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Low dose reirradiation in combination with hyperthermia: A palliative treatment for patients with breast cancer recurring in previously irradiated areas
Inl. .I. Rodiarion Oncology Bid. Phys., Vol. Printed in the U.S.A. All rights reserved.
IS,pp.1407-
0360-3016/88 53.00 + 00 copyright 0 1988 Pergamon Press PIG
14 I3
??Original Contribution
LOW DOSE REIRRADIATION IN COMBINATION WITH HYPERTHERMIA: PALLIATIVE TREATMENT FOR PATIENTS WITH BREAST CANCER RECURRING IN PREVIOUSLY IRRADIATED AREAS J. VAN DER ZEE, M.D., PH.D.,’ A. D. TREURNIET-DONKER, M.D.,2 S. K. P. A. HELLE, M.D.,2 J. J. SELDENRATH, M.D.,2 J. H. MEERWALDT, A. J. WIJNMAALEN, M.D.,* A. P. VAN DEN BERG, PH.D.,~ G. C. VAN M. P. BROEKMEYER-REURINK’ AND H. S. REINHOLD, M.D.,
A
THE, M.D., PH.D.,~ M.D., PH.D.,~ RHOON, B.Sc.,’ PH.D.~,~
‘Dept. of Hyperthermia, ‘Dept. of Radiotherapy, The Dr. Daniel den Hoed Cancer Center, Rotterdam Radio-Therapy Institute, Rotterdam; 3Dept. of Experimental Radiotherapy, Erasmus University, Rotterdam; and 4Radio-Biological Institute, TN0 Rijswijk, The Netherlands Ninety-seven patients with breast cancer recurring in a previously irradiated area (mean dose 44 Gy) were reirradiated in combination with hyperthermia and had evaluable tumor responses. In the reirradiation series, radiotherapy was given twice weekly in most patients, with a fraction size varying from 200 to 400 cGy, the total dose varying from 8 to 32 Gy. Hyperthermia was given following the radiotherapy fractions. The combined treatment resulted in 35% complete and 55% partial responses. Duration of response was median 4 months for partial response and 26 months for complete response, respectively. The median survival time for all patients was 12 months. Acute skin reaction was mild, with more than moderate erythema in only 14/97 patients. Thermal burns occurred in 44/97 patients, generally at sites where pain sensation was decreased, and therefore they did not cause much inconvenience. In the 19 patients who survived more than 2 years, no late radiation damage was observed. When patients who received a “high dose” (>29 Gy and hyperthermia) were compared with those who received a “low dose” (~29 Gy and hyperthermia), a higher complete response rate was observed in the high dose group (58% vs. 24%), whereas no difference in acute toxicity was found. We conclude that reirradiation with 8 X 4 Gy in combination with hyperthermia twice weekly is a safe, effective and well tolerated method for palliative treatment of patients with breast cancer recurring in previously irradiated areas. Breast cancer, Reirradiation, Hyperthermia,
Local recurrence.
INTRODUCTION
apy Institute, patients with tumor recurrences in previously irradiated areas were seldomly treated with reirradiation before 1979. In 1979 techniques for the induction of local hyperthermia were developed and by that this study was started. Hyperthermia is presently considered to be a valuable supplement to the established treatment modalities in cancer therapy. Laboratory data indicate that combination with radiotherapy is very effective. Various nonrandomized clinical matched lesion studies have indeed consistently shown an increased complete response rate when hyperthermia was added to radiotherapy (Table 1). Hyperthermia has both additional and enhancing effects upon radiotherapy, which are at least partly tumor selective. The subject has been extensively reviewed.5y7326It
Locoregional recurrences of breast carcinoma cause symptoms that markedly impair the quality of life, without being life threatening at short term. Local treatment is considered worthwhile, either in addition to systemic therapy or alone. When local excision is not possible, radiotherapy is the treatment of choice. When tumor progression occurs in a previously irradiated area, the possibilities of radiotherapy are limited. Generally, reirradiation is not considered appropriate for various reasons: (a) the dose to be given is limited by the normal tissue’s tolerance and (b) fibrotic changes resulting from the previous irradiation induce hypoxia, which reduces radiosensitivity. In the Rotterdam Radio-Ther-
Reprint requests to: J. van der Zee, Dept. of Hyperthermia, Rotterdam Radio-Therapy Institute, Groene Hilledijk 30 1, 3075 EA Rotterdam, The Netherlands. Acknowledgements-This study was financially supported by
the Netherlands Cancer Foundation “Koningin Fonds”, grants nos EUR 77-4 and RRTI 83-4. Accepted for publication 29 June 1988. 1407
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Table 1. Comparison
radiotherapy
December 1988, Volume 15,Number 6
vs. radiotherapy
+ hyperthermia
in matched lesions
Complete response chance following treatment with Reference
Tumor histology
11 27 12 24 1 14 8 21 16 15 10
Various* Various Malignant melanoma-i Various? Various Various? Malignant melanoma Malignant melanoma Various Various? Various
All authors
RT
RT+HT
7128 l/7 25154 12/31 28174 913 1 317 2110 7160 7128 712 1
25% 14% 46% 39% 38% 29% 43% 20% 12% 25% 33%
23132 617 31145 2713 1 66189 21/31 8/10 1 l/15 24 160 16128 9114
72%$ 86%$ 69%$ 87%$ 74%$ 68%$ 80% 73%$ 40%$ 57%$ 64%
108135 1
31%
2421362
67%
* Malignant melanoma excluded. t Large tumors combined treatment; small tumors radiotherapy alone. $ Significant difference (Fisher’s exact test 2p < 0.05). Note: Various authors have compared the results of radiotherapy alone (RT) with those of radiotherapy (same dose) combined with hyperthermia (RT + HT) in “matched lesions”: two or more tumors from the same origin within one patient. All authors found an increased complete response rate following the combined treatment. A summation of all data shows about a doubling of the complete response rate when radiotherapy is combined with hyperthermia.
is generally assumed that tumors contain areas with a relatively low blood flow. 6,23With increasing temperature this blood flow does not increase to the same extent as in normal tissues. 25When external heating is applied, the lower bloodflow in tumors will result in a higher temperature increase in tumor tissue than in normal tissue, as the local cooling depends mainly on tissue blood flow. Because of environmental factors (hypoxia, low pH, and low nutrient levels), 18,29tumor tissue is more sensitive to hyperthermia than normal tissue. Furthermore, the radiosensitizing effect of hyperthermia decays more slowly in tumor tissue than in normal tissue.” For these reasons the addition of local hyperthermia to radiotherapy is expected to yield a higher therapeutic ratio. This promising experimental background, the availability of techniques for induction of superficial local hyperthermia, and the lack of local treatment possibilities in the patient group described above, lead to the decision to start treatment with low dose reirradiation in combination with hyperthermia in this patient group. In the first period, most patients had been treated previously with all variations of local and systemic treatment possibilities available but when it became clear that the local results of the combined treatment are worthwhile, patients were referred at a somewhat earlier stage of their disease. This report describes the results obtained in the first 97 patients treated and in whom tumor response was evaluable. METHODS
AND MATERIALS
In the period October 1979 to July 1986, 122 patients with breast cancer recurring in a previously irradiated
area were treated with a low dose of radiotherapy in combination with hyperthermia. In 25 patients, tumor response was not evaluable as systemic therapy was started shortly after the end of the treatment series for tumor progression elsewhere in the body, or to loss to followup due to worsening of their general condition. The 97 patients with evaluable tumor response, 95 females and 2 males, aged 3 l-92, mean 6 1, years, were known to have cancer since 7 months to 17 years, with a mean duration of disease of 5 years. Most patients were in a good general condition, with Karnofsky indices of 100 (n = 74), 90 (n = 18) or 80 (n = 4), with only 1 patient having a Karnofsky index of 50. Most patients had been previously treated extensively by other modalities (Table 2). Fifty-four of the 97 patients were known to have metastatic disease on localizations outside the field treated by reirradiation with hyperthermia. During the reirradiation series, no systemic treatment was given, except to 6 patients who had received hormonal therapy for 1 month to more than 2 years (mean 9 months) with the tumor in the treatment area showing progression or stable disease. In these patients hormonal treatment was continued because of a good reaction (stable disease or response) of tumor lesions elsewhere in the body. Tumors
Malignancy was established in all patients by cytological or histological examination. Tumor histologic differentiation was known for 54/97 patients. Tumors were well or moderately differentiated in 6 patients, and poorly-or undifferentiated in 26 and 22 patients, respectively. Tumor recurrences were localized cutaneously or subcutaneously on the chest wall in 76 patients, within regional lymphnodes in 11 patients, within the
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77 cases. Previous irradiation had been given to the whole area in 76 patients, and to part of the area in 21 patients.
Table 2. Patient and tumor characteristics Patients 1979- 1986: 971122 patients evaluable for response Age 3 l-92, mean 6 1 years Duration of disease 7 months- 17 years, mean 5 years Previous systemic therapy 84197
Radiotherapy
Radiotherapy was given twice weekly, with each hyperthermia treatment, in 92/97 patients. Three, 4, or 5 radiation fractions each week were given in 1, 2, and 2 patients respectively. When the twice weekly-schedule was used, the fraction size was 400 cGy. In 90 patients electrons were used with an energy of on the average 10 MeV. Characteristics of previous irradiation and reirradiation are given in Tables 2 and 3. In the period October 1979 to August 1983, the reirradiation schedule for most patients was 6 X 4 Gy (n = 38). When no serious toxicity was observed, the treatment dose was increased to 8 X 4 Gy (n = 28).
Tumors Location (Sub-) cutaneously chest wall Regional lymphnodes Within breast Other Previous surgery same location Previous radiotherapy
76 11 6 4
77/97
same location
Total dose (Gy) Fraction size (cGy) Time interval with reirradiation (months)
Range
Mean
15-76 180-400
44 260
l-203
48
Hyperthermia
Tumor volume 0. I - 175 1 cm3, mean 64.6 cm3 CO.5 cm3 n= 8 0.5-15 cm3 n = 39 15-65 cm3 n = 36 a-65 cm3 n= 14
Hyperthermia was given twice weekly to avoid maximum thermotolerance, following radiotherapy with a mean time interval of 40 (range 20-90) minutes. Hyperthermia was induced non-invasively, using 27, 433 or 2450 MHz electromagnetic radiation, depending on tumor dimensions and depth. In 7 patients a combination of two of these frequencies was used, to achieve optimal heating in a minimum number of applications. Technical details have been presented in a previous paper.31 A typical hyperthermia treatment consisted of 60 minutes (generator time) up to the maximum tolerated temperature which was either indicated by the patient or by a temperature measurement within normal tissue exceeding 43°C. Surface cooling was performed in cases where healthy skin covered the tumor or at sites where hot spots
in 6 patients and at various other sites in 4 patients. Tumor volumes at the start of therapy ranged from 0.1 to 175 1 cm3 with an average value of 64.6 cm3 (Table 2). In those patients where the recurrence consisted of multiple lesions, the size of the largest nodule was used to calculate the tumor volume. This was the case in 3 l/47 patients with a tumor volume smaller than 15 cm3 and in 17/50 patients with larger tumors. The area treated had been subjected to surgery in the past in
breast
Table 3. Treatment
characteristics Range
Mean
SEM
8-28 200-400 40-96 35-738 l-10 39.3-45.0
22.3 365 66.7 221 5.9 42.2
0.45 8.0 1.14 21 0.17 0.16
31.8 390 75.6 176 7.7 42.0
0.10 5.4 1.56 21 0.23 0.25
“Low dose” n = 66 Radiotherapy total dose (Gy) Fraction size (cGy) Cumulative total dose (Gy) Field size (cm2) Hyperthermia number of treatments Tmaxmean (“C) Radiotherapy schedule 5~4Gy 6X4G; 7~4Gy other
n= 7 n=38 n= 3
I 63166
2 fr/wk
n= 18
“High dose” n = 3 1 Radiotherapy total dose (Gy) Fraction size (cGy) Cumulative total dose (Gy) Field size (cm2) Hyperthermia number of treatments Tmaxmean (“C) Radiotherapy schedule 8X4Gy lOX3Gy
30-32 300-400 47-90 30-432 2-10 39.7-44.8 n=28 n= 3
I
2913 1 2 frfwk
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occurred. Cooling was achieved using small water blankets or by directing a current of cool air. In cases where it was not possible to heat the entire tumor area with a single set of applicators, the area was divided into two or more sub-areas which were heated successively. A total treatment time of 120 minutes, considered to be the maximum tolerable for most patients, was not exceeded. When more than two fields were heated (in 8 patients), the treatment duration per field was therefore proportionally reduced. Thermometry was performed at 1 to 15 intratumoral sites and in most patients surface temperature measurements were carried out as well. The thermometry systems used have been described elsewhere.3’ In addition to thermocouple single point needles, probes with 3 to 5 measuring points within closed tip catheters (outer diameter 1.22 mm)32 were used. With the temperatures measured during each hyperthermia treatment calculations were performed by using a computer program in order to get representative values for the hyperthermia dose. This procedure has been described in detail in a previous paper.30 Tumor response Tumor dimensions were measured with callipers in two or three directions. From these dimensions the tumor surface area or volume was calculated. Tumor dimensions were measured before each treatment session and at intervals of 1 or 2 months following the end of the treatment. Tumor response was determined using the WHO criteria. ” In summary these comprise: 1. Progression: an increase in tumor volume of more than 25%; 2. No change (NC): less than 50% decrease and less than 25% increase in tumor volume; 3. Partial response (PR): at least 50% decrease in tumor volume; 4. Complete response (CR): total disappearance of the tumor. Response means partial or complete regression observed for a duration of at least 1 month. Duration of response was not evaluable in a number of patients as they were lost to follow-up for local disease, for example due to the start of systemic therapy, or to the death of the patient following tumor progression elsewhere in the body. Skin reaction The acute skin reaction was scored according to the schedule given by Catterall et aL4 Skin reaction was observed before each hyperthermia session and after 1 month following the end of the treatment series. The reaction was scored as follows: 0: no visible reaction; 0.5 in addition to scores l-3: dry desquamation: 1: slight erythema; 2: moderate erythema;
December 1988, Volume 15, Number 6
3: severe erythema (deep red or pink); 4: first sign of breakdown; 5: definite moist desquamation < 50% of the field; 6: moist desquamation > 50% of the field: 7: complete breakdown of the field. Evaluation of late radiation damage was not possible in most patients, since only 19 patients survived more than 2 years. Statistics The increase in reirradiation dose over the years made it possible to evaluate the results for two groups of patients. that is, the group that received a “low dose” (~29 Gy and on the average 5.9 heat treatments) and the group that received a “high dose” (>29 Gy combined with on the average 7.7 heat treatments). Differences in patient-, patient history- and tumor characteristics were checked with Student-T and Fisher’s exact tests.
