Short Communication
An Update on Chemohyperthermia for Non-Muscle Invasive Bladder Cancer
Conor McBride, Daniel C. Parker, Brionna M. Sandridge, Michael S. Cookson and Sanjay G.
Patel*
Department of Urology, University of Oklahoma College of Medicine and the Stephenson Oklahoma Cancer
Center, USA
*Corresponding author: Sanjay G. Patel, Department of Urology, University of Oklahoma College of Medicine, 920 SL Young Blvd, WP 3150 Oklahoma City, OK 73104, USA
Published: 28 Dec, 2017
Cite this article as: McBride C, Parker DC, Sandridge BM,
Cookson MS, Patel SG. An Update on
Chemohyperthermia for Non-Muscle
Invasive Bladder Cancer. Clin Surg.
2017; 2: 1844.
Keywords
Bladder cancer, Chemotherapy; Hyperthermia; Chemohyperthermia; Thermochemotherapy; Non-muscle invasive bladder cancer
Introduction
Urothelial Carcinoma (UC), the most common type of bladder cancer, is the 4th most common
cancer worldwide [1]. In the United States, an estimated 75,000 patients will be newly diagnosed
with UC, and 15,000 will die from the disease in 2017 [2]>. About 20% of newly diagnosed UC
cases are muscle invasive, which are treated with neo adjuvant chemotherapy followed by radical
cystectomy [3]. The other 80% of patients have Non-Muscle Invasive Bladder Cancer (NMIBC) and
are more complex to manage [4]. Despite adequate risk stratification, primary tumor eradication,
intravesical therapy administration, and surveillance, it is expected that 15% to 30% of patients
with de novo NMIBC will progress to muscle invasion and ultimately require cystectomy [5].
Chemohyperthermia (CHT-also known as thermochemotherapy) is a promising variation of
intravesical chemotherapy that appears to safely reduce or delay tumor recurrence and progression
in NMIBC by heating the treatment during instillation.
Hyperthermia: historical perspectives
Oncologists have used hyperthermia for decades as an adjuvant therapy to radiation or systemic
chemotherapy [6]. Tissue studies have shown that hyperthermia to >40°C increases the effectiveness
of chemotherapy through several mechanisms including vasodilation, direct cytotoxicity, and
induction of immunomodulation [6]. At temperatures >43°C, unchecked vasodilatory effects of
hyperthermia results in increased vascular permeability of tissues surrounding tumors resulting
in local perfusion steal and hypoxia [7]. Irreversible cell cycle growth arrest secondary to DNA
and RNA synthesis inhibition as well as impaired DNA repair mechanisms exemplify the direct
cytotoxic effects of hyperthermia [8]. Finally, heat causes alterations to the loco-regional adaptive
immune system via increased production of heat shock proteins and modulation of lymphocytic
and NK cell responses resulting in synergistic enhancement of anti-tumor immunity [9].
In the context of NMIBC, the application of hyperthermia to intravesical Mitomycin C (MMC)
solutions has been a focus of ongoing biomedical development. Indeed, heated MMC regimens
have been shown in vitro to increase tumor cell membrane permeability to the drug [10]. In the
next section, contemporary delivery systems which can safely heat intravesical MMC solutions will
be discussed.
Contemporary CHT Delivery Systems for NMIBC
Three techniques can be used to heat an intravesical aqueous solution of MMC. The Dutch
system Synergoincorporatesa microwave-emitting antenna to a Foley catheter which is inserted
transurethrally into the bladder. Thermocouple sensors continuously monitor the temperature at
the bladder wall while the MMC solution is cycled in a closed circuit with heat exchangers for
cooling. The British COMBAT system utilizes an external warming console and a three-way Foley
catheter to rapidly cycle fluid through the bladder thereby maintaining controlled hyperthermia.
Lastly, two commercially available systems, the BDS-2000 and AMC 70 MHz, achieve loco-regional
hyperthermia by radiofrequency wave generation via paired external antennae [11].
Synergo
The Synergo system is the most widely-studied device for CHT in NMIBC and the only method currently mentioned in EUA guidelines [12]. A 2011 systematic review
evaluated 22 studies which used the Synergo system to investigate
the effects of CHT in patients with NMIBC [13]. The combined data
showed a 59% reduction in the risk of cancer recurrence in patients
receiving heated MMC compared to patients receiving conventional
MMC (RR: 0.410, 95%CI: 0.290-0.579). The risk of adverse events
increased slightly with CHT, but most were low grade, transient effects
such as exacerbation of lower urinary tract symptoms (frequency,
dysuria, urgency and nocturia) and nonspecific rashes. These data
should be interpreted with caution, however, as the systematic review
was limited by inclusion of primarily retrospective studies with a
lack of design uniformity and inconsistent follow-up periods. A
multicenter randomized, controlled trial published in 2016 compared
the Synergo system with MMC to standard Bacillus Calmette-Guerin
(BCG) therapy in 190 patients with intermediate or high risk NMIBC
[14]. Participants were randomly assigned to receive either a 6-week
induction course of CHT with MMC followed by six maintenance
courses, or a similar regimen of BCG. The primary outcome studied
was recurrence-free survival at 24 months. In the intention-totreat
analysis, no significant difference was observed in 24-month
recurrence free survival between the two groups (CHT: 78.1% vs.
BCG: 64.8%, p=0.08). Analysis per-protocol, however, demonstrated
82% of CHT-treated patients were recurrence-free at 24-months
versus 65% of BCG-treated patients (p=0.02). There was no significant
difference in rates of disease progression between the two treatments
(CHT: 0% vs. BCG: 1.4%, p=1.0). In terms of adverse events, the
authors reported significantly more frequent lower urinary tract
symptoms in the CHT group than the BCG group; however no novel
safety concerns were reported with Synergo [14]. Unfortunately, the
applicability of these results is severely limited as the trial was subject
to numerous biases secondary to under powering (premature closure
due to slow accrual) and lack of blinding.
Combat
The commercial device COMBAT, that heats chemotherapy
fluid externally, was introduced in 2011 and has been established in
the literature through only a handful of preliminary clinical studies.
Recent shortages in manufactured BCG availability prompted
Griffiths et al., in the United Kingdom, to incorporate COMBAT
CHT into their risk-stratified NMIBC protocol [15]. In order to
ration BCG doses, MMC was delivered to 50 patients by COMBAT at
weeks 3, 4, and 5 of a standard 6-week intravesical therapy induction,
with BCG administered only at weeks 1,2, and 6. Three sets of 3-week
maintenance courses of MMC were also delivered by COMBAT to
complete a full year of therapy. According to unpublished results
presented at the 2017 national meeting of the American Urological
Association, 88% of participants were disease free after completing 1
year of treatment. 6% were designated treatment-unresponsive and
2 patients (4%) progressed to muscle invasive bladder cancer [15].
Two randomized, controlled trials are currently ongoing in
Europe to test the tolerability and safety of hyperthermic MMC
delivered by COMBAT in patients with intermediate risk NMIBC
[16]. The HIVEC I trial compares heated MMC in 30 min or 60
min instillations against standard solutions of MMC for a 4-cycle
induction followed by single, monthly treatments for 3 months.
HIVEC II compares heated MMC for 60 min instillations against
standard MMC for a 6-cycle induction. Neither trial is designed to
demonstrate oncologic efficacy. Interim analysis of 307 patients has
shown no significant differences in adverse events between heated
MMC and standard MMC [16].
BDS-2000 and AMC 70 MHz
A final technology that can be used for CHT in NMIBC is locoregional
hyperthermia, a technique that uses external antennae to
heat the target tissue with radiofrequency waves. Available devices,
including the BDS-2000 and AMC 70 MHz, require detailed planning
before treatment. Cross-sectional imaging of the patient is required to
predict how various tissue layers will respond to the radio frequency
waves. Using this data, a medical physicist determines an optimal
steering strategy and radiofrequency intensity for the antenna
array17. A 2016 systematic review of the use of regional hyperthermia
for bladder cancer was hampered by heterogeneous study designs
and non-standard reporting of adverse events 18. Nonetheless, the
authors conclude that loco-regional hyperthermia holds promise not
only for NMIBC, but also for select muscle invasive bladder cancer
patients with acceptable rates of toxicity.
Conclusion
No studies have yet directly compared CHT systems. Pending such analysis, we summarize the advantages and disadvantages of each system according to Liem, et al. [11] Loco regional hyperthermia systems, such as the BDS-2000, achieve deep heat penetration, can be used to treat a variety of organ systems, and are the only technology currently approved by the FDA for use in the United States. However, these are the most expensive systems to implement because of the upfront purchase costs as well as additional overhead to provide the device with a shielded room and trained personnel to operate it. The Synergo system is less expensive to purchase than the BSD-2000 and has a stronger foothold in the literature, as acknowledged by EAU guidelines. However, treatment with Synergo is still prohibitively expensive for most institutions and practitioners because of its complicated disposable antenna catheter and continuous patient monitoring by nursing personnel. The COMBAT system may achieve uniform bladder heating and is currently the most affordable to operate. While definitive efficacy data has not been formally published, preliminary results are promising.
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