Perioperative intravesical chemotherapy has a well-established role in the treatment of non-muscle invasive bladder cancer. There are multiple agents that can be used in this fashion with varying properties. Although chemical cystitis is the most common side effect and is usually self-limiting, significant toxicity can occur with intravesical chemotherapy. It is imperative that the urologist is aware of the acute and delayed side effects of intravesical chemotherapy and how to manage potential complications. Both local and systemic toxicities are discussed, as well as strategies to minimize and manage them.
Key points
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Absorption of intravesical chemotherapy agents is dependent on molecular weight, concentration, and lipophilic properties. Absorption may also be influenced by surgical technique.
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Toxicity from perioperative intravesical chemotherapy includes both local and systemic effects. Chemical cystitis, manifesting as urgency, dysuria, and suprapubic discomfort is the most common reported side effect occurring in 3.5% to 25% of cases. Systemic complications are unusual, with rates of myelosuppression generally around 1%. The notable exception is thiotepa due to its small molecular weight.
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Severe local toxicity from perioperative intravesical chemotherapy includes bladder calcification, ulceration, or transmural necrosis, which can lead to perivesical fluid collections. These may occur in the setting of missed perforation or in deep resections.
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Skin eruptions are most common with mitomycin C but can occur with other agents. Although the exact cause has not been elicited, the condition usually resolves with removal of the agent and does not result in significant long-term morbidity.
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The most important measure to prevent complications from intravesical chemotherapy is to withhold the agent in the setting of known bladder perforation. In cases of deep resection or clinical suspicion, cystography should be performed to rule out extravasation before administration.
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Patients with peritoneal signs or severe abdominal pain during instillation should be evaluated and treated promptly for chemotherapy extravasation to prevent long-term complications associated with the necrotizing effects of these agents.
Introduction
Non-muscle invasive bladder cancer is the most common newly diagnosed urothelial bladder cancer with an extremely high propensity for recurrence. The use of perioperative intravesical chemotherapy is an important modality in the management of non-muscle invasive bladder cancer, particularly to help reduce the risk of recurrence. Immediate postoperative instillation of cytotoxic chemotherapy has been reported to result in greater than a 39% reduction in recurrence compared with transurethral resection (TUR) alone. Both the American Urologic Association and European Association of Urology Guidelines recommend a single instillation of chemotherapy for patients with low-grade urothelial tumors. These cytotoxic agents have minimal absorption when administered into the bladder, and therefore systemic side effects are low. Compared with immunotherapy, there is no demonstrable effect on disease progression but given the known risks of systemic absorption with immunotherapy agents such as Bacillus Calmette-Guérin (BCG), intravesical chemotherapy remains the agent of choice in the perioperative setting for non-muscle invasive urothelial tumors.
In this article, some of the side effects and complications that may be encountered with the administration of commonly used intravesical agents in the perioperative setting and strategies to help manage these toxicities are reviewed. Most of the published data obtained from previous reports have attempted to describe the toxicity associated with induction courses (typically 6 weeks); however, this article highlights the toxicity, side effects, and management of a single perioperative instillation of intravesical chemotherapy.
Introduction
Non-muscle invasive bladder cancer is the most common newly diagnosed urothelial bladder cancer with an extremely high propensity for recurrence. The use of perioperative intravesical chemotherapy is an important modality in the management of non-muscle invasive bladder cancer, particularly to help reduce the risk of recurrence. Immediate postoperative instillation of cytotoxic chemotherapy has been reported to result in greater than a 39% reduction in recurrence compared with transurethral resection (TUR) alone. Both the American Urologic Association and European Association of Urology Guidelines recommend a single instillation of chemotherapy for patients with low-grade urothelial tumors. These cytotoxic agents have minimal absorption when administered into the bladder, and therefore systemic side effects are low. Compared with immunotherapy, there is no demonstrable effect on disease progression but given the known risks of systemic absorption with immunotherapy agents such as Bacillus Calmette-Guérin (BCG), intravesical chemotherapy remains the agent of choice in the perioperative setting for non-muscle invasive urothelial tumors.
