{niftybox width=180px,float=right,textalign=left}
Continued on separate pages:
1. Future directions in bladder cancer research- Genetic Markers;
Gigliola Sica -Chairman Institute of Histology and Embryology,
Faculty of Medicine Catholic University of the Sacred Heart Rome
2. Newer non-invasive diagnostic tools in bladder cancer
M J Bailey, St. George’s Hospital, London
3. ISUP-WHO tumor classification: really the gold standard?
Fabio M.Vecchio Ist. Anatomia Patologica, Università Cattolica Roma
4 .Markers of recurrence and progression Prof. Fred Witjes Radboud UMC Nijmegen, the Netherlands; Innovations in Urology: Bladder cancer Rome; December 2, 2005
Separate pages:
8.The effect of heat dose on clinical outcome A.G. van der Heijden;University Medical Centre Nijmegen The Netherlands
9.Local hyperthermia and intravesical chemotherapy for superficial TCC of the bladder Clinical studies: An overview; R. Colombo U.O. di Urologia Istituto Scientifico Universitario “Vita e Salute” San Raffaele, Milano
10.Thermo-chemotherapy: Preliminary results of current international studies Prof. Fred Witjes Radboud UMC Nijmegen, the Netherlands Innovations in Urology: Bladder cancer Rome, December 2, 2005
11.Thermochemotherapy – Current Italian Studies Rodolfo Hurle U.O. Urologia Humanitas Gavazzeni Bergamo
{/niftybox}Synergo® II Workshop Dec. 2005- Rome Synergo® Medical Enterprises
Congress Organizer/Chairman: Prof. PF Bassi, Chairman Department of Urology, Catholic University Medical School, University Hospital “A. Gemelli”
Auditorium Centro Congressi Europa, Universita Cattlolica del Sacro Cuore, Facolta de medicina e Chirurgia “A. Gemelli”
On this page – presentations 5 and 6:
5. Intravesical chemotherapy: Does it work? Prof. P.F. Bassi
Department of Urology Catholic University Medical School – Rome
6. Innovative Treatments: Newer Chemotherapeutic Drugs; C Barone, Oncologia Medica ,Università Cattolica S. Cuore, Roma. 2005
___________________________________________________
5. Intravesical chemotherapy: Does it work? Prof. P.F. Bassi
Department of Urology Catholic University Medical School – Rome
Reliable data
The impact of intravesical chemotherapy on tumor recurrence and progression is still an open question. In 2000 [Huncharek M., 2000] , a meta-analysis was done using 1672 citations which compared
Turb vs Turb + chemo
Primary vs Recurrent
? 1-yr follow-up
Endpoint: Recurrence
It was determined that only 11 out of the 1672 studies fit the criteria of a randomized, controlled clinical trial. A total of 3701 patient histories were examined using recurrence as an end point. It was determined that of the drugs: Thiotepa, Epirubicin, Mitomycin C and Mitoxantrone – Mitomycin C was the most effective. A single instillation can delay recurrence at 1 year by 30%, multiple instillations by 31% after 2 years.
Chemo vs BCG
In another meta-analysis, from 97 citations, 9 fit the required criteria [Huncharek M., 2003]: Randomized controlled clinical trials comparing intravesical chemotherapy to BCG, with a minimum of 2 years follow up and more than 20 patients per arm. A total of 2261 cases were examined; the conclusions were:
–There is little advantage of BCG over intravesical chemotherapy, about 11%
–The currently perceived superiority of BCG may be an artifact since most randomized trials include chemotherapy failures.
–47% of people who fail intravesical chemotherapy respond to BCG as second line treatment.
Chemo vs BCG on progression
Another meta-analysis [Huncharek M., 2004] failed to support a clear superiority of BCG over intravesical chemo regarding tumor progression. Mitomycin C was the more effective chemotherapy drug. Having failed intravesical chemotherapy causes a spurious finding of greater BCG effect.
Chemo vs BCG on Carcinoma in situ
A meta-analysis of randomized controlled trials with the inclusion criteria of primary, secondary or concurrent CIS was performed [Silvester R., 2005], From a total of 14 citations, 9 fit the criteria and 700 cases were examined. It was concluded that BCG had a superior effect on disease-free status, but no clear conclusions can yet be drawn regarding the impact of BCG on long term survival.
Problems with published data
The number of trials that fit criteria must be standardized
The number of patients included is not high enough to draw concrete conclusions
The follow-up lenghts vary
There are different treatment protocols used
No distinction is made between primary, secondary or recurrent CIS
While meta-analysis does support important information, more questions remain to be answered via properly designed and adequately powered randomized trials
Is there a solution?
Critical evaluation must lead to innovation and standardization regarding terminology, treatment strategies and methodology/end points.
What we can say about superficial bladder cancer is that it’s a peculiar disease known for:
-high incidence of recurrences
-negligible incidence of progression (>T2)
-relevant role of endoscopic treatment/management and intravesical therapy
-the limited role of imaging tools
The main questions that remain open are:
–who is the optimal candidate
–what’s the best drug? How does it work?
–what’s the optimal regimen- best time for beginning treatment?
–how long should the drug be kept in the bladder?
–what is the ideal interval between instillations?
–what dose should be given at each instillation?
–how long should the drug be administered? Maintenance, no maintenance?
–in what liquid and what volume should it be dissolved?
–will all tumor respond to the treatment?
–what’s theinfluences of diuresis, urinary pH, concentration, etc?
–what’s the overall cost/benefit ratio?
Factors altering the citotoxicity
–molecular weight
–lipophilicity
–pH
–osmolarity – concentration
–dosing volume
–dose
There is in fact little data to answer the above questions. The European guidelines currently support the approach of one intravesical chemotherapy instillation immediately following TUR [see:EORTC meta-analysis-Perspectives in bladder cancer on webcafe]
Principles of intravesical therapy: Possible benefits
–high drug concentration is possible
–direct contact is made between tumor and drug
–prolonged contact time
–decreased systemic side effects
The ideal drug should be
–active in eradicating the pre-existing disease and in preventing both recurrence and progression
–the simplest and shortest administration
–no side effects
–reasonable cost
The pivotal assessment of prognostic factors and risk categories must first be obtained:
patient’s history of disease
voided cytology
imaging -IVP, Ultrasound
Cystoendoscopy
–Transurethral Resection of Bladder Tumor(s) TURBT
–Bladder mucosa cold biopies
— Bimanual Palpation under Anesthesia
Check cytology/endoscopy
Dose vs activity vs toxicity
There is uncertainty regarding the best dose-activity ratio for intravesical chemo/immunotherapy; Generally the higher the dose, the higher the toxicity for both chemo and immunotherapeutic agents
Dose vs activity-
Epirubicin for Carcinoma in situ KURTH, J. UROL 199
| Dose | % complete reponse |
| 30mg | 43 |
| 50mg | 60 |
| 60 mg | 70 |
Multi-centered, EORTC randomized controlled clinical trials:
Single and early instillations:
Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group .Bouffioux C, Kurth KH, Bono A, Oosterlinck W, Kruger CB, De Pauw M, Sylvester R.University Hospital, Liege, Belgium. J Urol. 1995 Mar;153(3 Pt 2):934-41. PubMedAbstract
Early vs. Delayed instillations
A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. Oosterlinck W, Kurth KH, Schroder F, Bultinck J, Hammond B, Sylvester R. Department of Urology, University Hospital, Gent, Belgium. J Urol. 1993 Apr;149(4):749-52. European Organization for Research and Treatment of Cancer Genitourinary Group PubMedAbstract
Optimal time between instillations- very little data.
One randomized study [Burk, Urologe 1986] compared 3 similar groups:
Group 2: weekly instillatoins for 1 month
Group 2: 2-week interval instill. for 6 months
Group 3: monthly instill. for 1 year
Surprisingly no difference in outcomes were found.
