Drugs in Superficial Bladder Cancer
Since the introduction of thiotepa as an intravesical agent by Swinney et al. in 1961, drugs have been used in patients with superficial bladder cancer to try and both reduce the recurrence rate and prevent progression of superficial disease to invasive bladder cancer. Whilst new agents have been introduced as intravesical therapies and there is a greater understanding both of the progress of superficial disease and of the action of these agents on superficial bladder cancer since that time, optimal therapy, optimal timing and an optimal agent still remain to be definitively identified.
Rationale for intravesical therapy
Because even patients with well-differentiated superficial bladder tumours have a high recurrence rate of the order of 70% and because with the risk of recurrence the possibility of both progression of stage and grade can occur, the elimination of superficial disease is essential. Although the rate of progression, at possibly 20% overall, is smallest in the pTa Gl lesion (at 2-3%) and greatest in the pTl G3 lesion, at possibly 40%, the treatment of muscle-invasive disease carries both a significant morbidity and a mortality and even in patients having early aggressive therapy 5-year survivals are little better than at 50%.
Intravesical chemotherapy has been utilized both prophylactically (once the initial superficial lesions have been extirpated) and therapeutically in order to remove both clinical and subclinical areas of tumour.
Although there is a decided association with increasing grade and stage from Ta Gl to Tl G3 as to the risks of progression, clinical trials in superficial bladder cancer have demonstrated that other prognostic factors have a role and are independent predictors of disease progression. These include
1 multiplicity of tumours;
2 a rapid recurrence rate;
3 Tl or associated carcinoma in situ;
4 a grade 3 tumour with adjacent dysplasia or carcinoma in situ;
5 a positive urine cytology in the absence of overt lesions within the bladder;
6 a positive urethral biopsy;
7 initial large tumour size.
All the above are independent factors both for increased chance of recurrence and for disease progression.
During the last 20 years an attempt at a more systematic approach, based on the results of clinical trials, has been made in the utilization of intravesical cancer therapy of the bladder, but as will be demonstrated in discussion of individual agents that have been used, most of this has evolved by serendipity rather than a rigorous dose-ranging regime, with due attention paid to the pharmacological concepts of optimizing drug therapy. Historically, this has occurred because of the excellent response that early papers have demonstrated with intravesical regimes of both chemotherapy and immunotherapy. Surprisingly, very little clinical attention has been paid to factors that need to be utilized in systemic chemotherapeutic regimes and are known to be capable of altering the cytotoxic effect of chemotherapeutic or immunotherapeutic regimes (such as the effect on the molecular weight of the compound, lipophilicity, optimum pH in which it is utilized, osmol-ality, dose concentration, dose volumes and the frequency and timing of installations). In only comparatively recent times have attempts been made to control some of the above factors and trials have looked at different dosing regimes, although very frequently only in phase II studies.
Simple factors such as the optimal time for an agent to be left in the bladder have tended to be judged by the initial reported studies, which probably from convenience have used only 1 or 2 h. There are little or no studies that have investigated whether the control of intravesical recurrence of bladder tumours has any bearing on the inevitable dilution effect that occurs the longer the agent is retained in the bladder and, although most regimes recommend that patients attempt to bring the whole of the bladder into contact with the intravesical agent by rotating themselves through 360° no studies demonstrated whether this actually has the desired effect.
In this chapter the currently available agents for intravesical treatment of superficial bladder cancer are discussed. In the past, attempts have been made to use systemic therapy and small studies using methotrexate and retinoids as oral preparations have failed because of drug toxicity and, in essence, 100% noncompliance by the patients. The difficulty with oral preparations is that in almost all cases, except the odd patient with carcinoma in situ who has superficial bladder cancer, there are no symptoms and any agent that gives rise to problems exemplified by the above two agents will be rapidly discarded.
The role of immunotherapy will be investigated by looking at the possible utilization of other biological response modifiers and the role of photodynamic therapy in superficial bladder cancer and finally by discussing possible novel therapies that can be utilized.
Intravesical chemotherapeutic agents
Immunotherapy
Photodynamic therapy
Photodynamic therapy is a treatment that uses a photosensitizing drug that when activated by light in the presence of oxygen produces local cell death. Focal light Photodynamic therapy was first described in the bladder in 1976 with whole-bladder wall laser Photodynamic therapy following in 1984. Since then more than 350 patients with superficial bladder cancer have been treated and most of the reported series, however, have been those with carcinoma in situ. Whilst the remaining patients have had multiple recurrent Ta Tl disease, 3-month response rates in these small numbers, ranging from 33% to 100% and importantly a 50% response rate in patients with previously resistant carcinoma in situ and papillary disease, have been encouraging. The clinical acceptance of photodynamic therapy has been limited by its complexity and the reported adverse side-effects. These are usually related to the porphyrins that have led to skin photosensitization and this has meant that patients have had to stay out of sunlight for many weeks following this treatment. There have also been serious local effects including bladder fibrosis and associated contracture in more than 10% of reported patients.
