Skip to main content

Advertisement

SpringerLink
Log in

Intravesical thermo-chemotherapy based on conductive heat: a first pharmacokinetic study with Mitomycin C in superficial transitional cell carcinoma patients

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate, for the first time, the mitomycin C (MMC) pharmacokinetics during intravesical hyperthermia treatment based on conductive heat and the stability and recovery of the drug at the end of the instillation period.

Methods

Eleven patients with recurrent intermediate-risk superficial transitional cell carcinoma of the bladder were treated weekly for six cycles with intravesical MMC (40 mg MMC in 50 ml) in local hyperthermia (45 °C) with Unithermia® system. Each instillation lasted 45 min, with the solution being replaced after the first 22 min. The MMC recovery at the end of the two instillation period and the plasmatic pharmacokinetics of MMC were evaluated by high-pressure liquid chromatography.

Results

Nine patients completed all the six planned cycles, whereas two patients missed the last cycle because of allergic reactions. No other systemic toxicity was observed, and the local toxicities were mild. Median MMC concentration in the instillation residual solution decreases from the initial 0.8 to 0.22 mg/ml for the 0–22-min instillation period and to 0.38 mg/ml for the 22–45-min instillation period; the median percentage of MMC recovered after instillation was 66.2 and 99.6, respectively. In all patients, MMC plasmatic C max resulted considerably lower than the toxic threshold (400 ng/ml).

Conclusions

The MMC is stable during the instillation, and its absorption occurs mainly during the first minutes of the treatment. The plasmatic MMC concentration is always well below the threshold level for myelosuppression, as confirmed by the total lack of hematological toxicity evidenced by the patients. In order to evaluate the efficacy of the treatment performed with UniThermia® in reducing the disease recurrence rate in short- and long-term follow-up, we are currently carrying out a clinical multicentric study involving a larger number of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Epstein JI, Amin MB, Reuter VR, Mostofi FK (1998) The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 22(12):1435–1448

    Article  CAS  PubMed  Google Scholar 

  2. Vogeli TA (2005) The management of superficial transitional cell carcinoma of the bladder: a critical assessment of contemporary concepts and future perspectives. BJU Int 96(8):1171–1176. doi:10.1111/j.1464-410X.2005.05928.x

    Article  PubMed  Google Scholar 

  3. Witjes JA, Hendricksen K (2008) Intravesical pharmacotherapy for non-muscle-invasive bladder cancer: a critical analysis of currently available drugs, treatment schedules, and long-term results. Eur Urol 53(1):45–52. doi:10.1016/j.eururo.2007.08.015

    Article  PubMed  Google Scholar 

  4. Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374(9685):239–249. doi:10.1016/S0140-6736(09)60491-8

    Article  CAS  PubMed  Google Scholar 

  5. Shelley MD, Mason MD, Kynaston H (2010) Intravesical therapy for superficial bladder cancer: a systematic review of randomised trials and meta-analyses. Cancer Treat Rev 36(3):195–205. doi:10.1016/j.ctrv.2009.12.005

    Article  PubMed  Google Scholar 

  6. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester R, Burger M, Cowan N, Bohle A, Van Rhijn BW, Kaasinen E, Palou J, Shariat SF (2013) European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol. doi:10.1016/j.eururo.2013.03.032

    Google Scholar 

  7. Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG Jr, Pagano F, Alfthan O, Brosman S, Fisher HA, Jakse G et al (1989) Complications of Bacillus Calmette-Guerin immunotherapy: review of 2602 patients and comparison of chemotherapy complications. Prog Clin Biol Res 310:335–355

    CAS  PubMed  Google Scholar 

  8. Horvath A, Mostafid H (2009) Therapeutic options in the management of intermediate-risk nonmuscle-invasive bladder cancer. BJU Int 103(6):726–729. doi:10.1111/j.1464-410X.2008.08094.x

    Article  CAS  PubMed  Google Scholar 

  9. Bohle A, Jocham D, Bock PR (2003) Intravesical Bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 169(1):90–95. doi:10.1097/01.ju.0000039680.90768.b3

    Article  CAS  PubMed  Google Scholar 

  10. Dalbagni G (2007) The management of superficial bladder cancer. Nat Clin Pract Urol 4(5):254–260. doi:10.1038/ncpuro0784

    Article  PubMed  Google Scholar 

  11. Gwynn ES, Clark PE (2006) Bladder cancer. Curr Opin Oncol 18(3):277–283. doi:10.1097/01.cco.0000219258.75961.1a

    Article  PubMed  Google Scholar 

  12. Hendricksen K, Witjes JA (2007) Current strategies for first and second line intravesical therapy for nonmuscle invasive bladder cancer. Curr Opin Urol 17(5):352–357. doi:10.1097/MOU.0b013e3281c55f2b

    Article  PubMed  Google Scholar 

  13. Shen Z, Shen T, Wientjes MG, O’Donnell MA, Au JL (2008) Intravesical treatments of bladder cancer: review. Pharm Res 25(7):1500–1510. doi:10.1007/s11095-008-9566-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Gofrit ON, Shapiro A, Pode D, Sidi A, Nativ O, Leib Z, Witjes JA, van der Heijden AG, Naspro R, Colombo R (2004) Combined local bladder hyperthermia and intravesical chemotherapy for the treatment of high-grade superficial bladder cancer. Urology 63(3):466–471. doi:10.1016/j.urology.2003.10.036

    Article  CAS  PubMed  Google Scholar 

  15. Lammers RJ, Witjes JA, Inman BA, Leibovitch I, Laufer M, Nativ O, Colombo R (2011) The role of a combined regimen with intravesical chemotherapy and hyperthermia in the management of non-muscle-invasive bladder cancer: a systematic review. Eur Urol 60(1):81–93. doi:10.1016/j.eururo.2011.04.023

    Article  PubMed  Google Scholar 

  16. Rampersaud EN, Vujaskovic Z, Inman BA (2010) Hyperthermia as a treatment for bladder cancer. Oncology (Williston Park) 24(12):1149–1155

    Google Scholar 

  17. Colombo R, Da Pozzo LF, Salonia A, Rigatti P, Leib Z, Baniel J, Caldarera E, Pavone-Macaluso M (2003) Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 21(23):4270–4276. doi:10.1200/JCO.2003.01.089

    Article  PubMed  Google Scholar 

  18. Colombo R, Salonia A, Leib Z, Pavone-Macaluso M, Engelstein D (2010) Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 107(6):912–918. doi:10.1111/j.1464-410X.2010.09654.x

    Article  PubMed  Google Scholar 

  19. Colombo R, Da Pozzo LF, Lev A, Salonia A, Rigatti P, Leib Z, Servadio C, Caldarera E, Pavone-Macaluso M (1998) Local microwave hyperthermia and intravesical chemotherapy as bladder sparing treatment for select multifocal and unresectable superficial bladder tumors. J Urol 159(3):783–787

    Article  CAS  PubMed  Google Scholar 

  20. Colombo R, Lev A, Da Pozzo LF, Freschi M, Gallus G, Rigatti P (1995) A new approach using local combined microwave hyperthermia and chemotherapy in superficial transitional bladder carcinoma treatment. J Urol 153(3 Pt 2):959–963

    CAS  PubMed  Google Scholar 

  21. Colombo R, Salonia A, Da Pozzo LF, Naspro R, Freschi M, Paroni R, Pavone-Macaluso M, Rigatti P (2003) Combination of intravesical chemotherapy and hyperthermia for the treatment of superficial bladder cancer: preliminary clinical experience. Crit Rev Oncol Hematol 47(2):127–139

    Article  CAS  PubMed  Google Scholar 

  22. Paroni R, Salonia A, Lev A, Da Pozzo LF, Cighetti G, Montorsi F, Rigatti P, Colombo R (2001) Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma. Br J Clin Pharmacol 52(3):273–278

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Joseph G, Biederbick W, Woschee U, Theisohn M, Klaus W (1997) Sensitive and convenient high-performance liquid chromatographic method for the determination of mitomycin C in human plasma. J Chromatogr B Biomed Sci Appl 698(1–2):261–267

    Article  CAS  PubMed  Google Scholar 

  24. Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL (1991) Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 51(19):5144–5152

    CAS  PubMed  Google Scholar 

  25. Maffezzini M, Campodonico F, Manuputty EE, Puntoni M, Martelli A, Marini V, Tamagno S, Mattioli F (2013) Systemic absorption and pharmacokinetics of single-dose early intravesical mitomycin C after transurethral resection of non-muscle-invasive bladder cancer. Urology 82(2):400–404. doi:10.1016/j.urology.2013.03.036

    Article  PubMed  Google Scholar 

  26. Cordeiro ER, Geijsen DE, Zum Vorde Sive Vording PJ, Schooneveldt G, Sijbrands J, Hulshof MC, de la Rosette J, de Reijke TM, Crezee H (2013) Novel multisensor probe for monitoring bladder temperature during locoregional chemohyperthermia for nonmuscle-invasive bladder cancer: technical feasibility study. J Endourol 27(12):1504–1509. doi:10.1089/end 2013.0179

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, Corso Raffaello 31, 10125, Turin, Italy

    Paola Milla, Silvia Arpicco & Luigi Cattel

  2. Urologia 1, University of Turin, Turin, Italy

    Chiara Fiorito, Francesco Soria & Paolo Gontero

Authors
  1. Paola Milla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiara Fiorito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Soria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Arpicco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luigi Cattel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paolo Gontero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Milla.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Milla, P., Fiorito, C., Soria, F. et al. Intravesical thermo-chemotherapy based on conductive heat: a first pharmacokinetic study with Mitomycin C in superficial transitional cell carcinoma patients. Cancer Chemother Pharmacol 73, 503–509 (2014). https://doi.org/10.1007/s00280-014-2381-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2381-4

Keywords

Search

Navigation