The usefulness of added courses of chemotherapy after treatment failure
40 patients with carcinoma in situ were treated with either Adriamycin or Mitomycin [Solsona, Eur. Urol. 1991]:
Response-52%
Non response-48%
Of the non-responders, 12 of them went on to a second course, of these patients the rate of response was:
Response-57%
No response-43%
Additional course of 6 wks BCG
| Publication | No.pts | +reponse | median follow up (mos.) |
| Catalona, JUrology ’87 | 49 | 20% | 15.8 |
| Kavaoussi, JUrology ’86 | 57 | 60% | 17.5 |
| Bassi, JUrology ’92 | 44 | 50% | 21 |
BCG maintenance vs. No Maintenance
A SWOG (Southwest Oncology Group) study [Lamm, 2001, JUrology] presented data showing improved disease free status, favoring additional BCG maintenance for carcinoma in situ and Ta, T1 tumors:
+Maintenance: 83% vs 65% no maintenance
+Maintenance:Ta – T1: 83% vs 50% -no maintenance
Polichemotherapy
There is some ‘in vitro’ evidence [Seraphim JUrol.1991] that intravesical chemo agents work synergistically:
Doxorubicin + Thiotepa
Doxorubicin + Mitomycin C
This approach was tested in vivo [Ferraris ,Cancer 1988] 60 Pts, stage Ta – T1, treated with TUR followed by doxorubicin, 50 mg /30 ml + Mitomycin C, 20 mg/20ml, for 6 weeks + 10 months maintenance, for a response rate of 70% at mean follow up 28 months.
Question: What is the optimal timing?
Chemo followed by immuontherapy?
Immunotherapy followed by chemotherapy
Chemo followed by chemotherapy?
Immunotherapy followed by immunotherapy?
Second line chemo after chemo-some results
| agent | #pts. | treatment | %response | author |
| MMC after TIPA | 23 | Proph/Ter | 43% | Prout, J.Urol, ’82 |
| MMC after TIPA | 57 | Proph/Ter | 42% | Issel, Cancer, ’84 |
| TIPA after MMC | 5 | Prophylactic | 60% | Zincke, J.Urol ’85 |
| MMC after ADM | 31 | Prophylactic | 42% | Bassi, Urol.Int. ’92 |
Second line chemo after BCG:
| agent | #pts. | treatment | %response | author |
| MMC | 4 | prophylactic | 100% | Pinon, J.Urol, ’88 |
| MMC | 11 | Proph/Ter | 82% | Rintala, Eru.Urol, ’91 |
‘Rescue’ BCG therapy for relapse after successful BCG treatments:
Response -78%
Non response -22% (PROG. 5%)[Bassi J.Urol 1993]
Investiagative agents:
Oral Bropirimine-immunotherapy -Sarosdy, J. Urol. 1992
Oral megadose vitamin – Lamm, J. Urol. 1994
Oral Lactobacillus -Aso, Eur. Urol. 1995
Conclusions, What we do know with certainty:
No ideal drug exists yet
Optimal conditions for I.V. administration established but not applied
Value of:
Single instillations
Early course
Maintenance Therapy
Additional course
Second line therapy
Intravesical therapy is not strictly necessary
“THE ILLUSION OF KNOWLEDGE IS THE MAJOR OBSTACLE TO THE PROGRESS” Prof. Bassi
___________________________________________________
6. Innovative Treatments – Newer Chemotherapeutic Drugs; C Barone, Oncologia Medica ,Università Cattolica S. Cuore, Roma. 2005
This presentation covers new agents being tried for superficial and advanced baldder cancer.
