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Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors: A prospectively controlled randomized study by the radiation therapy oncology group
Int. J. Radiation
Biol.
Phys., Vol. 34, No. 5, pp. 1097- 1104, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .OO
0360-3016(95)02137-X
ELSEVIER
l
Oncology
Hyperthermia Original Contribution PHASE III STUDY OF INTERSTITIAL THERMORADIOTHERAPY COMPARED WITH INTERSTITIAL RADIOTHERAPY ALONE IN THE TREATMENT OF RECURRENT OR PERSISTENT HUMAN TUMORS: A PROSPECTIVELY CONTROLLED RANDOMIZED STUDY BY THE RADIATION THERAPY ONCOLOGY GROUP BAHMAN EMAMI, M.D., * CHARLES SCOTT, PH.D., ’ CARLOS A. PEREZ, M.D., * SUCHA ASBELL, M.D., * PATRICK SWIFT, M.D., g PERRY GRIGSBY, M.D., * ANGELICA MONTESANO, M.D.,’ PHILIP RUBIN, M.D.,l WALTER CURRAN, M.D.,# JOHN DELROWE, M.D., * * HYDER ARASTU, M.D., $ KAREN Fu, M.D.$ AND EDUARDO MOROS, PH.D.* *Radiation Oncology Center, Mallinckrodt Institute of Radiology, WashingtonUniversity School of Medicine, St. Louis, MO, ‘Radiation Therapy Oncology Group, Philadelphia,PA, *Albert EinsteinUniversity, Philadelphia,PA, qUniversity of California San Francisco,San Francisco,CA, %niversity of RochesterMedical Center, Rochester,NY. #Fox ChaseCancerCenter, Philadelphia,PA, * *Montefiore Medical Center, Bronx, NY Purpose: The objectives of this randomized trial were to determine if interstitial thermoradlotherapy (ITRT) improves tumor regression/control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the skin and soft tissue complications with either modality. Methods and Materials: From January 1986 to June 1992,184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstltlal radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG). One hundred seventythree cases were analyzed (87 patients in the IRT group and 86 in the ITRT arm). The two arms were well balanced regarding stratification criteria. Most tumors were in the head and neck (40% in the IRT group and 46% in the ITRT group,) and pelvis (42% and 43%, respectively). Eighty-four percent of patients in both arms had prior radiation therapy (2 40 Gy); 50% and 40%, respectively, had prior surgery, and 34% in each arm had prior chemotherapy. The dose of radiation therapy admhdstered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy. Hyperthermla was delivered in one or two sessions, either before or before and after interstitial implant. The intended goal of the hyperthermia was to maintain a mlnlmal tumor temperature of 425°C for 30 to 60 min. Results: There was no dllerence in any of the study end points between the two arms. Complete response (CR) was 53% and 55% in both arms. Two-year survival was 34% and 35%, respectively. Complete response rate for persistent lesions was 69% and 63% in the two treatment arms as compared with 40% and 48% for recurrent lesions. A set of minimal adequacy criteria for the delivery of hyperthermla was developed. When these criteria were applied, only one patient had an adequate hyperthermla session. Acute Grade 3 and 4 toxicities were 12% for IRT and 22% for ITRT. Late Grade 3 and 4 toxicities were 15% for IRT and 20% for ITRT. The difference was not significant. Conclusions: Interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone. Delivery of hyperthermia remains a major obstacle (since only one patient met the basic minimum adequacy criteria as defined in this study). The benefit of hypertherrmla in addition to radiaton therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved. Interstitial
hyperthermia,
Interstitial
radiotherapy,
Brachytherapy.
