Radiation Oncology: A Question-Based Review

58
Bladder Cancer

Richard Tuli and Alexander Lin

image Background


How prevalent is bladder cancer in the U.S.?

In the U.S., bladder cancer is the 4th most commonly diagnosed cancer in men behind prostate, lung, and colorectal malignancies and the 9th most commonly diagnosed cancer in women.

How do race and gender affect the prognosis of bladder cancer?

With bladder cancer, blacks have a poorer prognosis than whites, and women have a poorer prognosis than men.

Approximately how many cases of bladder cancer are diagnosed and how many deaths occur annually in the U.S.?

There are ~70,000 cases of bladder cancer and ~14,000 deaths annually in the U.S.

What are common risk factors for bladder cancer?

Common risk factors for bladder cancer:

1.     Smoking

2.     Chronic bladder irritation (nephrolithiasis, urinary tract infection [UTI], etc.)

3.     Chemical exposures (Cytoxan, amino biphenyl, naphthylamines, etc.)

4.     Prior pelvic irradiation

5.     Schistosoma haematobium infection (squamous cell carcinoma [SCC] only)

What is the median age at Dx of bladder cancer?

The median age at Dx of bladder cancer is 65 yrs.

Is bladder cancer more common in men or women?

In the U.S., bladder cancer is diagnosed 3 times more frequently in men than women. For squamous histology, the incidence between men and women are equal.

What is the most common histologic subtype of bladder cancer in developed and developing countries?

In developed countries, 90% of bladder cancers are transitional cell carcinomas (TCCs). In developing countries, 75% of bladder cancers are SCCs.

What are the different histopathologic types of bladder cancer in order of decreasing frequency?

The most common histology of bladder cancer in the U.S. is TCC/urothelial carcinoma (94%) > SCC (3%) > adenocarcinoma (2%) > small cell tumors (1%).

What % of newly detected bladder tumors are Ta/Tis/T1 lesions?

~70% of all newly diagnosed bladder cancers are exophytic papillary tumors, with 70% of these confined to the mucosa (Ta/Tis) and 30% confined to the submucosa (T1). (Herr HW et al., Cancer: Principles and practice of oncology. 6th ed. 2001)

What are important prognostic factors in pts with bladder cancer?

Bladder cancer prognostic factors:

1.     Tumor grade

2.     DOI

3.     Stage

4.     Histologic subtype

Approximately what % of bladder cancer pts have metastatic Dz at presentation, and what are the common sites of mets?

~8% of newly diagnosed bladder cancer pts have metastatic Dz at presentation, usually involving the bone, lungs, or liver.

image Workup/Staging


What are the common presenting signs and Sx of bladder cancer?

In pts with bladder cancer, the most common presenting Sx is hematuria → urinary frequency and pelvic/flank pain.

What are the initial steps in the workup of a pt suspected to have bladder cancer? What additional workup is needed after a cancer Dx is made?

Pts suspected to have bladder cancer should 1st obtain urine cytology or undergo cystoscopy. If a lesion is identified, they should proceed to have a transurethral resection of bladder tumor (TURBT) and EUA. If the lesion identified by cystoscopy is solid, of high grade, or suspicious for muscle invasion, then CT abdomen/pelvis should be performed. If a cancer Dx is made, image the upper urinary tract (intravenous pyelogram, retrograde pyelogram, renal US, or MRI urogram) and chest (CXR or CT). Consider bone scan if there is locally advanced Dz. Recommended blood work includes CBC/CMP. (NCCN 2010)

In the initial TURBT sample of a bladder tumor, what should be present in the pathologic specimen?

The Bx specimen should contain muscle from the bladder wall to properly stage the tumor. If there is presence of muscle-invasive Dz, the pathology specimen should also contain perivesicular fat to assess the extent of Dz.

What are the indications for re-resection after initial TURBT?

Repeat resection should be performed after initial TURBT when there is incomplete initial resection, no muscle in tissue sample, a large lesion, any T1 lesion, or insufficient sample to definitively call a T2 lesion.

What is the AJCC 7th edition (2009) T-stage criteria for bladder cancer?

1.     Ta: noninvasive papillary carcinoma

2.     Tis: CIS (“flat tumor”)

3.     T1: tumor invades subepithelial connective tissue

4.     T2a: tumor invades superficial muscularis propria (inner half)

5.     T2b: tumor invades deep muscularis propria (outer half)

6.     T3a: microscopic invasion of perivesical tissue

7.     T3b: macroscopic invasion of perivesical tissue (extravesical mass)

8.     T4a: tumor invades prostatic stroma, uterus, vagina

9.     T4b: tumor invades pelvic wall, abdominal wall

What is the probability of pelvic nodal involvement based on the T stage of a bladder tumor?

