18 juli 2020: Bron: The Lancet. 2020 Apr 18; 395(10232): 1268–1277.

Chemotherapie met een combinatie van gemcitabine met cisplatin of carboplatin die binnen 90 dagen na een nieroperatie - nefrodetectomie werd gestart, verbeterde de ziektevrije overleving op drie jaars meting met 25 procent in vergelijking met een wait-and-see programma bij patiënten met lokaal gevorderde UTUC - kanker van de bovenste urinewegen (Urotheel carcinoom). Kanker van de bovenste urinewegen is een vorm van kanker die overigens zelden voorkomt, gemiddeld bij 2 op de 100.000 mensen. Het is wel bijzonder dat na een nieroperatie er toch chemotherapie wordt gebruikt. Want voor nierkanker werkt chemotherapie niet.

Uit het studierapport:

Urotheliale carcinomen van de bovenste urinewegen (UTUC's) zijn zeldzaam, met een slechtere prognose voor elk stadium dan urotheelcarcinomen van de urineblaas. Er bestaat geen internationale consensus over het voordeel van adjuvante chemotherapie voor patiënten met UTUC's na nefureterectomie met curatieve intentie.

De Engelse onderzoekers hebben POUT - een fase III, open-label, gerandomiseerde gecontroleerde studie uitgevoerd bij 291 patiënten gehaald uit maar liefst 71 ziekenhuizen in het VK.

Zij kozen patiënten met UTUC nadat een robot gestuurde kijkoperatie van een nier - nefrodetectomie was uitgevoerd. De deelnemers werden gerandomiseerd (1: 1) toegewezen aan een surveillancegroep - wait-and-see (N = 129) en aan een groep (N = 132) die vier kuren van 21 dagen met chemotherapie kregen. Chemotherapie was ofwel cisplatin (70 mg / m2) of carboplatin intraveneus toegediend op dag 1 en gemcitabine (1000 mg / m2) intraveneus toegediend op dag 1 en 8; chemotherapie werd gestart binnen 90 dagen na de nieroperatie - nefrodetectomie.

Aanvullende chemotherapie verbeterde significant de ziektevrije overleving (hazard ratio 0,45, 95% BI 0,30 - 0,68; p = 0 0001) bij een mediane follow-up van 30-3 maanden (IQR 18 · 0–47 · 5). De ziektevrije percentages voor drie jaar zonder recidief waren respectievelijk 71% voor de chemotherapiegroep (95% BI 61–78) en 46% (36–56) voor de surveillancegroep.
55 (44 %) van de 126 deelnemers die chemotherapie hadden gehad hadden bijwerkingen van acute graad 3 of erger tijdens de behandeling. Deze bijwerkingen kwamen overeenkwamen met vaak gerapporteerde bijwerkingen voor dit chemotherapieschema. Vijf (4%) van de 129 patiënten uit de surveillancegroep, hadden acute graad 3 of erger optredende bijwerkingen. Er zijn geen behandelingsgerelateerde sterfgevallen gemeld.

Het volledige studierapport, gepubliceerd in The Lancet: Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial is gratis in te zien.

Hier het abstract van de studie:

. 2020 Apr 18; 395(10232): 1268–1277.

doi: 10.1016/S0140-6736(20)30415-3

PMCID: PMC7181180

PMID: 32145825

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial

Alison Birtle, MD,a,b,* Mark Johnson, MD,c John Chester, Prof, PhD,d Robert Jones, Prof, PhD,e David Dolling, PhD,f Richard T Bryan, PhD,g Christopher Harris,h,† Andrew Winterbottom,i,† Anthony Blacker, MBChB,j James W F Catto, Prof, PhD,k Prabir Chakraborti, MD,l Jenny L Donovan, Prof, PhD,m Paul Anthony Elliott, PhD,n Ann French, MSc,o Satinder Jagdev, MDRB,p Benjamin Jenkins, MSc,f Francis Xavier Keeley, Jr, MD,q Roger Kockelbergh, MBChB,r Thomas Powles, Prof, PhD,s John Wagstaff, Prof, MD,t Caroline Wilson, PhD,m Rachel Todd, MSc,f Rebecca Lewis, BSc,f and Emma Hall, Prof, PhDf

Author information Copyright and License information Disclaimer

Summary

Background

Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.

Methods

We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve 4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.

Findings

Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.

Interpretation

Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.

Funding

Cancer Research UK.

References

1. Roupret M, Babjuk M, Comperat E. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol. 2018;73:111–122. [PubMed] [Google Scholar]

2. Audenet F, Yates DR, Cussenot O, Rouprêt M. The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC) Urol Oncol. 2013;31:407–413. [PubMed] [Google Scholar]

3. International Collaboration of Trialists 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;29:2171–2177. [PMC free article] [PubMed] [Google Scholar]

4. Loehrer PJ, Sr, Einhorn LH, Elson PJ. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066–1073. [PubMed] [Google Scholar]

5. Sternberg CN, Skoneczna I, Kerst JM. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16:76–86. [PubMed] [Google Scholar]

6. Moschini M, Shariat SF, Roupret M. Impact of primary tumor location on survival from the European Organization for the Research and Treatment of Cancer advanced urothelial cancer studies. J Urol. 2018;199:1149–1157. [PubMed] [Google Scholar]

7. Chitale S, Mbakada R, Irving S, Burgess N. Nephroureterectomy for transitional cell carcinoma: the value of pre-operative histology. Ann R Coll Surg Engl. 2008;90:45–50. [PMC free article] [PubMed] [Google Scholar]

8. Leow JJ, Martin-Doyle W, Fay AP, Choueiri TK, Chang SL, Bellmunt J. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol. 2014;66:529–541. [PubMed] [Google Scholar]

9. Hellenthal NJ, Shariat SF, Margulis V. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration. J Urol. 2009;182:900–906. [PubMed] [Google Scholar]

10. Necchi A, Lo Vullo S, Mariani L. Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int. 2018;121:252–259. [PubMed] [Google Scholar]

11. Donovan JL, Rooshenas L, Jepson M. Optimising recruitment and informed consent in randomised controlled trials: the development and implementation of the Quintet Recruitment Intervention (QRI) Trials. 2016;17:283. [PMC free article] [PubMed] [Google Scholar]

12. De Santis M, Bellmunt J, Mead G. 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;30:191–199. [PMC free article] [PubMed] [Google Scholar]

13. Galsky MD, Chen GJ, Oh WK. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol. 2012;23:406–410. [PubMed] [Google Scholar]

14. Guo R, Zhu Y, Xiong G, Li X, Zhang K, Zhou L. Role of lymph node dissection in the management of upper tract urothelial carcinomas: a meta-analysis. BMC Urol. 2018;18:24. [PMC free article] [PubMed] [Google Scholar]

15. Hoffman-Censits J, Puligandla M, Trabulsi E. Phase II trial of neoadjuvant chemotherapy followed by extirpative surgery for patients with high grade upper tract urothelial carcinoma (HG UTUC): results from ECOG-ACRIN 8141. J Urol. 2018;199(suppl 4):e1166–e1167. (abstr LBA26). [Google Scholar]

16. Porten S, Siefker-Radtke AO, Xiao L. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer. 2014;120:1794–1799. [PMC free article] [PubMed] [Google Scholar]

17. Geldart T, Chester J, Casbard A. SUCCINCT: an open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma. Eur Urol. 2015;67:599–602. [PMC free article] [PubMed] [Google Scholar]

18. Galsky MD, Hahn NM, Powles T. Gemcitabine, cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer. Clin Genitourin Cancer. 2013;11:175–181. [PubMed] [Google Scholar]

19. Rosenberg JE, Ballman KV, Halabi S. CALGB 90601 (Alliance): randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma. Proc Am Soc Clin Oncol. 2019;37(suppl 15) abstr 4503. [Google Scholar]

20. Moss TJ, Qi Y, Xi L. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017;72:641–649. [PubMed] [Google Scholar]

21. van Oers JM, Zwarthoff EC, Rehman I. FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur Urol. 2009;55:650–657. [PubMed] [Google Scholar]

22. Robinson BD, Vlachostergios PJ, Bhinder B. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun. 2019;10 [PMC free article] [PubMed] [Google Scholar]

23. Bahleda R, Italiano A, Hierro C. Multicenter phase I study of erdafitinib (JNJ-42756493), oral pan-fibroblast growth factor receptor inhibitor, in patients with advanced or refractory solid tumors. Clin Cancer Res. 2019;25:4888–4897. [PubMed] [Google Scholar]

24. Siefker-Radtke AO, Necchi A, Park SH. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt) Proc Am Sco Clin Oncol. 2018;36(suppl 15) abstr 4503. [Google Scholar]

25. Papadopoulos KP, El-Rayes BF, Tolcher AW. A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017;117:1592–1599. [PMC free article] [PubMed] [Google Scholar]

26. Nogova L, Sequist LV, Perez Garcia JM. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35:157–165. [PMC free article] [PubMed] [Google Scholar]

27. Bellmunt J, de Wit R, Vaughn DJ. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015–1026. [PMC free article] [PubMed] [Google Scholar]

28. Powles T, Durán I, van der Heijden MS. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391:748–757. [PubMed] [Google Scholar]

29. Balar AV, Galsky MD, Rosenberg JE. 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;389:67–76. [PMC free article] [PubMed] [Google Scholar]

nephroureterectomy, nierkanker, kanker van de bovenste urinewegen, UTUC, chemotherapie, gemcitibine, cisplatin, carboplatin, fase III studie, overall overleving, ziektevrije overleving, recidief