INTRODUCTION Hyperthermia in conjunction with radiation therapy has been used in the treatment of recurrent or persistent tu-
mors during the last 2 decades. Numerous single-institution clinical trials have demonstrated promising results (1, 2, 23, 25, 30). Most clinical experience reported in
Reprint requeststo: BahmanEmami,M.D., RadiationOncology Center,4939 Children’sPlace, Suite 5500, St. Louis,
MO 63110. Accepted for publication 11 September1995. 1097
1098
1. J. Radiation Oncology 0 Biology 0 Physics
Table
1. Pretreatment
characteristics
Pretreatment characteristics Lesion size Lesion type Lesion site
Histology
Prior radiation Prior surgery Prior chemotherapy Sex KPSf *IRT = Interstitial
t4 cm 24 cm Recurrent Persistent Head & neck Breast Abdomen Pelvis Extremities Back Other Adenocarcinoma Squamous cell Melanoma Other Unknown <4OGy >40Gy Female Male 90-100 60-80
by protocol
treatment
IRT* (n = 88)
ITRT’ (n = 88)
31 (35%) 57 (65%) 49 (56%) 39(44%) 35 (40%) 3(4%) 2(2%) 37(42%) 1 (1%) 2(2%) 8(9%) 28 (31%) 53 (63%) 4(5%) 2(2%) 1 (1%) 14 (16%) 74 (84%) 44 (50%) 31 (35%) 57 (65%) 31 (35%) 50(57%) 38 (43%)
30 (34%) 58 (66%) 48 (55%) 40 (45%) 40(46%) 6(7%)
3 (i%) 1 (1%) 22(25%) 64(73%) 0 2(2%) 0 15 (17%) 73 (83%) 36(41%) 31 (35%) 48(55%) 40(45%) 55 (62%) 33(38%)
radiotherapy.
the literature deals with the treatment of superficial, accessible tumors with external microwave applicators ( 1, 25, 30). There have been significant problems with this type of hyperthermia, most importantly, the inability of external applicators to deliver heat to any target volume with a thickness beyond 2 to 3 cm (7, 24). Indeed, a recently reported phase III trial from a Radiation Therapy Oncology Group (RTOG) study (81-04) did not demonstrate an advantage of superficial hyperthermia plus irradiation over radiatiotherapy alone except in tumors less than 3 cm in size (24). It has been postulated that there is an advantage to interstitial hyperthermia over treatment with external waveguide applicators (9, 15 ) as a result of (a) better uniformity of heat within the target (implanted) volume; (b) adequate and more reliable thermometry; (c) better sparing of surrounding normal tissue; and (d) Table 2. Example of intratumoral temperatures as recorded in the hyperthermia treatment flowsheets of heat 10 20 30 40 50 60
Table 3. Percentage of intratumorai temperatures at and above a certain index temperature for the data given in Table 1 --~Temperature index (T,nrJC 38.0 38.5 39.0 39.5 40.0 40.5 41.0 41.5 42.0
38 (403%)
+ITRT = Interstitial thermoradiotherapy. * KPS = Kamofsky performance score.
Minutes
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#1
#2
#3
#4
38.4 38.6 39.2 40.2 39.9 39.7
39.9 41.3 41.9 41.9 41.9 42.7
41.8 43.2 43.6 43.1 43.4 42.9
40.9 42.4 42.4 42.8 43.1 43.0
(24/24) 100.0 (23124) 95.8 (22124) 91.7 (21/24) 87.5 (18/24) 75.0 (17/24) 70.8 (16/24) 66.7 (14/24) 58.3 111124) 45.8
suitability for both superficial and deep-seated tumors. Several institutional clinical trials, which have been published during the last 2 decades, have suggested promising results (3, 4, 8, 9, 14, 15, 19, 27, 29, 31, 32). Clearly, to demonstrate any advantages of combined heat and irradiation over interstitial radiation therapy alone require a direct comparison in a randomized clinical trial. To test whether interstitial thermoradiotherapy (ITRT) improves tumor regression or control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the complications of either regimen, the RTOG initiated a phase III, randomized trial in 1986. This ttial was completed in June 1992. We report here the results of this study. METHODS
AND MATERIALS
A total of 184 patients with recurrent or persistent epithelial tumors (not responding to conventional radiation therapy) were accessioned to this protocol. Tumors of any primary site were eligible. Eleven patients were excluded from analysis, mostly because they did not receive protocol treatment. One hundred seventy-three cases were evaluable: 87 patients in the IRT arm and 86 in the ITRT arm. All patients have a minimum of 1 year of followup. All tumors had to be measurable in at least in two perpendicular dimensions, and the entire tumor volume with margin had to be encompassed within the brachyTable 4. Best primary
response by protocol
Best primary response
IRT* (n = 87)
Complete Partial Stable Progression Inevaluable Unknown
47 (54%) 21(24%) 16(18%) 0 k&4%)
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy.
treatment
ITRT+ (n = 87) 50(57%) L2(14%) 16(18%) 4(5%) 4(5%) ICI%)
Phase III study of interstitial therrnoradiotherapyl E. EMAMI
1099
et al.
