In the third of a series of articles charting the history of hyperthermic treatment for bladder cancer, Johannesburg-based urologist Dr Steven Cornish looks at the development of different intravesical drug treatments for hyperthermic chemotherapy, including some handy tips for use. Originally published in Urology, Uro-Oncology and Sexology Update (vol 2, issue 2, 2023)
“Is it safe?” This was the question Laurence Olivier asked of Dustin Hoffman in Marathon Man. Unfortunately for Hoffman, he couldn’t answer, and Laurence took great delight in drilling holes in his healthy teeth with the panache born of years spent as a Gestapo dentist. I hope in this article that I will convince the reader that hyperthermic chemotherapy of the bladder is not only safe but is better tolerated than the gold standard of BCG therapy. This is a dry subject at best, but I hope to make it less painful to digest than a freshly drilled dental nerve…
Mitomycin C
For a long time, mitomycin C was the only drug used for thermal intravesical therapy. It had a long track record of use in the cold setting (room temperature) when BCG had failed, was not available, or when adverse reactions accompanied its use. Urologists have had a relatively long experience of using this drug in either the post-cystoscopy setting for prophylaxis or to treat non-muscle-invasive disease. Its use was first described in the 1970s.
I am not sure if everyone is aware of how toxic this substance can be. In terms of handling, it’s not very nice. Mitomycin C is classified as a hazardous substance because it is a mutagen that can affect the kidneys of its handlers. It’s important to wear protective clothes and gloves when handling it and if any gets on the skin or in the eyes, the affected surface must be washed immediately. Pregnant women should not handle it. When mixed, the crystals give off fumes which can be inhaled. Therefore, it should be mixed in its ampoule and care taken not spill any.
For the first six hours after treatment, patients should void urine by sitting down so as not to splash, and the toilet bowel should be flushed twice with the lid down. (Oddly enough, according to the OSHA – Occupational Health and Safety Administration – which quantifies drug hazards, drinking mitomycin C is not too dangerous.)
Following mitomycin C therapy, urine may turn blue-green for up to 48 hours, and dysuria can occur, as well as abdominal cramps and diarrhoea. If the patient experiences a skin rash on the palms of the hands, soles of the feet, and genitals, mitomycin C management should be abandoned. Sometimes steroids are needed to resolve the rash. A very rare side effect is reduction in bladder capacity. Some may develop a urinary infection and this needs to be managed appropriately. Rarely, the drug can cause pancytopaenia. The overall incidence of adverse events has been reported at 22-25%, with dysuria making up 5.5%.
Gemcitabine
Gemcitabine has been used in an intravesical setting since around 2010. When handling the drug, safety precautions should be similar to mitomycin C. Gemcitabine is not quite as toxic and is more likely to target the lungs. As with mitomycin C, it should be washed off the skin or the eyes immediately, and pregnant women should not handle it.
Gemcitabine is currently becoming the most commonly used chemotherapeutic drug in intravesical therapy because of a shortage of mitomycin C – a shortage which started in 2019 and was attributed to manufacturing problems. Gemcitabine is an antimetabolite that targets components of the cell division process.
In 2011, Cao et al reported that gemcitabine’s adverse event rate was similar to mitomycin C’s. In 2020, Li et al published work comparing gemcitabine to mitomycin C. The researchers looked at chemical cystitis, haematuria, rash and hepatorenal toxicity. In terms of side effects visually demonstrated on forest plots, there was a clear advantage in favour of gemcitabine.
A meta-analysis by Zigi Ye et al published in 2018 looked at the adverse rates of gemcitabine versus BCG and concluded that there was a significant difference in favour of gemcitabine for the categories of dysuria, fever, haematuria and miscellaneous adverse events. However, a study published in 2021 by Kuperus showed that gemcitabine had a greater incidence of fatigue and chills compared with BCG, although duration of symptoms was longer with BCG and haematuria was a lot worse. As with mitomycin C, gemcitabine very rarely causes a reduction in bladder volume.
