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Thèse de doctorat/ PhD Thesis Citation APA:

Zlotta, A. (s.d.). BCG immunotherapy for superficial bladder cancer: further insights into its mechanism of action (Unpublished doctoral dissertation).

Université libre de Bruxelles, Faculté de Médecine – Médecine, Bruxelles.

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(English version below)

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ALEXANDRE R. ZLOTTA

FURTHER INSIGHTS INTO ITS MECHANISM OF ACTION

Department of Urology

Erasme Hospital - University Clinics of Brussels Brussels - Belgium

Thesis

submitted to obtain the degree of Doctor in Medical Science

Proirrotor: Prof. C. Schulman

Co-promotor: Prof. J.-P. Van Vooren

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ALEXANDRE R. ZLOTTA

BCG IMMUNOTHERAPY FOR SUPERFICIAL BLADDER CANCER:

FURTHER INSIGHTS INTO ITS MECHANISM OF ACTION

Department of Urology

Erasme Hospital - University Clinics of Brussels Brussels - Belgium

Thesis

submitted to obtain the degree of Doctor in Medical Science

Promotor: Prof. C. Schulman

Co-promotor: Prof. J.-P. Van Vooren

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Chapter 1

Introduction

1.1

Introduction p.9

1.2

Bladder cancer p.l3

1.2.1. Epidemiology

1.2.2. Pathology

1.2.3. Natural History

1.2.4. Prognostic factors for récurrence and progression of superficial

bladder tumors

1.2.5. Bladder cancer treatment - OverView

1.2.5.1. Endoscopie Resection

1.2.5.2. Objectives of intravesical therapy 1.2.5.3. Intravesical chemotherapy

1.2.5.4. Photodynamic therapy

1.2.6. Intravesical immunotherapy: Bacillus Calmette-Guérin (BCG)

1.2.6.1. Clinical Efficacy

1.2.6.2. Comparison of BCG and intravesical chemotherapy - récurrence rates 1.2.6.3. Comparision of BCG and intravesical chemotherapy - progression rates 1.2.6.4. Effects of BCG maintenance on récurrence and progression rates

1.2.6.5. BCG in carcinoma in situ

1.2.6.6. Indications of BCG: Who should and who should not be treated ?

1.2.6.7. Side effects of BCG: Contraindications and limitations of BCG administration 1.2.6.8. What is the optimal BCG strain ?

1.2.6.9. The optimal treatment schedule and dose

1.2.6.9.1. Efforts to increase the response rate 1.2.6.9.2. Efforts to reduce side effects

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3

1.3 The Bacillus Calmette-Guérin and mycobacterial

diseases p.57

1.3.1. Introduction- BCG development

1.3.2. Mycobacteria: characteristics and categories

1.3.2.1. Types and classification

1.3.2.2. Structure

1.3.2.3. Secreted proteins, antigens and culture filtrate

1.3.3. Mycobacterium tuberculosis

1.3.3.1. Epidemiology

1.3.3.2. Microbiology and diagnosis of tuberculosis

1.3.3.3. General overview of the problems : latency and réactivation 1.3.3.4. Pathogenesis

1.3.4. Immunity to tuberculosis

1.3.4.1. Immune compartments

1.3.4.2. The prototypic immune response to infection

1.3.4.3. Immunological responses to M. tuberculosis infection 1.3.4.4. New aspects of immunity to tuberculosis

1.3.4.5. Mycobacterial antigens and immunity to tuberculosis 1.3.4.6. BCG vaccine : clinical efficacy

1.3.4.7. BCG vaccine : immune responses

1.4 BCG and tumors p.l31

1.4.1. Tumor immunology : a brief overview

1.4.2. Mode of action of BCG in bladder cancer

1.4.2.1. Immunological responses during intravésical BCG therapy 1.4.2.2. Immunohistological studies

1.4.2.3. Cytokine sécrétion in the urine

1.4.2.4. The cellular component of the immune response during BCG therapy 1.4.2.5. The effector phase and cells involved in tumor cell killing

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1.4.2.7. Predicting the clinical response to BCG therapy

Chapter 2 p.l60

Aims ofthe thesis

Chapter 3 p.l63

Paper 1 Evolution and clinical significance ofthe T-cell proliférative and

cytokine response directed against the fibronectin binding Antigen 85 complex

ofbacillus Calmette-Guérin during intravesical treatment of superficial bladder

cancer

Chapter 4 p.l64

Paper 2 Humoral response against beat shock proteins and other mycobacterial

antigens after intravesical treatment ivith bacille Calmette-Guérin (BCG) in

patients with superficial bladder cancer

Chapter 5 p.l65

Paper 3 Superficial bladder tumors and increased reactivity against

mycobacterial antigens before Bacillus Calmette-Guérin therapy

Chapter 6 p.l66

Paper 4

6.1.

Corrélation and prognostic significance of p53,

and Ki-67

expression in patients with superficial bladder tumors treated with

bacillus Calmette-Guérin intravesical therapy

Paper 5

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5

Chapter 7 p.l67

Paper 6 What is the optimal regimen for B CG intravesical tkerapy? Are six

weekly instillations necessary?

Chapter 8 p.l68

Paper 7 What are the immunologically active components of bacille Calmette-

Guerin in therapy of superficial bladder cancer?

Chapter 9 p.l69

General Discussion

1. Does BCG intravesical therapy induce systemic immune responses against

purified BCG antigens?

2. Does BCG intravesical therapy also induce a systemic humoral response against

mycobacterial antigens and in particular against heat shock proteins?

3. Is there a possible cross-reactivity between BCG and bladder tumor cells,

suggesting that the antitumor response could be in part at least spécifie?

4. Can we predict the clinical outcome of BCG-treated patients by analyzing the

immune (cellular and humoral) response directed against mycobacterial antigens? Rôle of TH-1 and TH-2 responses

5. Can we predict the clinical outcome of BCG-treated patients analyzing

biological markers of the bladder tumor?

6. What is the optimal regimen for BCG intravesical therapy? Are six weekly

instillations really necessary for ail patients or do some patients require fewer instillations?

Are there immunological data available to support the need of a maintenance BCG therapy after the initial 6 instillations to reinforce the iiiunune response?

7. What are the immunologically active components of BCG and what type of

immune response do they elicit?

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Hypothesis: proposed mechanism of action ofBCG in superficial hladder cancer

therapy

1. Controlling the mycobacteria

2. The tumor control

Chapter 11 p.228

CONCLUSION: Future prospects for B CG therapy

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7

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CHAPTER 1

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9

1.1 INTRODUCTION

The attenuated strain of Mycobacterium bovis Bacille Calmette-Guérin (BCG) is used worldwide to prevent tuberculosis, an infections disease that has plagued man over the last several centuries and which remains a leading cause of mortality, More people hâve received BCG than any other vaccination. But we should not forget that BCG is also one of the most widely used and successful immunotherapeutic agents. Indeed, during the past 30 years, BCG has been used with success against superficial bladder cancer, the second most common urological malignancy. The deliberate introduction of BCG in the bladder has been shown particularly effective at preventing superficial bladder tumor récurrences, and is the most effective endovesical treatment for high-risk superficial bladder cancer.

Urologists hâve learned that the intravesical route of administration is the most effective one, hâve defined indications and which patients may benefit from BCG. They also are aware of the side effects associated with its use.

Despite three décades of BCG intravesical therapy, this immunothrerapy remains deeply rooted in empiricism and is often likened to a black box because of the complex and incompletely understood variables that affect clinical outcome. Many questions remain unanswered to date. Among others:

1. Treatment outcome is often unpredictable and a variable percentage of patients do not respond to intravesical BCG therapy.

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introduced in 1976 totally empirically and had not been really challenged for many years.

4. We hâve not precisely determined which are the active components ot the BCG mycobacteria responsible for its anti-tumor efficacy.

Because intravesical BCG is undoubtedly a very effective therapy for preventing bladder tumor récurrences, but because there is also clearly room for improving its use, BCG therapy deserves more investigations and refinements.

During this thesis, when considering BCG's action against bladder tumors, we asked ourselves what could be learned from studies on immunity against tuberculosis and from BCG use as an antituberculosis vaccine.

Already ten years ago. Grange et al suggested that there might be parallels in host responses and therapeutic approaches between tuberculosis and cancer [Grange et al, 1995]. Tuberculosis is due to a mycobacterium and elicits 2 very opposite immune responses during infection. One is protective and is partly based on récognition and lysis of cells that harbor the stressed bacilli. Indeed, M. tuberculosis, the agent of tuberculosis is mainly an intracellular pathogen. The other type of immune response is highly dépendent upon the prédominant T-cell

maturation, THi or TH2. It is also determined by priming due to prior contacts with

environmental mycobacteria. Grange et al hypothesized that vaccination by BCG induces whichever response the subject is primed to mount, and this might contribute to the variable efficacy of BCG vaccine in prévention of tuberculosis. The authors even suggested that this concept might hold true in therapy of cancer as well. BCG would be a two-edged sword, depending upon the type of immune response elicited.

Using other mycobacterial préparations, it might be possible to suppress the indiscriminate necrosis and enhance THi regulated sélective destruction of tumor cells.

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In the présent thesis, we tried to answer some of the unsolved questions about intravesical BCG and to provide new insights into its antitumor mechanism of action. We paid interest to spécifie immune responses directed against purified mycobacterial antigens. Mycobacterial antigens bave been extensively studied in immunity against tuberculosis and when designing new vaccines.

We investigated both the cellular and humoral aspects of the spécifie immune responses against several purified mycobacterial antigens that can be detected in the peripheral blood of patients with superficial bladder cancer before, during and after their BCG instillations. The first originality of this work is that spécifie immune responses against mycobacterial antigens had not been investigated previously in patients with bladder tumors treated by intravesical BCG. The second feature is that since BCG is given intravesically, most studies analyzed locally the immune responses induced by BCG in the bladder. They did not, however, investigate whether intravesical BCG instillations were capable of eliciting systemic immune responses against the whole BCG or mycobacterial antigens.

Once having demonstrated that intravesical BCG indeed induced spécifie systemic immune responses against purified mycobacterial antigens, we then analyzed the évolution of these immune responses, and their relation with the timing of the BCG intravesical instillations. The idea was to get a further insight about the optimal number of BCG instillations which should be given. We also looked at the clinical prognostic significance of these spécifie cellular and humoral immune responses against purified mycobacterial antigens. We addressed the rôle of the bladder tumor itself on the clinical prognosis of patients treated with BCG instillations for superficial bladder tumors, focusing on biological markers.

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tumor cells. We investigated whether some of these purified mycobacterial antigens were able to stimulate peripheral blood lymphocytes, what kind of T helper immune response did they enhance and whether they could induce a cellular-mediated cytotoxicity against bladder tumor cell lines and other types of tumors. The underlying idea was to identify defined components responsible for a potential future use of purified BCG subcomponents instead of live mycobacteria in order to gain in efficacy while hopefully minimizing side effects.

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1.2. BLADDER CANCER

1.2.1. Epidemiology

Bladder cancer is a heterogeneous disease with a variable natural history. At one end of the spectrum, low-grade superficial tumors hâve a low progression rate and require endoscopie treatments and surveillance but rarely présent a threat to the patient. At the other extreme, high-grade tumors hâve a high malignant potential associated with significant progression and cancer death rates.

Bladder cancer is the second most common urological malignancy and second most common cause of death among genitourinary tumors. It affected 56,500 persons in the United States in 2002 and an estimated 12,600 men and women died of the disease Qemal et al, 2002]. The situation is similar in most Western nations, with incidence rates of 18 to 30 new cases per 100,000 men, placing bladder cancer as the 4* most common cancer among men and 8* most common cancer among women (fig.l) Overall 130,000 new cases per year are observed in the US and 5 European

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Cumulative Risk (%)

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1.2.2. Pathology

Bladder tumors are classified into superficial (affecting the mucosa and/ or muscularis mucosae) and muscle-invasive tumors, depending upon the depth of invasion of the bladder layers up to the perivesical fat (figures 2, 3 a and b).

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Fig 3 a and b

Superficial tumor Invasive tumor

Nearly 70-80% of ail patients who initially présent with bladder cancer hâve tumors confined to the mucosa or submucosa; they are so-called superficial bladder cancers. Among the superficial cancer group, approximately 70% présent as Ta lésions, 20% as Tl lésions, and 10% as carcinoma in situ (CIS, or Tis lésions).

Superficial bladder tumors are prone to recur and in approximately 10 to 30% of cases can progress to an invasive tumor, leading to death if not treated [Dalbagni et al, 2000]. Therefore, patients with superficial bladder cancer need long-term medical follow-up.

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Recently, in Belgium a new rénal disease called ’Chinese-herb nephropathy' (CHN) has been reported to occur in women (and one man) who had ingested slimming pills containing powdered extracts of the Chinese herb Stephania tetrandra (ST) [Nortier et al, 2000]. Moderate to end-stage rénal disease developed,

requiring rénal replacement therapy by dialysis or transplantation. Phytochemical analyses of the pills revealed the presence of aristolochic acids (AA) instead of tetrandrine, suggesting the substitution of ST (Han fang ji) by Aristolochia fangchi containing nephrotoxic and carcinogenic AA. A typical histological feature of CHN is a progressive interstitial fibrosis leading to a severe atrophy of the proximal tubules, as documented by the urinary excrétion rates of markers of tubular integrity.

Removal of the native kidneys and ureters in end-stage CHN patients provided a high prevalence (46%) of urothélial carcinoma of the cis type. Tissue samples

contained AA-related DNA adducts, which are not only spécifie markers of prior exposure to AA but are also directly involved in tumorigenesis. Exposure to Aristolochia species (spp.) is thus associated with the development of rénal interstitial fibrosis (CHN) and urothélial cancer in humans.

We are currently following close to 100 women who reported having ingested such pills. Several patients hâve developed bladder tumors in the remaining bladder after kidney transplantion and bi-nephroureterectomies. Some hâve been treated conservatively whereas others required cystectomy because of muscle-invasive disease [Nortier et al, 2001].

Over 90% of bladder cancers are of transitional cell type. The rest comprises:

a. Squamous cell carcinoma, which usually occurs in patients with chronic infections, such as bilharziosis.

b. Adenocarcinomas of the bladder, which are more often solitary with an exquisite location in the trigone. Their metastatic potential is very high.

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Bladder Cancer Staging

The classification of papillary urothélial neoplasms has been a long-standing source of controversy.

Depth of pénétration (stage) and degree of cellular différentiation (grade) are the most important factors for prognosis. The TNM System is the current staging classification.