Table 5. Best primary response before additional nonprotocol therapy for recurrent and persistent lesion types Persistent
Recurrent Best primary response
IRT* (n = 48)
ITRT’ (n = 47)
IRT* (n = 39)
ITRT’ (n = 40)
Complete response Partiai response
19 (40%) 17 (33%)
24 (51%) 8 (17%)
28 (72%) 4 (10%)
26 (63%) 4 (13%)
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy.
therapy volume. Eligibility
criteria included: (a) histological proof of malignancy; (b) no chemotherapy for 2 weeks prior to or during the course of protocol treatment; (c) age over 18 years; (d) Karnofsky’s score of at least 60; and (e) life expectancy of at least 6 months. All patients were informed of the investigational nature of this protocol and signed a special consent form. Patients were stratified according to size of the lesion (< 4 cm vs. 2 4 cm), prior irradiation ( < 40 Gy vs. 2 40 Gy), and Kamofsky performance score (KPS of 90-100 vs. 60-80). The two arms were well balanced according to stratification criteria. Patient characteristics are shown in Table 1.
Treatment Radiation therapy. Radiation therapy (RT) was identical in both arms. The dose of RT was dependent on the prior course of therapy, according to the following formula: previous RT (external and interstitial) dose to the study lesion + protocol interstitial tumor dose 5 100 Gy. The dose was considered to be the minimum tumor dose to a volume encompassing the target volume. Dose delivery was at the rate of 10 Gy & 10% per day (dose rate in the range of 0.40 to 0.50 Gy per h). Coverage of the entire palpable gross tumor with some margin (i.e., 0.5 to 1 cm) by the volume implant was a protocol requirement. Dose inhomogeneity in the range of 15% within the volume encompassed by the minimum tumor dose was suggested. Only afterloading techniques using “*Ir seeds or wires were used. The implantation procedure was left to the common practice of the participating institution.
Hyperthermia.
For hyperthermia
(HT) , electromag-
netic fields from coaxial microwave antennas or radiofrequency (RF) electric currents were used. The general frequency required was 300 to 2450 MHz for microwaves and 0.1 to 1.0 MHz for RF currents. The HT regimen consisted of either one or two sessions, each with a 43°C minimum measured tumor temperature for 60 min. The interval between heating sessions should have been at least 72 h. The heating session could be performed before or before and after interstitial implant (in the case of two hyperthermia sessions). The interval between the RT and HT treatments was not to exceed 60 min. Thermometry. Nonconducting temperature probes (e.g., Bowman, and Gal As, Luckstron probe) that are not perturbed by microwave fields were used. Satisfactory characterization of the thermal state of the heated tissue required that temperatures be monitored at a number of points throughout the volume receiving interstitial HT. The actual number of catheter tracks (and, therefore, thermometers) used to monitor and document interstitial thermometry administered to a given patient depended on the volume being heated. Protocol recommendations included at least one thermometer to be placed in the central region of the volume bounded by four antennas and extra thermometry points at the periphery. Therefore, temperature measurements in microwave interstitial HT using 12 antennas should have been carried out along at least three and perhaps as many as five tracks (for two rows of six antennas). Later in the course of this study, detailed specific recommendations were devised (7). Response assessment Tumor response was assessed as CR (complete disappearance of treated lesion) ; PR (over 50% regression of
Table 6. Best primary response before additional nonprotocol therapy for head and neck and pelvic sites Pelvis
Head and neck Response
IRT* (n = 35)
ITRT’ (n = 40)
IRT* (n = 37)
ITRT+ (n = 38)
Complete response Partial regression
18 (52%) 13 (37%)
24 (62%) 4 (10%)
21 (57%) 3 (8%)
23 (60%) 4 (10%)
* IRT = Interstitial radiotherapy. + ITRT = Interstitial thermoradiotherapy.
I. J. Radiation Oncology 0 Biology 0
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Physics
Table 7. Complete response according to tumor size, KPS and prior radiation dose Complete response Factor Tumor size <4 cm 24 cm KPS’ 90- 100 60-80 Prior RT dose <40 Gy 240 Gy
IRT:‘;
ITRTf
58% 52%
74% 49%
59% 47%
67% 42%
46% 55%
66% 56%
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy. ? KPS = Kamofsky Performance score. the treated tumor as measured in two or three dimensions); and NR (which is less than 50% regression). Tumor control was considered if treated lesion remained in complete response until the patient’s death or last follow-up. Toxicity was divided into acute (within 90 days of completion of treatment) or late (after 90 days of completion of treatment) and graded according to the RTOG toxicity score. Calculation of T,, Recently the parameter TW has been used as a prognostic variable ( 18). Therefore, this parameter was used to characterize the spatial-temporal temperature distributions induced in the lesions receiving two hyperthermia treatments in this protocol. TgO was calculated from the intratumoral temperature information given in the treatment flowsheets of the protocol forms. Table 2 shows an example of the temperature data from intratumoral probes (tumor center and periphery) recorded during a typical HT treatment. TgO for each treatment was the minimum temperature for 90% of the recorded temperatures during the treatment course. It was calculated from all of the available intratumoral temperature measurement locations and for times between 10 and 60 min after initiation of the hyperthermia treatment. The calculation was performed in the following manner: the percentage of data points equal to or greater than a specified temperature index ( Tindex) was calculated for Tin+x ranging from 38” to 42°C. The results of this calculation based on the treatment data shown in Table 2 were tabulated in Table 3. From tables such as this, T,,, was obtained by linear interpolation. For the data shown in Table 3, Tgo is equal to 39.2”C. Notice that this parameter was calculated from a limited number of data points (24 data points in this example ) . Statistical analysis Primary response was taken to be the best tumor response observed in follow-up prior to any subsequent
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treatment. Tests for differences in response rates were examined using the Fisher’s exact test (5). Patients who did not achieve a complete response were considered a failure at day I for local-regional control. Estimates t’o~ time-adjusted local control rates were obtained with the cumulative incidence method ( 12). Differences between treatment arms for local-regional control were analyzed using Gray’s test ( 13). Overall survival was measured from the date of randomization and estimated using the product-limit method ( 16). Tests for differences in survival were performed with the log-rank test ( 26 ).
RESULTS The best primary response between the IRT and ITRT arms is shown in Table 4. The complete response rate for IRT was 54% compared with 57% for ITRT. There was no statistically significant difference between the two XtllS.
At 2 years, the local control rate for IRT was 37% compared with 43% for ITRT. The results are not signiticantly different (p = 0.64). The response rate according to the type of lesion (recurrent or persistent) in the two arms are shown in Table 5. Overall, persistent lesions had better CR and PR as compared to recurrent lesions, although the difference was not statistically significant. Most patients accrued in this protocol had either primary head and neck or pelvic tumors. The results of the analysis for these primary sites are shown in Table 6. Again, the difference was not statistically significant. There were too few patients in sites other than head and neck and pelvis for analysis. The complete tumor response rates for lesions less than 4 cm for IRT and ITRT were 58% and 74%, respectively. The difference was not statistically significant (p = 0.11 ) . Complete response rates for lesions 2 4 cm for IRT and ITRT were 52% and 49%, respectively (Table 7 ). Complete response rate according to Karnofsky’s per8419
- HYPEffTHERMlA
SURVIVAL
CURVE
1 -
-0
3
6
9
12 nMEmMwTlf9
IRT (n E 87) ITRT (n = 86)
15
18
21
Fig. I. Survival by protocol treatment group.
