Bladder Cancer Treatment Regimens

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BLADDER CANCER TREATMENT REGIMENS

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Perioperative Chemotherapy (Neoadjuvant or Adjuvant)1,a

Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Dose-dense methotrexate + vinblastine + doxorubicin + cisplatin (DDMVAC) with growth factor support2,3

Day 1: Methotrexate 30mg/m2 IV

Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV

Day 4: Granulocyte colony-stimulating factor (G-CSF) 240μg/m2 subcutaneous (SQ) injection for 7 consecutive days (days 4 through 10). May be extended for up to a total of 14 consecutive days.

Repeat every 2 weeks for 3–4 cycles.

Gemcitabine + cisplatin4–6

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes

Day 2: Cisplatin 70mg/m2.

Repeat every 4 weeks for 4 cycles.

Cisplatin + methotrexate + vinblastine (CMV)7

Day 1: Methotrexate 30mg/m2 IV bolus plus vinblastine 4mg/m2 IV bolus

Day 2: Cisplatin 100mg/m2 IV infusion; followed by hydration; followed by leucovorin 15mg orally or IV every 6 hours for 4 doses (commencing 24 hours after methotrexate on day 1)

Day 8: Methotrexate 30mg/m2 IV bolus plus vinblastine 4mg/m2 IV bolus

Day 9: Leucovorin 15mg orally every 6 hours for 4 doses after methotrexate on day 8.

Repeat every 3 weeks for 3 cycles.

Principles of Chemotherapy Management

• 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.2,8,9

• Meta-analysis suggests a survival benefit to adjuvant therapy for pathologic T3, T4, or N+ disease at cystectomy.9

• Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy on a higher level of evidence data.

• DDMVAC is preferred over standard MVAC based on category I evidence showing DDMVAC to be better tolerated and more effective than conventional MVAC in advanced disease.3,10 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 I evidence showing equivalence to conventional MVAC in the setting of advanced disease.5,6

• 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.11

• 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 35mg/m2 on days 1 and 2 or days 1 and 8; category 2B). Although safer, the relative efficacy of the cisplatin-containing combination administered with such modifications remains undefined.

• For patients with borderline renal function, estimate glomerular filtration rate to assess eligibility for cisplatin.

First-Line Chemotherapy for Locally Advanced or Metastatic Disease1,a

Cisplatin Eligible (Standard Regimens)

Gemcitabine + cisplatin (Category 1)6

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes

Day 2: Cisplatin 70mg/m2.

Repeat every 4 weeks for a maximum of 6 cycles.

DDMVAC with growth factor support (Category 1)3,10

Day 1: Methotrexate 30mg/m2 IV

Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV

Day 4: G-CSF 240μg/m2 SQ injection for 7 consecutive days (days 4 through 10). May be extended for up to a total of 14 consecutive days.

Repeat every 2 weeks for 3–4 cycles.

OR

Day 1: Methotrexate 30mg/m2 IV

Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV

Day 3: G-CSF SQ injection for 5 consecutive days (days 3 through 7).

Repeat cycle every 15 days.

Cisplatin Ineligible (Standard Regimens)

Gemcitabine + carboplatin12

Days 1 and 8: Gemcitabine 1,000mg/m2 over 30 minutes IV

Day 1 (every 3 weeks): Carboplatin (4.5 × [glomerular filtration rate + 25]) over 1 hour IV.

Atezolizumab13

Atezolizumab 1200mg IV infusion over 60 minutes every 3 weeks.

Pembrolizumab14

Pembrolizumab 200mg every 3 weeks.

Principles of Chemotherapy Management

• The presence of both visceral metastases and Eastern Cooperative Oncology Group 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.18

• 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.

Cisplatin Ineligible (Alternative Regimens)

Gemcitabine15

Gemcitabine 1200mg/m2 administered weekly x3 on a 4-week cycle.

Gemcitabine + paclitaxel16

Gemcitabine 2500mg/m2 over 30 minutes, plus paclitaxel 150mg/m2 over 3 hours given every 2 weeks.

Ifosfamide + doxorubicin + gemcitabine17 (For patients with good kidney function and good performance status)

Days 1–4: Ifosfamide 1500mg/m2 infused over 3 hours daily, plus MESNa 225mg/m2 over 15 minutes at hours 0, 3, 7, and 11

Day 3: Doxorubicin 45mg/m2 over 15 minutes via peripheral IV or up to 12–18 hours via central line on day 3 only

Days 2 and 4: Gemcitabine 150mg/m2 over 30 minutes.