TNM staging System for bladder cancer (1997)

Tis In situ change (primary, concomitant and secondary)

Ta Papillary tumor not invading lamina propria

Tl Tumor invading lamina propria, but not detrusor muscle*

T2 Tumor invading superficial detrusor muscle

T3 Tumor invading, but not penetrating deep detrusor muscle (T3a) or invading

perivesical fat (T3b)

T4 Tumor invading surrounding structures (T4a - prostate or vagina; T4b - pelvic

side wall).

Nx Not assessed

NO No nodal metastasis

m

Single nodal metastasis (< 2 cm)

N2 Multiple nodal metastasis (< 5 cm) or single (2-5 cm)

N3 Nodal metastasis greater than 5 cm

Mx Presence of distant metastasis not assessed

MO No distant métastasés

Mi Distant métastasés (may be sub-classified according to site)

*Some pathologists mark the différence between tumors invading basement membrane (Tl a) and those invading true lamina propria (Tlb)

The 1997 TNM differs from the previous 1992 classification since T2 stage now includes ail bladder wall infiltration (T2a inner half, T2b outer half).

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having a worse prognosis. The proposed substaging divides stage Tl on either a two scale (Tla-Tlb) or three-scale basis (Tla-Tlc). In these Systems, Tla désignâtes

tumors not involving muscularis mucosa and Tlb-c represents invasion to or through the muscularis mucosa. However the invariable presence of muscularis mucosa makes it an unreliable histological landmark, and represents a major limitation for the practical application of this proposed System.

The neoplasm termed "bladder cancer" comprises thus in reality a very heterogeneous form of tumors. These tumors may range from low-grade superficial transitional cell carcinoma to high-grade transitional cell cancers that might invade deeply into the bladder wall.

Similarly, the term "superficial bladder cancer" is probably far from idéal (and is regularly questioned by many urologists and pathologists) because it comprises several different types of tumors with very different biological behavior, some behaving like "cats" and others like "tigers" (Fig. 4 a,b,c,d).

Fig 4 a,b,c and d

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Among the superficial cancer group, approximately 70% présent as Ta lésions, 20% as Tl lésions, and 10% as carcinoma in situ (CIS, or Tis lésions).

Papillary low-grade tumors (stage Ta) is associated with a high rate of récurrence (50 to 75%) but little likelihood of progression (< 5%) [Lee and Droller, 2000].

The second form, higher-grade papillary tumors, which infiltrate the lamina propria (stage Tl), is often associated with carcinoma in situ (cis) and has a substantially higher likelihood of progression (20 to 50%). Although both forms of superficial disease initially develop in a form that, by définition, is confined to the mucosa, they ultimately express very different behavioral patterns.

A particular case is represented by carcinoma in situ of the bladder (CIS, Fig. 5). Carcinoma in situ entity was only described in the 50's by Melikov and represents ~ 4-6% of ail newly diagnosed cases. Carcinoma in situ is a high-grade lésion not surgically accessible and removable in toto because of its diffuse surface- spreading behavior [Lamm, 1992]. Although carcinoma in situ looks like a superficial bladder cancer, it behaves like an invasive tumor. Primary Cis incidence varies between 4 and 8%. The concomitant form is more frequent, around 18%. Urinary cytology is positive in 85 to 100% of the cases.

Fig 5

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1.2.3.Natural history

There are 2 risks related to ail superficial bladder tumors: a risk of récurrence with no worsening of the stage (or grade), and a risk of progression leading to invasion of the bladder muscle and potentially to metastatic disease.

a) Natural History of Ta, Tl TCC

There is a major différence in natural history between tumors confined by the basement membrane (Ta) and those that invade the lamina propria (Tl). Already 2 years ago, the National Bladder Cancer Collaborative Group (NBCCG) project prospectively followed 207 patients (médian follow-up of 39 months) who were treated by resection of initial tumor(s) confined to mucosa or lamina propria. None of them received adjuvant therapy [Heney et al, 1983]. Progression was defined as the development of muscle invasive disease or metastasis. Only 4% of 144 patients with Ta disease progressed versus 30% of 63 patients who were diagnosed with Tl superficial tumors.

Similar progression rates hâve been consistently reported [Kurth, 1995].

b) Natural History of Carcinoma In-Situ (CIS)

Diffuse CIS with or without association with superficial papillary tumor has a high incidence of progression to invasive disease. In a review by Lamm, CIS had a 54%

O ver ail average progression to muscle invasive disease [Lamm, 1992]. In general,

diffuse, symptomatic CIS and CIS associated with papillary tumors are more likely to be associated with tumor invasion.

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1.2.4 Prognostic factors for récurrences and progression of superficial

bladder tumors

a. Preoperative parameters

Récurrence rate, multiple tumors, size of the tumors and grade are clearly of utmost importance in assessing the risk of récurrence and progression of superficial bladder neoplasms. One should clearly distinguish those superficial bladder tumors that are prone to recur only, from those which carry an important risk of progression.

Influence of tumor grade, size, multiplicity and CIS on the risks of récurrence and progression (based on 1529 patients, adapted from Milan Rodriguez et al)

N= 1529 patients OR

Risk of récurrence Multiple tumors 2

Tumor size > 3cm 1.65

CIS 1.6

Risk of progression Grade 3 19.9

Multiple tumors 1.9

Tumor size > 3cm 1.7

CIS 2.1

Recently, a combined analysis of 2596 patients from seven EORTC trials served as the basis for elaborating risk tables predicting récurrence and progression rates among individual patients with stage Ta or Tl bladder cancers [Sylvester et al, 2006].

A simple scoring was derived based on: a. number of tumors

b. tumor size

c. prior récurrence rate d. T category

e. grade

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Probablilities of récurrence and progression at one year vary tremendously according to these different variables, from 15 to 61% and from less than 1% to 17% respectively.

At five years, in this very large combined patients' database, probabilities of récurrence and progression ranged from 31% to 78% and from less than 1% to 45%. These figures clearly demonstrate the challenges posed by superficial bladder tumors. If a very large percentage of tumors tend to recur over time, some nearly never progress, whereas for some tumors still ranked as superficial neoplasms, the likelihood of progression peaks as high as 50% over a 5-years follow up period.

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Multivariate Analysis of Time to First Récurrence and Time to Progression [adapted from Sylvester et al, 2006]_____________ _______________________

Récurrence Progression

HR (95% CI) P Value HR (95% CI) P

Value Tumor Status: primary, récurrent 1.48 (1.07,2.03) 0.016

Prier Récurrence Rate: primary, récurrent < 1 rec/yr, récurrent > 1 rec/yr

1.35 (1.24,1.46) < .0001 Number of Tumors: single, multiple 1.70 (1.29,2.24) 0.0002 Number of Tumors: Single, 2 to 7, 8 or more 1.56 (1.42,1.71) < .0001 Tumor Size: < 3 cm, > 3 cm 1.54 (1.32,1.80) <.0001 1.89 (1.40, 2.55) < .0001 T Category: Ta, Tl 1.21 (1.07,1.37) 0.003 2.19 (1.67,2.86) < .0001

Carcinoma in Situ: no, yes 1.19 (.924,1.52) 0.180 3.41 (2.32, 5.01) < .0001 Grade: Gl, G2, G3 1.17 (1.07,1.28) 0.001

Grade G3: no, yes 2.67

(1.99,3.59)

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Weights Used to Calculate the Récurrence and Progression Scores

Factor Récurrence Progression

Number of Tumors Single 0 0 2to7 3 3 >8 6 3 Tumor Size < 3 cm 0 0 > 3 cm 3 3

Prier Récurrence Rate

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Probability of Récurrence and Progression According to Total Score

Récurrence Score Prob Récurrence 1 Prob Récurrence 5

Year (95% CI) Years (95% CI)

0 15% (10%, 19%) 31% (24%, 37%)

1-4 24% (21%, 26%) 46% (42%, 49%)

5-9 38% (35%, 41%) 62% (58%, 65%)

10-17 61% (55%, 67%) 78% (73%, 84%)

Progression Score Prob Progression 1 Prob Progression 5

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Calculation of the Total Score (Hypothetical Example)

Patient with 3 small (less than 3 cm diameter), récurrent (not more than 1 per year). Ta G1 tumors without CIS

Factor Récurrence Score Progression Score

Number of Tumors Single 0 0 2to7 3 3 3 3 >8 6 3 Tumor Size < 3 cm 0 0 0 0 > 3 cm 3 3

Prior Récurrence Rate

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Parameters that matter with respect to tumor récurrence differ from those prédictive of later progression.

The number of tumors, tumor size and prior récurrence rate are strong predictors of récurrence, whereas associated CIS, Tl stage and Grade 3 tumors are the most significant predictors of progression.

Recently, another important parameter for explaining récurrence rates among different institutions has been demonstrated; the surgeon himself !

Brausi et al analyzing 7 EORTC studies found that the quality of the endoscopie resection performed by the individual surgeons was a factor of variability in récurrence rates between patients of similar risk [Brausi et al, 2002].

b. Postoperative parameters

An early récurrence, three months after transurethral resection, is one of the most important parameters reflecting tumor aggressiveness [Merz et al, 1995; Solsona et al, 2000]. For instance in 191 patients with high risk superficial bladder cancer, 111 with secondary or associated bladder carcinoma in situ and 80 with stage Tl grade 3 disease treated with intravesical therapy, multivariate analyses on multivariate analyses the 3-month clinical response was a very significant prédictive factor for progression. The 3-month clinical response was the only independent factor prédictive of invasive progression in cases of absence of response in patients with stage Tl grade 3 tumors or CIS [Solsona et al, 2000].

Stage Tl grade 3 superficial bladder cancer

One particular form of superficial bladder tumors is represented by pTlG3 bladder

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be considered at very high risk not only for récurrent tumors but especially for progression. The decision on whether to attempt bladder conservation with intravesical therapy or to perform a cystectomy is one of the most difficult issue in the management of superficial bladder cancer today. Some authors (mainly in Germany and in some centers in the US) consider radical cystectomy as a first-line therapy for these G3T1 tumors. They believe that radical treatment is performed often too late for these superficial bladder tumors, which can sometimes progress very rapidly and invade the nearby bladder muscle layers. Furthermore tumors are often upstaged at cystectomy [Van der Meijden et al, 2000; Dutta et al, 2001, Bianco et al, 2004], Nowadays, many authors think that T1G3 tumors should be rebiopsied within 6 weeks of the initial transurethral bladder resection to rule out understaging by the first TUR even if the urologist thinks that his resection was complété. This is meant to exclude muscle-invasive bladder cancer, especially if no muscle was présent for analysis at the first TUR [Otto et al, 2003, Jackse et al, 2004, Miladi et al, 2004].

If tumor grade is undoubtedly an important parameter for predicting future tumor behavior, it is of course pathologist-dependent. Furthermore, tumors of similar grade may behave very differently. Numerous works hâve shown that distinct molecular alterations détermine carcinogenic pathways in superficial and muscle-invasive disease [Cordon-Cardo, 1999].

Therefore many recent investigations hâve been conducted to détermine whether new biological markers might help to predict more adequately bladder cancer évolution.

Among these new markers, alterations in protooncogenes (that when activated are characterized by a gain of function) and in tumor suppressor genes (characterized by a loss of function) hâve been identified in bladder cancer.

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1.2.5, Bladder cancer treatment - OverView

• In superficial disease, treatment of superficial transitional carcinoma of the bladder aims to eradicate the superficial neoplasm (usually by endoscopie surgery) and to prevent récurrences as well as its progression to muscle-invasive bladder cancer.

• In invasive disease (invading the detrusor muscle), radical therapy is advised depending on the general health status of the patient. Radical cystectomy (ileal conduit or bladder replacement) is currently the most widely accepted treatment modality although bladder-sparing modalities are investigated (for instance, endoscopie resection followed by adjuvant systemic chemotherapy). Five year survival rates for pT2 diseases treated with radical cytectomy alone vary between 89 and 78%, but sharply drop to 35% when régional lymph nodes are invaded by bladder tumor cells [Stein et al, 2001]. Radiotherapy is advocated in UK but favoured much less in the rest of Europe.

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1.2.5.1 Superficial tumors; Endoscopie resection

Endoscopie examination and resection (Transurethral resection or TUR) remain gold standards for diagnosis and treatment of superficial bladder tumors. In addition to its therapeutic rôle, transurethral resection allows valuable pathological information to be obtained, such as tumor grade and stage.

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Cold cup biopsies are used for very small tumors and to perform random biopsies or deep biopsies in the bed of the resection for sampling muscle tissue without compromising the pathological examination because of electrical coagulation (fig. 7).

Fig 7

When possible and this is often the case with small superficial tumors, endoscopie resection enables to eradicate the totality of visible tumors.

In case of very large tumors, this endoscopie diagnostic step is mandatory but might be incomplète and requires additional thérapies, as for instance radical cystectomy in case of muscle-invasive disease.

In case of multiple or récurrent or large or Tl or cis tumors, endoscopie resection alone might not be sufficient and additional endovesical thérapies are advised as described hereunder.

1.2.5.2 Superficial tumors: Objectives and indications of intravesical therapy

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introduction in the late 1950's, intravesical therapy has been used in the management of superficial bladder cancer with three spécifie goals.

1. Treating existent or residual tumor.

2. Preventing tumor récurrence after complété bladder tumor resection and preventing tumor seeding, which may occur during endoscopie resection. 3. Preventing progression of disease.

Clinical expérience suggests that intravesical therapy should be tailored according to the individual patient features. Grade 3 superficial bladder tumors or patients at high risk for récurrences or progression represent a well-accepted indication for intravesical therapy. In contrast, in the absence of other risk factors, in grade 1 Ta lésions without previous récurrences or without multiple or large tumors, intravesical therapy may not always be justified since the progression rate is very low. However, large prospective studies hâve shown that even one single intravesical instillation of a chemotherapeutic agent within 24 hours of the tumor resection might be justified in patients at low risk of récurrence because of the decreased récurrence rate at the cost of a very low morbidity profile [Oosterlinck et al, 1993, Solsona et al, 1999].

The extreme of the spectrum, CIS, often multifocal, which has a very high risk of disease progression and cannot be completely fulgurated with transurethral resection only, represents a prime target for intravesical therapy.

1.2.5.3 Intravesical chemotherapy

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local and systemic side effects should be minimal and its cost should be low. Unfortunately, no intravésical chemotherapy fits ail these numerous requirements.

Intravesical chemotherapeutic agents [Malmstrôm, 2003].

The most widely used chemotherapeutic agents are Mitomycin C, Epirubicin and Doxorubicin. The effects of cystostatic drugs on tumor cells are concentration dépendent.

Mitomycin C is an anticancer and antibacterial antibiotic isolated from a Streptomyces strain. It is an alkylating agent which crosslinks complementary DNA strands. Its use started in the late '60s. The classical scheme of administration of the Mitomycin C includes 4 to 8 intravesical instillations, using doses ranging from 20 to 60 mg, most frequently 40 mg. Forty mg are usually diluted in 20-60 ml of stérile water.

