Innovations in bladder cancer p.2

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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
–osmolarity – concentration
–dosing volume

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
–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]:
Non response-48%
Of the non-responders, 12 of them went on to a second course, of these patients the rate of response was:
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

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



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
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
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

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
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
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

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
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
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

Systemic absorption significantly limited, local toxicity, but no progressive bladder contraction; it seems to be less effective than Gemcitabine:

author VRB
Pts.(n.) Stage Results
Greenberg RE
Urology 1997
(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
Pts. (n.) Stage Results
Uchio EM
J Urol 2003
(MTD 153)
9 Refractory Spasm
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.