Hyperthermia and radiotherapy in bladder cancer

Abstract

Hyperthermia represents a unique, safe, and advantageous methodology for improving therapeutic strategies in the management of bladder cancer. This modality has shown promise in contributing to treatment regimens for both superficial and muscle-invasive disease. Especially in conjunction with intravesical chemotherapy, systemic therapy, and radiotherapy, hyperthermia shows particular synergistic benefit. As such, it should be explored further through clinical use and clinical trial in conjunction with currently available techniques and emerging technologies. However, to conceptualise the way forward, it is particularly important to understand the current challenges to widespread use of non-invasive, bladder-sparing approaches and the current state of bladder cancer care. As such, in the following article, we have focused on not only the rationale for concurrent radiotherapy and hyperthermia, but also the clinical landscape in bladder cancer as a whole.

Keywords:

• Bladder cancer
• hyperthermia
• radiation
• radiotherapy
• thermoradiotherapy

Bladder cancer – the clinical perspective

Modern oncological therapy has increasingly focused on organ-sparing techniques and modalities. Reducing the invasiveness and post-operative morbidity associated with radical surgeries or aggressive resections has become a particular priority. The management of bladder cancer is no exception, as increasingly patients and practitioners have pursued multimodality therapies with bladder preservation intent. In particular, in well-selected muscle-invasive cancer, many patients today receive concurrent chemoradiotherapy following maximal transurethral resection of the bladder tumor (TURBT), in an attempt to avoid radical cystectomy, and many are cured of their disease without the morbidity of bladder removal. With bladder cancer on the rise, this approach will likely see increased utilisation and clinical relevance [1].

Utilised in T2 (muscle-invasive) or less invasive disease, the first step in bladder preservation, TURBT, is generally a piecemeal, estimated resection, preferably until there is no visual evidence of residual disease. The information gleaned is imperfect but essential for risk-stratifying patients for therapeutic decision-making. For patients with T1 disease, and thus no clear evidence of muscle involvement, various methods have been suggested to prognosticate on or predict for recurrence/progression based upon clinical and pathological findings. Most commonly, studies have cited poorly differentiated, high grade (grade 3) cells as an important risk factor [2–9]. The European Organisation for Research and Treatment of Cancer (EORTC) developed a scoring system for estimating a patient’s risk of both recurrence of disease as well as progression to muscle-invasive disease [10]. For recurrence, the number of tumours present, the size of the tumours, and rate of prior recurrences were most prognostic. For progression, the presence of carcinoma in situ disease, T stage, and grade of disease proved most important. The differences amongst risk groups were vast. Recurrence risk was rated from 0 to 17 with the lowest group (score 0) having a 31% risk of recurrence at 5 years, while the highest risk group (score 10–17) exhibited a 78% chance of recurrence. Progression to muscle-invasive disease (scored 0–23) showed similar trends: lowest risk group (score 0) 0.8% at 5 years, highest risk (score 14–23) 45%.

Patients with very low risk non-muscle-invasive disease are likely the ideal candidates for TURBT with either subsequent observation or adjuvant intravesical chemotherapeutic installation. This remains a standard of care option for this group [11]. However, as suggested in the EORTC risk grouping, there is clearly a group of T1 patients who have an exceedingly high risk of recurrence or progression despite TURBT and intravesical chemotherapy [10]. The authors here also posit that these patients may be good candidates for earlier, more aggressive local therapy such as cystectomy. These patients are thought to have disease with outcomes more akin to their muscle-invasive counterparts, and in truth, under-sampling by TURBT may leave these patients with occult T2 cancer, staged at T1 [12–16].

In muscle-invasive disease, cystectomy remains a standard of care, but this is not without substantial and often life-altering morbidity. Radical cystectomy with pelvic nodal dissection (with strong consideration for neoadjuvant systemic therapy) remains the category 1 recommendation of the National Comprehensive Cancer Network for muscle-invasive disease patients; while these are only an expert panel’s recommendations as to approach to therapy, they are a frequent resource for practitioners looking for guidance [11]. This surgery requires complete removal of the native bladder with prostatectomy in men, and frequently hysterectomy in women. Urinary diversion may be achieved with an orthotopic neobladder, created from a loop of bowel in the original bladder position with urethral anastomosis, or by continent or incontinent conduit with a stoma [17]. Each of these options is accompanied by considerable recovery time, operative risk, potential morbidity, and patient adjustment requirement.

