trimodality management carcinoma bladder

1. BLADDER PRESERVATION
APPROACH IN CA UB
DR SHIPRA GUPTA

8. Radical cystectomy with neoadjuvant cisplatin-based chemotherapy is the
standard approach for the treatment of muscle-invasive urothelial bladder
cancer.
For patients who are not candidates for radical cystectomy or who desire
preservation of their native bladder, trimodality therapy (TMT)
incorporating maximal transurethral resection of bladder tumor (TURBT)
followed by radiation therapy (RT) with concurrent chemotherapy is an
appropriate alternative

9. Comparing survival outcomes for TMT with radical cystectomy using
prospective series is extremely challenging due to differences in
patient selection, and data are conflicting.
Prospective studies evaluating bladder-preserving TMT necessarily
analyze patients treated based upon clinical staging, whereas radical
cystectomy series report pathologic staging. Numerous observational
studies have compared TMT with radical cystectomy.

11. meta-analysis based upon data from 9000 patients in eight
studies found no significant difference in overall survival, DSS,
or progression-free survival at 5 or 10 years
The cystectomy arms had higher rates of early major
complications, whereas rates of minor complications were
similar between the 2 treatments.

12. By contrast, an observational study of approximately 18,000
evaluable patients with muscle-invasive bladder cancer demonstrated
a higher five-year OS in those treated with radical cystectomy versus
TMT (40 versus 30 percent)

17. PRETREATMENT EVALUATION
clinically staging.
cystoscopy with transurethral resection of bladder tumor (TURBT)
along with an examination under anesthesia to assess the local
extent of disease.
Imaging studies to rule out disseminated disease in the chest,
abdomen, and pelvis.
Because urothelial carcinoma can be multifocal, upper tract urothelial
carcinoma of the ureters or renal pelvis should be ruled out as well.
If obtained, bladder MRI should be performed before TURBT, as it
may be difficult to distinguish between tumor and postsurgical

18. MORTALITY WITH RC
Even among patients with minimal medical comorbidities, radical
cystectomy is associated with a treatment-related mortality risk of 1 to 2
percent
Furthermore, urothelial carcinoma is a disease of the older population,
and the median age at diagnosis is 73 years
The 90-day perioperative mortality rates for patients ≤69, 70 to 79, and
≥80 years old have been reported to be as high as 2, 5, and 9 percent,
respectively
Furthermore, cigarette smoking is an etiologic factor for bladder cancer,
and many patients have one or more tobacco-related comorbidities that

19. PATIENT SELECTION
no absolute criteria
important factors include:
●Urothelial histology – Prospective studies evaluating the use of TMT
have been performed exclusively in patients with urothelial histology
and thus cannot be generalized to patients with less common
histologies (squamous cell carcinoma, adenocarcinoma,
micropapillary).
In addition, nonurothelial carcinoma histologies - respond less

20. Maximal TURBT – A visibly complete TURBT is associated with a
higher CR rate after CRT, decreased rates of salvage cystectomy, and
improved OS
Clinical T2 to T3a disease – Increasing tumor (T) stage is associated
with decreased rates of complete response after chemoradiation
single-institution series of 348 patients, in which clinical T2 disease
had a complete response rate of 81 percent compared with 64
percent in clinical T3 to T4 disease

21. Although patients with clinical T2 to T3a disease may be more
favorable candidates for TMT, the large institutional experiences,
Radiation Therapy Oncology Group (RTOG) prospective studies, and
BC2001 trial used clinical T4a disease (ie, disease extension into the
prostatic stroma in men or uterus/vagina in women) as the upper
limit of clinical T stage acceptable for TMT.
However, neoadjuvant chemotherapy followed by radical cystectomy
is preferred for patients with extensive T3b or T4 disease in those
patients who are appropriate surgical candidates.

22. Absence of tumor-associated hydronephrosis – Patients with tumor-
associated hydronephrosis are less likely to achieve a complete
remission to chemoradiation (64 percent in patients without
hydronephrosis versus 38 percent in patients with hydronephrosis)
Renal function – Adequate renal function is necessary to receive
cisplatin-based concurrent chemotherapy. However, the combination
of fluorouracil and mitomycin represents a reasonable alternative
concurrent chemotherapy regimen for patients with compromised
renal function.

23. Absence of extensive CIS – In a single-institution experience of 40
patients, extensive carcinoma in situ (CIS) was associated with a trend
toward a higher bladder tumor recurrence rate compared with those
without CIS (40 versus 6 percent)
Unifocal tumors <6 cm in maximum diameter.
Good bladder function and capacity (ie, a bladder worth sparing).