Whether additional instillations after the initial 4-8 injections are of real benefit is still the subject of controversy. These additional instillations are given monthly. Cystitis and allergie reactions are the most commonly reported side effects.

Doxorubicin (Adriamycin) is an anthracycline antibiotic that has many actions: intercalating between DNA base pairs, inactivating DNA topoisomerase II, and

production of oxygen radicals leading to membrane disruption. As a resuit of its high molecular weight (580 kDa) absorption of Doxorubicin is low. Reported complications include Chemical cystitis and sporadically, shrinking of the bladder. Local side effects vary between 4 and 56% [Bôhle and Jocham, 2000].

Epirubicin is often given at the dose of 50 mg diluted in 50 ml whereas Doxorubicin is given at 50 mg in 150 ml of physiologie sérum.

Recently intravesical instillations Gemcitabine hâve been studied.

Clinical ejficacy of intravesical chemotherapies: effects on récurrences

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significantly more effective than the other [Malmstrôm, 2003]. The impact of intravesical chemotherapy on superficial bladder tumor récurrences has been evaluated in large meta-analyses [Huncharek étal, 2001]. Out of 1672 published papers, Huncharek and co-workers selected 8 randomized trials comprising a total of 1609 patients and 14 treatment arms. A mean 38% decrease in reccurrence rate at 1 year was observed as compared to resection alone, benefits sharply decreasing at 2 and 3 years after the resection.

Another meta-analysis from 5 Japanese studies comprising 1732 patients treated with Adriamycin or Epirubicin demonstrated a 30-50% advantage in terms of récurrence as compared to control, benefits fading already after 1.5 years [Hinotsu et al, 1999]. In these different trials, patients included had either low or medium-risk tumors. According to the available data, intravesical chemotherapy is indicated especially in low- and medium-risk superficial bladder tumors.

Intravesical chemotherapy is not considered as standard treatment for G3 tumors and high-risk tumors because immunotherapeutic agents are more effective (see further).

Regarding cis, responses hâve been observed with mitomycin C mainly, rates averaging 50% but remain suboptimal as compared to intravesical immunotherapy [Bôhle and Jocham, 2000]. In patients in whom BCG has failed, rates of response to Mitomycin C are usually below 20% [Malmstrôm, 1999].

New trend towards early single intravesical chemotherapeutic instillations

The new trend is to administer intravesical chemotherapeutic instillations very early within the first 24 hours after the endoscopie resection of low risk superficial bladder tumors [Oosterlinck et al, 1993; Solsona et al, 1999]. The administration of the chemotherapy beyond 24 hours was shown to increase the risk of récurrence by 2!

Clinical effïcacy of intravesical chemotherapies: effects on progression

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disease progression rates [Kurth et al, 1997] and did not ensure a great effectiveness against CIS or in high-risk patients [Rintala et al, 1995].

So far no chemotherapeutic regimen given intravesically has proven efficacious on tumor progression. Superficial bladder tumors prone to progress (especially G3T1 and cis neoplasms) will do so despite intravésical instillations of chemotherapy.

Thermochemotherapy

The combination of thermal energy and intravesical chemotherapy offers potentially several advantages over chemotherapy alone. Drug uptake by malignant cells and intracellular distribution could be improved while the linking of MMC to the DNA of tumors might be accelerated. Several studies hâve shown promising results with thermochemotherapy in the management of superficial bladder tumors [Colombo et al, 2003].

I.2.5.4. Photodynamic Therapy (PDT)

Its mecharûsm inyolves the intrayenous administration of a photosensitizer with subséquent in situ intravesical activation using whole bladder laser therapy with visible light. A higher accumulation rate of the photosensitizer occurs in rapidly proliferating tissue.

The tumor-localized photosensitizer is activated to generate singlet oxygen causing vascular damage and tumor cell destruction (fig. 8).

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PDT efficacy in éradication and prophylaxis of superficial TCC has been assessed in varions studies. An important application of PDT might be the treatment of BCG- refractory CIS. Durable responses achieved in 30 to 50% of patients resulted in avoiding cystectomy. For instance in 31 patients, mostly affected by primary or concomitant Cis, Berger et al showed a 50% tumor free rate with a 40% response rate in previously BCG treated patients [Berger et al, 2003]. PDT was sometimes associated with severe side effects. Previously most sensitizers had to be applied intravenously, resulting in systemic accumulation and skin phototoxicity.

Additional complications of first génération photosensitizers such as bladder shrinkage resulted from the lack of selectivity between urothelium and detrusor muscle.

Intravesical application now prevents photosensitivity which lasts no longer than 24 hours. Post PDT syndrome is a cystitis-like syndrome which occurred after treatment with the first génération sensitizers Qichlinski and Leisinger, 2001],

1.2.6. Intravesical immunotherapy : bacillus Calmette-Guérin (BCG)

I.2.6.I. Clinical efficacy

The shortcomings of intravesical chemotherapy against high-risk superficial bladder tumors and CIS hâve prompted to look at new agents and especially immunotherapeutic agents. These thérapies are based on the modulation of the immune response of the host, since some tumors might be sensitive to the targeted action of the immune System.

Among the immunotherapeutic agents, the use as intravesical instillations of Calmette-Guérin (BCG) bacillus, a mycobacterium which is an attenuated strain of M bovis, initially used extensively as an anti-tuberculosis vaccine, represents one of the most significant advances in the treatment of human solid tumors. Intravesical

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bladder tumor resection to avoid the potential passage of live mycobacteria through an unhealed urothelium directly into the blood stream.

In nearly 3 décades, since the first patients were treated in 1976 [Morales et al, 1976], intravesical BCG has been acknowledged as the undisputed most effective intravesical agent for preventing bladder tumor récurrences in high-risk superficial bladder tumors and the treatment of choice for carcinoma in situ [Dalbagni and Herr, 2000; Lamm, 1995]. Its effects on disease progression hâve been demonstrated in some studies but not unanimously accepted. A recent meta-analysis on 4,863 patients by Sylvester et al showed a protective effect of BCG on progression (in those patients treated with maintenance therapy) but the mean follow-up was 2.5 years only. Therefore the long-term efficacy of BCG to prevent tumor progression remains to be proven, especially because very few trials were adequately powered.

The majority of randomized studies, especially in high-risk patients but also including, as in a recent one from the EORTC, medium-risk patients [Van der Meijden et al, 2001] found an advantage for BCG against intravesical chemotherapy for preventing superficial bladder tumor récurrences.

This advantage in clinical efficacy of intravesical BCG over intravesical chemotherapy should be balanced by the increased side effects profile associated with the use of attenuated mycobacteria (see further).

Anoter systematic review and meta-analysis compared the relative effectiveness of intravesical mitomycin C and bacillus Calmette-Guerin (BCG) for tumor récurrence, disease progression and overall survival in patients with medium and high-risk Ta and Tl bladder cancers [Shelley et al, 2004].

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favoured BCG and, in this case, was highly significant (P < 0.001). In conclusion, in this meta-analysis tumor récurrence was significantly lower with intravesical BCG than with mitomycin C only in those patients at high risk of tumor récurrence.

