Abstract
Purpose The aim of this retrospective study was to evaluate the tolerance and early as well as late toxicity of high dose rate brachytherapy (HDRBT) boost combined with interstitial hyperthermia (IHT) in patients treated for prostate cancer.
Material and methods Between January 2011 and June 2013 76 patients diagnosed with prostate cancer received treatment consisting of external beam radiotherapy (EBRT), followed by a HDRBT boost combined with IHT. IHT was performed before each brachytherapy fraction.
Results The median follow-up time was 26.3 months (range 7–43 months). Early genitourinary (GU) grade 1 and 2 toxicities were common, but only two patients (2.6%) experienced acute urinary retention requiring temporary catheterisation (grade 2 toxicity). No grade 3 or 4 genitourinary or gastrointestinal toxicities were observed. In the group analysed, 59 of 76 patients had follow-up times longer than 18 months. The incidence of grade 2 late toxicity in the group studied did not exceed 23.7%. There were no late grade 2 or higher complications from the gastrointestinal tract.
Conclusions The tolerance of HDRBT boost combined with IHT is good. The profile and the percentage of early and late complications are acceptable.
Purpose
The two main methods of prostate cancer treatment are radical prostatectomy and radiotherapy. The effectiveness of these two methods is similar [Citation1,Citation2]. Radiation therapy is an alternative to surgical treatment in patients with low and intermediate risks of recurrence, and is the treatment of choice for patients in whom cancer extends beyond the prostate capsule, with local stage T3a and beyond [Citation3]. In the treatment of prostate adenocarcinoma, high dose rate brachytherapy (HDRBT) is usually combined with external beam radiotherapy (EBRT), but HDRBT can also be used alone, as monotherapy. HDRBT may also be used in the treatment of local recurrence after previous definitive EBRT [Citation3–6]. The rates of 5-year biochemical disease-free survival (bDFS) in groups of low, intermediate and high risk patients with locoregionally advanced prostate carcinoma treated with brachytherapy are 85–100%, 80–98%, 51–96%, and 34–85%, respectively [Citation6,Citation7]. To minimise the risk of recurrence, especially in patients at high and intermediate risk, androgen deprivation therapy (ADT) is applied. Most recurrences are located at the sites of originally dominant tumours [Citation8], suggesting primary tumour resistance to radiation.
Hyperthermia (HT) is one of the most potent radiosensitisers, enhancing the effect of radiation without any significant increase in adverse events. This effect of HT was demonstrated in preclinical studies, in prostate cancer cell lines in vitro [Citation9,Citation10]. In several non-randomised studies good tolerance and effectiveness of combining hyperthermia with radiation therapy for prostate cancer has been confirmed [Citation11–13]. The Thermal Enhancement Ratio (TER) for human prostate cancer cells was estimated at 1.4–2.1 [Citation10]. Sensitisation of prostate cancer cells to brachytherapy depends on the timing of heat and radiation. Combination of these two methods is most effective if heating directly precedes the delivery of radiation [Citation9]. Most preclinical studies strongly support the use of radiotherapy combined with hyperthermia in treating prostate cancer. University of California at Los Angeles researchers [Citation14] reported the risk of reducing the amount of androgen receptor in human prostate cancer cells under such treatment, possibly resulting in hormone-resistance. According to these authors, this effect is apparent if the tumour remains at a temperature of over 44 °C for over 60 min, conditions difficult to achieve in vivo. However, these authors also confirm the radiosensitising effect of hyperthermia and the heat-induced cytotoxicity [Citation14].
So far, no randomised phase III studies of prostate cancer treated with hyperthermia have been conducted. Most of the available publications concerning phase I and II studies refer to deep hyperthermia [Citation2,Citation11–13,Citation15] and transrectal hyperthermia [Citation16], with only a few studies on interstitial hyperthermia [Citation17–20].
The aim of this retrospective study is to evaluate the tolerance, and early as well as late toxicity of HDRBT combined with interstitial hyperthermia (IHT) in patients treated for prostate cancer.
Material and methods
Between January 2011 and June 2013 at the Centre of Oncology in Krakow 76 prostate cancer patients were treated using EBRT and HDBRT boost combined with IHT.