24. Advanced age is not a contraindication for a combined-modality
approach. While older patients are more likely to have significant
comorbidities, a bladder preservation approach should be considered
in this population given its generally good tolerability.

25. TURBT The goal of transurethral resection of bladder tumor (TURBT)
is to maximally resect all visible tumor in a safe manner.

26. CONCURRENT CHEMORADIATION
RTOG pooled analysis — A pooled analysis of six NRG/RTOG studies
demonstrated the efficacy of chemoradiation as part of a bladder-preserving
trimodality therapy (TMT) approach.
These studies employed variable radiation doses and schedules, as well as
different concurrent cisplatin-based chemotherapy regimens.
This analysis included 468 patients with clinical T2 to T4a tumors; patients were
excluded if they had evidence of biopsy-proven nodal or metastatic disease.
At median follow-up of over four years among all patients, the main results
included the following:
●The complete response rate following chemoradiation was 69 percent.

27. The 5- and 10-year disease-specific survival (DSS) rates were 71 and
65 percent, respectively.
The 5- and 10-year rates of muscle-invasive local failure were 13
and 14 percent, respectively; the 5- and 10-year rates of non-
muscle-invasive recurrence were 31 and 36 percent, respectively; and
the 5- and 10-year rates of distant metastases were 31 and 35
percent, respectively.
●The 5- and 10-year overall survival (OS) rates were 57 and 36
percent, respectively. However, most deaths were not attributable to
bladder cancer, which was the cause of death in only 24 percent of
patients who had died by year 5.

28. •Radiation therapy technique — intensity-modulated radiation therapy
(IMRT) - highly conformal techniques allow more accurate delivery of
the required high dose of radiation to the tumor and adjacent areas
at risk.
•The dose, frequency of treatment, fields, and restaging paradigms
have not been standardized, and there are significant differences
between centers.
•An adequate dose of radiation is required to eradicate all tumor and
to treat adjacent areas of bladder that are at high risk for local
recurrence.
•At the same time, careful attention is required to minimize the dose
of radiation to adjacent normal tissues that are more radiosensitive
(colon, rectum, small intestine, hips, and normal bladder) and are at
risk for significant toxicity.
•The general approach is to give approximately 40 to 45 Gy to the
entire bladder, prostatic or proximal urethra, and the adjacent lymph
node basin in the pelvis.
•An additional boost to 10 to 15 Gy is then given to the entire bladder,

30. •In patients who are candidates for cystectomy, an alternative approach,
known as "split-course chemoradiation" may be offered.
•In this approach, a restaging cystoscopy with repeat TURBT and biopsies
may be obtained following the initial 40 to 45 Gy of radiation (induction
course), and if a patient has a complete response or has only Ta or Tis
residual disease that can be managed intravesically, consolidation
concurrent chemoradiation is continued to the total dose of 64 to 65 Gy
•We most commonly administer a continuous course of chemoradiation to full
dose without treatment break, although there are limited data demonstrating
superiority of this approach over split-course chemoradiation.
•Other groups, including those in the United Kingdom (UK), treat only the
bladder (without a pelvic nodal field), to a total dose of 64 Gy in 2 Gy daily
fractions. This is then followed by restaging cystoscopy.

32. •Moderately hypofractionated regimen may be a reasonable alternative
to conventional fractionation.
•A meta-analysis of individual patient data from two randomized
phase III trials in the UK suggested that a hypofractionated schedule
of 55 Gy in 20 fractions is noninferior to conventional fractionation
(64 Gy in 32 fractions) with regard to invasive locoregional control
and toxicity.
•These studies, however, did not include pelvic nodal fields.
Additionally, data also suggest increased dose-limiting toxicity for
hypofractionation in combination with checkpoint inhibitor
immunotherapy on trial
•Whether RT is optimally delivered on a twice-per-day or once-a-day
schedule has not been resolved in randomized trials. Most commonly
used is a once-a-day schedule.
•Previous RTOG protocols utilized a twice-a-day schedule, logistically
challenging for some patients.