RESULTS The combined treatment resulted in the total group of patients in 35% complete response and 55% partial response (Table 4). In the remaining 10% of patients no change was observed; in none of the patients the tumor was progressive. Duration of response was 2-6 months for no change (median 3 months), l-9 months for partial response (median 4 months) and l-70+ months for complete response (median 26 months). In many patients the follow-up period ended before local tumor progression occurred. The total survival time for the whole group of patients ranged from 3 to 7 1+ months, with a median of 12 months. Acute skin reaction varied from a score of 0.5 to maximum 4 in the total group of patients (Table 5). More than moderate erythema was found in only 14/97 patients. Thermal burns occurred in 44/97 patients. In 6 patients, these were very small and healed within 1 month. In 33 patients 2nd degree burns (blisters) had developed as a consequence of the heat treatment and these healed in on the average 2.4 (range l-5) months. In 5 other patients, deeper, 3rd degree burns had developed which needed on the average 6.8 (range 3-9) months to heal. These 3rd degree burns were, if necessary, treated
Table 4. Tumor
“Low dose” (n = 66) “High dose” (n = 3 1) Overall
resnonse
NC%
PR %
12 6 10
64
24
35 55
58 35
Median duration of response: NC = 3 months; CR = 26 months. Median overall survival: I2 months. NC = No change; PR = Partial response; response.
CR%
months; PR = 4 CR = Complete
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with locally applied sulfadiazine (Flammazine@). Burns generally (in 87% of the cases) developed at sites where scar tissue resulted from previous surgery. Third degree bums always developed in scar tissue and never when a water bolus system was used for surface cooling. The results achieved with the patients who had received a “high dose” were compared with those achieved with the patients who had received a “low dose” combination therapy. Patient- and history-characteristics did not show significant differences between these two groups, except for the number of systemic treatments previously received (i.e. on the average 3 in the “low dose” group and 2 in the “high dose” group). There was a significantly higher number of tumors smaller than 0.5 cm3 in the “high dose” group, i.e. 6/3 1 versus 2/66 in the “low dose” group (Fisher’s exact, 2p 0.012) (Table 6). A summary of radiotherapy dose and schedule for both groups is given in Table 3. The patients in the “high dose” group received an average of 7.7 heat treatments, whereas the patients in the “low dose” group received 5.9 heat treatments. There was no difference between the both groups in hyperthermia dose, as represented by the mean ofthe maximum temperatures achieved (the mean ofthe maximum temperature values observed at all measuring sites during all hyperthermia sessions). The complete response rate was considerably higher in the “high dose” combination therapy group: it had increased from 24 to 58% (Table 4). This difference was still significant (Fisher’s exact, 2p 0.012) when the tumors with the smallest volume were excluded from the comparison (Table 6). In both groups the complete response rate decreased with increasing tumor volume (Table 6). With the schedule 8 X (4 Gy + hyperthermia) the complete response rate was 6 1%. No difference in acute skin reaction was observed and there was also no increase in the incidence of acute thermal damage with an increasing number of hyperthermia treatments (Table 5). In the 19 patients who survived more than 2 years, no indication of late radiation damage to skin or bone was observed.
Table 5. Toxicity “Low dose” n = 66
Acute skin reaction O-3.5 “mean” 1.35 a3.0
n = 9
n= 3 Burns: Minor 2nd degree n = 22 3rd degree n = 3
138%
“High dose” n = 3 1 Acute skin reaction O-4.0 “mean” 1.40 a3.0 n = 5 Burns: Minor n= 3 2nd degree n = 11 3rd degree n = 2
142%
Table 6. Complete response rate in relation to tumor volume Complete response rate
Tumor volume CO.5 cm3 0.5-l 5 cm3 15-65 cm3 a65 cm3 aO.5 cm3
“Low dose” group l/2 9128 5126 l/l0
50% 32% 19% 10%
15164
23%
“High dose” group 516 9/l 1 3110 l/4 13125
83% 82% 30% 25% 52%
DISCUSSION
The overall response rate of 90%, including 35% complete response, obtained with radiation doses of only 832 Gy, is an indication of the effectiveness of additional hyperthermia. Radiotherapy doses as low as used in this study are expected to give a very low response rate, especially in this situation of reirradiation and with regard to the relatively large tumor volumes. Literature on the effectiveness of radiotherapy for locoregional breast cancer recurrences usually reports higher doses. Bedwinek et ~1.~demonstrated the importance of the radiation dose in achieving local control of breast cancer recurrences. For small lesions (< 1 cm diameter: equivalent to a tumor with a volume of ~0.5 cm3), a total dose of at least 55 Gy is needed to reach 100% local control, for lesions of l-3 cm diameter (equivalent to lesions with a volume ranging from 0.5 to 15 cm3) a dose of 60 Gy is required and for lesions > 3 cm diameter, a dose of 65 Gy. In a more recent paper on the results of radiotherapy for breast cancer recurrences, Bedwinek et ~1.~ report that the rate ofin-field persistence or regrowth was 76% if the total tumor dose was less than 45 Gy. Horwich’ describes the results achieved in 18 patients who were treated for chest wall or regional recurrences with radiotherapy doses “lower than the standard dose” of 1770 ret (equivalent to 30 X 2 Gy in 6 weeks). In these patients he observed only 17% complete response and 44% partial response. Laramore et al. l3 report to have achieved complete response in 1 l/ 13 (85%) chest wall recurrences treated with reirradiation at doses of 36-60 Gy. Unfortunately, they give no information on tumor volumes or extension of the recurrences. Furthermore, their results may have been influenced by the administration of chemotherapeutic and/or hormonal therapy during and following radiotherapy. It is difficult to compare the results mentioned above with our results, as these data concern mostly patients treated with a first series of radiotherapy, and the fractionation schedule applied generally was conventional, that is, fractions of 2 to 3 Gy five times weekly. In our own experience with a subgroup of the patients evaluated in this study, the complete response rate obtained with radiotherapy alone with doses of 20-24 Gy was 7% (l/ 15), and with doses of 30-36 Gy, this was 20% (2/ 10). In
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the 20-24 Gy group, the fractionation schedule had been 4 Gy twice weekly in 11 cases, 4 Gy 5 times weekly in 1 case, 2.5 Gy 4 times weekly in 2 cases and 3 Gy twice weekly in 1 case, respectively. The one complete response observed was following 6 X 4 Gy in 3 weeks. In the 30-36 Gy group, the fractionation schedule had been 3 Gy 5 times weekly in 8 cases and 4 Gy twice weekly in 2 cases, respectively. The two complete responses in the 30-36 Gy alone group were achieved with the 10 X 3 Gy schedule (2/8; 25%). The recently reported results on the RTOG 8 l-4 study22 includes data which may be comparable to ours. In the group of patients with breast/adenocarcinoma, the complete response rate following radiotherapy alone, 8 X 4 Gy in 4 weeks, was 33% (13139). This rate is significantly lower than the 6 1% that was achieved with the combined treatment in our patient group (Fisher’s exact test, 2p = 0.014). Furthermore, a recent report by Lindholm et al.” shows a complete response rate of 35% (6/ 17) following 10 X 3 Gy in 2 weeks in patients with breast cancer, which is similar to the 25% observed by us with the same radiotherapy alone. An increase in complete response rate by the addition of hyperthermia to radiotherapy has been observed in a number of comparative, non randomized, “matched lesion” studies (Table 1). The method of choice to demonstrate the effectiveness of hyperthermia is of course a randomized prospective comparative study. For head and neck tumors, such a study has shown an increased complete response rate (82% versus 37%) by adding hyperthermia to radiotherapy. 28The execution of such a study in the category of patients described in this report however, has been hampered by the consideration that it is unethical to withhold a promising treatment from individual patients who are in the need of palliation. Reirradiation was not considered to be of any use for the patients concerned before the radiotherapy plus hyperthermia schedule was introduced, whereas with the combined treatment of 8 X 4 Gy plus hyperthermia, a complete response rate of 6 1% has been achieved. However, the results of the RTOG 8 l-4 study,22 which unfortunately failed to show a significant improvement in therapeutic outcome by the addition of hyperthermia to radiotherapy, have revived the discussion. This has now resulted in the decision to start a comparative study, to prove the supposed therapeutic benefit of additive hyperthermia. The palliative effect of the combined treatment has been found especially worthwhile when a complete response is achieved, which is then maintained for a median period of 26 months. The increase in the probability of complete response from 24 to 58% without increased acute skin toxicity by increasing the reirradiation dose from on the average 22.3 Gy to 3 1.8 Gy plus hyperther-
December 1988. Volume 15, Number 6
mia is therefore important. The increase in complete response rate with the higher radiotherapy dose is not surprising, as the relation between radiotherapy dose and response chance is well known. The absolute level of response rate however appears to be determined by the addition of hyperthermia to radiotherapy, as discussed above. The relatively higher number of tumors smaller than 0.5 cm3 in the “high dose” group does not exclusively account for this difference, as the difference still remains significant (Fisher’s exact test 2p = 0.0 12) after exclusion of these tumors from the comparison. The acute skin reaction was mild, with more than moderate erythema in only 14/97 patients. It was possible to compare the acute skin reaction following radiotherapy alone and radiotherapy combined with hyperthermia in those patients (n = 28) in whom the radiotherapy field was somewhat larger than the hyperthermia field. In none of these cases the score for skin reaction was higher in the combined treated field. This absence of thermal enhancement of skin reaction may be caused by the lower skin temperature, resulting from the higher blood flow in the skin and/or the use of skin cooling, but also to the time interval between the radiotherapy and hyperthermia treatment, as maximum thermal enhancement of radiotherapy is only achieved with true simultaneous treatment.” Thermal burns occurred in a relatively large number of patients. Burns generally developed at sites where scar tissue resulted as a consequence of previous surgery. In scar tissue the blood flow is reduced, which increases the risk of a hot spot by local electromagnetic heating and may also cause an increased thermal sensitivity by the induction of hypoxia. Moreover, a hot spot may not be signalled by the patient as pain sensation is often reduced due to the scar. Although, the absence of pain sensation makes the inconvenience due to the burn minimal in most patients, and therefore, the quality of life is not significantly affected. Even in the patients in whom a 3rd degree burn had developed, the ulceration caused few symptoms, the only treatment required was local application of sulfadiazine. We conclude that: (a) reirradiation with a dose schedule of 8 X 4 Gy in 4 weeks combined with hyperthermia can be given without causing severe toxicity; (b) hyperthermia combined with low dose radiotherapy provides a satisfactory palliative treatment for patients with breast cancer recurring in previously irradiated areas; and (c) increasing the radiotherapy dose from 24 to 32 Gy considerably improves the results without significantly increasing toxicity. Although these results strongly indicate that hyperthermia in addition to radiotherapy does improve therapeutic results, only a prospective randomized comparative study can prove this. Such a study has been started recently within our institute.
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9th meeting of the European Society for Hyperthermic Oncology, 1987. Miller, A.B., Hoogstraten, B., Staquet, M., Winkler. A.: Reporting results of cancer treatment. Cancer 47: 207214, 1981. Overgaard, J.: Effect of hyperthermia on malignant cells in vivo. Cancer 39: 2637-2646, 1977. Overgaard, J.: Simultaneous and sequential hyperthermia and radiation treatment of an experimental tumor and its surrounding normal tissue in vivo. Int. J. Radiat. Oncol. Biol. Phys. 6: 1507-1517, 1980. Overgaard, J.: Importance of true simultaneous treatment for maximal hyperthermic radiosensitization. Znt. J. Hyperther. 3: 584-585, 1987. Overgaard, J., Overgaard, M.: Hyperthermia as an adjuvant to radiotherapy in the treatment of malignant melanoma. Int. J. Hyperther. 3: 483-501, 1987. Perez, C.A.. Gillespie, B.. Hornback, N.. Emami, B., Moylan, D.. Baerwald, W.H., Seegenschmiedt, M.H., Bauer, M., Pakuris. E.: Difficulties in assessing therapeutic results of clinical hyperthermia in an RTOG trial. Int. J. Radiat. Oncol. Biol. Phya. 13: 164, 1987. Reinhold, H.S., Endrich, B.: Tumour microcirculation as a target for hyperthermia. Int. J. Hyperther. 2: 11 l- 137. 1986. Scott, R.S., Johnson, R.J.R., Kowal, H.. Krishnamsetty, R.M., Story, K., Clay, L.: Hyperthermia in combination with radiotherapy: A review of five years experience in the treatment of superficial tumors. Int. J. Rudiat. Oncol. Biol. Phys. 9: 1327-1333, 1983. Song, C.W., Rhee, J.G., Levitt, S.H.: Blood flow in normal tissues and tumors during hyperthermia. J. Nat/. Cancer Inst. 64: 119-124, 1980. Stewart, J.R., Gibbs, F.A.: Hyperthermia in the treatment of cancer. Cancer 54: 2823-2830. 1984. U, R., Noell, K.T., Woodward, K.T.. Worde, B.T., Fishburn, R.I., Miller, L.S.: Microwave-induced local hyperthermia in combination with radiotherapy of human malignant tumors. Cuncer 45: 638-646, 1980. Valdagni. R., Amichetti. M., Pani, G., Ambrosini, G.: A prospective randomized clinical trial of radical irradiation alone versus radical irradiation combined with hyperthermia in the treatment of N3 metastatic neck nodes: preliminary results (Abstr.). Int. J. Hyperther. 2: 4 1 1, 1986. Wike-Hooley, J.L., Haveman, J., Reinhold, H.S.: The relevance oftumour pH to the treatment of malignant disease. Radiother. Oncol. 2: 343-366, 1984. Zee, J. van der. Putten. W.L.J. van, Berg, A.P. van den, Rhoon, G.C. van, Wike-Hooley. J.L., Broekmeyer-Reurink, M.P., Reinhold, H.S.: Retrospective analysis of the response of tumours in patients treated with a combination of radiotherapy and hyperthermia. Int. J. Hyperther. 2: 337-349. 1986. Zee, J. van der, Rhoon, G.C. van, Wike-Hooley, J.L., Reinhold, H.S.: Clinically derived dose effect relationship for hyperthermia given in combination with low dose radiotherapy. Br. J. Rudiol. 58: 243-250. 1985. Zee. J. van der, Rhoon, G.C. van, Broekmeyer-Reurink, M.P., Reinhold, H.S.: The use of implanted closed-tip catheters for the introduction of thermometrv orobes during local hyperthermia treatment series. Int. J.‘Hyperther. 3: 337-345, 1987.
IS,pp.1407-
0360-3016/88 53.00 + 00 copyright 0 1988 Pergamon Press PIG
14 I3
??Original Contribution
LOW DOSE REIRRADIATION IN COMBINATION WITH HYPERTHERMIA: PALLIATIVE TREATMENT FOR PATIENTS WITH BREAST CANCER RECURRING IN PREVIOUSLY IRRADIATED AREAS J. VAN DER ZEE, M.D., PH.D.,’ A. D. TREURNIET-DONKER, M.D.,2 S. K. P. A. HELLE, M.D.,2 J. J. SELDENRATH, M.D.,2 J. H. MEERWALDT, A. J. WIJNMAALEN, M.D.,* A. P. VAN DEN BERG, PH.D.,~ G. C. VAN M. P. BROEKMEYER-REURINK’ AND H. S. REINHOLD, M.D.,
A
THE, M.D., PH.D.,~ M.D., PH.D.,~ RHOON, B.Sc.,’ PH.D.~,~
‘Dept. of Hyperthermia, ‘Dept. of Radiotherapy, The Dr. Daniel den Hoed Cancer Center, Rotterdam Radio-Therapy Institute, Rotterdam; 3Dept. of Experimental Radiotherapy, Erasmus University, Rotterdam; and 4Radio-Biological Institute, TN0 Rijswijk, The Netherlands Ninety-seven patients with breast cancer recurring in a previously irradiated area (mean dose 44 Gy) were reirradiated in combination with hyperthermia and had evaluable tumor responses. In the reirradiation series, radiotherapy was given twice weekly in most patients, with a fraction size varying from 200 to 400 cGy, the total dose varying from 8 to 32 Gy. Hyperthermia was given following the radiotherapy fractions. The combined treatment resulted in 35% complete and 55% partial responses. Duration of response was median 4 months for partial response and 26 months for complete response, respectively. The median survival time for all patients was 12 months. Acute skin reaction was mild, with more than moderate erythema in only 14/97 patients. Thermal burns occurred in 44/97 patients, generally at sites where pain sensation was decreased, and therefore they did not cause much inconvenience. In the 19 patients who survived more than 2 years, no late radiation damage was observed. When patients who received a “high dose” (>29 Gy and hyperthermia) were compared with those who received a “low dose” (~29 Gy and hyperthermia), a higher complete response rate was observed in the high dose group (58% vs. 24%), whereas no difference in acute toxicity was found. We conclude that reirradiation with 8 X 4 Gy in combination with hyperthermia twice weekly is a safe, effective and well tolerated method for palliative treatment of patients with breast cancer recurring in previously irradiated areas. Breast cancer, Reirradiation, Hyperthermia,
Local recurrence.
INTRODUCTION
apy Institute, patients with tumor recurrences in previously irradiated areas were seldomly treated with reirradiation before 1979. In 1979 techniques for the induction of local hyperthermia were developed and by that this study was started. Hyperthermia is presently considered to be a valuable supplement to the established treatment modalities in cancer therapy. Laboratory data indicate that combination with radiotherapy is very effective. Various nonrandomized clinical matched lesion studies have indeed consistently shown an increased complete response rate when hyperthermia was added to radiotherapy (Table 1). Hyperthermia has both additional and enhancing effects upon radiotherapy, which are at least partly tumor selective. The subject has been extensively reviewed.5y7326It
Locoregional recurrences of breast carcinoma cause symptoms that markedly impair the quality of life, without being life threatening at short term. Local treatment is considered worthwhile, either in addition to systemic therapy or alone. When local excision is not possible, radiotherapy is the treatment of choice. When tumor progression occurs in a previously irradiated area, the possibilities of radiotherapy are limited. Generally, reirradiation is not considered appropriate for various reasons: (a) the dose to be given is limited by the normal tissue’s tolerance and (b) fibrotic changes resulting from the previous irradiation induce hypoxia, which reduces radiosensitivity. In the Rotterdam Radio-Ther-
Reprint requests to: J. van der Zee, Dept. of Hyperthermia, Rotterdam Radio-Therapy Institute, Groene Hilledijk 30 1, 3075 EA Rotterdam, The Netherlands. Acknowledgements-This study was financially supported by
the Netherlands Cancer Foundation “Koningin Fonds”, grants nos EUR 77-4 and RRTI 83-4. Accepted for publication 29 June 1988. 1407
Wilhelmina
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Table 1. Comparison
radiotherapy
December 1988, Volume 15,Number 6
vs. radiotherapy
+ hyperthermia
in matched lesions
Complete response chance following treatment with Reference
Tumor histology
11 27 12 24 1 14 8 21 16 15 10
Various* Various Malignant melanoma-i Various? Various Various? Malignant melanoma Malignant melanoma Various Various? Various
All authors
RT
RT+HT
7128 l/7 25154 12/31 28174 913 1 317 2110 7160 7128 712 1
25% 14% 46% 39% 38% 29% 43% 20% 12% 25% 33%
23132 617 31145 2713 1 66189 21/31 8/10 1 l/15 24 160 16128 9114
72%$ 86%$ 69%$ 87%$ 74%$ 68%$ 80% 73%$ 40%$ 57%$ 64%
108135 1
31%
2421362
67%
* Malignant melanoma excluded. t Large tumors combined treatment; small tumors radiotherapy alone. $ Significant difference (Fisher’s exact test 2p < 0.05). Note: Various authors have compared the results of radiotherapy alone (RT) with those of radiotherapy (same dose) combined with hyperthermia (RT + HT) in “matched lesions”: two or more tumors from the same origin within one patient. All authors found an increased complete response rate following the combined treatment. A summation of all data shows about a doubling of the complete response rate when radiotherapy is combined with hyperthermia.
is generally assumed that tumors contain areas with a relatively low blood flow. 6,23With increasing temperature this blood flow does not increase to the same extent as in normal tissues. 25When external heating is applied, the lower bloodflow in tumors will result in a higher temperature increase in tumor tissue than in normal tissue, as the local cooling depends mainly on tissue blood flow. Because of environmental factors (hypoxia, low pH, and low nutrient levels), 18,29tumor tissue is more sensitive to hyperthermia than normal tissue. Furthermore, the radiosensitizing effect of hyperthermia decays more slowly in tumor tissue than in normal tissue.” For these reasons the addition of local hyperthermia to radiotherapy is expected to yield a higher therapeutic ratio. This promising experimental background, the availability of techniques for induction of superficial local hyperthermia, and the lack of local treatment possibilities in the patient group described above, lead to the decision to start treatment with low dose reirradiation in combination with hyperthermia in this patient group. In the first period, most patients had been treated previously with all variations of local and systemic treatment possibilities available but when it became clear that the local results of the combined treatment are worthwhile, patients were referred at a somewhat earlier stage of their disease. This report describes the results obtained in the first 97 patients treated and in whom tumor response was evaluable. METHODS
AND MATERIALS
In the period October 1979 to July 1986, 122 patients with breast cancer recurring in a previously irradiated
area were treated with a low dose of radiotherapy in combination with hyperthermia. In 25 patients, tumor response was not evaluable as systemic therapy was started shortly after the end of the treatment series for tumor progression elsewhere in the body, or to loss to followup due to worsening of their general condition. The 97 patients with evaluable tumor response, 95 females and 2 males, aged 3 l-92, mean 6 1, years, were known to have cancer since 7 months to 17 years, with a mean duration of disease of 5 years. Most patients were in a good general condition, with Karnofsky indices of 100 (n = 74), 90 (n = 18) or 80 (n = 4), with only 1 patient having a Karnofsky index of 50. Most patients had been previously treated extensively by other modalities (Table 2). Fifty-four of the 97 patients were known to have metastatic disease on localizations outside the field treated by reirradiation with hyperthermia. During the reirradiation series, no systemic treatment was given, except to 6 patients who had received hormonal therapy for 1 month to more than 2 years (mean 9 months) with the tumor in the treatment area showing progression or stable disease. In these patients hormonal treatment was continued because of a good reaction (stable disease or response) of tumor lesions elsewhere in the body. Tumors
Malignancy was established in all patients by cytological or histological examination. Tumor histologic differentiation was known for 54/97 patients. Tumors were well or moderately differentiated in 6 patients, and poorly-or undifferentiated in 26 and 22 patients, respectively. Tumor recurrences were localized cutaneously or subcutaneously on the chest wall in 76 patients, within regional lymphnodes in 11 patients, within the
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Results of reirradiation and hyperthermia 0 J. VAN DER ZEE etal.
77 cases. Previous irradiation had been given to the whole area in 76 patients, and to part of the area in 21 patients.
Table 2. Patient and tumor characteristics Patients 1979- 1986: 971122 patients evaluable for response Age 3 l-92, mean 6 1 years Duration of disease 7 months- 17 years, mean 5 years Previous systemic therapy 84197
Radiotherapy
Radiotherapy was given twice weekly, with each hyperthermia treatment, in 92/97 patients. Three, 4, or 5 radiation fractions each week were given in 1, 2, and 2 patients respectively. When the twice weekly-schedule was used, the fraction size was 400 cGy. In 90 patients electrons were used with an energy of on the average 10 MeV. Characteristics of previous irradiation and reirradiation are given in Tables 2 and 3. In the period October 1979 to August 1983, the reirradiation schedule for most patients was 6 X 4 Gy (n = 38). When no serious toxicity was observed, the treatment dose was increased to 8 X 4 Gy (n = 28).
Tumors Location (Sub-) cutaneously chest wall Regional lymphnodes Within breast Other Previous surgery same location Previous radiotherapy
76 11 6 4
77/97
same location
Total dose (Gy) Fraction size (cGy) Time interval with reirradiation (months)
Range
Mean
15-76 180-400
44 260
l-203
48
Hyperthermia
Tumor volume 0. I - 175 1 cm3, mean 64.6 cm3 CO.5 cm3 n= 8 0.5-15 cm3 n = 39 15-65 cm3 n = 36 a-65 cm3 n= 14
Hyperthermia was given twice weekly to avoid maximum thermotolerance, following radiotherapy with a mean time interval of 40 (range 20-90) minutes. Hyperthermia was induced non-invasively, using 27, 433 or 2450 MHz electromagnetic radiation, depending on tumor dimensions and depth. In 7 patients a combination of two of these frequencies was used, to achieve optimal heating in a minimum number of applications. Technical details have been presented in a previous paper.31 A typical hyperthermia treatment consisted of 60 minutes (generator time) up to the maximum tolerated temperature which was either indicated by the patient or by a temperature measurement within normal tissue exceeding 43°C. Surface cooling was performed in cases where healthy skin covered the tumor or at sites where hot spots
in 6 patients and at various other sites in 4 patients. Tumor volumes at the start of therapy ranged from 0.1 to 175 1 cm3 with an average value of 64.6 cm3 (Table 2). In those patients where the recurrence consisted of multiple lesions, the size of the largest nodule was used to calculate the tumor volume. This was the case in 3 l/47 patients with a tumor volume smaller than 15 cm3 and in 17/50 patients with larger tumors. The area treated had been subjected to surgery in the past in
breast
Table 3. Treatment
characteristics Range
Mean
SEM
8-28 200-400 40-96 35-738 l-10 39.3-45.0
22.3 365 66.7 221 5.9 42.2
0.45 8.0 1.14 21 0.17 0.16
31.8 390 75.6 176 7.7 42.0
0.10 5.4 1.56 21 0.23 0.25
“Low dose” n = 66 Radiotherapy total dose (Gy) Fraction size (cGy) Cumulative total dose (Gy) Field size (cm2) Hyperthermia number of treatments Tmaxmean (“C) Radiotherapy schedule 5~4Gy 6X4G; 7~4Gy other
n= 7 n=38 n= 3
I 63166
2 fr/wk
n= 18
“High dose” n = 3 1 Radiotherapy total dose (Gy) Fraction size (cGy) Cumulative total dose (Gy) Field size (cm2) Hyperthermia number of treatments Tmaxmean (“C) Radiotherapy schedule 8X4Gy lOX3Gy
30-32 300-400 47-90 30-432 2-10 39.7-44.8 n=28 n= 3
I
2913 1 2 frfwk
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occurred. Cooling was achieved using small water blankets or by directing a current of cool air. In cases where it was not possible to heat the entire tumor area with a single set of applicators, the area was divided into two or more sub-areas which were heated successively. A total treatment time of 120 minutes, considered to be the maximum tolerable for most patients, was not exceeded. When more than two fields were heated (in 8 patients), the treatment duration per field was therefore proportionally reduced. Thermometry was performed at 1 to 15 intratumoral sites and in most patients surface temperature measurements were carried out as well. The thermometry systems used have been described elsewhere.3’ In addition to thermocouple single point needles, probes with 3 to 5 measuring points within closed tip catheters (outer diameter 1.22 mm)32 were used. With the temperatures measured during each hyperthermia treatment calculations were performed by using a computer program in order to get representative values for the hyperthermia dose. This procedure has been described in detail in a previous paper.30 Tumor response Tumor dimensions were measured with callipers in two or three directions. From these dimensions the tumor surface area or volume was calculated. Tumor dimensions were measured before each treatment session and at intervals of 1 or 2 months following the end of the treatment. Tumor response was determined using the WHO criteria. ” In summary these comprise: 1. Progression: an increase in tumor volume of more than 25%; 2. No change (NC): less than 50% decrease and less than 25% increase in tumor volume; 3. Partial response (PR): at least 50% decrease in tumor volume; 4. Complete response (CR): total disappearance of the tumor. Response means partial or complete regression observed for a duration of at least 1 month. Duration of response was not evaluable in a number of patients as they were lost to follow-up for local disease, for example due to the start of systemic therapy, or to the death of the patient following tumor progression elsewhere in the body. Skin reaction The acute skin reaction was scored according to the schedule given by Catterall et aL4 Skin reaction was observed before each hyperthermia session and after 1 month following the end of the treatment series. The reaction was scored as follows: 0: no visible reaction; 0.5 in addition to scores l-3: dry desquamation: 1: slight erythema; 2: moderate erythema;
December 1988, Volume 15, Number 6
3: severe erythema (deep red or pink); 4: first sign of breakdown; 5: definite moist desquamation < 50% of the field; 6: moist desquamation > 50% of the field: 7: complete breakdown of the field. Evaluation of late radiation damage was not possible in most patients, since only 19 patients survived more than 2 years. Statistics The increase in reirradiation dose over the years made it possible to evaluate the results for two groups of patients. that is, the group that received a “low dose” (~29 Gy and on the average 5.9 heat treatments) and the group that received a “high dose” (>29 Gy combined with on the average 7.7 heat treatments). Differences in patient-, patient history- and tumor characteristics were checked with Student-T and Fisher’s exact tests.
RESULTS The combined treatment resulted in the total group of patients in 35% complete response and 55% partial response (Table 4). In the remaining 10% of patients no change was observed; in none of the patients the tumor was progressive. Duration of response was 2-6 months for no change (median 3 months), l-9 months for partial response (median 4 months) and l-70+ months for complete response (median 26 months). In many patients the follow-up period ended before local tumor progression occurred. The total survival time for the whole group of patients ranged from 3 to 7 1+ months, with a median of 12 months. Acute skin reaction varied from a score of 0.5 to maximum 4 in the total group of patients (Table 5). More than moderate erythema was found in only 14/97 patients. Thermal burns occurred in 44/97 patients. In 6 patients, these were very small and healed within 1 month. In 33 patients 2nd degree burns (blisters) had developed as a consequence of the heat treatment and these healed in on the average 2.4 (range l-5) months. In 5 other patients, deeper, 3rd degree burns had developed which needed on the average 6.8 (range 3-9) months to heal. These 3rd degree burns were, if necessary, treated
Table 4. Tumor
“Low dose” (n = 66) “High dose” (n = 3 1) Overall
resnonse
NC%
PR %
12 6 10
64
24
35 55
58 35
Median duration of response: NC = 3 months; CR = 26 months. Median overall survival: I2 months. NC = No change; PR = Partial response; response.
CR%
months; PR = 4 CR = Complete
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Results of reirradiation and hyperthermia 0 .I. VAN DER ZEE ef al.
with locally applied sulfadiazine (Flammazine@). Burns generally (in 87% of the cases) developed at sites where scar tissue resulted from previous surgery. Third degree bums always developed in scar tissue and never when a water bolus system was used for surface cooling. The results achieved with the patients who had received a “high dose” were compared with those achieved with the patients who had received a “low dose” combination therapy. Patient- and history-characteristics did not show significant differences between these two groups, except for the number of systemic treatments previously received (i.e. on the average 3 in the “low dose” group and 2 in the “high dose” group). There was a significantly higher number of tumors smaller than 0.5 cm3 in the “high dose” group, i.e. 6/3 1 versus 2/66 in the “low dose” group (Fisher’s exact, 2p 0.012) (Table 6). A summary of radiotherapy dose and schedule for both groups is given in Table 3. The patients in the “high dose” group received an average of 7.7 heat treatments, whereas the patients in the “low dose” group received 5.9 heat treatments. There was no difference between the both groups in hyperthermia dose, as represented by the mean ofthe maximum temperatures achieved (the mean ofthe maximum temperature values observed at all measuring sites during all hyperthermia sessions). The complete response rate was considerably higher in the “high dose” combination therapy group: it had increased from 24 to 58% (Table 4). This difference was still significant (Fisher’s exact, 2p 0.012) when the tumors with the smallest volume were excluded from the comparison (Table 6). In both groups the complete response rate decreased with increasing tumor volume (Table 6). With the schedule 8 X (4 Gy + hyperthermia) the complete response rate was 6 1%. No difference in acute skin reaction was observed and there was also no increase in the incidence of acute thermal damage with an increasing number of hyperthermia treatments (Table 5). In the 19 patients who survived more than 2 years, no indication of late radiation damage to skin or bone was observed.
Table 5. Toxicity “Low dose” n = 66
Acute skin reaction O-3.5 “mean” 1.35 a3.0
n = 9
n= 3 Burns: Minor 2nd degree n = 22 3rd degree n = 3
138%
“High dose” n = 3 1 Acute skin reaction O-4.0 “mean” 1.40 a3.0 n = 5 Burns: Minor n= 3 2nd degree n = 11 3rd degree n = 2
142%
Table 6. Complete response rate in relation to tumor volume Complete response rate
Tumor volume CO.5 cm3 0.5-l 5 cm3 15-65 cm3 a65 cm3 aO.5 cm3
“Low dose” group l/2 9128 5126 l/l0
50% 32% 19% 10%
15164
23%
“High dose” group 516 9/l 1 3110 l/4 13125
83% 82% 30% 25% 52%
DISCUSSION
The overall response rate of 90%, including 35% complete response, obtained with radiation doses of only 832 Gy, is an indication of the effectiveness of additional hyperthermia. Radiotherapy doses as low as used in this study are expected to give a very low response rate, especially in this situation of reirradiation and with regard to the relatively large tumor volumes. Literature on the effectiveness of radiotherapy for locoregional breast cancer recurrences usually reports higher doses. Bedwinek et ~1.~demonstrated the importance of the radiation dose in achieving local control of breast cancer recurrences. For small lesions (< 1 cm diameter: equivalent to a tumor with a volume of ~0.5 cm3), a total dose of at least 55 Gy is needed to reach 100% local control, for lesions of l-3 cm diameter (equivalent to lesions with a volume ranging from 0.5 to 15 cm3) a dose of 60 Gy is required and for lesions > 3 cm diameter, a dose of 65 Gy. In a more recent paper on the results of radiotherapy for breast cancer recurrences, Bedwinek et ~1.~ report that the rate ofin-field persistence or regrowth was 76% if the total tumor dose was less than 45 Gy. Horwich’ describes the results achieved in 18 patients who were treated for chest wall or regional recurrences with radiotherapy doses “lower than the standard dose” of 1770 ret (equivalent to 30 X 2 Gy in 6 weeks). In these patients he observed only 17% complete response and 44% partial response. Laramore et al. l3 report to have achieved complete response in 1 l/ 13 (85%) chest wall recurrences treated with reirradiation at doses of 36-60 Gy. Unfortunately, they give no information on tumor volumes or extension of the recurrences. Furthermore, their results may have been influenced by the administration of chemotherapeutic and/or hormonal therapy during and following radiotherapy. It is difficult to compare the results mentioned above with our results, as these data concern mostly patients treated with a first series of radiotherapy, and the fractionation schedule applied generally was conventional, that is, fractions of 2 to 3 Gy five times weekly. In our own experience with a subgroup of the patients evaluated in this study, the complete response rate obtained with radiotherapy alone with doses of 20-24 Gy was 7% (l/ 15), and with doses of 30-36 Gy, this was 20% (2/ 10). In
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the 20-24 Gy group, the fractionation schedule had been 4 Gy twice weekly in 11 cases, 4 Gy 5 times weekly in 1 case, 2.5 Gy 4 times weekly in 2 cases and 3 Gy twice weekly in 1 case, respectively. The one complete response observed was following 6 X 4 Gy in 3 weeks. In the 30-36 Gy group, the fractionation schedule had been 3 Gy 5 times weekly in 8 cases and 4 Gy twice weekly in 2 cases, respectively. The two complete responses in the 30-36 Gy alone group were achieved with the 10 X 3 Gy schedule (2/8; 25%). The recently reported results on the RTOG 8 l-4 study22 includes data which may be comparable to ours. In the group of patients with breast/adenocarcinoma, the complete response rate following radiotherapy alone, 8 X 4 Gy in 4 weeks, was 33% (13139). This rate is significantly lower than the 6 1% that was achieved with the combined treatment in our patient group (Fisher’s exact test, 2p = 0.014). Furthermore, a recent report by Lindholm et al.” shows a complete response rate of 35% (6/ 17) following 10 X 3 Gy in 2 weeks in patients with breast cancer, which is similar to the 25% observed by us with the same radiotherapy alone. An increase in complete response rate by the addition of hyperthermia to radiotherapy has been observed in a number of comparative, non randomized, “matched lesion” studies (Table 1). The method of choice to demonstrate the effectiveness of hyperthermia is of course a randomized prospective comparative study. For head and neck tumors, such a study has shown an increased complete response rate (82% versus 37%) by adding hyperthermia to radiotherapy. 28The execution of such a study in the category of patients described in this report however, has been hampered by the consideration that it is unethical to withhold a promising treatment from individual patients who are in the need of palliation. Reirradiation was not considered to be of any use for the patients concerned before the radiotherapy plus hyperthermia schedule was introduced, whereas with the combined treatment of 8 X 4 Gy plus hyperthermia, a complete response rate of 6 1% has been achieved. However, the results of the RTOG 8 l-4 study,22 which unfortunately failed to show a significant improvement in therapeutic outcome by the addition of hyperthermia to radiotherapy, have revived the discussion. This has now resulted in the decision to start a comparative study, to prove the supposed therapeutic benefit of additive hyperthermia. The palliative effect of the combined treatment has been found especially worthwhile when a complete response is achieved, which is then maintained for a median period of 26 months. The increase in the probability of complete response from 24 to 58% without increased acute skin toxicity by increasing the reirradiation dose from on the average 22.3 Gy to 3 1.8 Gy plus hyperther-
December 1988. Volume 15, Number 6
mia is therefore important. The increase in complete response rate with the higher radiotherapy dose is not surprising, as the relation between radiotherapy dose and response chance is well known. The absolute level of response rate however appears to be determined by the addition of hyperthermia to radiotherapy, as discussed above. The relatively higher number of tumors smaller than 0.5 cm3 in the “high dose” group does not exclusively account for this difference, as the difference still remains significant (Fisher’s exact test 2p = 0.0 12) after exclusion of these tumors from the comparison. The acute skin reaction was mild, with more than moderate erythema in only 14/97 patients. It was possible to compare the acute skin reaction following radiotherapy alone and radiotherapy combined with hyperthermia in those patients (n = 28) in whom the radiotherapy field was somewhat larger than the hyperthermia field. In none of these cases the score for skin reaction was higher in the combined treated field. This absence of thermal enhancement of skin reaction may be caused by the lower skin temperature, resulting from the higher blood flow in the skin and/or the use of skin cooling, but also to the time interval between the radiotherapy and hyperthermia treatment, as maximum thermal enhancement of radiotherapy is only achieved with true simultaneous treatment.” Thermal burns occurred in a relatively large number of patients. Burns generally developed at sites where scar tissue resulted as a consequence of previous surgery. In scar tissue the blood flow is reduced, which increases the risk of a hot spot by local electromagnetic heating and may also cause an increased thermal sensitivity by the induction of hypoxia. Moreover, a hot spot may not be signalled by the patient as pain sensation is often reduced due to the scar. Although, the absence of pain sensation makes the inconvenience due to the burn minimal in most patients, and therefore, the quality of life is not significantly affected. Even in the patients in whom a 3rd degree burn had developed, the ulceration caused few symptoms, the only treatment required was local application of sulfadiazine. We conclude that: (a) reirradiation with a dose schedule of 8 X 4 Gy in 4 weeks combined with hyperthermia can be given without causing severe toxicity; (b) hyperthermia combined with low dose radiotherapy provides a satisfactory palliative treatment for patients with breast cancer recurring in previously irradiated areas; and (c) increasing the radiotherapy dose from 24 to 32 Gy considerably improves the results without significantly increasing toxicity. Although these results strongly indicate that hyperthermia in addition to radiotherapy does improve therapeutic results, only a prospective randomized comparative study can prove this. Such a study has been started recently within our institute.
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