Patient characteristics
Prostate adenocarcinoma was confirmed in all patients by core biopsy. Initial staging included at least digital rectal examination, serum prostate-specific antigen (PSA) level test and imaging studies — transrectal ultrasound (TRUS), pelvic ultrasound and/or computed tomography (CT) and/or magnetic resonance imaging (MRI), chest X-ray and bone scans. Patients were classified into low-, intermediate- or high-risk groups, according to the National Comprehensive Cancer Network (NCCN) guidelines [Citation3], based on initial PSA value, Gleason score, and clinical tumour stage.
IHT was offered as an optional treatment modality to all eligible patients. Patients gave their full informed consent for the proposed treatment. The patient characteristics are shown in .
Table 1. Patient characteristics.
Eligibility and ineligibility criteria
Patients diagnosed with prostate cancer were qualified for HDRBT at our centre according to GEC/ESTRO [Citation4,Citation21] and American Brachytherapy Society criteria [Citation6]. All patients met the eligibility and technical criteria qualifying them for brachytherapy: prostate volume less than 60 cm3; no pubic symphysis interference; distance between the posterior margin of the prostate and rectum ≥ 5 mm and if transurethral resection of the prostate was performed, at least 6 months should have passed to qualify. Patients were also required to have no contraindication for spinal anaesthesia. The contraindications for hyperthermia treatment were: craniocaudal prostate dimension ≥ 45 mm, metal implants in the pelvic region, or bleeding tumour.
Treatment description
An internal protocol of combining HDRBT with IHT was implemented at the centre in Krakow in 2008. Initially, combined therapy was used in patients with locally recurrent prostate cancer after EBRT failure, treated with salvage HDRBT.
Since January 2011, the combined treatment was implemented as a boost after EBRT, which was a part of radical treatment of primary prostate cancer (76 patients). In this case, the patients initially received EBRT to a dose of 50 Gy in 25 fractions over 5 weeks. The irradiated area covered the prostate gland and base of the seminal vesicles, and included the area of regional lymph nodes (obturator, presacral, iliac), if the risk of lymph node involvement was estimated to exceed 15% (according to the Roach formula [Citation22]). In all, 73 patients received a dose of 21 Gy in two fractions, one patient received a total dose of 19.5 Gy in two fractions, and two patients received a dose of 15 Gy in a single fraction.
Hyperthermia was scheduled before every HDRBT fraction. We did not take into account the pre-clinically estimated TER value [Citation10] to calculate new fractionation schemes, deciding rather to maintain their current dosage and to follow up these patients prospectively.
ADT was part of the combined treatment in almost all patients (N = 74, 97.4%). Usually ADT consisted of a luteinizing hormone-releasing hormone agonist (goserelin, triptorelin or leuprolide) with an antiandrogen (in most cases, flutamide). In intermediate- and high-risk patients, ADT was commenced as neoadjuvant therapy (1–3 months) and was continued as adjuvant treatment (3–12 months in intermediate-risk and 12–21 months in the high-risk group). However, most of these patients were referred to our centre by urologists after their ADT had commenced. The median duration of hormone therapy was 19 months (range 4–75 months).
Brachytherapy and hyperthermia procedures
The procedure of HDRBT combined with IHT has been described elsewhere [Citation17] and is briefly summarised here. The goal of IHT was to heat the prostate to 41–43 °C for 60 min immediately before delivering each HDRBT fraction. After insertion of a Foley catheter into the bladder and following spinal anaesthesia, plastic needles (ProGuide Needles, 6F, sharp, Nucletron, Veenendaal, The Netherlands) were inserted into the prostate under TRUS control. These catheters served as guides for antennae and for the thermistor probes of the hyperthermia system (BSD500, BSD Medical, Salt Lake City, UT, USA), and also as guides for the HDR brachytherapy source (Ir192). At least eight antennas (MA-251) and at least four thermometers should be placed in the prostate to properly carry out hyperthermia. The larger the volume of the prostate, the more catheters should be used for heating the target volume. Bowmann thermistor probes were placed in at least two catheters in the prostate to map and continually monitor the tumour-related temperature, one close to the urethra and one or two in the rectum (in catheters attached to the TRUS probe). In most cases individual sensors were ‘mapped’ twice during the hyperthermia session manually, over the length of 6–8 cm, starting from the tip of the catheter.
