialist team.

Neoadjuvant chemotherapy is a must, provided patients are fit enough to receive poly-chemotherapy including cisplatin before surgery. It is associated with a 5% absolute (19% relative) survival benefit. Carboplatin has no place in this situation. The toxicity of GC (gemcitabine-cisplatin), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) or DD MVAC (dose dense MVAC) must lead to a detailed discussion but usually precludes their use in patients above 75 years of age, even if physiologically fit.

RC in the senior adult is a major procedure, associated with a 90-day mortality rate of around 7%. However, the key driver of mortality is not age, but mainly the initial nutritional status and comorbidities. There is a trend suggesting a decreased mortality with a higher case load. Significant morbidity is frequent, mainly medical (e.g. infection, cardiovascular, pulmonary infections, disorientation) or surgical (mainly ileus and wound problems). Increased age is associated with increased morbidity, but again the key drivers are the initial comorbidities and the impaired cardiopulmonary reserve. In senior adults, morbidities are characterised by a prolonged recovery period. To optimise the outcome, the key is to implement a team including a surgeon, an anaesthesiologist and also a paramedical team.

Ileal neobladder is feasible beyond 75 years and can be discussed in male patients. However, there is a clear decreased continence rate with increasing age, as well as an increased self-catheterisation need. Therefore, the ileal conduit is the standard in senior adults.

Initial comorbidity evaluation is mandatory. The Charlson score is not designed for everyday use in clinic. This evaluation is best done by a comprehensive geriatric assessment which will detect frail and vulnerable patients, allow the optimisation of the patient's medical conditions, finally leading to optimised treatment decisions. It is time consuming, and limited by the availability of a geriatrician. An effective screening tool is available (the G8) that allows for an effective discrimination of those patients in need of the comprehensive geriatric assessment.

Alternative procedures to the standard RC have been developed. A very aggressive deep and extended TURB monotherapy is feasible for very selected patients. Similar results have been suggested with partial cystectomy, provided the lesion is located on the mobile part of the bladder. The most studied alternative however is the combination of pelvic and bladder radiotherapy associated with chemotherapy. Most studies have used cisplatin-based chemotherapy or the combination of mitomycin C and 5-fluorouracil (which allows renal function down to 25 ml/min). Radiotherapy is usually given at a dose of 65 Gy to the bladder and 45 Gy to the pelvis. The main results are a well-functioning bladder, improved local control, but a lack of survival benefit compared with radiotherapy monotherapy. A formal comparison with radical surgery is lacking, but this modality represents an acceptable alternative for unfit patients or those unwilling to undergo a cystectomy. In all of these conservative approaches, the best survival results have been obtained in patients with a single T2 lesion, less than 3 cm, without Cis and hydronephrosis. The combination of radiotherapy with concomitant chemotherapy is also effective in more advanced lesions. Patients must be aware that the remaining bladder carries a risk of relapse in up to approximately 50% of NMIBC, requiring a standard approach and close to 20% of MIBC, where radical cystectomy is the standard of care, provided it is feasible.

In the frailest patients, external beam radiotherapy is effective for palliation, and hypofractionation is an attractive modality.

Treatment of metastatic MIBC

Metastatic BC is associated with an overall poor prognosis. It might be approached using the Bajorin classification based on performance status (PS), location of the metastases and haemoglobin level. The median survival is around 36 months (Karnofsky PS > 80, no visceral metastases, normal haemoglobin level) compared with 12 months if PS < 80, visceral metastases and anaemia are present.

The standard regimen is cisplatin-based polychemotherapy (either MVAC, DD MVAC or GC). The response rate is around 50%, the complete response rate around 20%, and the overall median survival around 14 months. The main prerequisite is an adequate renal function, either estimated using the MDR formula, or a real measured renal clearance.

There are limited data on senior adults as they are under-represented in clinical trials. Furthermore, they often have a decreased bone marrow reserve. At least 50% are unfit for cisplatin either due to poor renal function (creatinine clearance < 60 ml/min) and/or an ECOG PS < 2. In cases where one of these two criteria is MET, the options are limited to carboplatin-based combination regimens (such as carboplatin –gemcitabine). When both criteria are met, based on the very poor outcome, a detailed discussion is mandatory as best supportive care/palliative care might often represent the best treatment option.

Relapse after first-line treatment is associated with a median survival between 5 to 12 months, depending on several risk factors. In theory if the relapse is more than 6-12 months after the first regimen, another platinum-based regimen is standard of care, if feasible. This will be the exception in senior adults. Provided the patient has a PS 0-1, a vinflunine-based regimen might be discussed. Otherwise best supportive/palliative care will be the standard.

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