A meta-analysis also compared BCG vs MMC in terms of tumor récurrence and toxicity [Bôhle et al, 2003]. In 11 eligible clinical trials 1,421 patients were treated with BCG and 1,328 were treated with mitomycin C. Within the overall médian followup time of 26 months 38.6% of the patients in the BCG group and 46.4% of those in the mitomycin C group suffered from tumor récurrence. In 7 of 11 studies BCG was significantly superior to mitomycin C, in 3 studies no significant différence was found, while in 1 study mitomycin C was significantly superior to BCG. An overall statistically significant superiority of BCG versus mitomycin C efficacy in reducing tumor récurrence was detected (OR 0.56, 95% CI 0.38 to 0.84, p = 0.005). The results suggest superiority of BCG over mitomycin C for prévention of tumor récurrences in the combined data and particularly in the BCG maintenance treatment subgroup, irrespective of the actual (intermediate or high) tumor risk status.

Overall, most randomized prospective trials hâve thus demonstrated an advantage for BCG over intravesical chemotherapy but some results are contradictory too. For instance, the three-arm prospective randomized Dutch Southeast cooperative group failed to show any advantage for the BCG arm, comparing 2 different BCG strains with mitomycin C [Witjes et al, 1993].

However those trials that failed to demonstrate an advantage for BCG usually included predominantly low risk rather than intermediate or high risk patients.

The major advantage of BCG over intravesical chemotherapy has been observed mainly in high-risk patients. In these patients, several randomized prospective studies consistently showed an advantage for BCG in terms of récurrence [Krege et al, 1996; Lundholm et al, 1996; Malstroem et al, 2001]. Side effects were more frequent with BCG and there were no différences in progression or survival.

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Another meta-analysis of comparative studies on the therapeutic efficacy of intravesical BCG versus MMC on progression of Ta or Tl bladder cancers including 1277 patients treated with BCG and 1133 with MMC showed, within the o ver ail médian follow-up of 26 months, a statistically significant superiority for BCG compared with MMC for the prévention of tumor progression only if BCG maintenance therapy was provided [Bôhle and Bock, 2004]

However, although BCG seems to decrease récurrence and progression in patients with Tl tumor, a 54% progression rate was reported in patients followed up for 6 years, indicating that BCG is not effective in half of patients if observed long enough [Dalbagini and Herr, 2000]. In a 5-year follow-up of a randomized comparison of mitomycin C and bacillus Calmette-Guérin (BCG) in patients with superficial bladder carcinoma including 261 patients (primary Tis, dysplasia G2, Tl G3 and multiple récurrent Ta/Tl Gl-2 disease), therapy with BCG was superior to mitomycin C for récurrence prophylaxis but no différence was found for progression and survival [Malmstrom et al, 2001]. In a study carried out in 1988, Herr and colleagues analyzed the effects of BCG on tumor progression and survival [Herr et al, 1988],

Radical cystectomy was required because of tumor progression in 42% of the control patients as compared to 26% only in BCG-treated patients. With a mean follow-up of 6 years, the increase in mean survival of the BCG-treated patients was statistically significant (p = 0.0032).

Following their patients for an additional 7 years, the same authors were able to demonstrate once again a réduction in the bladder tumor spécifie mortality from 37 to 12% [Herr et al, 1995].

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I.2.6.2. Comparison of BCG and intravesical chemotherapy: récurrence rates

Référencés BCG (%) Thiotepa (%) Doxorubicin (%) Epirubicin Mitomycin C (%) Plevel

Brosman et al, 1982 0 47 < .01 Netto et al, 1983 7 43 < .01 Martinez-Pineiro et al, 1990# 17 36 43 < .01 BCG/thiotepa average 7 42

3WOG, Lamm et al, 1991# 63 83 < .01

BCG/doxorubicin average 38 63 Debruyne et al, 1988# 30 25 NS [uahianen et al, 1990 29 62 < .01 Finnbladder group, Rintala et al, 1991# 7 38 0.01 Lundholm et al, 1996# 51 65 0.03 Malmstrom et al, 2001# 0.04

Witjes et al, Dutch Cooperative Group, 1993# 29 (RIVM) 34 (TIGE) 26 NS NS 5WOG 8795,1993# 20 33 < .01 BCG/ mitomycin average 29 36

van der Meijden et al, EORTC Genito-Urinary Group, 2001# 35 51 0.0001 BCG average 25 Chemotherapy average 43 #: Randomized trials

Comparison of BCG vs MMC: Effects on tumor récurrence with OR as effect size - (From Bôhle et al, 2003)

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1.2.6.3 Comparison of BCG and intravesical chemotherapy: progression rates

Meta Analysis: BCG vs. MMC - progression

Citation llalrrtMidmc* Lwor üppmr NTolal BCGtuM MMCrVM

Ayad t99fi ym% ji7 19 1.21 11 152 12/109 9^43

1992 no 3» SS 16 3# 13 32$ 6/188 2MB7 Jaiiiülneri y«8 50 .04 3.72 .37 91 1/4S 2/46

199B no 2.30 -67 7.M U 314 8/103 4/112 Lamm, 1995 m 62 .31 1.23 17 363 15/182 23/161 hlM^strOm. 1999 y«f 69 .36 1.31 26 250 20/125 27/IM MUbkMïodiigiwr 2000y«» SO 41 1,46 47 418 20/207 25/311 htofiueiitu 20OQ no ie .02 1.26 05 210 1/98 7/112 Vagt<<iotrtMn«a 199S no 1 02 42 2.46 97 387 lS/2Sf 8/136 Flx«d Co«M(n«d <•} J7 ,57 1S3 .06 2410 88/1377 107/1131 CofntiteMd <91 .71 .64 1,13 .19 1410 MM277 107/1131 0.01 0.1 1 10 IM

Meta Analysis: BCG vs. MMC - progression by BCG-maintenance

üstnttnMC* Citation Bfet Lowar Uppor PValut MTotol BCG nW MMC n/H no DeOruyne. 19SZ 3.267 .65 16.36 .13 325 6/158 2/167 no K/«g*. 1990 2,30 .67 7:68 .16 214 6/102 4/112 no NoguAint, 2000 .16 .02 1.2S .06 210 t« 7/112 no VegKomblneO.19951.02 .42 2.46 .07 367 15/251 8/136 FIxtid no (4) 1.1« .88 2.07 .81 1138 36/609 21/827 FUiidom no (4) 1.23 .46 3.32 .88 1138 30/609 21/827 y»* Ay*d. 1998 .47 18 1.21 11 152 12/100 0H3 yo8 Jadhioinen, 1969 .50 .04 6.72 .57 91 IMS 2/46 Lanm. 1995 .62 .31 1.23 .17 363 15/182 23/181 y«» Ma/mUrOm, 1999 .69 .36 1.31 26 250 20/12S 27/125 y«» umàn, 2000 .80 43 148 .47 418 20(207 25/211 Flxod yo6 (S) M ,47 ,94 .02 1274 88/668 86/606 R^rndom f9 (6) M AT J3 .02 1274 W06n 86/608 Flxod Combifwl (9) .77 ,«T 1JÏ3 .08 2410 W/1277 107/1133 Rondom Cembifiod (1) .78 .54 1.13 .10 2410 88/1277 107/1133 0.01 0.1 t 10 100