The radiation oncologist delineated the contours of the prostate, urethra, rectum and, optionally, the bladder and tumour tissue, basing on TRUS images continuously imported into the SWIFT or Oncentra Prostate™ brachytherapy planning system (Nucletron, Veenendaal, The Netherlands). The medical physicist then prepared a treatment plan. The HDRBT dose to the prostate capsule and/or the tumour margin (local stage T3a-b) was specified. The margin from the tumour edge ranged from 0 to 2 mm, depending on the radiation oncologist’s decision based on TRUS images interpretation (clear tumour picture versus blurred neighbouring fat tissue suggesting infiltration). The therapy plan aimed at achieving 90% of the prescribed dose in at least 95% of the target volume (D90 > 95%) while not exceeding 80% and 120% of the prescribed dose to the rectum and the urethra, respectively. From the year 2012 onwards we have changed dose constraints for organs at risk in our department. At present we use volumetric dose constraints (D0.1 cm3, D2 cm3) instead of Dmax for the urethra and rectum. shows the earlier and current criteria for acceptance of the HDRBT treatment plan.
Table 2. Criteria for acceptance of HDRBT treatment plans.
In cases of excessive patient mobility during brachytherapy or hyperthermia procedure due to early recovery from anaesthesia, the time of hyperthermia was shortened or IHT was abandoned completely. In addition, if the patient requested to shorten the duration of the procedure, it was possible to abandon the IHT.
IHT was performed according to RTOG guidelines [Citation23].
Criteria for evaluation of adverse events
Genitourinary (GU) and gastrointestinal (GI) toxicity was assessed according to Common Terminology Criteria for Adverse Events, version 4 [Citation24]. The data were extracted from International Prostate Symptom Score (IPSS) questionnaires and from patients’ medical histories. We did not monitor changes in sexual function.
Adverse events which occurred within the time of treatment or up to 6 months after its completion were considered as early complications. Symptoms that occurred or persisted later than 6 months after the completion of the treatment were considered late complications.
Statistical analysis
To evaluate differences observed in the material studied, Student's t-test (HDRBT and hyperthermia parameters) and Kruskal–Wallis (reactions) were applied. The level of statistical significance was set at p ≤ 0.05. Overall survival, disease-free survival, local control and biochemical control rates were calculated using the Kaplan–Meier method.
Results
Outcomes
Three-year actuarial overall survival, metastasis-free survival, biochemical control and estimated local control rates were 100%, 100%, 100% and 94.2% respectively. Only one patient developed local relapse 27 months post-treatment. The median follow-up time was 26.3 months (range 7–43 months).
Hyperthermia and brachytherapy parameters
A total of 150 sessions of hyperthermia were planned for 76 patients. Ultimately 138 (92%) were actually performed. Two patients were planned to receive one IHT session, 74 were planned to receive two sessions. In total 64 patients (84%) completed their planned hyperthermia treatment. Ultimately, 12 patients underwent one IHT session, and 64 patients completed two sessions. The reasons for hyperthermia withdrawal were as follows: a failure of the IHT system (seven sessions, 58.3%), saddle block (two sessions, 16.7%), a patient’s request (one session, 8.3%), excessive patient mobility (two sessions, 16.7%). As mentioned above, 58.3% of IHT withdrawals were caused by a failure of our equipment to perform the calibration of temperature sensors and to carry out temperature measurements.
During all sessions, temperatures in the planned target volume (PTV) and within the rectum were monitored in stationary mode. The thermal parameters of hyperthermia are summarised in .
Table 3. Hyperthermia (IHT) parameters.
The total number of HDRBT fractions performed was 150, to 76 patients. To 74 patients two brachytherapy fractions were delivered. Two patients of the intermediate-risk group received one HDRBT fraction. The dosimetry parameters of the treatment plans are shown in .
Table 4. Dose–volume histogram parameters of HDRBT.
Toxicity of the combined treatment
The median follow-up time for all 76 patients was 26.3 months (range 7–43). The evaluation of late complications was performed only in 59 patients with follow-up times longer than 18 months (we have excluded patients lost to follow-up and those with a shorter observation time). Median follow-up time in this group was 29.7 months (range 18.4–43.0).
The prevalence and severity of early complications in a total of 76 patients are summarised in .
Table 5. Acute complications of HDRBT boost combined with IHT (N = 76). Median follow-up time 26.3 months.
The most common early complications of combined treatment in patients described in this study were: nocturia, urinary frequency, obstruction, transient haematuria, urgency to urinate, and symptoms of non-infectious inflammation of the lower urinary tract. These symptoms usually resolved spontaneously and did not require pharmacological treatment. Temporary urinary Foley catheter insertion was necessary for two patients (2.6%) within a few days after the first fraction of brachytherapy, due to retention and obstruction (grade 2 complications). There were no early grade 3 or higher complications.
Complications associated with the HDRBT + IHT procedure are summarised in .
Table 6. Procedure-related adverse events.
Late complications were assessed in 59 of 76 patients with follow-up times longer than 18 months. They are summarised in . The toxicity profile was similar to that of early complications.
Table 7. Late toxicities of HDRBT combined with IHT (N = 59). Median follow-up time 29.7 months (range 18.4–43.0).
Discussion
Clinical outcomes
HDR brachytherapy as monotherapy or as a boost in the treatment of localised prostate adenocarcinoma shows encouraging results of survival rates and control of the disease [Citation7,Citation25]. It is also delivered to patients with local recurrence after previous definitive radiation therapy [Citation26,Citation30]. With a median follow-up of 26.3 months we obtained the 3-year estimated biochemical disease control in 100% of patients. Other statistics on the 3-year outcomes and control of the disease in our series of patients were within those reported in the literature, which confirms that HDR brachytherapy boost combined with interstitial hyperthermia is an effective treatment for prostate cancer confined to the gland. It should be noted that most of our patients (97.4%) received androgen blockade. To confirm the effectiveness of hyperthermia in addition to brachytherapy it is necessary to conduct randomised clinical trials to evaluate its impact on the outcome.
Evaluation of HDRBT + IHT tolerance
The tolerance of HDRBT of the prostate combined with IHT in the analysed group of patients was good. All patients received treatment at the scheduled times. For the vast majority of patients (96.1%), complications occurring immediately after the procedure did not require any prolonged hospitalisation. Perineal, lower abdomen or penis pain usually resolved spontaneously within 24 h after treatment. Most patients did not require any additional analgesics apart from those routinely mandated by the anaesthesiologist.
In the spinal anaesthesia procedure applied to so many patients one should expect individual cases of adverse symptoms associated with this procedure. In the group of patients analysed, anaesthesia-related complications occurred in one patient (post-lumbar puncture headache). Two patients complained of discomfort around the anus over a few days, associated with the long-term presence of the TRUS probe in their recta. These complications were resolved spontaneously or were treated symptomatically.
Evaluation of early HDRBT + IHT complications
In the group of patients studied there were no early grade 3 or higher complications, i.e. such as would require additional hospitalisation or invasive treatment.
The most common early complications of prostate radiotherapy are symptoms from the genitourinary system and gastrointestinal tract (bladder, rectum, urethra and neurovascular bundles). Mostly, these symptoms occur already during treatment. They are mild or moderate in nature and are resolved within three months after the completion of therapy (∼50% of patients reported acute dysuria, the narrowing of the urinary stream, frequent urination, and/or pain with voiding). In the case of regional lymph node irradiation, diarrhoea is a very common complication [Citation27].
Symptoms of urinary tract irritation after HDRBT (urgency, non-infectious inflammation of the urethra and bladder, urinary frequency, retention), are usually resolved within 3 months after therapy, and their severity in about 5% of patients may achieve grade 3. Early complications of the lower urinary tract (obstruction, urinary frequency, haematuria) are expected in most patients undergoing treatment with HDRBT + IHT, but the severity of these symptoms rarely exceeds grade 2. No more than 5% of patients treated require catheterisation due to chronic urinary retention or obstruction [Citation6,Citation7,Citation28,Citation29].
The profile of early toxicity in the analysed group of patients was similar to that reported in the literature, although in the available reports the emphasis is primarily on the proportion of late complications following HDRBT, while not much information on early reactions is available. Likewise, reports of complications associated with HDRBT + IHT are scarce. The group of patients which we analysed in two earlier articles published in 2013 and 2014 [Citation17,Citation18] largely overlaps with the patient group analysed in this work, thus obviating any comparative effort.
Most patients studied here received the standard treatment for urinary tract symptoms: alpha-blockers for irritated bladder or anticholinergic drugs in spastic bladder. While we did not routinely monitor the patient’s sexual functions, their reported erectile dysfunction was treated with 5-phosphodiesterase inhibitors (i.e. sildenafil).
Evaluation of late HDRBT + IHT complications
As mentioned earlier in this paper, late toxicities were evaluated only in 59 patients, who had follow-up times of at least 18 months.
The incidence of late grade 2 genito-urinary (GU) complications in the studied group was 23.7%, where the most common symptom was nocturia (which is usually ignored in the literature, probably due to the coexistence of benign prostatic hyperplasia in a significant proportion of patients with prostate cancer). In the material presented, during follow-up we found in 15.3% of patients a significant frequency, in 13.6% cumbersome urgency, in 11.9% of patients voiding impediment not requiring instrumental intervention, and in 8.5% - residual urine after voiding. There were no late grade 2 or higher gastro-intestinal (GI) complications. These observations are in agreement with those published by other authors, who find that the average rate of grade 2 complications of the urinary tract is 11%, and gastrointestinal 7% [Citation7]. The longer the follow-up period after treatment, the fewer grade 1 and 2 complications, and the higher the risk of grade 3 complications [Citation7,Citation30].
Late grade 2–4 GU complications following HDRBT + IHT include urethral stenosis, urinary incontinence, haematuria or cystitis, their frequency, or rate after a total dose of 70 Gy being 4–7%. Late GI complications are chronic inflammation of the rectum with or without ulceration (8%) and chronic diarrhoea (3%) [Citation27]. Researchers from the Memorial Sloan Kettering Cancer Center, NewYork, estimated that the type and scale of early complications may be a predictor for the occurrence of late complications. They found that dose escalation to 81 Gy increased the incidence of grade 2 or higher late GU complications from 12% to 20%. The use of the Intensity-modulated radiation therapy, as compared with three-dimensional conformal radiation therapy, reduced the incidence of late grade 2 or higher GI complications from 13% to 5% [Citation31]. The patient’s ability to maintain an erection 1 and 2 years after EBRT was 55%, and 52% respectively, while in the case of EBRT combined with brachytherapy 60% of patients maintained this ability [Citation32].
The most common late grade 3 complications after HDRBT used in the treatment of primary prostate cancer (as mono- or boost therapy) are urethral strictures, usually in the bulbar or membranous portion (less than 15%). Urinary incontinence or bleeding from the rectum are rare (less than 3%). An extremely rare late complication is rectal fistula (less than 1%) [Citation7,Citation33–37]. In several papers investigators used the RTOG/EORTC scale to assess the severity of late complication. This scale appears to be less useful than the CTCAE criteria, as no distinction is made between the different symptoms of late complications.
Due to the relatively short median follow-up of our patients (26.4 months in the whole group, and 31.1 months in the group with observation time longer than 18 months, as mentioned earlier), we may have underestimated the rate of late complications.
Conclusions
The tolerance of HDRBT combined with IHT for the treatment of prostate cancer is good, the profile and the percentage of early complications being acceptable. In the group of patients analysed there were no serious early adverse events of grade 3 or higher. The risk of late grade 3 complications is minimal, and the rate of grade 2 symptoms does not exceed 17%. The clinical results of combined treatment are similar to the results of irradiation, so only randomised trials can give an answer as to whether the addition of hyperthermia improves the outcomes.
Acknowledgements
We wish to thank the brachytherapy and hyperthermia team for providing excellent care to the patients, Marian Reinfuss and Jerzy Jakubowicz for their support, and Michael Waligórski for consulting the manuscript.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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