Systemic chemotherapy is reserved for higher stage disease as:
Neoadjuvant Therapy
Adjuvant Therapy
Palliative Therapy (Metastatic Disease)
New drugs for advanced (metastatic) disease:
| Drug | Response Rate % – phase II trials |
| Gemcitabine | 28 |
| Paclitaxel | 42 |
| Docetaxel | 31 |
| Pemetrexed | 26 |
| Epothilones | n.e. |
| Vinflunine | n.e. |
| Irinotecan | n.e. |
| J107088 | n.e. |
Gemcitabine: Deoxycitidine analogue, pyrimidine antimetabolite, that interferes with DNA synthesis via a direct inhibition of ribonucleotide reductase or by means of incorporation of difluorodeoxycitine monophosphate into DNA. As final results GMC inhibits cell growth and trigger apoptosis
Pemetrexed: Folate analogue, that enter the cell through the reduced folate carrier; undergoes polyglutamation and is retained into the cell
Epithilones: Semisynthetic analogues of the natural Epothilones A and B, which have a mode of action similar to taxanes (microtubules stbilization)
Active in both paclitaxel sensitive and refractory tumours; Twice as potent as Paclitaxel in-vitro
Vinflunine: A novel fluorinated Vinca alkaloid
Advanced/Metastatic Bladder Cancer – Molecular Targets
| Target | Comment |
| EFGR | Overexpressed in 31-48% BLC; Associated with poorer outcome and higher stage |
| HER2/neu | Overexpressed in 40% BLC |
| Bcl-2 | Overexpressed in BLC |
| Ras | Mutated in 1-80% BC Activating mutation in 10% BC |
Inhibitors of EGFR/HER Family
Mabs:Trastuzumab, Cetuximab, Panitumumab
TKIs: Gefitinib, Erlotinib, Lapatinib, ZD6474, etc.
Advanced Transitional Cell Cancer Targeted Drugs
| Author | Drug | Mechanism of Action | Results |
| Petrylak D, ASCO ’03 | Gefitinib | ErbB1 TKI | RR3% |
| Machiels JP, ASCO ’04 | GW572016 | ErbB1/ErbB2 TKI | 10% |
| Wulfing L, ASCO ’05 | Lapatinib | ErbB1/ErbB2 TKI | RP3%, SD 20% |
| Rosenberg JE, Cance, ’05 | Tipifarnib | Farnesyl transferase inhibitor | RP 18% (naive) SD 56% (pretr.) |
*RR-Response rate; RP-partial response; SD-stable disease
Incorporation of New Cytotoxic Drugs in Clinical Practice
Gembcitabine –1) GMC+CDDP[Gemcitabine+cisplatin] vs M-VAC : the rationale is that the newer combination of GC gives result very similar to the gold standard, M-VAC but with much less toxicity
| GC | M-VAC | |
| Pts. | 203 | 202 |
| Complete reponse% | 12 | 12 |
| Partial response% | 37 | 34 |
| Overall response% | 49 | 46 |
| Median survival | 13.8 | 14.8 |
Gemcitabine 2) Doublets with CBDCA/CDDP[carboplatin/cisplatin]:
| author | treatment | pts (n.) | RR% | MS (m) |
| Carles J Oncol 2000 |
GMC+CBDCA | 17 | 56 (CR 12%) | – |
| Lippert CM ASCO 2004 |
GMC+CDDP or CBDCA | 19 | 45 (CR18%) | – |
| Hussain SA BJC 2004 |
GMC+fractioned CDDP |
32 | 65.5 (CR12%) | 16 |
| Hoshi S Int JCO 2004 |
GMC+CBDCA | 16 | 47 (19%) | – |
| Linardou H Urol 2004 |
GMC+CBDCA | 56 | 36 | 7.2 |
Gemcitabine– 3) Doublets without Platinum: The taxanes are also being tried:
| author | treatment | Pts.(n.) | RR(%) | MS (m) |
| Sternberg C Cancer 2001 |
GMC+TXL | 40 | 60 (CR 33%) | 14.4 |
| Meluch AA JCO 2001 |
GMC+TXL | 54 | 54 (CR 7%) | 14.4 |
| Boyer MJ ASCO 2003 |
