Upper tract urothelial carcinoma

Section editor
	Ali Raza Khaki, MD Stanford University Palo Alto, CA, USA LinkedIn

For placebo or observational studies in this condition, please visit this page.

3 regimens on this page 6 variants on this page

Note: the page has regimens specific to upper tract urothelial carcinoma. Please see the urothelial carcinoma page for regimens intended more generically for urothelial cancer.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Bladder Cancer.

Adjuvant therapy

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin

Regimen variant #1, 4.5/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Birtle et al. 2020 (POUT)	2012-2017	Phase 3 (E-esc)	Observation	Superior DFS1 (primary endpoint) DFS60: 62% vs 45% (HR 0.55, 95% CI 0.38-0.80) Might have superior OS1 (secondary endpoint) OS60: 66% vs 57% (HR 0.68, 95% CI 0.46-1.00)

¹Reported efficacy is based on the 2024 update.
Note: carboplatin was administered if GFR was less than 50 mL/min.

Preceding treatment

• Nephroureterectomy with pathologic stage pT2–T4 pN0–N3 M0 or pTany N1–3 M0 performed within preceding 90 days

Chemotherapy

• Carboplatin (Paraplatin) AUC 4.5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

Regimen variant #2, 5/1000

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Birtle et al. 2020 (POUT)	2012-2017	Phase 3 (E-esc)	Observation	Superior DFS1 (primary endpoint) DFS60: 62% vs 45% (HR 0.55, 95% CI 0.38-0.80) Might have superior OS1 (secondary endpoint) OS60: 66% vs 57% (HR 0.68, 95% CI 0.46-1.00)

¹Reported efficacy is based on the 2024 update.
Note: carboplatin was administered if GFR was less than 50 mL/min.

Preceding treatment

• Nephroureterectomy with pathologic stage pT2–T4 pN0–N3 M0 or pTany N1–3 M0 performed within preceding 90 days

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. POUT: Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, Harris C, Winterbottom A, Blacker A, Catto JWF, Chakraborti P, Donovan JL, Elliott PA, French A, Jagdev S, Jenkins B, Keeley FX Jr, Kockelbergh R, Powles T, Wagstaff J, Wilson C, Todd R, Lewis R, Hall E. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020 Apr 18;395(10232):1268-1277. Epub 2020 Mar 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01993979
   1. Update: Birtle AJ, Jones R, Chester J, Lewis R, Biscombe K, Johnson M, Blacker A, Bryan RT, Catto JWF, Choudhury A, Das P, Jagdev S, Powles T, Wagstaff J, Cheung KC, Cafferty F, Hall E. Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. J Clin Oncol. 2024 May 1;42(13):1466-1471. Epub 2024 Feb 13. link to original article link to PMC article PubMed

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Birtle et al. 2020 (POUT)	2012-2017	Phase 3 (E-esc)	Observation	Superior DFS1 (primary endpoint) DFS60: 62% vs 45% (HR 0.55, 95% CI 0.38-0.80) Might have superior OS1 (secondary endpoint) OS60: 66% vs 57% (HR 0.68, 95% CI 0.46-1.00)

¹Reported efficacy is based on the 2024 update.

Preceding treatment

• Nephroureterectomy with pathologic stage pT2–T4 pN0–N3 M0 or pTany N1–3 M0 performed within preceding 90 days

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles

References

1. POUT: Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, Harris C, Winterbottom A, Blacker A, Catto JWF, Chakraborti P, Donovan JL, Elliott PA, French A, Jagdev S, Jenkins B, Keeley FX Jr, Kockelbergh R, Powles T, Wagstaff J, Wilson C, Todd R, Lewis R, Hall E. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020 Apr 18;395(10232):1268-1277. Epub 2020 Mar 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01993979
   1. Update: Birtle AJ, Jones R, Chester J, Lewis R, Biscombe K, Johnson M, Blacker A, Bryan RT, Catto JWF, Choudhury A, Das P, Jagdev S, Powles T, Wagstaff J, Cheung KC, Cafferty F, Hall E. Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial. J Clin Oncol. 2024 May 1;42(13):1466-1471. Epub 2024 Feb 13. link to original article link to PMC article PubMed

Pirarubicin monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ito et al. 2013 (THP Monotherapy Study Group Trial)	2005-2008	Randomized Phase 2 (E-esc)	Observation	Seems to have superior RFS (primary endpoint)

Pirarubicin was given within 48 hours after nephroureterectomy.

Preceding treatment

• Nephroureterectomy

Chemotherapy

• Pirarubicin (THP) 30 mg in 30 mL normal saline intravesicularly, delivered through a catheter into the bladder, and retained for 30 minutes

1 dose

References

1. THP Monotherapy Study Group Trial: Ito A, Shintaku I, Satoh M, Ioritani N, Aizawa M, Tochigi T, Kawamura S, Aoki H, Numata I, Takeda A, Namiki S, Namima T, Ikeda Y, Kambe K, Kyan A, Ueno S, Orikasa K, Katoh S, Adachi H, Tokuyama S, Ishidoya S, Yamaguchi T, Arai Y. Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol. 2013 Apr 10;31(11):1422-7. Epub 2013 Mar 4. link to original article contains dosing details in manuscript PubMed UMIN000004039

Definitive therapy

Mitomycin pyelocalyceal monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy	Toxicity
Kleinmann et al. 2020 (OLYMPUS)	2017-2018	Non-randomized Phase 3 (RT)	Primary endpoint CR 59% (95% CI 47-71) ORR 70%	Serious AE: 27% (e.g. ureteric stenosis, hydronephrosis, flank pain, urosepsis)

Chemotherapy

• Mitomycin pyelocalyceal (Jelmyto) 4 mg/mL gel to renal pelvis and calyces via retrograde ureteral catheter
  • Instilled volume for each patient determined by averaging three fluoroscopically guided volumetric measurements of patient's renal pelvis and calyces
  • Reverse thermal properties of UGN-101 allows for local administration as a liquid with subsequent conversion to semi-solid gel depot following instillation into upper tract; normal urine flow dissolves gel depot, allowing tissue exposure to mitomycin over 4 to 6 hrs

7-day cycle for 6 cycles

References

1. OLYMPUS: Kleinmann N, Matin SF, Pierorazio PM, Gore JL, Shabsigh A, Hu B, Chamie K, Godoy G, Hubosky S, Rivera M, O'Donnell M, Quek M, Raman JD, Knoedler JJ, Scherr D, Stern J, Weight C, Weizer A, Woods M, Kaimakliotis H, Smith AB, Linehan J, Coleman J, Humphreys MR, Pak R, Lifshitz D, Verni M, Adibi M, Amin MB, Seltzer E, Klein I, Konorty M, Strauss-Ayali D, Hakim G, Schoenberg M, Lerner SP. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020 Jun;21(6):776-785. Epub 2020 Apr 29. link to original article contains dosing details in abstract PubMed NCT02793128

Urine assays

These are assays intended/being investigated as adjuncts to urine cytology and cystoscopy.

• Cxbladder (uRNA-2), a "urine based bladder cancer test (uRNA-2) which detects RNA markers in urine."
• ImmunoCyt™/uCyt+™, a cell-based detection assay which "uses fluorescent-labeled antibodies to 3 markers that are commonly found on malignant exfoliated urothelial cells."
• UroVysion (Abbott Molecular) "designed to detect aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer."