Borstkanker: Hyperthermie bij recidief van borstkanker geeft in combinatie met bestraling een significant beter resultaat op totale remissie in vergelijking met alleen bestraling, aldus overzichtstudie

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22 november 2010: Bron: International Journal of Hyperthermia, special edition

22 november 2010: Bron: International Journal of hyperthermia 2010, Vol. 26, No. 7 , Pages 612-617 (doi:10.3109/02656736.2010.487194)

Hyperthermie gegeven samen met bestraling aan vrouwen met borstkanker met een recidief in voorheen bestraald gebied geeft significant meer totale remissies dan alleen bestraling. Dit blijkt uit een overzichtstudie van gerandomiseerde studies van de afgelopen jaren. Hieronder de resultaten uit het studieverslag in het Engels en spreekt voor zich lijkt ons. Er wordt in de conclusie wel opgemerkt dat de bijwerkingen soms wel groot zijn, alhoewel minder dan bij bestraling alleen. Hier wordt bijna alleen gesproken over hyperthermie waarbij kans op verbranden groot is. De electro hyperthermie die in principe geen bijwerkingen geeft wordt bijna niet genoemd omdat daarvan geen of weinig gerandomiseerde studies beschikbaar zijn. Het volledige studierapport kunt u lezen als u hier klikt.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data

Timothy M. Zagar1, James R. Oleson1, Zeljko Vujaskovic, MD, PhD1*, vujas001@mc.duke.edu Mark W. Dewhirst1, Oana I. Craciunescu1, Kimberly L. Blackwell2, Leonard R. Prosnitz1, Ellen L. Jones3
1Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina

2Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina

3Department of Radiation Oncology, University of North Carolina Cancer Hospital, Chapel Hill, North Carolina, USA

*Correspondence: Zeljko Vujaskovic, MD, PhD, Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710, USA (919) 5221 (919) 668-7345 vujas001@mc.duke.edu

There are numerous reports in the literature detailing the results of combined hyperthermia and radiation therapy for chest wall/superficial recurrences of breast cancer [30–42]. Many are single institution retrospective accounts, but there are several large prospective randomised trials with a primary endpoint of percentage achieving a clinical complete response (CR) [30–32], (Table I). Watch:: http://informahealthcare.com/action/showPopup?citid=citart1&id=T0001&doi=10.3109/02656736.2010.487194

The first randomised trial was run by the Radiation Therapy Oncology Group (RTOG), protocol 8104, and included 307 patients with superficially measurable tumours, 245 of which had single lesions and were available for analysis. Their treatment consisted of a radiation dose of 32 Gy, given in 4 Gy twice weekly fractions, with two hyperthermia sessions (goal 42.5°C, 45–60 min). Approximately 30% (68 patients) of those included had superficial disease in the breast or chest wall. Their primary endpoint was rate of CR, and overall, they did not find a statistically significant increase in local control with the addition of heat to radiotherapy . On subset analysis, those patients with breast or chest wall/flank lesions had a CR rate of 62% with the addition of heat, compared to 40% without. In addition, patients with a lesion diameter <3 cm had a CR rate of 52% with heat, versus 39% with radiotherapy alone (p = 0.02). A caveat of their results that was pointed out, which has been borne out in other studies, was the quality of treatment delivered. Only 52% in the combined HT/RT group received full RT dose and 8 HT treatments; 42% and 31% of lesions <3 cm and >3 cm received ‘good’ heating, respectively, defined as at least 4 HT sessions of 42.5°C for 45 min at the temperature reference point . The authors noted that the poor survival of their patients (22% alive at 1 year), could also help explain their low control rates, in that patients need to survive long enough for full clinical impact to be appreciated in both arms. All toxicities were similarly balanced in the two groups, except that 30% of the patients who received RT and HT developed thermal blisters, versus 0% in the RT only arm. No mention was made as to the severity of the thermal injury, nor to the methods of treatment if necessary.

Shortly after RTOG 8104 began accruing patients, both Stanford and Thomas Jefferson Universities ran single institution randomised trials to address the question of whether one or two hyperthermia treatments should be given weekly , . Both of these trials, which included a heterogeneous group of patients (mostly chest wall), found no difference in rate of CR if HT was given once or twice weekly. Radiotherapy was similar in the two trials for recurrences in the previously unirradiated chest, but when patients with chest wall recurrences required re-irradiation, the fractionation was different. Thomas Jefferson utilised a more hypofractionated regimen (40 Gy in 4 Gy fractions), whereas Stanford used more traditional fractionation (21.6–36 Gy in 1.8–2 Gy fractions). Both trials evaluated similar thermal profiles and both found Tmin to be the only thermal predictor for durable local control. The Stanford trial found a trend for increased local control with a Tmin ≥ 41°C, versus <41°C (p = 0.08), whereas the Thomas Jefferson found a median local control to be 12 months with a Tmin ≤ 39.5°C, versus 23 months for a Tmin > 39.5°C (p = 0.01).