It was felt that these problems were inherent with the early systemically administered photosensitizers, which have typically been porforin or haematoporphyrin derivatives that were slowly metabolized and were associated with poor tumour to detrusor selectivity and that resulted in Photodynamic therapy damage to the bladder muscle. Although careful light dissymmetry could alleviate bladder contractory completely it was claimed that this added a further level of complexity to the delivery of this therapy.
Recently a new ‘second generation’ intravesically delivered photosensitizer 5-amino levulinic acid has enabled a re-evaluation of Photodynamic therapy for superficial bladder transitional cell carcinoma. Preclinical studies have shown that there is active uptake of the metabolite of 5-amino levulinic acid within the urothelium and transitional cell carcinoma but virtually none within the detrusor. In addition, patients have not been troubled in the small group of patients hitherto studied with photosensitivity because of the rapid metabolization of 5-amino levulinic acid.
The treatment is still complex, requiring a special laser light delivery source and the utilization of graded intravesical dosing but a recent article suggests that these second-generation photodynamic therapy agents can be given intravesically under a local anaesthetic. This may make them more useful and acceptable to patients.
Comparisons of intravesical chemo- and immunotherapy
When direct studies comparing the utility of intravesical chemotherapy or of immunotherapy have been used different results were apparent. The studies of Lamm have shown a clear superiority of Bacille Calmette-Guerin over Adriamycin and appear to do the same for mitomycin C only at a relatively low dosage. However, Witjes et al. in a well-constructed study using Bacille Calmette-Guerin RIV (the Dutch-produced Bacille Calmette-Guerin strain) against mitomycin found no difference between the two agents both in recurrence rate and in short-term progression rates. It remains contentious whether any form of intravesical therapy has the ability to prevent progressive disease. Certainly the longer-term follow-up of even those patients with complete responses to both Bacille Calmette-Guerin and mitomycin tends to suggest that the bladder is always at risk of superficial bladder cancer and that long-term progression can occur after either type of therapy.
Novel therapies
The initial goal of intravesical treatment was to reduce recurrence rates and the currently used agents discussed in this chapter achieve this to varying degrees. The more important and less well documented goal is to prevent cases in which an initial superficial cancer progresses to invasive disease, which is the primary goal of any novel therapy for superficial bladder cancer. The important work of pooling the extensive European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council prospective randomized studies in superficial bladder cancer, has clearly defined patients that can be apportioned to low-, intermediate-and high-risk categories. In the high-risk category patients, up to 40% may subsequently demonstrate an invasive bladder cancer. The EORTC has also pioneered the utility of the marker lesion and this enables novel therapies to be assessed for therapeutic utility against a marker lesion, but their ability to affect the most-at-risk patients can be decided by looking at them in high-risk category tumours in carefully constructed prospected phase II/III trials.
Although there still remains a place for a synthetic intravesical agent that can clear bladders and prevent recurrence, it is more likely, with our greater understanding, that the new era of biological therapy will actually produce the next generation of intravesical drugs. Intravesical treatment is useful because the bladder is accessible; has a large surface area, which enables prolonged contact with any novel therapy; and can rapidly and frequently be monitored for side-effect. Vectors such as a virus can be used to carry either replacement or genetically neutralizing proteins into the tumour to prevent progression of disease, because undoubtedly the bladder mucosa will be unstable. The possibility of modifying or reversing that instability should have a very fruitful opening and the benefits previously described for retinoids may, by utilizing new biological methods of transfection, enable these plastic and neoplastic changes to be reversed as they have been demonstrated to be reversed in the laboratory with retinoids more than 30 years ago.
Conclusions
Thiotepa in the early 1960s and subsequently Bacille Calmette-Guerin in the mid-1970s have provided useful tools for the consistent reduction of superficial bladder cancer recurrence. No drug, however, has consistently prevented recurrence nor have they consistently prevented progression. Large trials carried out in the 1980s by the Medical Research Council and EORTC, which remain the bedrock of our understanding of the therapy of superficial bladder cancer, have identified three coherent and consistent groups of patients at low, intermediate and high risk of recurrence and subsequent progression. This means that with novel therapies, which may more effectively interfere and indeed reverse the processes leading to potential invasion, the right group of patients can be identified and in prospective randomized trials, hopefully, fruitful answers will come quickly rather than in the serendipitous way that drugs in superficial bladder cancer have evolved in the last 30 years.
Posted in: Urological Oncology