GMC+TXT | 31 | 50 (CR 10%) | – |
| Srinivas S ASCO 2004 |
GMC+TLX | 17 | 65 (CR 17%) | 7.5 |
| Ardavanis A BJC 2004 |
GMC+TXT | 31 | 52 (CR 13%) | 15 |
Other doublets without Platinum:
| author | treatment | Pts. (n.) | RR(%) | MS (m) |
| Krege S J Urol 2001 |
IFX+TXT | 22 (pre-treated) | 18 | – |
| Garcia d Moro BJC 2002 |
CDDP+TXT | 38 | 58 (CR 18%) | 10.4 |
| Chaudhary VB ASCO 2005 |
GMC+IRI | 10 | 80 (CR 20%) | – |
Triplets with CDDP : Due to the increased toxicity with three drugs, carboplatin may be preferred to cisplatin:
| author | treatment | Pts. (n.) | RR (%) | MS (m) |
| Bellmunt J JCO 2000 |
GMC+TXL+CDDP | 58 | 78 (CR 28%) | 15.8 |
| Maluf F ASCO 2000 |
GMC+DOX?IFX+TXL+CDDP | 21 | 86 (CR 43%) | – |
| Bajorin D Cancer 2000 |
IFX+TXL+CDDP | 45 | 68 (CR23%) | 20 |
| Clark PE ASCO 2004 |
GMC+TXL+CDDP | 29 | 52 (CR28%) | 10.7 |
Triplets without CDDP
| author | treatment | Pts. (n.) | RR (%) | MS (m) |
| Lara PN Cancer 2004 |
GMC+TXL+MTX | 21 | 57 (CR 28) | – |
| Chahine GY ASCO 2004 |
GMC+TXT+CBDCA | 21 | 47.6 (CR 19%) | 7.1 |
| Chen AC ASCO 2004 |
GMC+TXT+CBDCA | 20 | 45 (CR 20%) | – |
Combination of Targeted Drugs with Cytotoxic Drugs
| author | treatment | Pts. | comment |
| Hussain M ASCO 2005 |
HER+GMC+CBDCA+TXL | 44 | RR 72.7% CR 11% HER2 overexpressing 54% Gene amplification 13% |
| Philips G ASCO 2003 |
GEF+CDDP+GMC | – |
Other Biological Agents in Pre-clinical Models
| agent | comment |
| Endostatin | Inhibitor of angiogenesis Inhibits bladder cancer growth |
| TPN-470 | Inhibitor of VEGF derived from Asperg. fumigatus Inhbits the development of limphonodal metastases |
| Bortezomib | Proteosome inhibitor Inhibits bladder cancer growth |
| Antisense OG directed at bcl2 |
Reverses CDDP resistance |
| Antisense OG at clusterin |
Confers a more chemosensitive phenotype |
Combination of Biological Agents and Cytotoxic Drugs in Preclinical Models
| agent | comment |
| CET + TXL | Synergism |
| IFNa2a+retinoic acid | Synergism; IFN induces retinoic acid receptor ß Retinoids increase IFN-related gene expression |
| TNP-470+GMC | Inhibit tumour growth and metastases |
Superficial Bladder Cancer (SBC)- New Drugs
| agent | pharmacology |
| Gemcitabine | Deoxycytidine analogue |
| Valrubicin | Semisynthetic derivative of doxorubicin |
| Suramin | Polysulfonated naphtyl-urea |
| Tipifarnib | Farnesyl-transferase inhibitor |
| Difluoromethylornithine | False metabolite of ornithine decarboxylase |
| Fenretinide | Retinoid |
| Celecoxib | Specific ciclooxygenase inhibitor |
| y-linoleic acid | Essential fatty acid |
| Mistletoe extracts | Lectins |
Gemcitabine: Characteristics for intravesical use
__Significant activity against invasive BLC
__Molecular weight (299 D) sufficiently low for penetrating bladder mucosa, but high enough to prevent systemic absorption
__ Favourable pharmacokinetics and negligible ionisation
Various phase I research has led to the conclusion that Gemcitabine should be used at dose: 2000 mg/sqm/wk (40 mg/ml in 50 ml); Dalbagni G, JCO 2002; Laufer M, JCO 2003; Witjes JA, Eur Urol 2004; Palou J, J Urol 2004.
