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age at diagnosis is 73 years,2 medical comorbidities are a tain quality of life. Numerous agents with differ-
frequent consideration in patient management. ent mechanisms of action have antitumor effects
The clinical spectrum of bladder cancer can be di- on this disease. The goal is how to use these agents
vided into 3 categories that differ in prognosis, manage- to achieve the best possible outcome.
ment, and therapeutic aims. The first category consists
of non–muscle-invasive bladder cancer, for which treat-
ment is directed at reducing recurrences and preventing Histology
progression to a more advanced stage. The second group More than 90% of urothelial tumors originate in
encompasses muscle-invasive bladder cancer (MIBC). the urinary bladder, 8% originate in the renal pel-
The goal of therapy is to determine whether the blad- vis, and the remaining 2% originate in the ureter
der should be removed or if it can be preserved with- and urethra. Urothelial carcinomas are classified
out compromising survival, and to determine whether as low- or high-grade as defined by the extent of
the primary lesion can be managed independently or nuclear anaplasia and architectural abnormalities.
if patients are at high risk for distant spread requiring Urothelial (transitional cell) carcinomas are
systemic approaches to improve the likelihood of cure. the most common histologic subtype in the Unit-
The critical concern for the third group, consisting of ed States and Europe and may develop anywhere
metastatic lesions, is how to prolong quantity and main-
Text cont. on page 1254.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1242
aSee Principles of Imaging for Bladder/Urothelial Cancer (BL-A*). tSee Principles of Systemic Therapy (BL-G 1 of 4).
bSee Principles of Surgical Management (BL-B*). uSee Principles of Systemic Therapy (BL-G 3 of 4).
eThe modifier “c” refers to clinical staging based on bimanual examination vSee Principles of Radiation Management of Invasive Disease (BL-H).
under anesthesia and endoscopic surgery (biopsy or transurethral wThere are data to support equivalent survival rates. Not all institutions
resection) and imaging studies. The modifier “p” refers to pathologic have experience with these multidisciplinary treatment approaches, which
staging based on cystectomy and lymph node dissection. require a dedicated team.
rConsider PET/CT scan (category 2B). xOther options may include TURBT, best supportive care, or observation
sClinically suspicious nodes. depending on patient and tumor characteristics.
BL-4
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1243
NCCN Clinical Practice Guidelines in Oncology
aSee Principles of Imaging for Bladder/Urothelial Cancer (BL-A*). tSee Principles of Systemic Therapy (BL-G 1 of 4).
bSee Principles of Surgical Management (BL-B*). uSee Principles of Systemic Therapy (BL-G 3 of 4).
eThe modifier “c” refers to clinical staging based on bimanual examination vSee Principles of Radiation Management of Invasive Disease (BL-H).
under anesthesia and endoscopic surgery (biopsy or transurethral wThere are data to support equivalent survival rates. Not all institutions
resection) and imaging studies. The modifier “p” refers to pathologic have experience with these multidisciplinary treatment approaches, which
staging based on cystectomy and lymph node dissection. require a dedicated team.
rConsider PET/CT scan (category 2B). xOther options may include TURBT, best supportive care, or observation
sClinically suspicious nodes. depending on patient and tumor characteristics.
BL-5
Version 5.2017, 05-25-17 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be
reproduced in any form without the express written permission of NCCN®.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1244
aSee Principles of Imaging for Bladder/Urothelial Cancer (BL-A*). sClinically suspicious nodes.
bSee Principles of Surgical Management (BL-B*). tSee Principles of Systemic Therapy (BL-G 1 of 4).
eThe modifier “c” refers to clinical staging based on bimanual examination uSee Principles of Systemic Therapy (BL-G 3 of 4).
under anesthesia and endoscopic surgery (biopsy or transurethral vSee Principles of Radiation Management of Invasive Disease (BL-H).
resection) and imaging studies. The modifier “p” refers to pathologic yIf technically possible.
staging based on cystectomy and lymph node dissection.
zSee Principles of Systemic Therapy (BL-G 2 of 4).
rConsider PET/CT scan (category 2B).
BL-6
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1245
NCCN Clinical Practice Guidelines in Oncology
• Bone scana if clinical Node only Consider biopsy of nodesy (See BL-6)
suspicion or symptoms of
bone metastases
Metastaticaa • Chest CT
• Consider CNS imaginga
• Estimate GFR to assess See Treatment of Recurrent
eligibility for cisplatin Disseminated Systemic therapyz or Persistent Disease
(BL-8)
BL-7
Version 5.2017, 05-25-17 ©2017 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be
reproduced in any form without the express written permission of NCCN®.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1246
Cystectomyb,h
or
Chemoradiotherapy (if no prior RT)u,v
Invasive or
Palliative TURBT
Local recurrence and
or persistent
Best supportive care
disease;
Preserved bladder
No
Intravesical BCG j Cystectomyb,h,bb
Tis, Ta, response
or
or T1
Cystectomyb,h
aSee Principles of Imaging for Bladder/Urothelial Cancer (BL-A*). vSee Principles of Radiation Management of Invasive Disease (BL-H).
bSee Principles of Surgical Management (BL-B*). zSee Principles of Systemic Therapy (BL-G 2 of 4).
hSee Follow-Up (BL-E*). bbIf not a cystectomy candidate, consider concurrent chemoradiotherapy
jSee Principles of Intravesical Treatment (BL-F*). (See BL-G 3 of 4) (if no prior RT), change in intravesical agent, or a
uSee Principles of Systemic Therapy (BL-G 3 of 4). clinical trial.
BL-8
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1247
NCCN Clinical Practice Guidelines in Oncology
BL-B
1 AND 2 OF 3
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reproduced in any form without the express written permission of NCCN®.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1248
Urethrectomy
• Male patients with T2 primary carcinoma of the urethra in the bulbar urethra may be treated with a urethrectomy with or without a
cystoprostatectomy.
• Male patients with T2 primary carcinoma of the urethra in the pendulous urethra may receive a distal urethrectomy. Alternatively, a partial
penectomy can be considered. A total penectomy may be necessary in cases of recurrence.
• Female patients with T2 primary carcinoma of the urethra may be treated with urethrectomy with cystectomy.
• Neoadjuvant chemotherapy (category 2B) or chemoradiation should be considered.
• Distal urethrectomy may include inguinal lymph node dissection in selected cases.
• Total urethrectomy may include inguinal lymphadenectomy in selected cases.
Regional Lymphadenectomy
• Recommended for patients with high-grade upper GU tract tumors tumors
• Left-sided renal pelvic, upper ureteral, and midureteral tumors
Regional lymphadenectomy should include at a minimum the paraaortic lymph nodes from the renal hilum to the aortic bifurcation.
Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
• Right-sided renal pelvic, upper ureteral, and midureteral tumors
Regional lymphadenectomy should include at a minimum the paracaval lymph nodes from the renal hilum to the aortic bifurcation.
Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
• Distal ureteral tumors
Regional lymphadenectomy should be performed and include at a minimum the common iliac, external iliac, obturator, and hypogastric
lymph nodes
BL-B
3 OF 3
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1249
NCCN Clinical Practice Guidelines in Oncology
• For patients who are not candidates for cisplatin, there are no data to support a recommendation for perioperative chemotherapy.
• Randomized trials and meta-analyses show a survival benefit for cisplatin-based neoadjuvant chemotherapy (3 or 4 cycles) in patients
with muscle-invasive bladder cancer.1,6,7
• Meta-analysis suggests a survival benefit to adjuvant therapy for pathologic T3, T4 or N+ disease at cystectomy.7
• Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy on a higher level of evidence data.
• DDMVAC is preferred over standard MVAC based on category 1 evidence showing DDMVAC to be better tolerated and more effective than
conventional MVAC in advanced disease.2,8 Based on these data, the traditional dose and schedule for MVAC is no longer recommended.
• Perioperative gemcitabine and cisplatin is a reasonable alternative to DDMVAC based on category 1 evidence showing equivalence to
conventional MVAC in the setting of advanced disease.4,9
• For gemcitabine/cisplatin, both 21- and 28-day regimens are acceptable. Better dose compliance may be achieved with fewer delays in
dosing using the 21-day schedule.10
• Neoadjuvant chemotherapy may be considered for select patients with upper tract urothelial carcinoma, particularly for higher stage and/or
grade tumors, as renal function will decline after nephroureterectomy and may preclude adjuvant therapy.
• Carboplatin should not be substituted for cisplatin in the perioperative setting.
For patients with borderline renal function or minimal dysfunction, a split-dose administration of cisplatin may be considered
(such as 35 mg/m2 on days 1 and 2 or days 1 and 8) (category 2B). While safer, the relative efficacy of the cisplatin-containing
combination administered with such modifications remains undefined.
• For patients with borderline renal function, estimate GFR to assess eligibility for cisplatin.
• The presence of both visceral metastases and ECOG performance score ≥2 strongly predict poor outcome with chemotherapy. Patients
without these adverse prognostic factors have the greatest benefit from chemotherapy.
• For most patients, the risks of adding paclitaxel to gemcitabine and cisplatin outweigh the limited benefit seen in the randomized trial.17
• A substantial proportion of patients cannot receive cisplatin-based chemotherapy due to renal impairment or other comorbidities.
Participation in clinical trials of new or more tolerable therapy is recommended.
BL-G
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reproduced in any form without the express written permission of NCCN®.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1250
Radiosensitizing chemotherapy given concurrently with conventionally fractionated radiation for palliation of metastases or for
pelvic recurrence after cystectomy
• Cisplatina
• Taxane (docetaxel or paclitaxel) (category 2B)
• 5-FU (category 2B)
• 5-FU and mitomycin (category 2B)
• Capecitabine (category 3)
• Low-dose gemcitabine (category 2B)
References on BL-G 4 of 4
aCarboplatin is not an effective radiation sensitizer and should not be substituted for cisplatin with radiation. (Rödel C, Grabenbauer GG, Kühn R, et al.
Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002; 20:3061.)
BL-G
3 OF 4
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
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NCCN Clinical Practice Guidelines in Oncology
1Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy 17Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III
plus cystectomy compared with cystectomy alone for locally advanced study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin
bladder cancer. N Engl J Med 2003;349:859-866. in patients with locally advanced or metastatic urothelial cancer without
2Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol
III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and 2012;30:1107-1113.
cisplatin (MVAC) chemotherapy and recombinant human granulocyte 18Bellmunt, de Wit R, Vaughn D, et al. Pembrolizumab as second-line therapy
colony-stimulating factor versus classic MVAC in advanced urothelial tract
for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-1026.
tumors: European Organization for Research and Treatment of Cancer
19Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients
Protocol no. 30924. J Clin Oncol 2001;19:2638-2646.
3Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine with locally advanced and metastatic urothelial carcinoma who have
plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a progressed following treatment with platinum-based chemotherapy: A single-
retrospective experience. Cancer 2008;113:2471-2477. arm, multicentre, phase 2 trial. Lancet 2017; 387:1909-1920.
4Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin 20Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic
versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre,
or metastatic bladder cancer: results of a large, randomized, multinational, single-arm, phase 2 trial. Lancet Oncol 2017.
multicenter, phase III study. J Clin Oncol 2000;18:3068-3077. 21Powles T, et al. Updated efficacy and tolerability of durvalumab in locally
5Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing
advanced or metastatic urothelial carcinoma [abstract]. J Clin Oncol
neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for
2017;35: Abstract 286.
muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J
22Apolo AB, Infante JR, Patel MR, et al. Avelumab, an anti-programmed death-
Clin Oncol 2011;29:2171-2177.
6Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma:
chemotherapy in invasive bladder cancer: update of a systematic review Results from a multicenter, phase Ib study. J Clin Oncol 2017; Apr 4.
and meta-analysis of individual patient data advanced bladder cancer (ABC) 23Patel M, Ellerton J, Infante J, et al. Avelumab in patients with metastatic
meta-analysis collaboration. Eur Urol 2005;48:202-205; discussion 205-206. urothelial carcinoma: Pooled results from two cohorts of the phase 1b
7Advanced Bladder Cancer Meta-analysis Collaboration. Adjuvant JAVELIN Solid Tumor trial [abstract]. J Clin Oncol 2017;6S:Abstract 330.
chemotherapy in invasive bladder cancer: a systematic review and meta- 24McCaffrey JA, Hilton S, Mazumdar M, et al: Phase II trial of docetaxel in
analysis of individual patient data Advanced Bladder Cancer (ABC) Meta- patients with advanced or metastatic transitional-cell carcinoma. J Clin
analysis Collaboration. Eur Urol 2005;48:189-199; discussion 199-201.
Oncol 1997;15:1853-1857.
8Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of
25Sweeney CJ, Roth BJ, Kabbinavar FF, et al: Phase II study of pemetrexed
an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and
for second-line treatment of transitional cell cancer of the urothelium. J Clini
G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J
Cancer 2006;42:50-54. Oncol 2008;24:3451-3457.
9von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of 26Ko YJ, Canil CM, Mukherjee SD, et al: Nanoparticle albumin-bound
a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, paclitaxel for second-line treatment of metastatic urothelial carcinoma: a
vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin single group, multicentre, phase 2 study. Lancet Oncol 2013;14:769-776.