Thermal injury was not statistically different in patients treated with one versus two weekly HT sessions. In the Stanford analysis, only 3/58 patients’ complications required medical treatment, and 2/58 required surgical intervention . Nearly 40% of the patients at Thomas Jefferson were reported to have no skin reactions related to therapy; 11/56 heated fields developed thermal blistering, which was equally balanced between the two groups .

The reason this question was posed deals with the phenomenon of thermotolerance; that is, that most mammalian cells become resistant to the effects of heat at temperatures below 43°C, or at 37°C after exposure to temperatures greater than 43°C . As more research has been done in this area, the tolerance to heat has been found to be related to heat shock proteins (HSPs), which are up-regulated by hyperthermia . As a consequence, most advocate an interval between HT sessions of at least 48–72 h, so as to allow adequate time for their removal. However, there is some data to suggest that thermal radiosensitisation is not subject to thermotolerance. Armour et al. found that the protein synthesis inhibitor cycloheximide prohibited the induction of thermotolerance, but did not influence radiation sensitisation . Given this biological finding, a more aggressive hyperthermia fractionation scheme may be warranted, but to date has not been attempted.

The largest collection of prospective data for combining radiotherapy and hyperthermia for the treatment of superficial breast cancer was compiled in a collaborative effort by the UK Medical Research Council, European Society for Hyperthermic Oncology, Dutch Hyperthermia Group and the Princess Margaret Hospital/Ontario Cancer Institute . There were five simultaneous ongoing prospective trials being conducted by the aforementioned groups. Due to poor patient accrual it was decided to pool their data so as to increase statistical power. As one might expect, by combining multiple trials there is a large degree of heterogeneity in the patient populations, as well as the treatment delivered. In this meta-analysis of the European and Canadian series there were three identifiable patient groups: untreated primary inoperable breast cancer, recurrent disease in sites not previously irradiated, and those with recurrences in sites having previously been irradiated; 71% had recurrences on their chest wall .

Radiotherapy was administered ‘radically’ (range of ‘effective’ dose 60–69.3 Gy) if the patient's failure was not in a previously irradiated field, or ‘palliatively’ (range 39.8–47.2 Gy) if it had been . Their goal with respect to hyperthermia was to achieve a minimum intratumour temperature of 43°C (42.5°C in one of the five trials). Their primary endpoint was the rate of CR, which was 59% and 41% with and without hyperthermia, respectively (p < 0.001, OR 2.3, 95%CI 1.4–3.8). In patients that had previously been irradiated, their rate of CR was 57% versus 31% (OR 4.7, 95%CI 2.4–9.5), and this was with ‘palliative’ doses of radiation. This represents a significant improvement in complete response with the addition of hyperthermia to irradiation. While overall survival was not a primary endpoint of this collection of trials, it was evaluated on subset analysis. There was no statistically significant difference in survival in patients irradiated with or without hyperthermia, due largely in part to the high percentage of patients that developed metastatic disease in both groups; median overall survival was 18 months, regardless of randomisation. However, given the natural history of recurrent breast cancer, a local therapy would not necessarily be expected to improve overall survival.

It should be noted that the majority of patients did not reach the minimum intratumour temperature defined at the outset of the trial. Sherar et al. examined the thermal dosimetry of 120 patients that were enrolled, and sought to find reliable treatment parameters that might predict for response to therapy . Five thermal endpoints were evaluated, of which two were found to be correlated with rates of CR; the Max (TDmin), and the Sum (TDmin), with the TDmin being the lowest recorded temperature during treatment. They highlighted that those patients without distant metastatic disease at entry–difficult to extrapolate from, as only one of the five trials vigorously evaluated for distant disease prior to enrolment–had better outcomes, including increased CR rate, local disease-free survival, time to local failure and overall survival, with improved quality of hyperthermia (with cut-offs of ≤10 or >10 min) .

With respect to toxicity of HT combined with RT, the authors note that ‘a small number’ of patients did not complete their planned HT secondary to pain; they did not cite exactly how many. They found little difference in the rates of erythema and desquamation with the addition of HT to RT, but reported an 11% rate of thermal blistering in the combined group, versus a 2% rate in the RT alone patients . They noted that acute treatment-related toxicities healed with conservative measures alone. Three late treatment-related complications were identified in patients receiving HT plus RT (bone necrosis, bone fracture and brachial plexopathy), thus underscoring the importance of long-term follow-up of surviving patients .