From Bôhle and Bock, 2004

I.2.6.4. Effects of BCG maintenance on récurrence and progression rates

Mainten. Citation OR Lowar Upper P NTotal BCG n/N MMC n/N 0,01 0,1 1 no DeBruyne, 1992 1,279 ,818 2,001 .280 325 66/158 60/167 1 • no Krege. 1996 .935 ,508 1,723 .829 214 26/102 30/112 « no Lee. 1992 ,396 ,125 1.250 ,109 61 19/31 24/30 • no Nogueira. 2000 .438 .213 ,900 ,022 210 13/98 29/112 no Vegt, 1995 1,616 1,061 2,462 .025 387 137/251 58/136 ■ Fixed no (5) 1,084 ,848 1,385 ,521 1197 261 / 640 201 / 557 ♦ Random no (5) ,912 ,558 1,490 ,713 1197 261 / 640 201 / 557 yes Ayed. 1998 ,382 ,223 ,652 .000 270 72/189 50/81 ■ yes Jauhiainen. 1989 122 .033 454 ,000 91 3/45 17/46 • yes Larnm, 1995 .594 ,392 ,900 .014 363 78/182 101/ 181 ■■m-yes Lundholm, 1996 ,533 ,320 ,886 ,015 250 63/125 82/125 ■m yes Millân, 2000 ,395 ,271 ,578 .000 464 70/218 134 / 246 m-yes Pagano, 1987 ,094 ,012 .729 .006 114 1 /22 31/92 Fixed yes (6) ,430 ,346 ,533 ,000 1552 287 / 781 415/771 ♦ Random yes (6) .419 ,302 ,582 ,000 1552 287 / 781 415/771 Fixed Combinsd (11) ,642 ,547 ,754 .000 2749 548/1421616/1328 ♦ Random Combinée! (11) ,561 ,375 ,841 .005 2749 548/1421616/1328 Favors BCG Favors MMC

Effects on tumor récurrence- comparison between

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1.2.6.5. BCG in carcinoma in situ

No one questions the use of intravésical BCG for diffuse carcinoma in situ. It has become the treatment of choice for this disease. This condition is difficult if not impossible to eradicate by resection alone. If cis is treated by surgery alone it progresses to invasion of the muscle in 60% of cases and one third of patients are dead within five years [Nseyo and Lamm, 1996]. A meta-analysis of 18 sériés

comprising 718 patients with carcinoma in situ found an overall complété response rate of 70% with six weekly BCG instillations, increasing to 82% if additional three instillations were given at three months. Some sériés even

demonstrated results in over 90% of the cases [Lamm, 1992].

By comparison, the best results obtained with chemotherapy for cis average 50% and, in general, fewer than 20% of the patients treated with chemotherapy remain disease- free over the long run [Lamm, 1992].

A recent study by the EORTC demonstrated that although short-term BCG is an effective treatment modality in cis (83%), the recurrence-free rate at 5-year dropped to 60%, a resuit still acceptable but which may be even lower at 10 or 15 years Qackse et al, 2001].

1.2.6.6. Indications of BCG; Who should and who should not be treated?

BCG is clearly not effective in muscle-invasive disease. One report even has suggested that it may worsen the prognosis of invasive tumors [Rosenbaum et al, 1996]. It has been also shown that when BCG is not in direct contact with the tumors -those ones invading the prostate or located in the upper tract for instance- BCG is ineffective. However, in contrast, transitional cell tumors of the upper tract hâve been effectively treated when BCG was poured directly into the upper collecting System [Clark étal, 1999].

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intermediate-risk group (patients with primary, multiple, récurrent (1-3 récurrences/year) G1-G2 tumors), BCG is more effective than chemotherapy but also more toxic and these side effects should be balanced against a slight advantage in récurrence rate. In the high-risk group (patients with primary, multiple, or récurrent G3 tumors, tumors more than 3 cm in diameter and patients with primary or concomittant cis), BCG is the first-line therapy. In this group of patients, the benefit of therapy largely exceeds the risks of possible side effects.

SUMMARY (EAU guidelines) of indications for intravesical chemo or immunotherapy

Low risk tumors One single chemotherapeutic agent

instillation immediately after TUR

Intermediate risk tumors Additional 4-8 week courses of

chemoagent

High risk tumors and CIS BCG intravesical therapy

I.2.6.7. Side Effects of BCG contraindications and limitations of BCG administration

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comparing BCG and MMC, adverse events were slightly more frequent with BCG. Local toxicity (dysuria, cystitis, frequency and haematuria) was more frequently associated with BCG than mitomycin C (44 vs 30%). Systemic toxicity, e.g. chills, fever and malaise, occurred with both agents (12% with MMC and 19% with BCG) although skin rash was more common with MMC [Shelley et al, 2004], These symptoms usually are évident by the third or fourth dose and are self-limited, lasting about 24 hours.

In another metanalysis by Bohle et al, in 4 of the 5 studies with reported data on toxicity BCG associated cystitis was significantly more frequent than in the mitomycin C group (53.8% versus 39.2%). The combined cystitis OR was 1.81 (95% CI 1.48 to 2.23, P <0.001). The OR for cystitis in the BCG maintenance group did not significantly differ from that in the nonmaintenance therapy group [Bohle et al, 2003].

Severe side effects affect less than 5% of the patients with rarely BCG sepsis. Severe side effects are usually due to traumatic catheterization.

Deaths hâve been documented after BCG sepsis but remain anecdotal.

Clinical récognition of intravesical BCG side effects

Local Systemic

• Chemical cystitis • Fever

• Bacterial cystitis > 38.5°C

- Micturition frequency • Malaise

- Microscopie hematuria • Rigor

- Gross Hematuria • Rash

- Hypogastric pain • Myalgia / Arthralgia

- Micturition urgency • Lung / Liver involvement

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The tables hereunder summarize the major adverse reactions observed in large trials.

Major adverse reactions in 2,602 patients ffrom Lamm et al, 2002]

Total No. % of total

Fever 75 2.9 Hematuria 24 0.9 Granulomatous prostatitis 23 0.9 Pneumonitis/ hepatitis 18 0.7 Arthralgia 12 0.5 Epididymitis 10 0.4 Sepsis 10 0.4 Rash 8 0.3 Urétéral obstruction 8 0.3 Contracted bladder 6 0.2 Rénal abscess 2 0.1 Cytopenia 2 0.1

Local side effects in 487 patients treated by BCG [van der Meijden et al, 20031

Type Yes any degree Yes with delay in

BCG therapy

Yes, reason to stop

Bacterial cystitis 126 (25.9%) 55 (11.3%) 10 (2.1%) BCG cystitis 231 (47.4%) 29 (6.0%) 59 (12.1%) Other local 174 (35.7%) 39 (8.0%) 17 (3.5%) Frequency > 1/ h 153 (31.4%) Macroscopie hematuria 168 (34.5%)

Ail local side effects

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Systemic side effects in 487 patients treated by BCG fvan der Meijden et al, 20031

Type Yes any degree Yes, reason to stop

Fever>39°C 72 (14.8%) 23 (4.7%) Lung infection 1 (0.2%) 1 (0.2%) BCG sepsis 0(0.0%) 0(0.0%) Skin rash 16 (3.3%) 1 (0.2%) General malaise 113 (23.2%) 15 (3.1%) Other 92 (18.9%) 6 (1.2%)

Ail systemic side effects

192 (39.4%) 72 (14.8%)

Of note, in one EORTC trial analyzing 487 patients who received BCG with maintenance BCG, the majority of local and systemic effects were already seen during the induction and the first half-year of maintenance [yan der Meijden et al, 2003],

What are the contraindications and limitations of intrayesical BCG administration?