Oncol 2005;23:4602-4608. 27Witte RS, Elson P, Bono B, et al: Eastern Cooperative Oncology Group
10Soto Parra H, Cavina R, Latteri F, et al. Three-week versus four-week phase II trial of ifosfamide in the treatment of previously treated advanced
schedule of cisplatin and gemcitabine: results of a randomized phase II urothelial carcinoma. J Clin Oncol 1997;15:589-593.
study. Ann Oncol 2002;13:1080-1086. 28Mitin T, Hunt D, Shipley W, et al. Transurethral surgery and twice-daily
11De Santis M, Bellmunt J, Mead G, et al: Randomized phase II/III trial
radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective
assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine
bladder preservation and adjuvant chemotherapy for patients with muscle
in patients with advanced urothelial cancer who are unfit for cisplatin-based
invasive bladder cancer (RTOG 0233): a randomized multicentre phase 2
chemotherapy: EORTC study 30986. J Clinl Oncol 2012;30:191-199.
trial. Lancet Oncol 2013;14:863-872.
12Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line
29Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of
treatment in cisplatin-ineligible patients with locally advanced and metastatic
urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet selective bladder preservation by combined-modality therapy for invasive
2017;389:67-76. bladder cancer: The MGH experience. Eur Urol 2012; 61:705-711.
13Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first- 30James ND, Hussain SA, Hall E, et al; BC2001 Investigators. Radiotherapy
line therapy in cisplatin-ineligible advanced urothelial cancer: Results with or without chemotherapy in muscle-invasive bladder cancer. N Engl J
from the total KEYNOTE-052 study population [abstract]. J Clin Oncol Med 2012;366:1477-1488.
2017;6S:Abstract 284. 31Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality
14Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent
program with selective organ preservation for invasive bladder cancer:
gemcitabine in previously untreated patients with metastatic urothelial
results of Radiation Therapy Oncology Group phase II trial 8802. J Clin
cancer. J Clin Oncol 1997;15:3394-3398.
Oncol 1996;14:119-126.
15Calabro F, Lorusso V, Rosati G, et al: Gemcitabine and paclitaxel every 2
32Kent E et al. Combined-modality therapy with gemcitabine and radiotherapy
weeks in patients with previously untreated urothelial carcinoma. Cancer
2009;115:2652-2659. as a bladder preservation strategy: results of a phase I trial. J Clin Oncol
16Siefker-Radtke AO, Dinney CP, Shen Y, et al: A phase 2 clinical trial of 2004;22:2540-2545.
33Choudhury A, Swindell R, Logue JP, et al. Phase II study of conformal
sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and
gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally hypofractionated radiotherapy with concurrent gemcitabine in muscle-
advanced urothelial cancer: final results. Cancer 2013;119:540-547. invasive bladder cancer. J Clin Oncol 2011; 29:733-738.
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reproduced in any form without the express written permission of NCCN®.
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Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
All recommendations are category 2A unless otherwise indicated.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
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NCCN Clinical Practice Guidelines in Oncology
Baumann BC, Bosch WR, Bahl A, et al. Development and validation of consensus contouring guidelines for adjuvant radiation therapy for bladder cancer after
Radical cystectomy. Int J Radiat Oncol Biol Phys 2017;96:78-86.
Baumann BC, He J, Hwang WT, et al. Validating a local failure risk stratification for use in prospective studies of adjuvant radiation therapy for bladder cancer.
Int J Radiat Oncol Biol Phys 2017;95:703-706.
Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer:
the MGH experience. Eur Urol 2012;61:705.
Efstathiou JA, Zietman AL. Bladder Cancer. In Gunderson & Tepper, editors. Clinical Radiation Oncology. Churchill Livingstone Elsevier 2015.
James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366:1477.
Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet 2017.
Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality
therapy: A pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32:3801.
Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder
preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): A randomised multicentre phase 2 trial. Lancet Oncol
2013;14:863.
Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic
review. Eur Urol 2014; 66:120.
Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin
Oncol 2002; 20:3061.
Shipley WU, Prout GR, Kaufman SD, Perrone TL. Invasive bladder carcinoma. The importance of initial transurethral surgery and other significant prognostic
factors for improved survival with full-dose irradiation. Cancer 1987;60:514–520.
Weiss C, Wolze C, Engehausen DG, Ott OJ, et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: An alternative to intravesical
therapy or early cystectomy? J Clin Oncol 2006;24:2318-2324.
Zaghloul MS, Christodouleas JP, Smith A, et al. Adjuvant sandwich chemotherapy and radiation versus adjuvant chemotherapy alone for locally advanced
bladder cancer [abstract]. Int J Radiat Oncol Biol Phys 2017;96:Abstract S94.
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1254 NCCN Clinical Practice Guidelines in Oncology
transitional epithelium is present, from the renal pel- the genitourinary tract but not of urothelial origin
vis to the ureter, bladder, and proximal two-thirds (eg, tumors of müllerian type, melanocytic tumors,
of the urethra. Variant histology is common with mesenchymal tumors) are beyond the scope of these
higher grades. The fourth edition of the WHO Clas- guidelines.
sification of Tumors has reclassified these histologic
subtypes into the following: infiltrating urothelial
carcinoma with divergent differentiation; nested, Muscle-Invasive Urothelial
including large nested; microcystic; micropapillary; Bladder Cancer
lymphoepithelioma-like; plasmacytoid/signet ring Additional Workup
cell/diffuse; sarcomatoid; giant cell; poorly differ- Several workup procedures are recommended to accu-
entiated; lipid-rich; and clear cell.3 Two review ar- rately determine clinical staging of MIBC. Laboratory
ticles highlight the changes between the third and studies, such as a complete blood cell count and chem-
fourth additions of this classification.4,5 The pres- istry profile, including alkaline phosphatase, must be
ence of histologic variants in urothelial carcinoma performed, and the patient should be assessed for the
should be documented, because data suggest that presence of regional or distant metastases. This evalu-
the subtype may reflect the risk of disease progres- ation should include chest imaging and a bone scan in
sion and different genetic origin, and subsequently patients with symptoms or clinical suspicion of bone
determine whether a more aggressive treatment ap- metastasis (eg, elevated alkaline phosphatase, focal
proach should be considered (see “Bladder Cancer: bone pain). Imaging studies help assess the extent of
Non-Urothelial and Urothelial With Variant His- tumor spread to lymph nodes or distant organs.8 An
tology” in the complete version of these guidelines, abdominal/pelvic CT or MRI is used to assess the lo-
at NCCN.org). In some cases with a mixed histol- cal and regional extent of disease. Unfortunately, CT
ogy, systemic treatment may only target cells of uro- scans, ultrasound, and MRI cannot accurately predict
thelial origin and the nonurothelial component can the true depth of invasion.
remain. The overwhelming majority of muscle-invasive
Squamous cell neoplasms of the urothelial tract tumors are high-grade urothelial carcinomas. Further
are a second histologic subtype, which constitute 3% treatment following initial transurethral resection of
of the urinary tumors diagnosed in the United States. bladder tumor (TURBT) is often required for mus-
In regions where Schistosoma is endemic, this sub- cle-invasive tumors, although select patients may be
type is more prevalent and may account for up to treated with TURBT alone.9,10 Different treatment
75% of bladder cancer cases. The distal third of the modalities are discussed herein, including radical
urethra is dominated by squamous epithelium. The cystectomy, partial cystectomy, neoadjuvant or ad-
diagnosis of squamous cell tumors requires the pres- juvant therapy, bladder-preserving approaches, and
ence of keratinization in the pathologic specimen.6 chemotherapy for advanced disease.
Squamous cell carcinoma of the bladder is morpho-
logically indistinguishable from squamous cell carci- Radical Cystectomy
noma of other sites and generally presents at an ad- Radical surgical treatment of bladder cancer involves
vanced stage. The 3 variants within this subtype are a cystoprostatectomy in men and a cystectomy and
pure squamous cell carcinoma, verrucous carcinoma, commonly a hysterectomy in women, followed by
and squamous cell papilloma. the formation of a urinary diversion. This surgery can
Other histologic subtypes derived from cells of be performed in an open or robotic manner. Prosta-
urothelial origin include glandular neoplasms, epi- tectomy includes removal of the prostate, seminal
thelial tumors of the upper urinary tract, and tu- vesicles, proximal vas deferens, and proximal ure-
mors arising in a bladder diverticulum. Glandular thra. Hysterectomy should include removal of the
neoplasms include adenocarcinoma and villous ad- uterus, ovaries, fallopian tubes, urethra, and part of
enoma. Urachal tumors are nonurothelial tumors, the vagina. Forms of urinary diversion include an il-
most commonly adenocarcinomas, which arise from eal conduit or directing urine to an internal urinary
the urachal ligament and involve the midline/dome reservoir (such as a continent pouch), with drain-
of the bladder secondarily.7 Tumors arising within age to the abdominal wall or the urethra (orthotopic
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NCCN Clinical Practice Guidelines in Oncology 1255
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1256 NCCN Clinical Practice Guidelines in Oncology
in 49% of patients receiving neoadjuvant ddMVAC urothelial tumors. In the MVEC trial, patients who
with a similar safety profile.25 An additional neoad- experienced relapse in the control arm did not re-
juvant clinical trial of ddMVAC with bevacizumab ceive chemotherapy, which is not typical of more
reported 5-year survival outcomes of 63% and 64% contemporary treatment approaches. Many of these
(OS and disease-specific survival, respectively; medi- trials were not randomized, raising the question of
an follow-up, 49 months), with pT0N0 and ≤pT1N0 selection bias in the analysis of outcomes.
downstaging rates of 38% and 53%, respectively.26 A meta-analysis of 6 trials found a 25% mortality
Bevacizumab had no definitive impact on overall reduction with adjuvant chemotherapy, but the au-
outcomes. An international, multicenter, random- thors pointed out several limitations of the data and
ized trial (BA06 30894) investigating the effective- concluded that evidence is insufficient for treatment
ness of neoadjuvant cisplatin, methotrexate, and decisions.34 Interestingly, the follow-up analysis in-
vinblastine (CMV) in 976 patients showed a 16% cluded 3 more studies for a total of 9 trials (N=945
reduction in mortality risk (hazard ratio [HR], 0.84; patients).29 A 23% risk reduction for death was ob-
95% CI, 0.72–0.99; P=.037) at a median follow-up served in the updated analysis (HR, 0.77; 95% CI,
of 8 years.22 0.59–0.99; P=.049) and improved DFS was achieved
The NCCN Panel strengthened the recommen- (HR, 0.66; 95% CI, 0.45–0.91; P=.014). Patients
dations for neoadjuvant chemotherapy for patients with node-positive disease had an even greater DFS
with cT2, cT3, and cT4a bladder cancer without benefit.29 An observational study evaluated 5,653
nodal disease and for adjuvant chemotherapy for pa- patients, of which 23% received adjuvant chemo-
tients with pT3 or pT4 disease or positive nodes (see therapy after cystectomy.28 Patients who received
cT2, Primary and Adjuvant Treatment [page 1242] adjuvant chemotherapy had an improved OS (HR,
and cT3, cT4a, Primary and Adjuvant Treatment 0.70; 95% CI, 0.06–0.76).28 Although evidence for
[page 1243]). Neoadjuvant chemotherapy followed adjuvant therapy is not as strong as for neoadjuvant
by radical cystectomy is a category 1 recommenda- therapy, the growing body of data support the admin-
tion. Patients with hearing loss or neuropathy, poor istration of adjuvant chemotherapy for patients with
performance status, or renal insufficiency may not be a high risk for relapse who did not receive neoadju-
eligible for cisplatin-based chemotherapy. If neoad- vant therapy.
juvant cisplatin-based chemotherapy cannot be giv- The NCCN Guidelines suggest that adjuvant
en, neoadjuvant chemotherapy is not recommended. chemotherapy may be given to patients with high-
For patients with borderline renal function or mini- risk pathology who did not receive neoadjuvant che-
mal dysfunction, a split-dose administration of cis- motherapy, and it is considered a category 2A recom-
platin may be considered (category 2B). Although mendation. For highly select patients who receive a
split-dose is a safer alternative, the relative efficacy partial cystectomy, neoadjuvant chemotherapy is a
remains undefined. category 2A recommendation, with the option of
adjuvant chemotherapy for patients who did not re-
Adjuvant Chemotherapy ceive neoadjuvant chemotherapy.
Data are less clear regarding the role of adjuvant A minimum of 3 cycles of a cisplatin-based com-
systemic chemotherapy in invasive bladder cancer. bination, such as ddMVAC; gemcitabine plus cis-
Studies have shown that adjuvant chemotherapy platin (GC); or CMV, may be used in patients un-
may delay recurrences and improve OS,27–29 but no dergoing perioperative chemotherapy. Regimen and
randomized comparisons of adequate sample size dosing recommendations are mainly based on stud-
have definitively shown a survival benefit, in large ies in advanced disease.17,22,35–37 Carboplatin has not
part due to poor accrual.30 Clinical trials of adjuvant demonstrated a survival benefit and should not be
chemotherapy with cyclophosphamide, doxorubicin, substituted for cisplatin in the perioperative setting.
and cisplatin (CAP); MVAC; and methotrexate, It should be noted that patients with tumors that are
vinblastine, epirubicin, and cisplatin (MVEC) regi- ≤pT2 and have no nodal involvement or lympho-
mens have each suggested a survival advantage.31–33 vascular invasion after cystectomy are considered to
However, methodologic issues call into question have lower risk and are not recommended to receive
the applicability of these studies to all patients with adjuvant chemotherapy.