The most recently reported phase III trial of radiotherapy with or without hyperthermia was from Duke University . This study was rigorous in terms of meeting thermometry/thermal dose guidelines and included a ‘test dose’ of hyperthermia before randomisation to ensure that all patients were indeed heatable. Of the 122 patients enrolled, 108 patients were deemed heatable and were randomised. Of those patients, 65% had disease in their breast or chest wall. Overall, the CR rate was 66.1% for patients treated with both heat and radiotherapy, versus 42.3% in the radiotherapy alone arm (p = 0.02, OR 2.7, 95%CI 1.2–5.8). The thermal parameter used was the number of cumulative equivalent minutes at 43°C exceeded by 90% of monitored points within the tumour (CEM 43°C T90), which is similar to one of the two endpoints evaluated by Sherar et al. found to have a significant effect on CR (i.e. sum (TDmin), which is the CEM 43°C T100) , . Jones et al. found that the CEM 43°C T90 was a strong predictor for CR, as was found in a Medical Research Council analysis of their data . Like the Vernon meta-analysis , the patients that had the greatest benefit were those that had previously received radiation therapy, with CR rates of 68.2% and 23.5%, with and without hyperthermia, respectively. Not surprisingly, there were no differences in overall survival between the two groups.

As was the case with the previous trials, toxicity with the addition of HT to RT was manageable. Thermal burns occurred in 45% of patients randomised to HT plus RT, versus 5.7% in the RT alone group. Nearly half of the burns in the combined modality arm were first degree, with only three patients experiencing third-degree burns . Catheter-related toxicities were reported in six patients, which included pain requiring over the counter analgesics in three, infection requiring antibiotics in two, and wound management for bleeding in one .

Table I. Complete response (CR) rate in randomised trials involving irradiation with or without hyperthermia for chest wall recurrence/superficial breast cancer.

Shortly after RTOG 8104 began accruing patients, both Stanford and Thomas Jefferson Universities ran single institution randomised trials to address the question of whether one or two hyperthermia treatments should be given weekly , . Both of these trials, which included a heterogeneous group of patients (mostly chest wall), found no difference in rate of CR if HT was given once or twice weekly. Radiotherapy was similar in the two trials for recurrences in the previously unirradiated chest, but when patients with chest wall recurrences required re-irradiation, the fractionation was different. Thomas Jefferson utilised a more hypofractionated regimen (40 Gy in 4 Gy fractions), whereas Stanford used more traditional fractionation (21.6–36 Gy in 1.8–2 Gy fractions). Both trials evaluated similar thermal profiles and both found T_min to be the only thermal predictor for durable local control. The Stanford trial found a trend for increased local control with a T_min ≥ 41°C, versus <41°C (p = 0.08), whereas the Thomas Jefferson found a median local control to be 12 months with a T_min ≤ 39.5°C, versus 23 months for a T_min > 39.5°C (p = 0.01).

Thermal injury was not statistically different in patients treated with one versus two weekly HT sessions. In the Stanford analysis, only 3/58 patients’ complications required medical treatment, and 2/58 required surgical intervention . Nearly 40% of the patients at Thomas Jefferson were reported to have no skin reactions related to therapy; 11/56 heated fields developed thermal blistering, which was equally balanced between the two groups .

The reason this question was posed deals with the phenomenon of thermotolerance; that is, that most mammalian cells become resistant to the effects of heat at temperatures below 43°C, or at 37°C after exposure to temperatures greater than 43°C . As more research has been done in this area, the tolerance to heat has been found to be related to heat shock proteins (HSPs), which are up-regulated by hyperthermia . As a consequence, most advocate an interval between HT sessions of at least 48–72 h, so as to allow adequate time for their removal. However, there is some data to suggest that thermal radiosensitisation is not subject to thermotolerance. Armour et al. found that the protein synthesis inhibitor cycloheximide prohibited the induction of thermotolerance, but did not influence radiation sensitisation . Given this biological finding, a more aggressive hyperthermia fractionation scheme may be warranted, but to date has not been attempted.