As a result of the toxicity associated with radical surgical intervention, bladder-preservation approaches have been developed and have increased in utilisation in recent years. As previously alluded to, TURBT with maximal safe resection followed by intravesical chemotherapy remains an option to preserve the bladder in non-muscle-invasive disease. This approach has shown efficacy in reducing recurrence rates, especially in previous meta-analysis data [18–22]. However, in muscle-invasive disease or high risk/multiply recurrent non-muscle-invasive disease, the current standard of care alternative to cystectomy is known as trimodality therapy and requires maximal safe TURBT followed by chemoradiation.

The current format of bladder preservation therapy

Trimodality therapy (TURBT, radiotherapy, and chemotherapy) represents a somewhat daunting regimen for patients, but also a vast improvement in efficacy over TURBT alone or TURBT with unimodal adjuvant radiotherapy. Historically, in patients who were poor candidates for cystectomy or who were motivated to preserve natural bladder function, maximal safe TURBT could be followed by consolidative radiotherapy. However, multiple series have demonstrated an improvement in disease control with the further addition of concurrent chemotherapy [23–26]. The rationale for this approach is straightforward. Bladder cancer has a high proclivity for systemic dissemination, as autopsy and clinical series have evinced [27]. The addition of chemotherapy especially in systemic doses, as allowed by cisplatin administration, during the course of local therapy thus has clear advantages. Also, the agents commonly utilised are effective radiosensitisers, and this is demonstrated well by the increased local control and bladder preservation rates in the aforementioned trials [28]. The most common technique applies cisplatin chemotherapy concurrent with a mid-60s Gy dose of radiation, given in conventional fractionation, with or without split course to investigate response.

Though various radiation schedules and chemotherapy regimens have been employed, it is important to note that trimodality approaches have shown excellent disease response rates in large, prospective phase III series, which were designed to test various bladder preservation strategies [24,29–31]. With prompt salvage cystectomy only as indicated, trimodality therapy yields 5-year overall survival rates between 48–60%, relatively comparable to historical cystectomy series, with significantly improved toxicity profile [32–39]. Complete response rates have ranged from 60–93% in most large series [32–39]. Though there is a lack of head-to-head comparison between bladder preservation and cystectomy strategies, the outcomes, by most assessments, remain similar.

In late stage, locally advanced disease, systemic dissemination may drive survival primarily, but there remains a large demographic of patients who would vastly benefit from further improved complete response rates and bladder preservation rates [24,29,31,40–42].

Quadrimodality therapy

The rationale for thermoradiotherapy

Considering the rates of progression in high-risk T1 disease and the rates of salvage cystectomy (recurrence) in T2 disease, there are evident avenues for improvement of the bladder preservation approach. As this option increases in utilisation and further proves its viability in larger series, it is key that the therapeutic ratio be maximised in favour of efficacy and reduced toxicity to ensure that patients receive optimal care with the greatest chance of preserving their bladders.

With doses relatively maximised for chemotherapy and radiation in this disease, utilising currently widely available technologies and drugs, hyperthermia has arisen as a potential and promising fourth modality for attacking this locally aggressive carcinoma.

Hyperthermia has been recognised as a potential oncological therapeutic strategy since the 1950s. As accompanying chapters in this volume have detailed, hyperthermia alone has anti-tumoural effects by multiple mechanisms including direct and immune-based cytotoxicity. Perhaps most strikingly though, hyperthermia shows a clear synergistic response with selected chemotherapeutic agents – including several routinely utilised in bladder cancer – and especially with radiation therapy through its physiological ramifications. These effects can often elicit tumoural responses greater than the sum of the expected effects of each modality. As temperatures rise within locally heated tissues, blood perfusion increases. Initially, tissue thermoregulation limits local heating, but this generally exhibits a threshold response that may be overcome [43]. Vascularity in and around the tumour becomes more permeable, leading to oedema, vascular stasis, and sometimes haemorrhage. This can result in relatively preferential delivery of drug or nanoparticles into tumour parenchyma.

Aerobic metabolism may be slowed due to greater heat sensitivity as compared to anaerobic mechanisms [44]. Shifting metabolism thusly logically results in increased available unused intratumoural oxygen. Reoxygenation is key in propagating the indirect effects of radiotherapy which are effected through the creation of DNA-damaging oxygen radicals within the target [45]. In fact, hypoxic cells have been estimated to be three times more resistant to radiotherapy than aerobic cells. The range of achievable clinical temperatures in most tumours without significant patient discomfort is particularly suited to eliciting a reoxygenation effect. Evidence from human tumour xenograft testing and canine soft tissue sarcomas (Figure 1) has suggested that vascular damage reverses the oxygenation benefit over 44 °C and that temperatures between 41 and 43 °C may be better for exploiting this effect [45,46]. Though there are varying reports as to how intratumoural oxygen levels vary during the course of thermoradiotherapy, clinical response evidence from breast cancer and sarcoma studies seems to correlate hyperthermia-induced reoxygenation with improved outcomes [46–49]. In fact, reoxygenation after the first fraction of hyperthermia seems to be relatively predictive of pathological and clinical response rates [50]. Especially in the post-operative setting, a prerequisite in the bladder preservation approach, oxygenation may be particularly lacking due to decreased perfusion from disturbed vasculature. Many patients may have progressed from previously non-muscle-invasive disease and thus may have undergone multiple surgeries with subsequent recurrences. Hyperthermia offers logical potential advantages in this setting to improve oxygenation and thus tumour radiosensitivity.

Figure 1. The hypoxic fraction may be significantly reduced utilising moderate hyperthermia (HT) concurrent with radiotherapy as demonstrated in canine soft tissue sarcomas by Vujaskovic et al. [46] (data replotted with permission). However, temperatures above 44 °C seem to elicit worsening hypoxia.

Finally, cell-cycle synergism also seems to play a role in the effectiveness of thermoradiotherapy based on in vitro findings. Radiation therapy is classically most tumouricidal during the G2 and mitotic (M) phases of the cell cycle. For hyperthermia, nuclear fragility lends greater thermosensitivity during the synthesis (S) and M phases, likely secondary to the increased expression of adaptive heat-shock proteins during the gap (G) phases [51]. However, when combined, hyperthermia may induce the S phase into a more radiosensitive mode. In vitro studies have suggested that therapeutic hyperthermia inhibits DNA-polymerases α and β, staving off cellular repair mechanisms and converting sub-lethal radiation changes to lethal damage [52,53].

Hyperthermia and radiation in bladder cancer

Hyperthermia has been successfully and safely integrated into organ-sparing techniques for multiple disease sites and malignancies with excellent results. Several trials have utilised hyperthermia in conjunction with chemoradiotherapy and thus are clear correlates for the potential in bladder cancer. This combined approach has been employed successfully in head and neck cancer, melanoma, breast cancer, gliomas, cervical cancer, and rectal cancer amongst others, with excellent toxicity profiles and tumoural responses [54].

There is relatively limited data regarding the concurrent application of hyperthermia and radiation in the treatment of bladder cancer. The technical demands of deep hyperthermia have deterred many clinics with superficial hyperthermia capabilities from adopting deep treatment units. Furthermore, the relatively slow uptake of bladder-sparing techniques that employ radiotherapy in regular clinical practice has stemmed the flow of patients eligible for such an intervention. Finally, methods for accurate heat monitoring and effective hyperthermia dose estimation have proven challenging and elusive. Only recently have enhanced thermal therapy planning systems in conjunction with newer intravesicular and MR-based thermography monitoring techniques improved and simplified this process (Figure 2) [54]. Despite these hurdles, several important studies and two key prospective trials have been completed with promising results favouring thermoradiotherapy in bladder cancer (Table 1).

Figure 2. Treatment workflow for delivering bladder hyperthermia including simulation (a), hyperthermia modelling and planning (b), plan evaluation (c), and deep hyperthermia delivery with temperature monitoring (d). (Reproduced from Datta et al. [54] with permission.)

Table 1. Selected experiences utilising radiation therapy with concurrent hyperthermia in bladder cancer as well as intravesical and systemic therapies.

	Patients	Patients receiving HT	Concurrent radiation dose/Gy per fraction	Additional therapy	HT frequency	Complete response rate with HT (%)	Any response rate with HT (%)	Response rate in patients not receiving HT (%)
Matsui et al. [55]	56	40	40/4	Intravesical bleomycin	Daily	39	84	56 (50–70 Gy)
Takechi et al. [57]	5	5	15/3	Intravesical pirarubicin	Daily	60	60	–
Masunaga et al. [58]	49	28	24/4	–	Twice weekly	29	83	48
Noguchi et al. [59]	35	35	40/4	M-VAC systemic in 17 patients	Twice weekly	23	79%/64 (±M-VAC)	–
Wittlinger et al. [61]	45	45	50.4–59.4/1.8	Cisplatin/5FU systemic	Weekly	96	98	–
Van der Zee et al. [69]	101	52	66–70/2	–	Weekly	73	–	51 (CR)

HT: hyperthermia.

Several Japanese institutions have published their experiences with thermoradiotherapy in bladder cancer from the late 1970s through the early 1990s. Matsui et al. described a Yokohama City University series in 1991 [55]. Fifty-six patients were included in this report. Hyperthermia was delivered by warm water irrigation with bleomycin intravesical chemotherapy incorporated in the irrigation solution. Patients receiving 40 Gy over 4 weeks with concurrent hyperthermia were compared with those receiving radiation alone to between 50 and 70 Gy. Among patients with T2 to T3 disease, combination therapy produced an 84% response rate compared to 56% with radiation alone. Combination therapy was noted to cause some reduction in bladder capacity, though this tended to be reversible. The higher doses of radiotherapy in the monotherapy cohort, instead, often caused irreversible reductions in bladder capacity. The authors very reasonably concluded that concurrent hyperthermia seemed to improve the therapeutic ratio, enhancing efficacy while decreasing toxicity.

This group had previously published their experience through a protocol for treating patients who were either deemed poor surgical candidates, were scheduled for post-therapy cystectomy, or were assessed to be poor TURBT candidates based on multifocal disease [56]. Patients received between 35 and 40 Gy utilising a ⁶⁰Co machine over 4 weeks. Hyperthermia was administered 12–16 times for 1 h each session at 42–43 °C with intravesical bleomycin. Patients primarily had T1 to T3 disease at diagnosis, except one T4 patient. In total, 73% of patients experienced at least a partial response, with 42% undergoing complete response. Of the eight patients taken to cystectomy shortly after therapy, final pathology demonstrated five of these to have complete responses and the rest to have partial responses. All of the complete responses were in T1 to T2 grade 3 patients. The partial responses included one T2 and two T3 patients each again with grade 3 disease.

Takechi et al. described their employment of a hypofractionated, low dose course utilising 3 Gy per fraction radiotherapy in conjunction with intravesical pirarubicin and hyperthermia [57]. Five patients were treated in this small series with a total radiation dose goal of 15 Gy with pretreatment administration of pirarubicin and post-treatment hyperthermia daily of 42–43 °C for 35 min utilising an 8 MHz radiofrequency machine. One patient discontinued therapy secondary to urinary irritation, three achieved durable complete response, and one recurred by cytological examination.

A similar radiation regimen with 24 Gy in 4 Gy per fraction, three fractions per week, was employed with or without hyperthermia in a phase I/II neoadjuvant thermoradiotherapy trial at Kyoto University [58]. With 49 patients with T1–T4 node-negative disease enrolled, 28 patients underwent combined therapy while 21 were given radiation alone. Regional hyperthermia was delivered twice weekly for four total treatments, each lasting 35 to 60 min. Patients receiving hyperthermia were stratified by average intravesical temperature above or below 41.5 °C. The higher temperature group demonstrated improved tumour response and downstaging, demonstrating that the quality of hyperthermia is of vital importance with this approach. This also suggests a rationale for hyperthermia and radiotherapy as part of a preoperative strategy for downstaging.

In 1992 Noguchi et al. published a series employing a neoadjuvant regimen that included hyperthermia and radiation with or without systemic chemotherapy in patients with Ta–T4 bladder tumours [59]. M-VAC (methotrexate, vinblastine, Adriamycin, and cisplatin) was the chemotherapeutic course in this study, and it was dosed sequentially after neoadjuvant thermoradiotherapy, and adjuvantly after cystectomy. Seventeen patients were given all three neoadjuvant/adjuvant modalities, while 18 received radiation and hyperthermia only. Radiotherapy was delivered as 40 Gy in 10 fractions, twice weekly, with hyperthermia given again with an 8-MHz device. In the radiation and hyperthermia group, 12/18 patients presented with T2 or greater disease, while all but one (16/17) did so in the chemotherapy cohort. There were 12 patients with T3–T4 disease overall. Each patient’s disease was either grade 2 or 3, with the majority high grade. With seven patients unevaluable, the authors reported 64% and 79% (p not significant) response rates at cystectomy with and without chemotherapy, respectively, with each arm having four complete responses. Subcutaneous fat necrosis was experienced in about a sixth of patients and was attributed to hyperthermia. Otherwise, toxicities included tenesmus, diarrhoea, liver dysfunction, leucopenia, anaemia, and nausea/vomiting. Leucopenia, anaemia, and nausea/vomiting were clearly correlated with chemotherapy administration. It was suggested that earlier chemotherapy or concurrent regimens might prove more efficacious.

In the early 2000s, Ohguri et al. [60] published a three-patient study finally utilising high dose radiotherapy (66–70 Gy), M-VAC chemotherapy, and hyperthermia (3–12 fractions) together in two patients with T2N1 disease and in one with T2N0. All three experienced complete responses and remained free of disease at 16, 18, and 40 months. Despite these promising small series, larger studies with more homogeneous patient cohorts and treatment protocols were lacking until two more concerted efforts were published out of Germany and the Netherlands.

Between 2003 and 2007, the Department of Radio-oncology at the University of Erlangen enrolled 45 patients on a prospective trial employing ‘quadrimodal treatment’ for high risk T1 and T2 bladder cancer [61]. High risk T1 disease was defined as poorly differentiated tumours (grade 3), tumours with associated carcinoma in situ, multifocal disease, tumours with diameters greater than or equal to 5 cm, or tumours that had recurred/proven refractory following repeated TURBT with or without intravesical chemo/immunotherapy instillation. The treatment regimen employed maximal safe TURBT followed by chemoradiotherapy with concurrent deep hyperthermia. Radiotherapy was delivered by three-dimensional conformal radiotherapy (3D-CRT), usually with a traditional four-field box technique to a dose of 50.4 Gy in 1.8 Gy per fraction with an empty bladder set-up. A boost to between 55.8 Gy and 59.4 Gy was utilised dependent upon resection extent prior to therapy. Cisplatin and 5-FU chemotherapies were delivered in the first and fifth weeks of radiation. Hyperthermia was administered as regional deep hyperthermia with the BSD-2000 delivering electromagnetic microwaves from 90 to 100 MHz. Patients received between five and seven weekly hyperthermia treatments within 60 min before each fraction of radiation. Four probes were utilised for thermometry in the bladder cavity, rectum, anal fold, and oral cavity. Thermometry in the rectum and bladder were achieved through intraluminal insertions without invasive needles. Each administration was prescribed for 60–90 min at or above 41.5 °C. Cumulative equivalent minutes at 43 °C (CEM43) was calculated to assess thermal dose. Patients underwent restaging cystoscopy with resection of any residual disease at 6 weeks after completion of therapy. Persistence of tumour at this time-point was considered non-response, while absence of disease on sampling was considered pathological complete response (pCR). If urine cytology was negative as well, patients were observed with regular cystoscopy and cytology.

Wittlinger et al. reported results from this effort at a median follow-up of 34 months [61]. Forty-three of the patients were able to receive chemotherapy with 60% undergoing full dose and all cycles. The median number of hyperthermia treatments was five with two-thirds receiving five or more. The mean CEM43 was 57 min with a mean cumulative overall hyperthermia treatment time of 387 min. Radiation and hyperthermia were very well tolerated with the most significant side effects stemming from chemotherapy-induced haematological toxicity.

At the 6-week mark, 43 of the 45 patients (96%) showed a pCR to this quadrimodal therapy. The two patients that did not experience a pCR had initially T1 and T2 disease. The T2 patient underwent salvage cystectomy with no subsequent recurrence of disease, though the patient died several months later of a non-small cell lung cancer. The T1 patient was managed with two additional TURBT procedures and intravesical therapy without further evidence of progression. This patient achieved local control for 40 months prior to passing of heart disease.

Of the 43 pCR patients, 80% (36 patients) have remained free of disease. The other seven patients with eventual local recurrence were restaged at the time of recurrence with Tx, Ta, or Tis disease. All of these patients were managed with TURBT and instillation therapy, therefore not requiring salvage cystectomy. Of the total nine deaths on the trial, five were related to bladder cancer, and all of these were attributable to distant disease. These patients each had grade 3 disease, and 4 of the 5 had initially T2 disease with R1 resections. For the entire group, disease-free survival and overall survival were 71% and 80% at 3 years. Statistically significant prognostic factors for survival were T stage (p = 0.04), extent of resection (p = 0.001), and whether the patient received at least five hyperthermia fractions (p = 0.036).

From a quality of life standpoint, 80% of the patients treated were at least ‘mostly satisfied’ with their urinary condition. One patient experienced treatment-refractory haematuria requiring cystectomy without evidence of disease. Common Terminology Criteria for Adverse Events (CTCAE) grade 3 and 4 toxicity was relatively low at 24%, mostly relating to reduced bladder capacity and occasional incontinence.

This trial is particularly thought-provoking and hypothesis-generating for future use of concurrent hyperthermia and radiotherapy in bladder cancer. Importantly, it included 26 patients with non-muscle-invasive disease. Compared to TURBT with intravesical chemotherapy, there is a substantial improvement with this approach in local control of T1 disease. It has been estimated that 50–70% of patients with Ta or T1 disease will have a recurrence after TURBT and intravesical chemotherapy [62]. Wittlinger et al. reported only two patients (8%) with T1 disease at presentation who suffered either persistence or recurrence of disease [61]. These results also improve upon those of intravesical chemotherapy given in conjunction with hyperthermia [63–68]. While this approach is addressed in another chapter, this seems to be also a reasonable alternative with promising results.

Further, it is important to note that therapy was arguably not ideal on this trial. Patients received concurrent systemic therapy regardless of T stage or resection extent. In T1 patients it is conceivable that therapy could be de-escalated from this approach with still adequate local control, though further investigation is required for this hypothesis. Additionally, there was a statistically significant improvement in survival in patients receiving at least five treatments of hyperthermia. Twice-weekly hyperthermia treatment has become more common and could be explored as a way to intensify local therapy with limited additional toxicity expected. Finally, the radiation dose delivered here was relatively low compared to bladder cancer standards today. Use of intensity modulated (IMRT) techniques or other modalities (e.g. proton therapy) could allow for higher dose delivery with lower or at least similar toxicity.

Another source of evidence with a similar approach came earlier from the Dutch Deep Hyperthermia Group in 2000 [69]. Between 1990 and 1996, 358 patients were enrolled on a multicentre trial in the Netherlands. Patients with T2, T3, and T4 non-metastatic bladder cancer were included, though this trial also enrolled patients with cervical and rectal cancers. In total, 101 patients with bladder cancer were included, though most had T3 or T4 disease (T2 10 patients, T3 41 patients, T4 50 patients). All of these patients received 66–70 Gy of radiotherapy including a larger field encompassing regional draining lymphatics to 40 Gy. Patients were randomised as to whether to receive concurrent hyperthermia.

Hyperthermia in this trial was delivered on a once-weekly basis with institutionally variable applicators. It was delivered between 1 and 4 h after radiotherapy for a duration of 60 to 90 min with a goal of 60 min above 42 °C. The primary end points of this trial were complete response and local control. Of the 182 patients in the hyperthermia group, 135 (74%) were able to undergo at least four hyperthermia sessions, again speaking to the tolerability of this modality.

For bladder cancer patients, 73% (38 of 52 patients) and 51% (25 of 49 patients) (p = 0.01) showed complete responses to initial therapy with and without hyperthermia, respectively. At 3 years, local control was 42% and 33% (p not significant) in these two groups. However, it is important to note that 13 patients experienced early distant failure without further local investigation and thus were counted as local failures without direct evidence. This convention could very well explain the lack of difference in local control considering the small size of the bladder cancer cohort in this study. Overall survival was not different based on application of hyperthermia in bladder cancer (28% versus 22%, p = 0.33), though there was a large difference in cervical cancer (51% versus 27%, p = 0.009).

Treatment was well tolerated in this trial, though there were two grade 5 toxicities (one with and one without hyperthermia). Acute grade 3–4 toxicity was limited (4%) with slightly greater prevalence in the radiotherapy alone arm. Late toxicity was similar between the arms.

Results from this effort are, again, promising for the addition of hyperthermia in the management of muscle-invasive and even locally advanced bladder cancer. However, there may be several methods by which to further improve outcomes. It is likely that a well-selected cohort would benefit more from aggressive local approaches. The inclusion of higher stage disease patients in this trial may have masked significant differences based on higher rates of occult dissemination at presentation. Adding systemic chemotherapy to this regimen would likely lessen distant metastasis rates as well as intensify local therapy. Additionally, the administration of more hyperthermia sessions may further contribute to tumoural response rates and disease control.

Improved radiotherapy techniques with concurrent hyperthermia

Hyperthermia’s increased utilisation in recent years concurrent with radiotherapy has followed improvements in the delivery of radiation and techniques for treatment. Certainly, 3-dimensional planning approaches have been vital in improving the sparing of normal tissue while escalating tumoural/target dose. IMRT has permitted radiation oncologists to sculpt dose more sharply, especially reducing the high dose exposure to nearby critical structures. This has proven particularly useful in the pelvis where the rectum, bowel, uninvolved bladder, prostate, uterus, vagina, and genitalia are all at risk and in relatively close proximity.

Emerging technologies such as particle therapy may allow for even further improvements in the therapeutic ratio. Proton therapy has a rapidly expanding footprint especially in the USA and Europe. Proton radiotherapy has the added benefit of largely eliminating exit dose. With pencil-beam scanning techniques (also known as spot scanning), very conformal dose distributions may be achieved even above and beyond passive scattering proton techniques and IMRT. This further improvement may allow for dose escalation of radiotherapy without increased toxicity, paving the way for bladder-sparing approaches in higher burdens of disease or unresectable/non-operative patients [70]. Additionally, it has been argued that the radiobiological equivalence (RBE) of proton therapy may be greatly and disproportionately augmented by the addition of hyperthermia [71]. Potentially, this may raise its RBE to the level of carbon-ion therapy, which remains limited in its availability and challenging in its widespread implementation. It should be noted, however, that there are numerous challenges in delivering technically sound particle therapy to the bladder caused by the organ’s ability to shift within the body and to be variably filled.

Conclusions

Thermoradiotherapy, or concurrent hyperthermia and radiation therapy, has demonstrated promising results, though data is limited in bladder cancer. This represents an exceedingly well-tolerated regimen with little added toxicity over radiotherapy alone. Quadrimodality approaches may offer a particularly efficacious bladder-sparing option to patients with muscle-invasive or locally advanced disease.

Additional investigation is clearly indicated, preferably in the form of clinical trials. With the resurgence of interest in hyperthermia amongst radiation oncologists, this may now be logistically feasible. However, multi-institutional efforts will likely be required to achieve reasonable enrolment for the several questions to be asked. Hyperthermia in conjunction with radiation therapy should be examined in both non-muscle-invasive and muscle-invasive disease. It may also have roles in locally advanced disease, potentially as neoadjuvant therapy. Intermixed with improved radiotherapy techniques such as IMRT or proton radiotherapy, hyperthermia may show particular benefit.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.