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NCCN Clinical Practice Guidelines in Oncology 1257
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1258 NCCN Clinical Practice Guidelines in Oncology
ic observation with TURBT alone, chemotherapy nal).61 No late grade 4 toxicities or treatment-related
alone, and concurrent chemoRT (if no previous deaths were recorded.
RT) are potential treatment options. When possible, Chemotherapy Following TURBT as Primary
bladder-sparing options should be chosen in the con- Treatment for MIBC
text of clinical trials. Chemotherapy alone is considered to be inadequate
RT With Concurrent Chemotherapy Following without additional treatment to the bladder and re-
TURBT as Primary Treatment for MIBC: Sev- mains investigational. Studies showed that the pro-
eral groups have investigated the combination of portions of pathologic CR rates in the bladder using
concurrent or sequential chemotherapy and RT af- neoadjuvant chemotherapy alone were only up to
ter TURBT. First, an endoscopic resection that is as 38%.17 A higher proportion of bladders can be ren-
complete as possible is performed. Incomplete resec- dered tumor-free and therefore preserved when che-
tion is an unfavorable prognostic factor for the abil- motherapy is combined with concurrent RT.
ity to preserve the bladder.53–55 RT Following TURBT as Primary Treatment for
Radiation Therapy Oncology Group protocol MIBC: RT alone is inferior to RT combined with
89-03 compared concurrent cisplatin and RT with chemotherapy for patients with an invasive bladder
or without 2 cycles of induction CMV.52 No differ- tumor, and is not considered standard for patients
ence in complete clinical response or 5-year OS was who can tolerate combined therapy.62,63 In a random-
observed between the treatment arms. Other studies ized trial of 360 patients, RT with concurrent mito-
also reported no significant survival benefit for neo- mycin C and 5-FU improved the 2-year locoregional
adjuvant chemotherapy before bladder-preserving DFS rate from 54% (RT alone) to 67% (P=.01), and
chemotherapy with radiation therapy.54,56 5-year OS rate from 35% to 48% (P=.16), without
Conversely, results from several prospective tri- increasing grade 3/4 acute or late toxicity.63 Hence,
als have demonstrated the effectiveness of this ap- RT alone is only indicated for those who cannot
proach. In the RTOG 89-03 trial in which 123 pa- tolerate a cystectomy or chemotherapy because of
tients with clinical stage T2–T4a were treated with medical comorbidities.
RT plus concurrent cisplatin, with or without in-
duction CMV, 5-year OS was approximately 49% TURBT Alone as Primary Treatment for MIBC:
in both arms.52 The subsequent RTOG 95-06 trial TURBT alone may be an option for patients with
treated 34 patients with twice-daily irradiation and cT2, cT3, or cT4a disease who are not candidates for
concurrent cisplatin and 5-FU and reported a 3-year cystectomy. TURBT alone may be curative in select-
OS rate of 83%.57 In the RTOG 97-06 trial, 47 pa- ed cases that include solitary lesions <2 cm that have
tients received twice-daily irradiation and concur- minimally invaded the muscle. These cases should
rent cisplatin, and also received adjuvant chemo- also have no associated in situ component, palpable
therapy with CMV58; the 3-year OS rate was 61%. mass, or associated hydronephrosis.64
In the RTOG 99-06 study, 80 patients received If considered for TURBT alone, patients should
twice-daily irradiation plus cisplatin and paclitaxel, undergo an aggressive re-resection of the site within
followed by adjuvant cisplatin and gemcitabine; the 4 weeks of the primary procedure to ensure that no
5-year OS rate was 56%.59 In RTOG 0233, 97 pa- residual disease is present. If the repeat TURBT is
tients received twice-daily radiation with concurrent negative for residual tumor, patients can be managed
paclitaxel plus cisplatin or 5-FU plus cisplatin; the conservatively with repeat endoscopic evaluations
5-year OS was 73%.60 Taken together, the CR rates and cytologies every 3 months until a relapse is doc-
ranged from 59% to 81%. umented. The stage of the lesion documented at re-
Up to approximately 80% of long-term survivors lapse would determine further management decisions.
maintain an intact bladder, whereas others ultimate-
ly require radical cystectomy.51–59 A combined analy- Treatment of T2, T3, and T4a Tumors
sis of survivors from these 4 trials, with a median fol- The critical issues in the management and progno-
low-up of 5.4 years, showed that combined-modality sis of these patients are whether a palpable mass is
therapy was associated with low rates of late grade 3 appreciated at EUA and if the tumor has extended
toxicity (5.7% genitourinary and 1.9% gastrointesti- through the bladder wall. Tumors that are organ-
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
NCCN Clinical Practice Guidelines in Oncology 1259
confined (T2) have a better prognosis than those vation or completion of RT up to 66 Gy. If residual
that have extended through the bladder wall into disease is present, cystectomy is preferred.
the perivesical fat (T3) and beyond. T4a tumors in- In patients with extensive comorbid disease or
volve the prostatic stroma, uterus, or vagina and are poor performance status who are noncystectomy
typically surgically managed similar to T3 tumors. candidates, treatment options include concurrent
Primary surgical treatment for cT2, cT3, and chemoRT, RT alone, or TURBT alone. Based on
cT4a lesions with no nodal disease seen on abdomi- high-level evidence showing superiority to RT alone,
nal/pelvic CT or MRI scan is a radical cystectomy the NCCN Panel recommends chemoRT with cispl-
and pelvic lymphadenectomy. Neoadjuvant chemo- atin alone or 5-FU and mitomycin C.62,63 The over-
therapy is recommended (category 1). If no neoad- all tumor status should be reassessed 2 to 3 months
juvant cisplatin-based chemotherapy is given, post- after treatment. If no tumor is evident, the patient
operative adjuvant chemotherapy may be considered should be observed. If tumor is observed, chemother-
based on pathologic risk, such as positive nodes or apy, concurrent chemoRT (if no prior RT), palliative
pT3–T4 lesions. TURBT, or best supportive care may be given.
Partial cystectomy along with neoadjuvant cis-
platin-based chemotherapy can be considered for Treatment of T4b Disease or Positive Nodes
cT2 disease with a single tumor in a suitable loca- For patients with cT4b disease and negative nodes
tion and no presence of Tis. Partial cystectomy is not on abdominal/pelvic CT or MRI scans or biopsy, the
an option for cT3 or cT4a patients. If no neoadju- primary treatment recommendation includes 2 to
vant therapy is given, adjuvant RT or chemotherapy 3 courses of chemotherapy with or without RT fol-
based on pathologic risk (ie, positive nodes, positive lowed by evaluation with cystoscopy, EUA, TURBT,
margin, high-grade lesions, pT3–T4 lesions) may be and imaging of the abdomen and pelvis. If no evi-
considered.
dence of tumor is present after primary treatment,
Bladder preservation with maximal TURBT fol-
consolidation chemotherapy or completion of de-
lowed by concurrent chemoRT may be considered.
finitive RT may be considered. If a partial radiation
Candidates for this bladder-sparing approach include
dose of 40 to 45 Gy was given as primary treatment,
patients with tumors that present without hydrone-
completion of definitive RT is recommended. Al-
phrosis or with tumors that allow a visibly complete
ternatively, adjuvant treatment with chemoRT may
or a maximally debulking TURBT. RT with con-
be initiated if the patient did not receive prior RT.
current cisplatin-based chemotherapy or 5-FU plus
mitomycin as a radiosensitizer is the most common In general, cT4b disease is considered unresectable.
and well-studied chemoRT method used to treat However, in patients with disease that responds to
MIBC.50–54,62,63,65 The following radiosensitizing regi- treatment, cystectomy may be an option if the tumor
mens are recommended: cisplatin plus 5-FU; cisplat- becomes technically resectable.
in plus paclitaxel; and 5-FU plus mitomycin C. Dou- If residual disease is noted upon evaluation af-
blet chemotherapy is generally preferred. Cisplatin ter primary therapy, systemic therapy or cystectomy
alone or low-dose gemcitabine (category 2B) may be is recommended. Systemic therapy may include a
considered as alternative regimens. checkpoint inhibitor, chemoRT (if no prior RT), or
After a complete TURBT, 60 to 66 Gy of ex- a change in chemotherapy. Cystectomy, if feasible, is
ternal-beam RT is administered. Two doses of con- an option.
current radiosensitizing chemotherapy may be given For patients with abnormal nodes documented
on weeks 1 and 4 (although weekly schedules are by imaging, a biopsy should be considered, if techni-
possible as well). Alternatively, an induction RT cally possible, to confirm nodal spread. Patients with
dose of 40 to 45 Gy may be given following com- positive nodes should receive chemotherapy with or
plete TURBT. The overall tumor status should be without radiation and should be evaluated with cys-
reassessed 3 weeks after radiation if 40 to 45 Gy was toscopy, EUA, TURBT, and abdominal/pelvic imag-
initially administered, or 2 to 3 months after if the ing. If no residual tumor is detected, patients may
full dose of 60 to 66 Gy was delivered. If no residual receive a radiation boost or a cystectomy. If tumor
tumor is detected, appropriate options include obser- is still present following primary therapy, these pa-
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1260 NCCN Clinical Practice Guidelines in Oncology
tients should follow treatment of recurrent or persis- For patients with a preserved bladder, local re-
tent disease. currence or persistent disease should be evaluated as
a new cancer. Recurrences are treated based on the
Follow-up extent of disease at relapse, with consideration of
Results from a meta-analysis of 13,185 patients who prior treatment. As previously discussed, Tis, Ta, or
have undergone cystectomy reported a 0.75% to 6.4% T1 tumors are generally managed with intravesical
prevalence of upper tract recurrence.66 Surveillance bacillus Calmette-Guérin (BCG) therapy or cystec-
by urine cytology or upper tract imaging detected re- tomy. If no response is noted after BCG treatment,
currences in 7% and 30% of cases, respectively. a cystectomy is advised. Invasive disease is generally
Follow-up after cystectomy should include urine managed with radical cystectomy, and a second at-
cytology, liver function tests, creatinine, and electro- tempt at bladder preservation is not advisable. Cys-
lytes. Imaging of the chest, upper tracts, abdomen, tectomy may not be possible in a patient who has
and pelvis should be conducted at intervals based undergone a full course of external-beam RT and has
on the recurrence risk. Patients should be monitored bulky residual disease. For these patients, palliative
annually for vitamin B12 deficiency if a continent uri- TURBT and best supportive care is advised.
nary diversion was created. Consider urethral wash Subsequent-line therapy for metastatic disease
cytology for patients with an ileal conduit or conti- or local recurrence includes checkpoint inhibitors,
nent catheterizable diversion, particularly if Tis was chemotherapy, chemoRT (if no previous RT) or RT
found within the bladder or prostatic urethra. For (see “Follow-up” in the complete version of these
details of follow-up recommendations, see “Follow- guidelines, at NCCN.org [BL-E], “Recurrent or Per-
up” in the complete version of these guidelines, at sistent Disease” on page 1246, and “Metastatic Uro-
thelial Bladder Cancer,” below).
NCCN.org (page BL-E).
Follow-up after a partial cystectomy is similar to
that for a radical cystectomy, with the addition of Metastatic Urothelial Bladder Cancer
monitoring for relapse in the bladder by serial cyto-
Approximately 4% of patients have metastatic dis-
logic examinations and cystoscopies (may include
ease at the time of diagnosis.2 Additionally, about
selected mapping biopsy).
half of all patients relapse after cystectomy depend-
For patients who have a preserved bladder, there
ing on the pathologic stage of the tumor and nodal
is a risk for recurrence in the bladder or elsewhere
status. Local recurrences account for approximately
in the urothelial tract and distantly. Imaging studies 10% to 30% of relapses, whereas distant metastases
and laboratory testing should be performed as out- are more common.
lined under post-cystectomy follow-up. Addition-
ally, continued monitoring of the urothelium with Evaluation of Metastatic Disease
cystoscopy and urinary cytologies with or without If metastasis is suspected, additional workup to eval-
mapping biopsy is a routine part of the management uate the extent of the disease is necessary. This in-
of all cases in which the bladder is preserved. cludes a chest CT and a bone scan if enzyme levels
are abnormal or the patient shows signs or symptoms
Recurrence or Persistent Disease of skeletal involvement. Central nervous system im-
Metastatic disease or local recurrence may be man- aging should be considered. An estimated glomeru-
aged with cystectomy, systemic therapy, or palliative lar filtration rate (GFR) should be obtained to as-
TURBT and best supportive care. sess patient eligibility for cisplatin. If the evidence
A positive cytology with no evidence of disease of spread is limited to nodes, nodal biopsy should
in the bladder should prompt retrograde selective be considered and patients should be managed as
washings of the upper tract and a biopsy of the pros- previously outlined for positive nodal disease (see
tatic urethra. If the results are positive, patients are “Treatment of cT4b Disease or Positive Nodes,” page
managed as described in the following sections for 1259, and cT4b, Primary and Adjuvant Treatment,
treatment of upper genitourinary tract tumors or uro- page 1244). Patients who present with disseminated
thelial carcinoma of the prostate. metastatic disease are generally treated with systemic
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
NCCN Clinical Practice Guidelines in Oncology 1261
chemotherapy. Management of persistent dissemi- tients with compromised liver or renal status or se-
nated disease may involve chemotherapy, radiation, rious comorbid conditions. In patients who are not
or a combination. cisplatin-eligible, atezolizumab or pembrolizumab
are now appropriate first-line options (see “Targeted
Chemotherapy for Metastatic Disease Therapies,” page 1262). Alternatively, carboplatin
The specific chemotherapy regimen recommended may be substituted for cisplatin in the metastatic set-
partially depends on the presence or absence of medi- ting for cisplatin-ineligible patients, such as those
cal comorbidities, such as cardiac disease and renal dys- with a GFR <60 mL/min. A phase II/III study as-
function, along with the risk classification of the patient sessed 2 carboplatin-containing regimens in medi-
based on disease extent. In general, long-term survival cally unfit patients (performance status 2).69 The
with combination chemotherapy alone has been report- overall response rate was 42% for gemcitabine plus
ed only in good-risk patients, defined as those with good carboplatin and 30% for methotrexate, carboplatin,
performance status, no visceral (ie, liver, lung) or bone and vinblastine. However, the response rates dropped
disease, and normal alkaline phosphatase or lactic de- to 26% and 20%, respectively, with increased toxic-
hydrogenase levels. Poor-risk patients, defined as those ity among patients who were both unfit and had re-
with poor performance status or visceral disease, have nal impairment (GFR <60 mL/min).
consistently shown very poor tolerance to multiagent Taxanes have been shown to be active as both
combination programs and few complete remissions, front-line and palliative therapies. Based on these re-
which are prerequisites for cure. sults, several groups are exploring 2- and 3-drug com-
GC67,68 and ddMVAC23,35 are commonly used in binations using these agents, with and without cispla-
combinations that have shown clinical benefit. A tin, as initial therapy. A randomized phase III trial was
large, international, phase III study randomized 405 conducted to compare GC and GC plus paclitaxel in
patients with locally advanced or metastatic disease 626 patients with locally advanced or metastatic uro-
to GC or standard (28-day) MVAC.37 At a median thelial cancer.70 The addition of paclitaxel to GC re-
follow-up of 19 months, OS and time to progression sulted in higher response rates and a borderline OS
were similar in the 2 arms. Fewer toxic deaths were advantage, which was not statistically significant in
recorded among patients receiving GC compared the intent-to-treat analysis. Analysis of eligible pa-
with MVAC (1% vs 3%), although this did not reach tients only (92%) resulted in a small (3.2 months) but
statistical significance. A 5-year update analysis con- statistically significant survival advantage in favor of
firmed that GC was not superior to MVAC in terms the 3-drug regimen (P=.03); there was no difference
of survival (OS, 13.0% vs 15.3% and PFS, 9.8% vs in PFS. The incidence of neutropenic fever was sub-
11.3%, respectively).68 Another large, randomized, stantially higher with the 3-drug combination (13.2%
phase III trial compared ddMVAC with standard vs 4.3%; P<.001). Panelists feel that the risk of adding
(28-day) MVAC.23,35 At a median follow-up of 7.3 paclitaxel outweighs the limited benefit reported from
years, 24.6% of patients were alive in the ddMVAC the trial. The alternative regimens, including cispla-
cohort compared with 13.2% in the standard MVAC tin/paclitaxel,71 gemcitabine/paclitaxel,72 cisplatin/
cohort. There was 1 toxic death in each arm, but less gemcitabine/paclitaxel,73 carboplatin/gemcitabine/pa-
overall toxicity was seen in the dose-dense group. clitaxel,74 and cisplatin/gemcitabine/docetaxel,75 have
From these data, ddMVAC had improved toxicity shown modest activity in patients with bladder can-
and efficacy compared with standard MVAC; there- cer in phase I–II trials. Category 1 level evidence now
fore, standard (28-day) MVAC is no longer used. supports the use of checkpoint inhibitors in patients
Both GC and ddMVAC with growth factor support with advanced disease previously treated with a plat-
are category 1 recommendations for metastatic dis- inum-containing regimen (see “Targeted Therapies,”
ease. Alternative first-line regimens also include car- page 1262).
boplatin or taxane-based regimens (category 2B) or Although current data are insufficient to recom-
single-agent chemotherapy (category 2B). mend the above alternative regimens as routine first-
The performance status of the patient is a major line options, non-cisplatin-containing regimens may
determinant in the selection of a regimen. Regimens be considered in patients who cannot tolerate cis-
with lower toxicity profiles are recommended in pa- platin because of renal impairment or other comor-
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1262 NCCN Clinical Practice Guidelines in Oncology
bidities (see “Principles of Systemic Therapy,” page currence after cystectomy. However, concurrent
1249–1251). Additionally, 2 checkpoint inhibitors, chemotherapy is inappropriate if high-dose radia-
atezolizumab and pembrolizumab, have been FDA- tion (>3 Gy fractions) is used. The radiosensitiz-
approved for use as a first-line therapy in these pa- ing chemotherapy regimens remain controversial in
tients. Consideration of checkpoint inhibitors must this setting. Possible options include cisplatin (cat-
be integrated into the therapeutic planning for all egory 2A); docetaxel or paclitaxel (category 2B);
patients with locally advanced and metastatic dis- 5-FU with or without mitomycin C (category 2B);
ease (see “Targeted Therapies,” next column). The capecitabine (category 3); and low-dose gemcitabine
NCCN Panel recommends enrollment in clinical (category 2B). RT alone can also be considered as a
trials of potentially less toxic therapies. subsequent-line therapy for patients with metastatic
Independent of the specific regimen used, pa- disease.
tients with metastatic disease are re-evaluated after
2 to 3 cycles of chemotherapy, and treatment is con- Targeted Therapies
tinued for 2 more cycles in patients whose disease Platinum-based chemotherapy has been the standard
responds or remains stable. Chemotherapy may be of care in patients with metastatic disease, with an
continued for a maximum of 6 cycles, depending on OS of 9 to 15 months.68,80 However, in patients with
response. If no response is noted after 2 cycles or if disease that relapses after this type of chemotherapy,
significant morbidities are encountered, a change in the median survival is reduced to 5 to 7 months.81
therapy is advised, taking into account the patient’s Several new agents, notably checkpoint inhibitors
current performance status, extent of disease, and for the treatment of metastatic urothelial carcinoma,
specific prior therapy. A change in therapy is also have data supporting improved outcomes compared
advised for patients who experience systemic relapse with standard therapies. Cancers with higher rates
after adjuvant chemotherapy. of somatic mutations have been shown to respond
Studies have shown that surgery or RT may be
better to checkpoint inhibitors.82–87 Data from The
feasible in highly select cases for patients who show
Cancer Genome Atlas rank bladder cancer as the
a major partial response in a previously unresectable
third highest mutated cancer,88,89 suggesting that
primary tumor or who have a solitary site of residual
checkpoint inhibitors may have a substantial impact
disease that is resectable after chemotherapy. In se-
as a treatment option for this cancer.
lected series, this approach has been shown to afford
The FDA has approved the PD-L1 inhibitors at-
a survival benefit. If disease is completely resected,
ezolizumab, durvalumab, and avelumab as well as the
2 additional cycles of chemotherapy can be consid-
PD-1 inhibitors nivolumab and pembrolizumab for
ered, depending on patient tolerance.
Clinical trial enrollment is recommended by the patients with urothelial carcinoma. Pembrolizum-
NCCN Panel for all patients when appropriate, but ab, atezolizumab, nivolumab, durvalumab, and ave-
is strongly recommended for subsequent-line therapy, lumab are approved for the treatment of locally ad-
because data for locally advanced or metastatic dis- vanced or metastatic urothelial cell carcinoma that
ease treated with subsequent-line therapy are highly has progressed during or after platinum-based che-
variable. The available options depend on what was motherapy or that has progressed within 12 months
given as first line. Regimens used in this setting in- of neoadjuvant or adjuvant platinum-containing
clude checkpoint inhibitors, and the following che- chemotherapy, regardless of PD-L1 expression levels.
motherapies: docetaxel, paclitaxel, gemcitabine, or Additionally, atezolizumab and pembrolizumab are
pemetrexed monotherapy.76–79 Other options include approved as a first-line treatment option for patients
nab-paclitaxel; ifosfamide; methotrexate; ifosfamide, with locally advanced or metastatic urothelial cell
doxorubicin, and gemcitabine; gemcitabine and pa- carcinoma who are not eligible for cisplatin-contain-
clitaxel; GC; and ddMVAC. ing chemotherapy. All of these approvals as a subse-
quent treatment option have been based on category
Chemoradiotherapy for Metastatic Disease 2 level evidence, with the exception of pembroli-
Chemotherapy is sometimes combined with pal- zumab, which has category 1 level evidence support-
liative radiation to treat metastases or pelvic re- ing the approval.
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
NCCN Clinical Practice Guidelines in Oncology 1263
Pembrolizumab is a PD-1 inhibitor that has been of patients showing a CR. Median OS was 15.9
evaluated as second-line therapy for patients with months, and grade 3 or 4 treatment-related AEs oc-
bladder cancer who previously received platinum- curred in 16% of patients.94 A May 2017 press release
based therapy and subsequently progressed or me- reported that the phase III IMvigor211 study evalu-
tastasized.90 An open-label, randomized, phase III ating atezolizumab compared with chemotherapy in
trial compared pembrolizumab versus chemotherapy patients with metastatic urothelial carcinoma post-
(paclitaxel, docetaxel, or vinflunine) in 542 patients platinum treatment did not meet its primary end
with advanced urothelial carcinoma that recurred or point of OS.95 Further examination of the data is on-
progressed after platinum-based chemotherapy. Data going to better understand the results and define the
from this trial showed a longer median OS for pa- role of atezolizumab as a post-platinum treatment
tients treated with pembrolizumab compared with option for metastatic urothelial carcinoma.
chemotherapy (10.3 vs 7.4 months; P=.002). In ad- A phase II trial in patients with locally advanced
dition, fewer grade 3, 4, or 5 treatment-related ad- or metastatic urothelial carcinoma that progressed
verse events (AEs) occurred in the pembrolizumab- after at least 1 platinum-containing regimen report-
treated patients compared with those treated with ed an overall objective response in 52 of 265 patients
chemotherapy (15.0% vs 49.4%).91 Results from this (19.6%; 95% CI, 15.0–24.9) after treatment with
phase III trial have lead the NCCN Panel to assign nivolumab, which was unaffected by PD-1 tumor sta-
pembrolizumab a category 1 recommendation as a tus.96 Of the 270 patients enrolled in the study, grade
second-line therapy. A phase II trial evaluated pem- 3 or 4 treatment-related AEs were reported in 18%,
brolizumab as a first-line therapy in 370 patients with and 3 resulted from treatment.96 The median OS was
advanced urothelial carcinoma who were ineligible 8.74 months (95% CI, 6.05–not yet reached). Based
for cisplatin-based therapy. Data from this study on PD-L1 expression of <1% and ≥1%, OS was 5.95
showed an overall response rate of 29%, with 7% of to 11.3 months, respectively. These data are compa-
patients achieving a CR. Grade 3 or 4 treatment- rable to the early phase I/II data reporting an ORR of
related AEs occurred in 18% of patients treated with 24% (95% CI, 15.3%–35.4%) that was unaffected by
pembrolizumab.92 PD-1 tumor status.97 Of the 78 patients enrolled in
Data from a 2-cohort, multicenter, phase II trial this study, 2 experienced grade 5 treatment-related
evaluated atezolizumab in patients with metastatic AEs, and grade 3 or 4 treatment-related AEs were
disease. Cohort 2 of the trial enrolled 310 patients reported in 22% of patients.97
with metastatic urothelial carcinoma post-platinum Early results from a phase I/II multicenter study
treatment and showed a significantly improved over- of durvalumab for 61 patients with PD-L1–positive
all response rate compared with historical controls inoperable or metastatic urothelial bladder cancer
(15% vs 10%; P=.0058).93 Follow-up to date suggests whose tumor had progressed during or after one stan-
these responses may be durable, with ongoing re- dard platinum-based regimen showed that 46.4% of
sponses recorded in 38 (84%) of 45 responders with patients who were PD-L1–positive had disease that
a median follow-up of 11.7 months. Although a sim- responded to treatment; no response was seen in pa-
ilar response rate was seen regardless of PD-L1 status tients who were PD-L1–negative.98 A 2017 update
of tumor cells, a greater response was associated with on this study (N=103) showed a 29.5% ORR for
increased PD-L1 expression status on infiltrating im- PD-L1–high disease and a 7.7% ORR for PD-L1–
mune cells in the tumor microenvironment. Grade 3 low/negative disease. The OS rate at 6 months was
or 4 treatment-related or immune-mediated AEs oc- 68.4% for the PD-L1–high group and 44.7% for the
curred in 16% and 5% of patients, respectively. Fur- PD-L1–low/negative group. Median duration of re-
thermore, there were no treatment-related deaths in sponse was not yet reached at the time of data cut-
this trial, suggesting good tolerability. In cohort 1 of off. Grade 3 or 4 treatment-related AEs occurred in
the same phase II trial, atezolizumab was evaluated 5.2% of treated patients and 3 patients had a grade 3
as a first-line therapy in 119 patients with locally ad- or 4 immune-mediated AE.99
vanced or metastatic urothelial carcinoma who were Avelumab is another PD-L1 inhibitor currently
ineligible for cisplatin. Data from this study showed in clinical trials to evaluate its activity in the treat-
an objective response rate (ORR) of 23%, with 9% ment of bladder cancer. Results from the phase 1b
© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 15 Number 10 | October 2017
1264 NCCN Clinical Practice Guidelines in Oncology
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invasive bladder cancer by transurethral resection. Urology 2007;70:473–
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