Pelvic node involvement by bladder cancer T stage based on the surgical series by Stein JP et al.:

1.     Overall: 24% LN+

2.     T0-T1: 5%

3.     T2: 18%

4.     T3a: 26%

5.     T3b: 46%

6.     T4: 42%

(JCO 2001)

What is the AJCC 7th edition (2009) N- and M-stage criteria for bladder cancer?

1.     N0: no regional LN mets

2.     N1: single LN in true pelvis (hypogastric, obturator, external iliac, or presacral)

3.     N2: multiple LNs in true pelvis

4.     N3: mets to common iliac LN

5.     M0: no DM

6.     M1: DM

Define the AJCC 7th edition (2009) bladder cancer stage grouping based on TNM status.

1.     Stage 0a: Ta, N0, M0

2.     Stage 0is: Tis, N0, M0

3.     Stage I: T1, N0, M0

4.     Stage II: T2, N0, M0

5.     Stage III: T3 or T4a, N0, M0

6.     Stage IV: T4b or N+ or M1

image Treatment/Prognosis


Which pts with noninvasive bladder cancer can be observed after max TURBT?

Observation is indicated for non–muscle invasive bladder cancer pts after max TURBT with all of the following features:

1.     Completely resected

2.     Ta

3.     Grade 1

4.     No residual on urine cytology

What are the indications for adj therapy in pts with non–muscle invasive bladder cancer treated with TURBT?

Pts with non–muscle invasive bladder cancer s/p TURBT should be treated with intravesical therapies if:

1.     Grades 2–3

2.     T1

3.     Tis

4.     Multifocal or residual Dz

What agents are commonly used for intravesical therapy following TURBT for non–muscle invasive bladder cancer?

Immunotherapy (bacillus Calmette-Guerin [BCG]) is preferred over chemo (mitomycin) as intravesical Tx following TURBT for non–muscle invasive bladder cancer. This is based on 4 meta-analyses demonstrating the superiority of BCG to intravesicular chemo or TURBT alone in preventing tumor recurrence. Intravesicular therapy is usually initiated 3–4 wks after resection with a max of 2 inductions without CR.

What Tx options are available for pts with node–, muscle-invasive (cT2-T3) bladder cancer after TURBT?

Pts with cT2-T3 node–, muscle-invasive bladder cancer can be treated with:

1.     Radical cystectomy (+/− neoadj chemo)

2.     Partial cystectomy (for bladder dome lesions)

3.     Bladder preservation with concurrent cisplatin-based chemo and RT

What is involved in a radical cystectomy for bladder cancer?

Radical cystectomy involves removal of the bladder, distal ureters, pelvic peritoneum, prostate, seminal vesicles, uterus, fallopian tubes, ovaries, and the ant vaginal wall → urinary diversion. Urine can be diverted via a conduit to the abdominal wall or to an orthotopic neobladder. Bilat LND is also performed to include the common, internal and external iliac, and obturator nodes.

Estimate the LR (pelvic) rate after radical cystectomy by bladder cancer T stage (T2-T4).

Estimates for LR (pelvic) after radical cystectomy for all muscle-invasive bladder cancer range from 5%–19% but varies by T stage:

1.     T2: 7%

2.     T3a: 9%

3.     T3b: 29%

4.     T4: 48%

(Pollack A et al., J Urol 1995)

Describe the general paradigm behind bladder preservation in the management of pts with bladder cancer.

Based on promising survival outcomes of several phase II and single-institution studies, bladder preservation is an option for muscle-invasive bladder cancer. Following max complete TURBT, concurrent cisplatin (wks 1, 4) + EBRT (4 field, 40 Gy) is administered. 4 wks after induction CRT, a repeat cystoscopy with Bx and cytology is performed. If CR, additional 25 Gy EBRT + cisplatin × 1 is administered. If PR, salvage cystectomy is performed.

What should be done if after induction CRT the repeat cystoscopy and Bx reveals Tis Dz?

According to RTOG 9706, continuation of bladder preservation is allowed with residual Ta or Tis Dz after induction CRT.

What are contraindications to bladder preservation with concurrent CRT in pts with bladder cancer?

Contraindications to bladder preservation in pts with muscle-invasive bladder cancer:

1.     Hydronephrosis

2.     Multifocal CIS

3.     Persistently +margin on TURBT

4.     Non-TCC histology

5.     Inappropriate bladder capacity and function

6.     Inability to tolerate chemo

7.     Trigone involvement

8.     Stage IV Dz

9.     pT3b-T4 (relative)

Is there a role for neoadj chemo prior to CRT for bladder cancer?

The role of neoadj methotrexate/cisplatin/vinblastine (MCV) was evaluated in RTOG 89-03, which compared MCV × 2 → concurrent cisplatin + RT to cisplatin + RT in the management of pts with T2-T4a invasive bladder cancer. No difference in CR rates or 5-yr OS was observed between the 2 arms. The neoadj MCV arm was also poorly tolerated, with only 67% of pts completing the entire prescribed Tx. (Shipley WU et al., JCO 1998)

Is there a role for neoadj chemo prior to radical cystectomy in the management of locally advanced bladder cancer (cT2-T3)?

Yes. Multiple RCTs have shown a survival benefit with the use of neoadj chemo prior to radical cystectomy for pts with cT2-T3 bladder cancer (Grossman HB et al., NEJM 2003Sherif A et al., Eur Urol 2004). The survival benefit is 5% based on meta-analysis of these trials. Neoadj cisplatin-based combination chemo is recommended prior to cystectomy for T2 (category 2A recommendation) and T3 (category 1 recommendation) Dz. This may also be considered for highly selected T4a, LN– pts.

Is there a role for RT alone in the management of locally advanced bladder cancer?

Rarely. Multiple nonrandomized trials and 1 RCT (Coppin CM et al., JCO 2006suggest superior results with CRT, as well as cystectomy, compared to RT alone in the management of pts with muscle-invasive bladder cancer. RT alone, or in combination with a low-dose radiosensitizer (e.g., cisplatin or 5-FU), may be considered if surgery or full-dose chemo cannot be tolerated.

Is there data to support preop RT → cystectomy over definitive RT alone?

Yes. Several RCTs have compared preop and immediate cystectomy to RT alone for the Tx of bladder cancer, and results favor the surgery arms. Therefore, consider preop RT (or preop CRT) to convert unresectable to resectable tumors.

Danish National Cancer Group: 183 pts, 40 Gy + cystectomy vs. 60 Gy. 5-yr OS was not different, but local/pelvic failure favored the surgery arm (7% vs. 35%). (Sell A et al., Scand J Urol Neph 1991)

MDA RCT: 67 pts, 50 Gy + cystectomy vs. 60 Gy. 5-yr OS favored the surgery arm (45% vs. 22%, SS). (Miller LS, Cancer 1977)

What % of pts with muscle-invasive bladder cancer treated for bladder preservation achieve a CR after induction cisplatin-based CRT?

~70% of pts with muscle-invasive bladder cancer achieve a CR after Tx with induction cisplatin-based CRT. (Shipley WU et al., Urology 2002)

What % of pts with muscle-invasive bladder cancer achieve a CR after preop chemo?

~38% of pts with muscle-invasive bladder cancer achieve a CR with preop methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). (Grossman HB et al., NEJM 2003)

What % of pts with muscle-invasive bladder cancer achieve a CR after preop TURBT alone?

~15% of pts with muscle-invasive bladder cancer achieve a CR after preop TURBT alone. (Grossman HB et al., NEJM 2003)

What are the 5-yr OS outcomes of pts treated with cystectomy vs. bladder preservation?

CRT-based bladder preservation has not been directly compared to cystectomy alone in an RCT.

5-yr OS estimates for cystectomy alone:

1.     Ta: 95%

2.     T1: 50%–80%

3.     T2: 60%–80%

4.     T3b-T4: 20%–40%

5.     pN + : 15%–30%

5-yr OS estimates for bladder preservation:

1.     T2: 60%

2.     T3b-T4: 45%

(Shipley WU et al., Urology 2002Rodel C et al., J Clin Oncol 2002)

What are the predicted 5-yr OS rates based on stage?

Relative 5-yr OS rates for bladder cancer based on SEER data:

1.     Stage 0: 98%

2.     Stage I: 88%

3.     Stage II: 63%

4.     Stage III: 46%

5.     Stage IV: 15%

What is considered 1st-line chemo (neoadj, adj, or metastatic) in the management of bladder cancer?

Gemcitabine/cisplatin is the 1st-line chemo used in the neoadj, adj, or metastatic setting for pts with bladder cancer. This combination has led to equivalent outcomes but an improved toxicity profile when compared to MVAC in RCTs. (Roberts JT et al., Ann Oncol 2006)

What is the Tx strategy for pts with unresectable (cT4, fixed bladder mass, LN+) bladder cancer?

For pts with unresectable bladder cancer, chemo × 2–3 +/− RT is administered → restaging with cystoscopy and CT scan. If the tumor becomes resectable, the pt should proceed to cystectomy. If not, consolidation chemo +/− RT is indicated. For those who achieve a CR, consider observation.

How is locally recurrent bladder cancer treated after initial Tx with bladder preservation?

The type of intervention for LF after bladder preservation for bladder cancer is dependent on the extent of Dz. Recurrent noninvasive Dz may be treated with intravesical BCGInvasive Dz is treated with radical cystectomy. In the case of bulky Dz recurrence following >65 Gy EBRT, chemo alone may be considered.

How is metastatic bladder cancer treated?

Combination chemo (gemcitabine 1,000 mg/m2 days 1, 8, and 15 of a 28-day cycle and cisplatin 70 mg/m2 on day 2) should be used for pts with metastatic bladder cancer who have good performance status, no visceral or bone involvement, and normal alk phos and LDH levels. Alternatively, MVAC or taxane-based regimens may be considered. Pemetrexed may be used in cisplatin-refractory Dz. Local therapy (surgery or RT) may be considered depending on the extent of response to chemo.

What is the MS for untreated vs. treated metastatic bladder cancer?

MS is <6 mos for untreated and 13 mos for treated metastatic bladder cancer.

How should the histologic variants of urothelial carcinomas (e.g., SCC, adenocarcinoma, sarcomatoid, nested micropapillary subtypes, etc.) be treated?

Chemotherapeutic agents should be selected that target the individual variant histologies of bladder cancer.

How should bladder cancer pts be simulated in preparation for RT?

Bladder cancer pts should be planned using CT-based simulations. The pt should lie supine on appropriate immobilization (e.g., alpha cradle) with arms on the chest. The bladder should be empty.

What RT fields are typically used to treat bladder cancer pts?

Pts undergoing neoadj/definitive RT for bladder cancer are typically treated using a whole pelvis 4-field box.

AP/PA:

1.     Superior: ant aspect of S2-3 junction

2.     Inferior: at bottom of obturator foramen or 2 cm below tumor (whichever is lower)

3.     Lateral: 2 cm lat to pelvic inlet

Laterals (same sup/inf as AP/PA):

1.     Anterior: 2 cm ant to external iliac nodes

2.     Posterior: 2 cm post to bladder and internal iliac nodes

3.     Block the femoral head/neck or rectum/bowel as appropriate. Use conformal CD to boost gross tumor.

What RT dose is prescribed in the Tx of pts with bladder cancer?

Treat the whole bladder +/− pelvic LNs to 40–55 Gy → tumor boost to 64–66 Gy.

image Toxicity


What is the recommended follow-up for a pt treated with bladder preservation for locally advanced bladder cancer?

Following bladder preserving therapy for muscle-invasive bladder cancer, NCCN 2010 guidelines recommend urine cytology + cystoscopy + / − Bx q3mos for yr 1, then increasing intervals; imaging of upper tracts, abdomen, and pelvis q3–6mos for 2 yrs, then as clinically indicated; LFTs, Cr, electrolytes, and CXR q6–12 mos.

What are operative mortality rates and periop complication rates following radical cystectomy for bladder cancer pts?

Following radical cystectomy for bladder cancer, operative mortality rates approach 5% with periop morbidity rates of 30%. (Quek ML et al., J Urol 2006; Stein JP et al., JCO 2001)

What are short- and long-term toxicities associated with RT as part of organ preservation for bladder cancer?

1.     Short-term side effects: urinary frequency/urgency, dysuria, UTIs, bladder spasms, loose stools, RT dermatitis, fatigue

2.     Long-term side effects: hematuria, urinary frequency/urgency, dysuria, hematochezia, erectile dysfunction, increased risk of fracture, 2nd malignancies

What is the impact of organ preservation approaches on QOL in pts with bladder cancer?

QOL studies have been undertaken to assess long-term Tx-related morbidities in pts who rcv RT as part of an organ-sparing paradigm for bladder cancer. Lynch et al. found no difference in urinary/rectal function compared to a matched control group (Br J Urol 1992). Caffo et al. found pts treated with RT + / − chemo reported significantly better QOL compared to pts treated with cystectomy with urostomy (Cancer 1996).

What % of pts require cystectomy for palliation of Tx-related toxicities following bladder preservation?

Cystectomy rates performed for palliation of bladder preservation–related toxicities range from 0%–2%. (Rodel C et al., JCO 2002Shipley WU et al., Urology 2002)