Subsequent Systemic Therapy for Locally Advanced or Metastatic Disease1,a

Standard Regimens

Pembrolizumab (Category 1)19

Pembrolizumab 200mg every 3 weeks.

Atezolizumab20

Atezolizumab 1200mg IV winfusion over 60 minutes every 3 weeks.

Nivolumab21

Nivolumab 3mg/kg IV every 2 weeks.

Durvalumab22

Durvalumab 10mg/kg once every 2 weeks up to 12 months, unacceptable toxicity, or confirmed progressive disease.

Avelumab23,24

Avelumab 10mg/kg IV over 1 hour every 2 weeks.

Paclitaxel or docetaxel25,26

Paclitaxel 80mg/m2 every week

OR

Docetaxel 100mg/m2 over 1 hour every 21 days.

Gemcitabine15

Gemcitabine 1200mg/m2 administered weekly x3 on a 4-week cycle.

Pemetrexed27

Day 1: Pemetrexed 500mg/m2 IV every 21 days, plus vitamin B12, folic acid, and dexamethasone prophylaxis.

Alternate Regimens for Select Patients

Nab-paclitaxel28

Nab-paclitaxel at 260mg/m2 IV every 3 weeks.

Ifosfamide29

Ifosfamide to 1,500mg/m2 IV with MESNa 750 mg/m2 IV for 5 days every 3 weeks, with doses modified for hematologic, renal, and central nervous system toxicity.

Methotrexate

Follow usual protocols.

Ifosfamide + doxorubicin + gemcitabine17

Days 1–4: Ifosfamide 1500mg/m2 infused over 3 hours daily, plus MESNa 225mg/m2 over 15 minutes at hours 0, 3, 7, and 11

Day 3: Doxorubicin 45mg/m2 over 15 minutes via peripheral IV or up to 12–18 hours via central line on day 3 only

Days 2 and 4: Gemcitabine 150mg/m2 over 30 minutes.

Gemcitabine + paclitaxel16

Gemcitabine 2500mg/m2 over 30 minutes, plus paclitaxel 150mg/m2 over 3 hours given every 2 weeks.

Gemcitabine + cisplatin5

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV over 30–60 minutes

Day 2: Cisplatin 70mg/m2.

Repeat every 4 weeks for a maximum of 6 cycles.

DDMVAC3

Day 1: Methotrexate 30mg/m2 IV

Day 2: Vinblastine 3mg/m2 IV, plus doxorubicin 30mg/m2 IV, plus cisplatin 70mg/m2 IV

Repeat every 2 weeks for 3–4 cycles.

First-Line Radiosensitizing Chemotherapy Regimens1,a,b

First-line Standard Chemotherapy Regimens (Doublet Preferred)

Cisplatinc + 5-FU30

Days 1, 2, 3, 15, 16, and 17: IV hydration at a rate of 500mL/hour; followed by 5-FU 400mg/m2 IV push; followed by cisplatin 15mg/m2 IV over 1 hour as induction and consolidation therapy.

Cisplatinc + paclitaxel30,31

Days 1, 8, and 15: Paclitaxel 50mg/m2

Day 1–3, 8–10, 15–17: Cisplatin 15mg/m2; followed by twice-daily radiotherapy for 8 days.f

5-FU + mitomycin32

Day 1 of radiotherapy: Mitomycin 12mg/m2 IV bolus, plus

Week 1 (fractions 1–5) and Week 4 (fractions 16–20) of radiotherapy: 5-FU 500mg/m2 continuous IV infusion (10 days total).d

Alternate Regimens

Cisplatinc alone33

Cisplatin 100mg/m2 IV every 2 weeks for 3 cycles.

Low-dose gemcitabine (Category 2B)34,35

Gemcitabine 75mg/m2 IV weekly given concurrently with radiotherapy.