33. Options for chemotherapy regimens to administer concurrently with
RT are as follows:
Cisplatin-based chemotherapy (either cisplatin and FU or cisplatin
and paclitaxel, as evaluated in RTOG 02-33) is generally favored
•For patients with poor performance status or impaired kidney
function where cisplatin is contraindicated  combination of 5-FU
plus mitomycin.
•Single-agent paclitaxel is another option as used in RTOG 0524
(NCT00238420).
•Although carboplatin has been substituted for cisplatin for patients
with impaired renal function in other disease sites (eg, lung cancer),
but carboplatin - data suggest lower complete response rates

34. Another potential alternative to cisplatin is single-agent gemcitabine, which
was evaluated in several prospective studies
In the phase II RTOG 07-12 trial (NCT00777491), 70 patients (66 evaluable)
with muscle-invasive bladder cancer were randomly assigned to concurrent
chemoradiation with either cisplatin plus FU with twice-daily RT or low-dose
gemcitabine (27 mg/m2 twice per week) with once-daily RT
Response to treatment was reassessed after 40 Gy of RT; those with a
complete response received additional RT to 64 Gy, while those without a
complete response were to undergo a radical cystectomy.
Both approaches were associated with a distant metastasis rate of less than
25 percent at three years and suggested that the low-dose gemcitabine-
based regimen was associated with similar toxicity.

35. IS THERE A ROLE FOR
NEOADJUVANT OR ADJUVANT
CHEMOTHERAPY? —
The interest in neoadjuvant or adjuvant chemotherapy as part of a
combined-modality bladder preservation approach has been
extrapolated from the data in patients undergoing radical cystectomy.
Cisplatin-based combination chemotherapy prior to radical
cystectomy for muscle-invasive bladder cancer improves DFS and OS
compared with radical cystectomy alone.

36. In the RTOG 89-03 trial, 123 patients were randomly assigned to two
cycles of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV)
chemotherapy prior to concurrent chemoradiation or to concurrent
chemoradiation without neoadjuvant chemotherapy
The addition of neoadjuvant chemotherapy to concurrent
chemoradiation did not improve OS or the rate of distant metastases.
There were four treatment-related deaths in the arm that received
CMV (with three deaths due to neutropenic sepsis) and one in the
control arm.
Though supportive care has improved in the years since, these deaths
highlight the potential risks associated with chemotherapy.

37. •The British BC2001 study allowed but did not require neoadjuvant
chemotherapy prior to curative-intent radiation or chemoradiation
•Neoadjuvant chemotherapy was given in 33 percent of the
participants overall.
•The benefit from concurrent chemoradiation compared with RT alone
was similar in those who received neoadjuvant chemotherapy (HR
0.62, 95% CI 0.35-1.13)
• and in those who did not receive neoadjuvant chemotherapy (HR
0.71, 95% CI 0.46-1.10).

38. FOLLOW UP
The first two to three cystoscopies with transurethral resection of
bladder tumor (TURBT) after completion of treatment (as well as the
cystoscopy performed to assess response following the initial
chemoradiation, if pursuing split-course radiation therapy) should be
performed in the operating room.
If these initial cystoscopies with TURBT do not identify recurrent
disease, the patient can then be transitioned to office cystoscopies
and urine cytology, which should be performed every three months
for the first two years, every six months for years 2 to 5, and then

40. hypothesize that ICI concurrent to CRT (iCRT) is safe and may
improve treatment outcomes.
This multicenter, phase 1b, open-label, dose-escalation study
determined the safety of CRT with three ICI regimens in patients with
nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received
mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder.
Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg
and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and
ipilimumab 3 mg/kg (IPI3 + NIVO1).
The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia
(grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after
three out of six patients experienced DLT. In this dose-finding study
of iCRT, the regimens of nivolumab monotherapy and nivolumab 3
mg/kg with ipilimumab 1 mg/kg have acceptable toxicity.

43. PROTOCOL
55 Gy/20 # over 4wks
or 64 Gy /32 # over wks
Fluorouracil continuous infusion (500 mg/m2; Day 1 to 5 and Day 16
to 20 of RT.)
Mitomycin 12 mg/m2 bolus day 1.

44. CONCURRENT CHEMOTHERAPY
Paclitaxel group
Paclitaxel 50 mg/m2 on days 1,
8, and 15.
Cisplatin 15 mg/m2 on days 1–3,
8–10, and 15–17
Fluorouracil group
Fluorouracil 400 mg/m2 on days
1–3, 8–10, and 15–17.
Cisplatin 15 mg/m2 on days 1–3,
8–10, and 15–17.

45. CONSOLIDATION CHEMORADIATION
1.5 GY PELVIC RADIOTHERAPY DELIVERED TWICE PER DAY FOR 8
DAYS TO 24 GY (TOTAL DOSE: 64.3 GY TO THE TUMOUR AND 44.8 GY TO
THE PELVIC LYMPH NODES.
Paclitaxel
Paclitaxel 50 mg/m2 on days 1
and 8
Cisplatin 15 mg/m2 on days 1,
2, 8, and 9.
Flurouracil
Fluorouracil 400 mg/m2 on days
1–3 and 8–10
Cisplatin 15 mg/m2 on days 1,2,
8, and.