General_______________________________________________ - Active tuberculosis

- Congénital immunodeficiencies

- Acquired immune Deficiency Syndrome (including HlV-positiye patients without clinical manifestations)

- Hodgkin's disease

- Myeloproliferative syndromes - Organ transplant récipients - Pregnancy or lactation

- Systemic immunosuppressive treatments

- Concomitant administration of anticoagulants, some antibiotics (relative contraindication)

- Systemic complications as a resuit of previous treatment with BCG

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Management of BCG therapy adverse events [adapted from Rischmann et al, 2000]

Grade 1: moderate and <48hrs Grade 3: Local, régional, systemic and

immunoallergic Burning, frequency, hematuria, fever

(38.5 OC)

Treatment: symptomatic

Anticholinergics without antispasmodics, analgésies

Allergie

Skin rashes, joint pain and rheumatoid arthritis with or without ocular

involvement

Treatment: antihistamines with or without NSAID. If symptoms persist after 10-15 days: INH and RFP (3 months)

Epididymitis and prostatitis

INH and RFP (3 months) with or without fluoroquinolones

Spécifie infection oforgans (hepatitis, pneumonitis)

INH and RFP and ethambutol (6 months)

Grade 2: severe and >48hrs Grade 4: generalized BCGitis

Immediately sever symptoms Do not wait for urine culture results INH 300 mg/ day until resolution of symptoms

Suspend BCG therapy until complété resolution of symptoms and eventually restart with dose réduction

Multiple organ failure (no bacteriological evidence of BCG is necessary to start treatment).

Hospitalization-Intensive Care Unit INH 300 mg/d

RFP 600 mg/d

Ethambutol 1200 mg/d

Prednisolone 40 mg/d with or without quinolones

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I.2.6.8. What is the optimal BCG strain ?

Various centers worldwide dealing with the original Pasteur strain hâve developed an independent substrain. These substrains derived from the parent Pasteur strain are different because of culture methods or conditions different from those originally developed by Calmette and Guérin.

Inevitably, these substrains could also show différences in biological or even clinical activity.

Différences found clinically may be due to intrinsic variability in activity, State of

dispersion, relative numbers of living cells, or the total number of cells (dead or

alive) administered.

Initially in the early 80's, marked différences were noted between different strains and even between lots of BCG of the same strain [Groves, 1993].

The number of culturable particles ranged from 5 x 10^ to 1 x 10^ per vial.

Currently, most manufacturers are able to deliver a product with a relative constant quality, and viability. The dose is generally given in terms of the number of colony- forming units (CPU). The optimal dose of BCG is estimated around 10 ^ -10 ^ living bacilli (colony forming units, CPU).

Although BCG can also be grown by deep fermentation, it is usually grown as a surface pellicle of a liquid medium, for instance a Sauton growth medium. The pellicle develops over a 4 to 6 week period before medium is aspirated. At harvesting, the pellicle is ground in a bail mill to a paste. The final product contains not only living BCG bacilli but also dead microorganisms. The dispersion is responsible for a significant loss in viability, although lyophilization may also contribute to the overall loss of viability in the vaccine. Biological différences resulting from the different culturing and processing conditions hâve been reported [Groves, 1993].

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microorganisms. These factors, as well as the secreted proteins in the culture filtrate may account, at least in part, for the variability noted among differents substrains. The average bacterial cell size and State of vaccine dispersion are used to calculate the CFU content. There is concern however that the number of CFU is not a particularly good indicator of the actual bacterial dose.

Several studies hâve compared different BCG substrains and overall no différences in outcome hâve been reported between the different substrains [Groves, 1993, Vegt et al, 1995].

BCG use in intravesical therapy; doses and colony-forming units

Strain Weight/ampoule Colony-forming units (CFU)

Tice 50 mg 2-8x108 CFU

Pasteur F (Paris) 75 mg (or 120 mg) 6x108 CFU

Connaught 27 mg (x3) 8-32x108 CFU

Armand Frappier (Canada) 120 mg 107 CFU

Glaxo (Evans) 75 mg 8-26x106 CFU

Moreau (Brazil) 100 mg 2x109 CFU

RIVM (Dutch) 109 CFU

I.2.6.9. The optimal treatment schedule and dose

Despite two décades of BCG use, the optimal BCG course is still to be defined. There hâve been two major clinical approaches:

1.2.6.9.1. Efforts to increase the response rate

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carcinoma in situ who failed the first six week induction course showed a clinical response to the second additional course [Coplen et al, 1990; Gruenwald et al, 1997], However, others failed to show any advantage of a second 6-week course.

Another approach has been termed the "maintenance" therapy. Many maintenance regimens hâve been advocated. Several meta-analyses hâve clearly shown the advantage of maintenance BCG over no maintenance both on tumor récurrence and tumor progression [Bôhle et al, 2003; Bôhle et al, 2004, Sylvester et al, 2002]. The most convincing schedule consists of three weekly courses every at 3 months, 6 months and then every 6 months up to 3 years. This approach was proposed in a phase III randomized clinical trial by the SWOG group [Lamm et al, 2000],

Maintenance therapy significantly decreased the tumor récurrence rate and increased disease-free survival. Noteworthy, few patients received the full course of treatment because the maintenance schedule also notably increased the side effects. Other types of maintenance regimens hâve included 6 weekly instillations followed by monthly instillations [Badalament et al, 1987] or 1 instillation every 2 weeks [Witjes et al, 1993], No différence was observed between both groups. Of note, the EORTC GU group observed that maintenance BCG was not associated with increased toxicity [Van der Meijden et al, 2003]. The majority of local and systemic side effects were already seen during the induction and first half-year of maintenance.

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I.2.6.9.2. Efforts to reduce side effects

a. BCG dose réduction. Another approach, aiming initially not to increase efficacy but to decrease side effects bas evaluated low-regimen doses using a half or a third of the dose [Pagano et al., 1991]. It has been suggested that this approach might even increase efficacy.

In 70 consecutive patients with primary or secondary carcinoma in situ with or without concomitant solitary or multifocal papillary tumor treated with weekly instillations of 75 mg (half usual dose), low dose BCG seemed to be similarly effective as the full BCG dose, with a lower incidence of side effects [Losa et al, 2000

].

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Fig 9 Comparative toxicity of 27 vs 81 mg BCG

a

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StaïulartI RD

Patknts, Il (%) Ijxal .'îiy.'itcmjf lÀtcal Systemk'

With no toxicity With toxicity

84 (33.31 172 (h8.3l 112 (4S.Î) 209 184.6)

Grades 1-2 124 (49.2) 71 (28.2) 119 (48.2) 27 (10.9)

Grades 3-4 44 (17.5) 9 (3.f>) 16 (6.51 11 (4.4)

Withdraivn from study 23(9.1) 10 (4)

Instillations delayed 37 (16.8) 22 (8.81

P value, llnear Ireiid (no toxlcity. toxldty grades 1-2. loxidty grades 3~4). local <0.001. syslemlc 0.001 Fig. 10 From Martinez-Pineiro et al, 2002 (with permission)

An EORTC trial bas evaluated in 44 patients the ablative effects of a quarter dose of BCG on papillary marker lésions of the bladder and observed a 61 % response rate, thus warranting the launching of phase 111 trials [Mack et al, 2001].

Most studies found thus no différence in treatment outcome when a decreased BCG dose was administered. At the same time, side effects were less commonly observed.

b. Alternating immuno and chemotherapeutic instillations. Other groups hâve alternated the use of chimiotherapeutic agents with BCG, hoping to decrease side effects while maintaining the same efficacy observed with BCG given alone.

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effective than mitomycin C alone [Rintala et al, 1995, Kaasininen et al, 2003 (fig. 11)].

BCG • bacillws Calmet?e Giierin MMC • mitomycin C

Figure

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