Radiosensitizing Chemotherapy With Conventionally Fractionated Radiation1,a,e

Cisplatinc

Taxane (docetaxel or paclitaxel; Category 2B)

5-FU ± mitomycin (both Category 2B)

Capecitabine (Category 3)

Low-dose gemcitabine (Category 2B)

a Participation in clinical trials of new agents is recommended.

b For bladder-preserving chemoradiation following a maximal transurethral resection of bladder tumor.

c Carboplatin in not an effective radiation sensitizer and should not be substituted for cisplatin with radiation.

d On days 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy (with at least a 4-hour interfraction interval).

e For palliation of metastases or for pelvic recurrence after cystectomy.

f Upon complete or near complete response, patients received consolidation chemoradiation consisting of 1.5 Gy pelvic radiotherapy twice a day for 8 days to 24 Gy (total dose: 64.3 Gy to the tumor and 44.8 Gy to the pelvic lymph nodes) and paclitaxel 50mg/m2 days 1 and 8 and cisplatin 15mg/m2 on days 1, 2, 8, and 9.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Bladder Cancer. v 5.2017. Available at: http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed February 19, 2016.

2. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–866.

3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19(10):2638–2646.

4. Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471–2477.

5. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–3077.

6. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–4608.

7. Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171–2177.

8. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–205.

9. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Eur Urol. 2005;48(2):189–199.

10. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50–54.

11. Soto Parra H, Cavina R, Latteri F, et al. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002;13(7):1080–1086.

12. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012; 30(2):191–199.

13. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76.

14. Balar AV, Castellano DE, O'Donnell PH, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population. J Clin Oncol. 2017;35(suppl 6):284–285.

15. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997;15(11):3394–3398.

16. Calabrò F, Lorusso V, Rosati G, et al. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009;115(12):2652–2659.

17. Siefker-Radtke A, Dinney C, Shen Y, et al. A phase II clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine, followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: final results. Cancer. 2013;119(3):10.1002/cncr.27751.

18. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30(10):1107–1113.

19. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376 (11):1015–1026.

20. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–1920.

21. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–322.

22. Powles T, O'Donnell PH, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2017;35(suppl 6):286.

23. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti–programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase 1b study. J Clin Oncol. 2017 Apr 4: JCO2016716795. doi: 10.1200/JCO.2016.71.6795.

24. Patel MR, Ellerton JA, Infante JR, et al. Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor trial. J Clin Oncol. 2017;35(suppl 6):330.

25. Sideris S, Aoun F, Zanaty M, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016;4(6):1063–1067. doi:10.3892/mco.2016.821.

26. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15(5):1853–1857.

27. Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24(21):3451–3457.

28. Ko YJ, Canil CM, Mukherjee SD, et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013;14(8):769–776.

29. Witte RS, Elson P, Bono B, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997;15(2):589–593.

30. 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(9):863–872.

31. 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(4):705–711.

32. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366:1477–1488.

33. Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol. 1996;14:2901–2907.

34. Kent E, Sandler H, Montie J, et al. Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial. J Clin Oncol. 2004;22(13):2540–2545.

35. Choudhury A, Swindell R, Logue JP, et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol. 2011;29(6):733–738.

(Revised 7/2017)

© 2017 Haymarket Media, Inc.


Genitourinary Cancer Drug Monographs

Bladder, Kidney, And Other Urologic Cancers

AFINITOR AVASTIN CABOMETYX
Cisplatin COSMEGEN DEPO-PROVERA
Doxorubicin HCl Doxorubicin HCl Solution INLYTA
LENVIMA NEXAVAR OPDIVO
PROLEUKIN SUTENT TECENTRIQ
Thiotepa TICE BCG TORISEL
VALSTAR VINCASAR PFS VOTRIENT

Prostate And Other Male Cancers

Bleomycin CASODEX Cisplatin
COSMEGEN DELESTROGEN ELIGARD
EMCYT ESTRACE ETOPOPHOS
FIRMAGON Flutamide IFEX
JEVTANA Leuprolide acetate LUPRON DEPOT 7.5mg
LUPRON DEPOT-3 MONTH 22.5mg LUPRON DEPOT-4 MONTH 30mg LUPRON DEPOT-6 MONTH 45mg
MENEST Mitoxantrone HCl NILANDRON
PREMARIN PROVENGE TAXOTERE
TOPOSAR TRELSTAR VANTAS
Vinblastine for injection Vinblastine injection XOFIGO
XTANDI ZOLADEX ZOLADEX 3-MONTH 10.8mg
ZYTIGA

Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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