In this article, some of the side effects and complications that may be encountered with the administration of commonly used intravesical agents in the perioperative setting and strategies to help manage these toxicities are reviewed. Most of the published data obtained from previous reports have attempted to describe the toxicity associated with induction courses (typically 6 weeks); however, this article highlights the toxicity, side effects, and management of a single perioperative instillation of intravesical chemotherapy.
Properties and considerations of chemotherapies used intravesically in the perioperative setting
There is still ongoing debate with regard to the usefulness of perioperative chemotherapy. Some argue that the recurrences in this patient population are rarely invasive and in most cases they are amenable to office-based fulguration. Nonetheless, if a cytotoxic agent is to be administered in the perioperative setting, the benefits should outweigh the potential risks. With this in mind, there are several factors that may influence the urologists’ choice of a chemotherapeutic agent for intravesical instillation.
One of the first factors to be considered is the risk of absorption of the chemotherapeutic agents, which may result in systemic toxicity. Although some factors affecting absorption may be under the control of the operating surgeon (such as surgical technique and depth of resection), others are strictly related to the physical properties of the agent. Such properties include molecular weight, concentration, and liphophilicity. Although concentration of cytotoxic agents in bladder tissue is necessary, too much absorption may result in toxic side effects. On the other hand, compounds with poor absorptive qualities achieve lower tissue concentrations, mostly working on the bladder surface. To better define the optimal qualities of cytotoxic compounds instilled in the bladder, Mishina and colleagues determined that the ideal agent should have a pH between 6 and 7, a logP (partition coefficient) either between −0.4 and −1.2 or −7.5 and −8.0, and a molecular weight of at least 200.
Other factors that may increase absorption include agent dwell time, agent concentration, and bladder wall integrity (ie, bladder perforations). Therefore, if an intravesical instillation is being considered perioperatively and there is any question of perforation, an intraoperative cystogram should be performed to rule out extravasation. Complications of bladder necrosis, inflammation, fibrosis, and peritonitis have all been reported in cases of missed perforation and are discussed later.
Chemotherapeutic agents used intravesically
As mentioned previously, there are several cytotoxic agents for use in the perioperative period, some of which remain in clinical trials ( Table 1 ). Each has properties that help to explain its value as an intravesical agent and contribute to potential toxicities. Valrubicin is the only agent with US Food and Drug Administration (FDA) approval for intravesical use, although it is not routinely used in the immediate postoperative setting.
| Agent | Molecular Weight | Class | Dose (mg) |
|---|---|---|---|
| Mitomycin C | 335 | Antibiotic; inhibits DNA synthesis by crosslinking | 20–60 |
| Thiotepa | 190 | Alkylating agent; inhibits DNA synthesis by crosslinking | 30–60 |
| Doxorubicin | 580 | Anthracyline antibiotics; intercalate DNA and inhibit synthesis through several pathways | 10–100 |
| Epirubicin | 580 | ||
| Pirarubicin | 625 | ||
| Valrubicin | 720 | 800 | |
| Gemcitabine | 299 | Cytidine analogue; inhibits DNA synthesis through several pathways | 2000 |
Mitomycin C (MMC) is an alkylating agent that has been used systemically to treat a variety of neoplasms. It has a molecular weight of 334 and is isolated from the bacterium Streptomyces caespitosus . There are several proposed mechanisms of action including inhibition of DNA synthesis by DNA crosslinking and superoxide free radical production. FDA approval for systemic use in a variety of cancers was granted in 1974, although its use as an intravesical therapy is still considered off-label. Bone marrow suppression, manifesting as thrombocytopenia and leukopenia are the most common side effects reported when administered systemically. Extravasation of mitomycin C when it is being administered intravenously is classically known to cause local tissue necrosis, which can be devastating and require surgical debridement in severe cases. Other toxicities with systemic use include hemolytic uremic syndrome, and effects on cardiac, pulmonary, integumentary, and renal systems.
MMC is the most extensively studied agent in terms of establishing an intravesical pharmacokinetic profile. In an experiment in which dog bladders were instilled with 20 mg in 40 mL saline, tissue concentrations decreased sharply with depth through the mucosal and submucosal layers (50% decrease for every 500 μm). Concentrations at depths less than 2000 μm were at the lowest levels of detection (0.1 μg/g) and the plasma concentrations were less than 100 μg/L. This has also been shown in humans who were administered MMC before cystectomy; a logarithmic decrease in concentration of the agent with increasing depth up to 2000 μm was demonstrated. In a study of 18 patients receiving 40 mg of MMC intravesically followed by serial plasma measurements, the maximum systemic concentration was approximately 36 ng/mL with no evidence of bone marrow suppression. The investigators noted that, based on other studies, this systemic concentration is much lower than that obtained when administering intravenous MMC with a concentration of 2.0 μg/mL immediately after injection.
Doxorubicin and Derivatives
Doxorubicin is in the anthracycline class of cytotoxic agents, an antibiotic isolated from Streptomyces peucetius . Its proposed primary action is inhibition of DNA synthesis through intercalation, although the exact mechanism is not entirely clear. With a molecular weight of 580, its absorption through the bladder wall is minimal. The acute side effects of doxorubicin when administered systemically include bone marrow suppression, gastrointestinal upset, and alopecia. Delayed effects include cardiomyopathy, secondary hematologic malignancies, and hepatic disease. The current recommended dose for intravesical use ranges from 30 to 50 mg. Previous studies demonstrated that a postoperative instillation of 40 mg in 20 mL of doxorubicin allowed to dwell for 2 hours resulted in 1% of the dose being absorbed and detectable in the plasma at very low levels (>0.2 μg/L) in 6 of 8 patients.
Epirubicin is a derivative of doxorubicin, also with a molecular weight of 580 and minimal systemic absorption. When used systemically, it has been proposed to be as efficacious as doxorubicin but with less associated toxicity. It is commonly used in Europe both as an immediate instillation after TUR as well as an induction course. Detectable levels of epirubicin in plasma can be seen after immediate instillation. Tsushima and colleagues obtained blood samples from 10 patients at 30, 60, and 120 minutes after a 1-hour intravesical instillation of either 20 mg/40 mL or 50 mg/100 mL epirubicin. At both concentrations there were detectable levels of epirubicin in plasma (20 mg/40 mL, <2.0 ng/mL at 1 hour, then undetectable; 50 mg/100 mL, 4.4 ng/dL at 1 hour, <3.0 ng/dL at 2 hours, then undetectable). The low circulating levels found with administration may cause some systemic side effects, although the incidence from previous trials is around 1.3%.
Pararubicin and valrubicin are also derivatives of doxorubicin. Plasma pararubicin levels were studied in 20 patients who were given 30 mg of pararubicin intravesically at 2 concentrations for 1 hour after TUR. At all time points, pararubicin concentrations were less than detectable limits (2.5 ng/mL up to 120 minutes). The mean recovery percentage of the agent after draining the bladder was 73%. Valrubicin is currently the only FDA approved intravesical agent for use in BCG refractory carcinoma in situ. It has also been evaluated as an immediate instillation, although it is currently not approved for this use. Although its molecular weight of 723 is one of the largest of all the intravesical agents, it is highly lipophilic and rapidly absorbed into cell membranes, which could lead to increased absorption. Studies evaluating the pharmacokinetics of valrubicin used as an induction course have revealed minimal detectable levels in plasma, but in a pilot study of 22 patients in whom it was used in the perioperative setting, the systemic exposure was much higher, especially in cases of extensive resection and bladder perforation.
Thiotepa
Thiotepa is the oldest agent used for intravesical instillation, with results of a series described as early as 1961. As an alkylating agent, thiotepa produces a cytotoxic effect by DNA crosslinking. Its molecular weight of 189 makes thiotepa the smallest of all agents used intravesically. Previous investigators have shown significant systemic absorption of thiotepa when administered in the bladder. Jones and Swinney found that up to one-third of the dose was absorbed in 16 patients treated with an induction course. Lunglmayr and Czech demonstrated that approximately 20% of thiotepa was absorbed when given in patients with normal urothelium and this increased to near 100% in the setting of injured mucosa from fulguration or resection. Given these findings, thiotepa carries a more significant risk of absorption with resultant bone marrow suppression compared with some other contemporary agents used in the perioperative setting.
Newer Intravesical Agents
Gemcitabine is the newest chemotherapy agent that has been investigated as an intravesical agent in the immediate postoperative and adjuvant settings. Commonly used systemically for invasive and metastatic bladder cancers, this agent has been proposed to be ideal for intravesical use. A cytidine analogue, it has several inhibitory effects on DNA synthesis, including inhibition of DNA polymerase. It is typically administered in the immediate setting at a concentration of 20 to 40 mg/mL (2000 mg in 50 or 100 mL) with a dwell time of 30 to 40 minutes. In the only prospective randomized trial evaluating the effect of immediate intravesical gemcitabine on recurrence-free survival compared with placebo, patients were managed with continuous bladder irrigation for at least 20 hours after instillation. At 12 months there was no difference in recurrence-free survival between the treatment and placebo groups.
Despite the ongoing evaluation of this agent in terms of efficacy, previous studies have shown gemcitabine to be well tolerated when administered in the perioperative setting. Maffezzini and colleagues demonstrated detectable levels of gemcitabine in plasma after immediate instillation at a concentration of 40 mg/mL in a series of 15 patients. The degree of absorption was dependent on the extent of resection and peak levels were obtained at 15 minutes and were much less than the plasma concentration obtained with systemic administration. Toxicity was low with 1 patient developing grade 2 leukopenia (3000–3900/μL). A subsequent phase III trial of 358 patients randomized to placebo or immediate gemcitabine has also demonstrated a low risk of toxicity. Adverse events were similar in both groups (29.5% gemcitabine vs 26.5% placebo) and the investigators concluded that only about 6% of the adverse events in the treatment arm were likely attributed to intravesical instillation. Of these, postprocedural pain, pyrexia, and alopecia were reported in the treatment group (each 1.2%). Cases of myelosuppression were not reported. Investigational studies using gemcitabine are ongoing, including the results of the Southwest Oncology trial, which recently completed accrual, and although the exact role for its use has not been defined, it seems to be safe as an immediate instillation.
Apaziquone is a synthetic analogue of MMC and is being studied in the perioperative period in patients with non-muscle invasive bladder cancer. It requires reduction by the intracellular enzyme deoxythymidine-diaphorase for cytotoxicity. Because this enzyme has been reported to be increased in bladder cancer cells, this may lead to selectivity and could prove advantageous in terms of efficacy and safety. A pilot study evaluating the pharmacokinetics and side effect profile showed no detectable levels in plasma and similar toxicities to those reported in other series using MMC. Docetaxel and paclitaxel are chemotherapy agents that inhibit microtubule depolymerization and are being investigated for intravesical use.
Side effects of intravesical chemotherapy
Side effects from perioperative intravesical chemotherapy can be divided into 2 separate entities, local and systemic, both of which can further be described as minor or major. From the previous discussion, it is evident that systemic absorption of these agents is in general low and associated with minimal toxicity. However, local side effects are common but fortunately self-limiting in most cases. The following section discusses the local and systemic side effects that are associated with intravesical chemotherapy as well as treatment strategies to manage them.
The true incidence of both local and systemic side effects with intravesical chemotherapy when applied in the perioperative setting is difficult to assess. Much of the data describing adverse events with intravesical chemotherapy is limited to induction courses whereby patients undergo weekly instillations for variable lengths of time. Table 2 shows local and systemic adverse events that have been reported in previous clinical trials using intravesical chemotherapy in the immediate postoperative setting. Although the overall toxicity is low, reporting on toxicity among these trials is inconsistent and therefore may be underestimated.
| Series | Agent/Dose | Design | No. of Patients Treated | Local Symptoms | Comments | Systemic Symptoms |
|---|---|---|---|---|---|---|
| Tolley et al, 1996 | MMC 40 mg | 3 arms: (1) Immediate MMC (2) Immediate MMC + induction (3) Control | 149 | Very low | Delayed healing at resection site in a few cases | None reported |
| Solsona et al, 1999 | MMC 30 mg | 2 arms: (1) Immediate MMC (2) Control | 57 | Chemical cystitis 3.5% | No difference in catheterization period or hospital stay between groups | None reported No hematologic changes |
| EORTC30831 | MMC 30 mg | 2 arms: (1) Immediate treatment (2) Delayed treatment | 228/229 | Chemical cystitis 6% (both groups) | 3.0% required delay or discontinuation in arm 1 | Rash, dizziness, malaise 7% (severe 1.8%) |
| EORTC30832 | Doxorubicin 50 mg | 2 arms: (1) Immediate treatment (2) Delayed treatment | 189/188 | Chemical cystitis 9% (both groups) | 2.2% required delay or discontinuation in arm 1 | Rash, dizziness, malaise 7.1% (severe 0.8%) |
| Mostafid et al, 2006 | MMC | Single arm | 177 | Pain 1% | Catheter malfunction in 1 patient resulting in MMC contamination on skin | None reported |
| Oosterlinck et al, 1993 | Epirubicin 80 mg/50 mL | 2 arms: (1) Epirubicin (2) Control | 205 | Chemical cystitis 11.7% | Skin allergy 1% | No hematologic abnormalities |
| Ali-el-Dein et al, 1997 | Epirubicin 50 mg/50 mL | RCT, 3 arms: (1) Immediate treatment (2) Delayed treatment (3) Control | 55 | Chemical cystitis 22% (mild 16%, severe 6%) | None | |
| Okamura et al, 2002 | Pirarubicin 30 mg | RCT, 2 arms: (1) Doxorubicin-THP (2) Control | 84 | Chemical cystitis 25% | No systemic or hematologic abnormalities | |
| MRC Working Party on Urologic Cancer | Thiotepa 30 mg/50 mL | RCT, 3 arms: (1) Control (2) Immediate treatment (3) Immediate and induction treatment | 379 | Chemical cystitis <1% | Fluid retention/edema in 1 patient |
Local Side Effects
Administration of cytotoxic chemotherapy into the bladder can induce an array of irritative voiding symptoms including dysuria, frequency, urgency, suprapubic discomfort, gross hematuria, and pelvic pain, which collectively are referred to as chemical cystitis. In some cases, the onset of symptoms is immediate and may necessitate removal of an agent for alleviation. All chemotherapeutic agents can produce 1 or a combination of these symptoms. In a meta-analysis published by Sylvester and colleagues, that included perioperative instillations of epirubicin, thiotepa, MMC, or pirarubicin, the reported toxicity incidence of chemical cystitis was approximately 10%. The effects were described as mild and transient in nature. Table 2 shows a list of previous clinical trials using immediate intravesical chemotherapy that have information regarding local toxicity.
It is evident from review of the studies that the prevalence of symptoms related to chemical cystitis ranges from 1% to 25%. However, these data should be interpreted with caution, because the different methods of reporting toxicity were inconsistent across these studies. Furthermore, some trials did not even address specific data on treatment toxicity (not shown) and true rates of side effects are likely unknown or underestimated. Nonetheless, no serious events were reported in any of these trials.
Management of Chemical Cystitis
Symptoms of chemical cystitis are usually self-limiting and require no further treatment in the perioperative setting. Agents such as phenazopyridine (pyridium) and anticholinergics can be used in more bothersome cases. Powdered opium and belladonna alkaloids in a suppository form can also be used during instillation to provide relief of spasms and discomfort, and to help with retention of the intravesical agent. Other strategies to help reduce discomfort during treatment include ensuring the bladder is empty before instillation of agent and ensuring meticulous hemostasis at the end of resection to prevent accumulation of blood clots that may occlude the catheter and further exacerbate these symptoms. It is difficult to know whether many of the symptoms of cystitis are related to the intravesical agent or the procedure itself; however, management is the same for both. In addition, anecdotal recommendations of a short course of oral steroids have been advocated as significantly beneficial in alleviating severe cystitis-type symptoms (Chang, unpublished data).
Stoehr and colleagues described a novel technique in efforts to improve patient comfort during intravesical MMC instillation. They proposed that some of the pain associated with perioperative instillation resulted from the rigid resistance of a clamped catheter and proposed a technique of maintaining the agent in the bladder without clamping. By elevating the urine bag 1 m above the supine patient, MMC was retained in the bladder by hydrostatic pressure ( Fig. 1 ). In a randomized trial comparing this technique with the more traditional method of catheter clamping, they found that pain levels scores were significantly lower with the clampless technique and the mean instillation time was significantly longer (110 min vs 83 min).