Anthracycline antibiotics
A study published in 2014 looked at the safety and efficacy of valrubicin, a drug that had been reintroduced to the medical world after having been withdrawn at the beginning of the century because of concerns over manufacturing procedures. Valrubicin is an anthracycline antibiotic. Simplistically, this group of antibiotics damages DNA in cancer cells. In handling the drug, the usual rules will apply concerning protective clothing when drawing up this red-coloured solution. It should not be used with PVC products because a component of the drug leaches PVC. Instead, administration sets using polypropylene or polyolefin should be used.
The commonest side effects are the usual suspects of haematuria and pollakiuria. Four per cent of patients dropped out of the 2014 study because of serious adverse events. A rash on the palms and genitalia from voiding urine containing the drug is common. It’s important to wash one’s hands and genitalia carefully for the first 48 hours after the drug has been administered. Valrubicin can also cause a generalised rash, but treatment can be continued on topical steroids.
One noteworthy effect is red urine, not to be confused with haematuria. It can be ignored unless it continues for more than a day. Other side effects include nausea, vomiting, abdominal pain, diarrhoea, backache and headache. Overall, more than 90% of patients will have some form of symptoms during the six-week induction phase. The largest study to date reported 60% of patients having irritable bladder symptoms. The rate for urinary tract infections is 15%.
Pirarubicin and epirubicin are other red anthracycline drugs with very similar side effects to valrubicin. Similar precautions and safety aspects apply to these drugs.
Docetaxel
Docetaxel has been used successfully in sequential combination with gemcitabine for nearly 15 years. Until recently, both drugs have been administered in the room temperature setting. However, in 2020 a paper appeared by Rao et al reporting on their experience of thermal gemcitabine and docetaxel that began in 2007. They had 60 patients in the study, all of whom had refused radical cystectomy. Thirty-one patients had some local symptoms, and all completed their treatment course. The commonest symptoms reported were mild fatigue (20%), haematuria (20%), mild urinary frequency/urgency (13%), dysuria (10%), and nocturia (7%).
Gemcitabine is given before docetaxel because gemcitabine induces cell cycle arrest and docetaxel provides the coup de gras by promoting cell death. Docetaxel is a microtubule inhibitor that hinders cancer cell replication. The drug was first reported in intravesical therapy in 2006 by McKiernan et al in a phase 1 study. There was no systemic absorption, so the classical side effects of docetaxel did not occur. Protein size greater than 300 Daltons cannot penetrate the bladder wall and docetaxel weighs in at 862 Daltons. Once again, as with the other chemotherapeutic drugs, there were local side effects – mostly of the grade 1 variety. In terms of handling the drug there are again hazards. It is a flammable liquid and vaporises. It is suspected of causing genetic defects. The drug may damage fertility or the unborn child, and it may cause harm to breastfed babies. Docetaxel will cause eye irritation. It needs to be handled with protective clothing and washing of hands afterwards is essential.
Heat and drug safety
When is heat added to the equation, is the safety of each of the drugs mentioned altered? The first trial of mitomycin HIVEC was conducted by Colombo et al in 1995. The complete response rate was 70% and after a mean follow-up of 24 months, 16% recurred. Multiple studies have since followed. No one has reported any serious consequences of heating up these drugs in terms of patient safety from the drug itself.
In a meta-analysis of 12 trials involving 888 patients published in 2020 by Liu et al, the forest plot for all the recorded adverse events slightly favoured thermal therapy over the control. The drugs used in the various studies analysed included mitomycin C, gemcitabine and pirarubicin. Systemic side effects were minimal, and this makes sense. In my previous article covering the basic science of thermal therapy, we saw that there is very little systemic absorption of these drugs placed into the bladder during above-body thermal conditions.
The machinery for heating up the intravesical solutions also needs to be considered in the realm of patient safety. My articles have been written for the urologist and not large oncology units, so I am not going to consider the hugely expensive external radio frequency units like the Pyrexar, which cost many hundreds of thousands of dollars and require a specialist physicist to run them.
The Synergo system, which falls under the classification of a RITE system (radiofrequency-induced thermos chemotherapy effect), is also expensive and will probably only be affordable in large private or academic units. This device uses a catheter with a radio frequency transmitter built into it to heat the fluid bathing the bladder. It was on this device, however, that most of the original intravesical research was performed using mitomycin C.
Devices like the Combat BRS, which heated the fluid outside and circulated it through the bladder continuously, came later. These devices fall under the classification of CHT (conductive thermochemical therapy). These machines are a lot more affordable, and outcomes from these devices are now appearing more often in the literature.
Comparison between the radio frequency catheter systems and recirculating heated systems have shown similar clinical results. See part 2 of this series for further discussion.
NICE published an article in 2021 on various aspects of the Synergo RITE (radiofrequency-induced thermos chemotherapy effect) system, including its safety. The report was based on 19 separate studies. The item that was highlighted was pain that built up over the course of treatment. In most patients, however, the pain could be tolerated and managed by the nursing personnel. Implanted metal in the pelvis was associated with pain during the procedure. The posterior bladder wall tended to be burnt by the catheter, but the burn was superficial and would heal without incident or medical therapy. Patients with pacemakers needed to be monitored by a cardiologist during the treatment period.
With the Combat BRS and other systems such as Unithermia, the side effects are mostly some enhancements of the effects seen with cool intravesical chemotherapy, most notably with bladder pain or bladder spasm, haematuria and dysuria. It has been noticed that men tend to have more pain than women during the treatment, regardless of the device used.
There have not been any head-to-head comparisons with RITE devices and conductive thermochemical therapy (CHT) devices but in a pooled analysis by Zhou et al in 2022 there was a slight bias in favour of CHT over RITE, but no fair direct comparison could be made. In this analysis of 15 studies consisting of 1190 patients, thermal therapy adverse events were slightly worse than normothermia patients. On the forest plots, the RITE arms showed a greater difference in adverse events to the normothermia arm compared with a smaller noticeable difference between CHT and normothermia arms.
The physical devices have multiple safety mechanisms built in to monitor overheating, pump failure or over-pressurisation etc. So, once switched on, they do not have to be monitored on a continuous basis for fault monitoring.
General hints
Lastly, I would like to give some general hints for practitioners wishing to employ hyperthermic chemotherapy in their clinical practice. These include:
- Handlers and patients receiving these drugs should not be pregnant or planning to become pregnant.
- After the procedure, sexual activity should involve the use of a condom for the rst 48 hours in male patients and a female patient’s male partner should also use a condom.
- Women of childbearing age should be on some form of contraception for the duration of the treatment.
- Women breastfeeding will need to stop during the period of treatment.
- Patients should all receive counselling prior to the procedure in terms of providing information about the drugs, what to expect during catheterisation and what can be experienced during the hyperthermic treatment.
- Patients should be provided with a list of the possible side effects. This form should contain guidance on when it becomes imperative to contact the prescribing urologist.
- Patients should all fluid-restrict for eight hours so that during the procedure they are not producing large volumes of urine which would dilute the chemotherapeutic solution.
- Patients on routine diuretic therapy are asked to avoid these medications for six hours prior to the procedure and then to take the drug after the procedure.
- After the procedure, patients are asked to drink large volumes of water to wash the drug out of their system. In patients with heart failure, this advice would need to be somewhat tempered. The exception to this last rule is mitomycin C.
- Men should sit and void for the first day after treatment to avoid splashes.
- Caffeine, carbonated drinks, acidic drinks, alcohol and spicy foods should be avoided for the first 48 hours after treatment because of the irritant effects of these products on the bladder.
- Do not administer these drugs when a patient has an active urinary infection.
In summary, there is ample proof that hyperthermic chemotherapy devices are safe, and the side effect profile of the various drugs used with the devices is more than acceptable. When compared with standard BCG therapy, there is a lot of data now showing that the drugs are better tolerated. Urologists need to become au fait with handling toxicities. I leave with a quote from one of my heroes, Albert Einstein. “Concern for man himself and his safety must always form the chief interest of all technical endeavour.”
Full references available in Urology, Uro-oncology and Sexology Update