The largest collection of prospective data for combining radiotherapy and hyperthermia for the treatment of superficial breast cancer was compiled in a collaborative effort by the UK Medical Research Council, European Society for Hyperthermic Oncology, Dutch Hyperthermia Group and the Princess Margaret Hospital/Ontario Cancer Institute . There were five simultaneous ongoing prospective trials being conducted by the aforementioned groups. Due to poor patient accrual it was decided to pool their data so as to increase statistical power. As one might expect, by combining multiple trials there is a large degree of heterogeneity in the patient populations, as well as the treatment delivered. In this meta-analysis of the European and Canadian series there were three identifiable patient groups: untreated primary inoperable breast cancer, recurrent disease in sites not previously irradiated, and those with recurrences in sites having previously been irradiated; 71% had recurrences on their chest wall .

Radiotherapy was administered ‘radically’ (range of ‘effective’ dose 60–69.3 Gy) if the patient's failure was not in a previously irradiated field, or ‘palliatively’ (range 39.8–47.2 Gy) if it had been . Their goal with respect to hyperthermia was to achieve a minimum intratumour temperature of 43°C (42.5°C in one of the five trials). Their primary endpoint was the rate of CR, which was 59% and 41% with and without hyperthermia, respectively (p < 0.001, OR 2.3, 95%CI 1.4–3.8). In patients that had previously been irradiated, their rate of CR was 57% versus 31% (OR 4.7, 95%CI 2.4–9.5), and this was with ‘palliative’ doses of radiation. This represents a significant improvement in complete response with the addition of hyperthermia to irradiation. While overall survival was not a primary endpoint of this collection of trials, it was evaluated on subset analysis. There was no statistically significant difference in survival in patients irradiated with or without hyperthermia, due largely in part to the high percentage of patients that developed metastatic disease in both groups; median overall survival was 18 months, regardless of randomisation. However, given the natural history of recurrent breast cancer, a local therapy would not necessarily be expected to improve overall survival.

It should be noted that the majority of patients did not reach the minimum intratumour temperature defined at the outset of the trial. Sherar et al. examined the thermal dosimetry of 120 patients that were enrolled, and sought to find reliable treatment parameters that might predict for response to therapy . Five thermal endpoints were evaluated, of which two were found to be correlated with rates of CR; the Max (TD_min), and the Sum (TD_min), with the TD_min being the lowest recorded temperature during treatment. They highlighted that those patients without distant metastatic disease at entry–difficult to extrapolate from, as only one of the five trials vigorously evaluated for distant disease prior to enrolment–had better outcomes, including increased CR rate, local disease-free survival, time to local failure and overall survival, with improved quality of hyperthermia (with cut-offs of ≤10 or >10 min) .

With respect to toxicity of HT combined with RT, the authors note that ‘a small number’ of patients did not complete their planned HT secondary to pain; they did not cite exactly how many. They found little difference in the rates of erythema and desquamation with the addition of HT to RT, but reported an 11% rate of thermal blistering in the combined group, versus a 2% rate in the RT alone patients . They noted that acute treatment-related toxicities healed with conservative measures alone. Three late treatment-related complications were identified in patients receiving HT plus RT (bone necrosis, bone fracture and brachial plexopathy), thus underscoring the importance of long-term follow-up of surviving patients .

The most recently reported phase III trial of radiotherapy with or without hyperthermia was from Duke University . This study was rigorous in terms of meeting thermometry/thermal dose guidelines and included a ‘test dose’ of hyperthermia before randomisation to ensure that all patients were indeed heatable. Of the 122 patients enrolled, 108 patients were deemed heatable and were randomised. Of those patients, 65% had disease in their breast or chest wall. Overall, the CR rate was 66.1% for patients treated with both heat and radiotherapy, versus 42.3% in the radiotherapy alone arm (p = 0.02, OR 2.7, 95%CI 1.2–5.8). The thermal parameter used was the number of cumulative equivalent minutes at 43°C exceeded by 90% of monitored points within the tumour (CEM 43°C T₉₀), which is similar to one of the two endpoints evaluated by Sherar et al. found to have a significant effect on CR (i.e. sum (TD_min), which is the CEM 43°C T₁₀₀) , . Jones et al. found that the CEM 43°C T₉₀ was a strong predictor for CR, as was found in a Medical Research Council analysis of their data . Like the Vernon meta-analysis , the patients that had the greatest benefit were those that had previously received radiation therapy, with CR rates of 68.2% and 23.5%, with and without hyperthermia, respectively. Not surprisingly, there were no differences in overall survival between the two groups.

As was the case with the previous trials, toxicity with the addition of HT to RT was manageable. Thermal burns occurred in 45% of patients randomised to HT plus RT, versus 5.7% in the RT alone group. Nearly half of the burns in the combined modality arm were first degree, with only three patients experiencing third-degree burns . Catheter-related toxicities were reported in six patients, which included pain requiring over the counter analgesics in three, infection requiring antibiotics in two, and wound management for bleeding in one .

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data