GMC has antitumor activity comparable to BCG: Intravescical Gemcitabine
Intermediate risk Ta-T1, G1-G2 SBC
| author | GMC (mg/ml) |
q | Pts. | marker lesion | CR (%) |
| Van der Mejden APM BJC 1996 |
40 | wkly x 6 | 39 | 1 | 56 |
| De Berardinis E J Urol 2004 |
40 | wkly x 6 | 24 | 1 | 50 |
| Serretta V J Urol 2004 |
10-110 | wkly x 6 | 27 | >1 | 22 |
| Dalbagni G J Urol 2004 |
20 | Biwkly x 6 | 28* | – | 57 |
*BCG refractory high risk
Intravescical Gemcitabine Adjuvant Therapy after TURB:
| author | GMC (mg/ml) |
q | Pts | results |
| Bouzid K ASCO 2004 |
20 | Wkly x 6 | 29 | 0 relapse after 12 m follow-up (3-15) |
| Gunelli R ASCO 2005 |
40 | Biwkly x 6 | 32 | 3 relapse after 14 m follow-up |
Valrubicin-characteristics
Systemic absorption significantly limited, local toxicity, but no progressive bladder contraction; it seems to be less effective than Gemcitabine:
| author | VRB (mg/sqm) |
Pts.(n.) | Stage | Results |
| Greenberg RE Urology 1997 |
200-900/w (MTD 800) |
32 | Ta/T1 | CR 40.6% |
| Steinberg G J Urol 2000 |
800/w | 90 | Tis | Cr 21% TTF>18 m |
| Newling DW Eur Urol 2001 |
800/w | 40 | BCG-ref. | CR 46% TTF 8 m |
Suramin: Characteristics for intravescical use
_Inhibits proliferation and DNA synthesis
_Is a potent VEGF antagonist
_Blocks the binding of EGF to its receptor
_Large molecular size and negative charge inhibit bladder absorption
Intravesical Suramin, phase I studies:
| author | VSRM (mg/sqm) |
Pts. (n.) | Stage | Results |
| Uchio EM J Urol 2003 |
0.6-614/w (MTD 153) |
9 | Refractory | Spasm Reflux |
| Ord JJ BJC 2005 |
10-150/w 12 | 12 | Recurrent | No tox Minimal abs at =150 Urinary VEGF reduced |
Preliminary Results with other Agents – 1
| agent | results |
| Tipifarnib | A phase II study is ongoing |
| y-linoleic acid | >90% growth inhibition in BC lines 4/30 (13%) CR in a phase II trial (Harris NM, Eur Urol 2002) |
| DFMO | Suppresses the development of invasive BC in murine models Preventive effect Randomized phase III strial in low grade SBC ongoing |
Preliminary Results with other Agents – 2
| agent | results |
| Fenretinide | Preventive effect in murine models One preventive study showed no difference in molecular endpoints and RFS |
| Celecoxib | Reduces the development of chemically induced BC in mice |
| Lectins extracted from mistletoe | Enhance NK toxicity Stimulate cytokine secretion Induce cytotoxity and apoptosis in-vitro and in murine models In a phase II study recurrence rate (33%) in 30 G1-G2 pts comparable to historical BCG (Elsässer-Behe U, J Urol 2005) |
Conclusions 1.:
_GMC and TXNs are highly active in metastatic BC
_Doublets or triplets including GMC and/or TXNs are promising, but have to be compared with standard treatment (GC or M-VAC) in large phase III studies
_Other newer drugs (PEM, Vinflunine, etc) also seem active.
Conclusions 2.:
_ Targeted drugs are marginally active, but the preliminary studies have not been adequately designed
_They need to be evaluated in combination with cytotoxic drugs in patients at least expressing the specific molecular target
_GMC efficacy in SBC is comparable to that of BCG
_Other drugs are in early phase of study in SBC, including differentiating agents and some targeted drugs.
____________________________________________________
: