Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile

Abstract

Purpose: Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented.

Methods and materials: Thirty-seven patients enrolled on a phase II study of external beam radiation ± androgen suppression with two transrectal ultrasound hyperthermia treatments were assessed for short- and long-term toxicity. Prostatic and anterior rectal wall temperatures were monitored. Rectal wall temperatures were limited to 40°C (19 patients), 41°C (three patients) and 42°C (15 patients). Univariate logistic regression was used to estimate the log hazard of developing NCI CTC Grade 2 toxicity based on temperature parameters. Hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained for each of the parameters were calculated.

Results: Median follow-up was 42 months. Both short- and long-term GI toxicity were limited to grade 2 or less. Acute grade 2 proctitis was greater for patients with allowable rectal wall temperature of >40°C. Eleven of 18 patients in this group had acute grade 2 proctitis vs three of 19 patients with rectal wall temperatures limited to 40°C (p = 0.004). Long-term grade 2 GI and GU toxicity occurred in 5% and 19% of patients. No late grade 3 or greater toxicity occurred. Late GI and GU toxicity were not associated with the allowable rectal wall temperature.

Conclusion: Transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer is safe and well tolerated.

• Hyperthermia
• toxicity
• thermometry
• prostate cancer

Introduction

An important consideration in development of a new treatment strategy for prostate cancer is whether it is well tolerated by patients with acceptable short- and long-term toxicity profiles. Despite advances in radiation treatment delivery and improved understanding of the role of androgen ablation, a significant proportion of men with locally advanced disease suffer treatment failure. Quality of life also remains a primary concern in this group of men who often face years of therapy despite the lack of symptoms from their disease at the time of diagnosis. As onset of side effects near-term to treatment may have a very significant impact on quality of life, the safety profile of new treatment strategies must be carefully considered in moving towards clinical acceptance.

The short-term toxicity profile has previously been reported for 30 patients on this phase II trial, including association of thermal dose parameters with acute rectal toxicity [1]. The favourable long-term safety profile of transrectal ultrasound hyperthermia for treatment of prostate cancer in a phase I series with the device used in the trial was previously reported [2], [3]. These reports indicate, in regard to acute toxicity, hyperthermia can be safely administered with radiation. The present report confirms these prior findings for all 37 patients treated on a phase II trial and assesses the impact of hyperthermia on late toxicity in this patient population.

Methods

All patients were enrolled on a phase II study at the Dana-Farber Cancer Institute (DFCI) including men with clinical stage T2b–T3b disease by 4^th edition AJCC criteria. All patients received 6660 cGy ± 5% normalized to 95% with 180–200 cGy fractions. Two hyperthermia treatments were administered at least 1 week apart during the first 4 weeks of radiation. Radiation therapy was administered with a four field technique using ≥6 MV photons. Following accrual of the first four patients an amendment was made to the protocol to allow for use of androgen suppressive therapy (AST) to reflect changes in the standard of care for many patients eligible for the study [4–6]. The recommended study regimen called for a total of 6 months of combined LHRH agonist with a non-steroidal anti-androgen including 2 months of neo-adjuvant hormonal therapy before initiating radiation therapy.

Details of the transrectal hyperthermia system have been previously reported [1]. The ultrasound power was delivered from a water cooled 16 element partial-cylindrical intra-cavitary array. Power deposition was individually controlled for each of the 16 transducers and a closed heating/cooling system using degassed bolus water was used to control the anterior rectal wall temperature. The cooling water bolus was continuously circulated under a latex membrane secured over the ultrasound probe, which was inflated with the water once inserted in the rectum to provide coupling to the rectal wall for optimal transmission of ultrasound to the prostate. Between this first and a second latex membrane, three thermocouple sensors spaced 1 cm apart were positioned against the anterior rectal wall. Three interstitial temperature probes with seven thermocouple sensors per probe were used to monitor intra-prostatic temperatures and a single perfusion probe placed intra-prostatically so that blood flow within the prostate could be recorded before and after hyperthermia.

Patients were placed in the lateral decubitus position for treatment. Placement of the interstitial temperature and perfusion probes was accomplished via a transperineal route using transrectal ultrasound guidance. A pre-treatment biopsy was obtained on a voluntary basis. During this portion of the procedure most patients received propofol, a short acting IV general anaesthetic, supplemented with midazolam and fentanyl, while maintaining spontaneous ventilation. Once the probes were satisfactorily placed within the prostate, the transrectal hyperthermia probe was introduced into the rectum. Patients were then allowed to return to an alert state, but at times receiving further light IV sedation, sufficient for communication of any pain, positional or heat discomfort.

Power was then applied for a minimum goal of 60 min at therapeutic temperature, as defined by attainment of a temperature of 42.0°C by at least one intra-prostatic temperature sensor or allowing for 10 min of initial heating. The thermal treatment goal was to achieve a CEM T₉₀43°C of 10 min. This parameter is used to equate a range of actual temperatures achieved to a reference temperature (43°C). The temperature exceeded by 90% of the measured temperature points (T₉₀) when given over a period of time is converted to equivalent minutes (EM) at 43°C as defined by Sapareto and Dewey [7]. The cumulative equivalent minutes (CEM) T₉₀43°C is the summation of the EMT₉₀43°C for each hyperthermia session over the course of treatment.

The maximum rectal wall temperature at any single point was limited to 40°C (19 patients), 41°C (three patients) or 42°C (15 patients). The limitation of the rectal wall temperature to 40°C in the initial 19 patients hindered achievement of the thermal treatment goal for a majority of patients, since the applied power typically had to be reduced to keep the rectal wall temperature below 40°C. Since there was minimal rectal toxicity experienced with a rectal wall temperature limit of 40°C, the Dana-Farber Cancer Institute institutional review board allowed for an increase in allowable rectal wall temperature to 42°C in a step-wise manner, with three patients first treated at 41°C.

The cooling water bolus was initially set at 37°C and maintained between 33–37°C through the treatment to keep the maximum rectal wall temperature within treatment guidelines. In addition to the cooling water bolus temperature, rectal wall temperatures were also controlled by adjustment of the power applied to the transducers in the high temperature area. Thus, if the temperature at any rectal point exceeded the allowable temperature, either applied power in that area was reduced or the cooling water bolus temperature lowered. These interventions typically brought the rectal wall temperature back into the allowed range within 1 minute. Temperature profiles were obtained for each thermocouple in 30 s intervals over the course of treatment. Once the session was completed, all probes were removed, optional post-treatment biopsy was performed and anoscopy performed. Patients then received radiation within 1 hour of completion of hyperthermia.

Radiation therapy was administered with a conformal technique with CT treatment planning. The protocol specified a total dose as prescribed with 95% normalization of 6660 cGy (∼7000 cGy ICRU reference dose) with an allowed 5% variation. All patients were treated with an initial field inclusive of the prostate and seminal vesicles with a 1.5 cm margin followed by a prostate only boost with a 1.5 cm margin. In addition, after the initial four patients were treated an amendment was made to allow for use of androgen suppressive therapy (AST) with a recommended regiment of total androgen suppression beginning 2 months neoadjuvantly and continuing for a total of 6 months. For patients receiving AST, simulation was typically performed prior to initiation of treatment.

Proportions were compared using Fisher's exact test. The Wilcoxon rank sum test was used to test for differences in CEM T₉₀43°C between patients with allowable rectal wall temperature ≤ 40°C vs > 40°C. Logistic regression was used to estimate the log hazard of developing Grade 2 toxicity as defined by NCI CTC v2 criteria, based on several temperature parameters. Late toxicity was defined as any toxicity persisting or occurring more than 3 months from completion of radiation therapy. These parameters included allowable maximum rectal wall temperature, as well as the average maximum rectal wall temperature (T_max), median rectal wall temperature (T₅₀) and minimum rectal wall temperature (T_min) representing the highest average value for each parameter of the two treatments and average of both treatments per patient. Prostate temperature parameters including EqM T₉₀43°C, CEM T₉₀43°C and average prostate T_max, T₅₀ and T_min were also assessed. The hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained by each model was calculated.

Results

Thirty-seven patients received a total of 72 hyperthermia treatments between September 1997 and April 2002 on the DFCI phase II hyperthermia trial. Median follow-up was 42 months, median age was 64 (45–78) years, 1992 AJCC clinical stage T2b 19, T2c 8, T3a 5 and T3b 5 patients. Median Gleason score was 7 (6–9) and median PSA was 13.3 (2–65) ng/ml.All patients completed conformal radiation therapy with CT treatment planning to a median dose of 6700 cGy (6340–7200 cGy) as normalized to 95%. Thirty-three patients received androgen suppressive therapy initiated within 3 months prior to radiation therapy. All but two of these patients received 6 months of AST with one patient receiving 9 months and another 12 months of AST.

Thirty-five of 37 patients received two hyperthermia treatments. Median duration of treatment was 62.8 (39–80) min per treatment session and did not differ significantly between the first and second treatments. Temperature profiles are shown in Table I. The mean CEM T₉₀ 43°C for all 37 patients was 8.4 min. When assessed by allowable rectal wall temperature those with a rectal wall maximum of ≤40°C had a mean CEM T₉₀43°C of 5.6 min vs 11.4 min for patients with an allowable rectal wall temperature >40°C. A Wilcoxon rank sum test of the difference in median CEM T₉₀43°C for these two groups, 2.8 min vs 10.5 min, was significant (p = 0.004).

Table I.  Hyperthermia treatment profile.

	Min	Max	Ave
Time (min)	39.0	80.0	62.8
Tmin (°C)	37.5	41.8	40.1
Tave (°C)	39.2	42.8	41.2
Tmax (°C)	40.5	45.9	42.5
EMT9043	0.1	21.9	4.3
CEMT9043	0.4	27.2	8.4

The acute toxicity profile is shown in Table II. Overall, grade 2 GI or GU side effects occurred in 14 patients for each system. No acute grade ≥3 toxicity occurred. The rate of acute grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40°C. Eleven of 18 patients in this group experienced acute grade 2 proctitis as opposed to three of 19 patients in the group with rectal wall temperatures limited to 40°C (p = 0.007). There was no difference in acute GU toxicity between temperature groups (p = 1.00).

Table II.  Acute Grade 2 toxicity.

	RW ≤ 40°C	RW ≤ 41–42°C	p
GI	3/19	11/18	0.007
GU	7/19	7/18	1.000

The complete profile of late toxicity is shown in Tables III–V. Overall grade 2 GI or GU late side effects occurred in 5% and 19% of patients, respectively. As expected, both late GI toxicities as with acute GI toxicities were related to rectal symptoms. No late grade ≥3 side effects have occurred. Median time to occurrence of both late GI and GU toxicity was 13 months. Assessment of long-term toxicity revealed no differences in either GI or GU grade 2 toxicity between allowed rectal wall temperature groups with a median follow-up of 54 months and 36 months for the ≤40°C and >40°C temperature groups, respectively. In each temperature group, a single patient experienced late grade 2 GI toxicity (p = 1.00). Notably, all patients with acute grade 2 toxicity in the higher temperature group had their acute proctitis symptoms resolve by the time of first follow-up at 1 month after completion of radiation therapy. There was no significant difference in late grade 2 GU toxicity between low and high temperature groups, which occurred in four and three patients, respectively (p = 1.00).

Table III.  Late urinary toxicity.

	Grade
	0	I	II	III
Total	20	10	7	0
RW <40°C	11	4	4	0
RW >40°C	9	6	3	0

Table IV.  Late GI toxicity.

	Grade
	0	I	II	III
Total	25	10	2	0
RW <40°C	12	6	1	0
RW >40°C	13	4	1	0

Table V.  Late Grade II toxicity.

	RW ≤ 40°C	RW ≤ 41–42°C	p
GI	1/19	1/18	1.00
GU	4/19	3/18	1.00

As we previously established a relationship between acute grade 2 proctitis and thermal dose parameters [2], the same logistic regression model was applied to late grade 2 toxicity and overall grade 2 toxicity. No association was found between any of the parameters and late toxicity. When overall toxicity was assessed in univariate models, an association with average rectal wall maximum temperature was found (p = 0.03), as shown in Table VI.

Table VI.  Logistic regression models: any Grade 2 toxicity.

	Hazard ratio	95% Confidence interval	p-value	Proportion of variability explained (%)
Machine shut-off^a	2.69	0.71–10.18	0.14	4.3
Highest RW^b minimum	1.66	0.86–3.22	0.13	5.3
Average RW minimum	1.61	0.85–3.05	0.15	4.5
Highest RW average	2.10	0.90–4.86	0.09	7.3
Average RW average	2.12	0.95–4.72	0.07	7.8
Highest RW maximum	2.45	0.92–6.50	0.07	8.6
Average RW maximum	2.61	1.09–6.23	0.03	12.1
Average prostate min	1.64	0.74–3.62	0.22	3.0
Average prostage avg	2.12	0.79–5.65	0.13	4.8
Average prostate max	2.20	0.94–5.16	0.07	7.5
Cumulative equivalent minutes, T90 43°C	1.02	0.93–1.11	0.69	0.3

^aMachine shut-off: Power turned off due to exceeding allowable rectal wall temperature for more than 1 min, despite prior reduction of power or decreased temperature of cooling water bolus.

^bRW: rectal wall.

Discussion

There is growing interest in the use of thermal therapy for treatment of pelvic malignancies. The finding of improved overall survival with the addition of hyperthermia to radiation for treatment of cervical cancer [8] demonstrated that heat can significantly improve treatment outcome for deep seated tumours. Presently, the use of heat either for traditional hyperthermia or for ablation is in various stages of investigation in the primary treatment and salvage settings. A recent report of the use of hyperthermia with pelvic radiation including patients undergoing re-irradiation showed promise with this approach to treatment of symptomatic prostate cancer [9]. The safety and toxicity profile of hyperthermia directed to the pelvis remains to be fully defined. The specific area targeted, heating technique and other treatments used in combination with hyperthermia all impact on toxicity profile.

The use of hyperthermia in treatment of prostate cancer has been reported by several groups. In the past several years, van Vulpen et al. [10], [11] have reported results of combined external beam radiation with either regional or interstitial hyperthermia. 6600–7000 cGy was administered in 200 cGy fractions over 7 weeks to patients with T3 or T4 prostate cancer. Fourteen patients received five weekly regional hyperthermia treatments and 12 patients received one interstitial treatment. T₉₀ and T₅₀, the temperatures exceeded by 90% and 50% of measured temperature points in the prostate, were 40.2°C and 40.8°C for regional heating and 39.4°C and 41.8°C for interstitial hyperthermia. With a mean follow-up of 36 months (range 16–60 months), toxicity was limited with 27% and 23% of patients experiencing grade 2 GI and GU toxicities, respectively, and no patient experienced grade ≥3 toxicity [10], [11]. In a recent report on the use of interstitial hyperthermia with implanted self-regulating thermoseeds, Deger et al. [12] reported generally good treatment tolerance and promising initial PSA response in 57 patients with T1–T3 prostate cancer. 6840 cGy in 180 cGy fractions was administered concurrent with six hyperthermia treatments with implanted 55°C Curie thermoseeds. Acute urinary retention occurred in two patients during treatment which in both instances required transurethral resection at 3 and 6 months following completion of treatment respectively.

In a final report of the phase I trial preceding the current study, Algan et al. [3] noted no additional long-term toxicity when transrectal ultrasound hyperthermia was combined with radiation for treatment of prostate cancer. One patient did develop obstructive uropathy requiring transurethral resection 9 months after completion of a shortened course of radiation therapy, although it was noted this procedure had been recommended prior to treatment. The toxicity profile of the now completed phase II trial confirms that transrectal ultrasound hyperthermia can be safely added to standard dose external beam radiation and AST for treatment of locally advanced prostate cancer.

An increase in acute grade 2 proctitis was previously reported with increase in the allowed rectal wall temperature from 40–42°C. With eight additional patients now treated in the higher temperature group, this finding was still noted. Fortunately, all occurrences of acute grade 2 GI toxicity resolved within 1 month of completion of radiation therapy. Furthermore, this increase in acute GI toxicity did not translate into a greater risk of late rectal bleeding or proctitis. Late grade 2 GI toxicity was limited to a single event in both temperature groups. The possibility exists that additional late GI toxicity may yet occur with longer follow-up in the higher temperature group given shorter median follow-up of 36 vs 54 months. However, with a median time to occurrence of any late GI toxicity of 14.5 months and 13 months, respectively (10 and 16 months for the 2 grade 2 events), it is unlikely that a significant number of long-term events are yet to occur in either group.

The use of transrectal ultrasound hyperthermia with radiation therapy did not appear to notably increase the rate of late toxicity when compared with contemporary reports of toxicity with radiation alone. The finding of late GI and GU grade 2 toxicity rates of 5% and 19% are consistent with rates of grade 2 toxicity reported in the literature with conformal radiation for treatment of prostate cancer. In a phase III trial of dose escalation from the M.D. Anderson Cancer Center patients were randomized to receive a total dose of 7000 vs 7800 cGy. As the reported dose was to the centre of the prostate, the 7000 cGy received in the lower dose group compares well with the dose received by our patients. Rates of grade 2 GI and GU toxicity were 12 and 10%. Notably, 26% of patients in the 7800 cGy group experienced grade 2 rectal toxicity indicating dose escalation alone to achieve improved outcomes requires additional considerations in regard to external beam radiation delivery or consideration of complementary therapies such as androgen suppression or hyperthermia, as in the present trial [13]. Using IMRT to deliver a dose of 8100 cGy, Zelefsky et al. [14] reported rates of grade 2 GI and GU toxicity of 4% and 15%. Notably, as opposed to the current study, in both these trials a small number of patients experienced grade 3 toxicity.

The use of thermal therapy is presently increasing for treatment of prostate cancer. This increased utilization includes a combination of hyperthermia and high dose rate brachytherapy or external beam for re-treatment of local radiation failures or the use of thermal ablative temperatures. The finding of an acceptable toxicity profile in the present study is an important step towards implementation of thermal therapy for prostate cancer. Important questions remain, however, in regard to the impact of additional factors including specifics of thermal therapy technique, combination with additional treatment modalities on pelvic toxicity, as well as patient reported quality of life. Further study of the safety profile of thermal therapy should, therefore, remain central to the implementation of this treatment strategy for prostate cancer.

Acknowledgement

This work was supported by NCI grant #P-01 CA 31303.