24
Phase III study of interstitial thermoradiotherapy 0 E. EMAMI et nl. Table 8. A. I. Criteria for an AdeQuateTreatment: 1. The ratio (VR) of the-implanted volume to the lesion volume plus Margin Volume must be greater than or ecmal to 1.0 (VR 2 l.O), Implanted volume where VR = Lesion volume + Margin volume For a given margin this ratio can be written as alblcI VR = (aL + Ml b. + Ml (CL + M) where a,, b,, c,, a,., b,. and c,. are the orthogonal dimensions of the Implanted and LesionVolumes, respectively. For 1 cm margin, M = 1. 2. The numberof intramuraltemperaturesensors(NTI) must
be greaterthan or equal to that recommendedby RTOG guidelines,and 3. The minimumintratumoral temperature(TI,J (center or periphery of tumor, whichever is lower) between 10 and 60 min of treatmentmustbe 2 41.5”C for 30 min or more (TI,,, 2 41S”C for t 2 30 min), and 4. The temporalaverageintratumoral temperature(TI,,,)
(averageof all center and periphery sensorsor measurement
locations)
for the entire treatment must be
greaterthan or equal to 41.YC), and 5. The maximum temporal intratumoral temperature
(TI,,,) (center or periphery of tumor, whichever is higher) between 10 and 60 min of treatment must be equal to or larger than 43.5”C (TI,,,, 2 43.5”(Z), and
6. Typical spacingbetweenheat sources(S) must be less
than or equalto 2.0 (S 5 2.0).
formance score (KPS), for of patients with KPS of 90100, with IRT was 59% and for ITRT, 67%. For patients with KPS of 60-80, the complete responserates for IRT and ITRT were 47% and 42%, respectively (Table 7). There was no statistically significant difference between the IRT and ITRT arms whether the previous course of treatment was < 40 Gy or 2 40 Gy. For lesions previously receiving 2 40 Gy, the complete response rates for the two arms were 55% and 56%, respectively (Table 7 1. Overall survival for the two arms is shown in Fig. 1. At 2 years the survival rates for IRT and ITRT were 29% and 36%, respectively. Median survival for the two arms was 13.9 months and 12.9 months, respectively. Impact of quality of hyperthermia To assessthe quality of the hyperthermia sessionsand its impact on outcome, several criteria were listed that were, in part, based on RTOG quality assuranceguidelines for HT ( 10). Criteria for an “adequate HT treatment” are listed in Table 8. When the quality of HT sessionswas analyzed according to “adequacy of hyperthermia sessions” criteria, only one patient met the criteria for adequate HT sessions.Thus, it was impossible to assessthe response rate according to adequacy of the hyperthermia sessions.More detailed analysis of clinical results with physical parameters will be reported separately (21).
1101
Responseaccording to TsOand T9,, index Table 9 shows tumor responseaccording to the calculated TgOfor patients who received two HT treatments. For T9,, less than 40.5”C, the complete responserate was 53%, and for TgOequal to or greater than 40.5”C 68% (17 = 0.23, not statistically significant). Similar results were obtained for cutoff temperatures of 39.5” and 4O.o”C. Toxicity Acute and late toxicities for IRT and ITRT are listed in Tables 10 and 11. There was a slight increase in acute Grade IV toxicity with the addition of interstitial HT (3% vs. 10%). There was no difference in late toxicities between the two treatment arms.
DISCUSSION PhaseI/II of interstitial thermoradiotherapy trials from single institutions show CR rates of around 60% and PR rates of 30% to 35% (9-l 1, 17, 20). These studies usually had short follow-up with a smaller number of patients, except for a French multicenter report ( I 1) . When the results of these studies were compared with those of “historical controls” with apparently similar lesions who were treated with RT alone, superior results of ITRT over external and/or IRT were claimed. None of these studies were prospectively controlled randomized trials. Complete and partial responserates of 57% and 14%, respectively, for the ITRT arm of the present study are comparable to published series.However, when ITRT is compared directly with IRT alone, as it is done in the present study, there is no statistically significant difference between the two armsin tumor response,local tumor control. survival, acute or late toxicity. Grigsby et al. ( 14) reported on 69 patients treated with ITRT at Washington University with long-term follow-up. In their report CR rate was 53% and PR rate was 14%, comparable to those of the present study. They reported 35% long-term tumor control as compared to a 57% in the present study. Analysis of results from the literature does not show any correlation between tumor response and tumor site with the exception of a report by Shimm et al. (28 ), who found that CR demonstrated a significant univariate dependence on the site treated; 61% in head and neck tumors as compared to 29% for pelvic tumors, (p < 0.03 1) . The CR rate for the ITRT arm of this study for head and neck and pelvic sites was 62% and 60%, respec-
Table 9. Tumor response according to calculated T,,, and CR for patients that received two hyperthermia treatments (n = 63) T 90 <40.5”C ~4OS”C
CR
No CR
20/38 (53%) l7/25 (68%)
18138 (47%) 8/2S (32%)
I. J. Radiation Oncology l Biology 0 Physics
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Volume 34, Number 5, 1996
Table 10. Acute and late toxicities (within 90 days)
ITRT (n = 86) grade
JRT (n = 87) grade Acute toxicity Skin and subcutaneous
tissue
Mucous membrane Bladder Urethra
Small intestine Vagina
Other Worst acute toxicity reported for each patient
1
2
3
17 1.5 3 2 1 0 5
16 10 2 1 1 1 5
20
26
4
1
2
3
4
3 5 0 0 0 1 0
27 12 3 4 4 4 1
9 11 2 0 2 2 3
3 4 1 0 1 0 2
7 3 0 0 1 1 0
8
24
16
10 (if%)
tively. We found no correlation between the tumor site and the CR rate, which is in agreement with the report of Grigsby et al. (14). Several reports have correlated the size of the tumor and the response rate, with better results obtained with ITRT for small tumors. The present study showed no such correlation. Although IRT alone resulted in a significantly lower CR rate for recurrent lesions (40%) compared to persistent lesions (72%)) no statistically significant difference between these two groups was noticed in the ITRT arm. Regardless of the choice of technique for delivery of hyperthermia, the quality of hyperthermia has been shown to be one of the most important factors in achieving tumor control (6, 8, 9, 22). When we set a series of factors for minimum adequacy of hyperthermia session, only 1 of 87 patients met the minimum criteria. Obviously, no analysis can be done in this regard. Proper controlled and variable (for QA) heat delivery continues to be a major obstacle. The thermal parameter T9,, was calculated for 63 lesions that received two hyperthermia treatments. In this analysis the TN relates a single temperature value to the spatialtemporal temperature distributions induced in the lesions during a hyperthermia treatment. For each intratumoral temperature probe there were six recorded temperatures
in the protocol forms. Consequently, the calculation of TPO was performed with a relatively small number of data points. An important point is that if the measurements recorded in the protocol forms were from locations of maximum temperature, the calculated values of Tw would represent overestimates. However, a higher value of TgO does, in general, indicate higher temperatures for longer durations. Bearing this in mind, it must be pointed out that the lesions with higher Tw showed a higher CR rate, although it was not statistically significant. Overall, the results of the present randomized study point to: (a) inadequacy of current hyperthermia technology to heat tumors commonly seen in radiation therapy clinics; (b) lack of familiarity and compliance with minimal quality assurance guidelines for hyperthermia; and (c) lack of rigid quality assurance guidelines for ITRT and its compliance. Most often the coverage of the target or the implanted volume is the subjective/objective opinion of the radiation oncologist who performed the procedure. At present, there is no quantitative criteria to evaluate the implant in a clear and consistent manner. Last, although this study did not show any difference between ITRT and IRT in any of the endpoints studied, it should be noted that in almost all patients the quality of the hyperthermia sessions was less than adequate. The question of whether or not adding hyperthermia confers addi-
Table 11. Late toxicities (after 90 days) IRT (n = 76) grade Toxicity Skin and subcutaneous
tissue
Mucous membrane Small/large Vagina Bladder Urethra Other
intestine
Worst acute toxicity reported for each patient
ITRT (n = 79) grade
1
2
3
4
4 3 2 2 0 1 4
5 1 1 3 0 0 1
2 2 1 1 0 0 1
15
8
4
1
2
3
4
3 2 1 3 1 0 1
4 :
3 2
2 31
2 1
2 0
3 0
i
02
0
(9k)
8
8
(li%)
Phase III study of interstitial thennoradiotherapy 0 E. EMAMI
tional benefit in terms of local control and/or survival was not satisfactorily answered by this study becausethe
et al.
1103
majority of patients failed to meet the minimum adequacy requirements of hyperthermia sessions.
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28.
29.
tive study of 445 lung carcinomas with mediastinal lymph node metastases. J. Thorac. Cardiovasc. Surg. 80:390-397; 1980. Moros, E.; Emami, B.; Scott, C.; Perez, C.; Asbell, S.; Swift, P.; Grigsby, P.; Montesano, A.; Rubin, P.; Curran, W.; Delrowe, J.; Arastu, H.; Fu, K. Adequacy of interstitial thermoradiotherapy : An analysis of RTOG 84- 19. Endocuriether. Hypertherm. Oncol. (in preparation). Oleson, J.; Manning, M.; Sim, D.; Heusinkveld, R.: Aristizabal, S.; Cetas, T.; Hevezi, J.; Connor, W. A review of the University of Arizona human clinical hyperthermia experience. Front. Radiat. Ther. Oncol. 18:136-143; 1984. Overgaard, J. Fractionated radiation and hyperthennia: Experimental and clinical studies. Cancer 48: 1116- 1123; 1981. Perez, C.; Gillespie, B.; Pajak, T.; Homback, N.; Emami, B.; Rubin, P. Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: A report by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 16:551-558; 1989. Perez, C.; Pajak, T.; Emami, B.; Homback, H.; Tupchong, L.; Rubin, P. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors: Final report by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 14:133141; 1991. Petro, R.; Petro, J. Asymptomatically efficient rank invariant test procedures. J. R. Stat. Sot. 135:185-207; 1972. Puthawala, A.; Syed, A.; Shiek Khalid, M.; Rafie, S.; McNamara, C. Interstitial hyperthermia for recurrent malignancies. Endocuriether. Hypertherm. Oncol. 1: 125 - 13 1; 1985. Shimm, D.: Kittleson, J.; Oleson, J.; Aristizabal, S.; Barlow, L.; Cetas, T. Interstitial thermoradiotherapy: Thermal dosimetry and clinical results. Int. J. Radiat. Oncol. Biol. Phys. 18:383-387; 1990. Sneed, P.; Gutin, P.; Stauffer, P.; Phillips, T.; Prados, M.; Weaver, K.; Suen, S.; Lamb, S.; Ham, B.; Ahn, D.; Lam-
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born, I(.; Larson, D.; Wara, W. Thermoradiotherapy of recurrent malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 23:853-861; 1992. 30. Valdagni, R.; Kapp, D.; Valdagni, C. N3 (TNM-UICC) metastatic neck nodes managed by combined radiation therapy and hyperthermia: Clinical results and analysis of treatment parameters. Int. J. Hyperthetmia 2: 189-200; 1986. 31. Vora, N.; Luk, K.; Forell, B.; Findley, D.; Lipsett, J.;
Volume 34. Number 5. 1996 Pezner, R.; Desai, K.; Wong, .I.; Hill, B. Interstitial local current field hyperthermia for advanced cancers of the cervix. Endocuriether. Hypertherm. Oncol. 4:97 - 106: 1988. 32. Vora, N.; Shaw, S.: Forell. B.; Desai, K.; Archambeau. J.: Penzer, R.: Lipsett, J.; Covell, J. Primary radiation combined with hyperthermia for advanced (stage III-IV 1 and inflammatory carcinoma of the breast. Endocuriether. Hypertherm. 0~01. 2: 101 - 106; 1986.
Biol.
Phys., Vol. 34, No. 5, pp. 1097- 1104, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.00 + .OO
0360-3016(95)02137-X
ELSEVIER
l
Oncology
Hyperthermia Original Contribution PHASE III STUDY OF INTERSTITIAL THERMORADIOTHERAPY COMPARED WITH INTERSTITIAL RADIOTHERAPY ALONE IN THE TREATMENT OF RECURRENT OR PERSISTENT HUMAN TUMORS: A PROSPECTIVELY CONTROLLED RANDOMIZED STUDY BY THE RADIATION THERAPY ONCOLOGY GROUP BAHMAN EMAMI, M.D., * CHARLES SCOTT, PH.D., ’ CARLOS A. PEREZ, M.D., * SUCHA ASBELL, M.D., * PATRICK SWIFT, M.D., g PERRY GRIGSBY, M.D., * ANGELICA MONTESANO, M.D.,’ PHILIP RUBIN, M.D.,l WALTER CURRAN, M.D.,# JOHN DELROWE, M.D., * * HYDER ARASTU, M.D., $ KAREN Fu, M.D.$ AND EDUARDO MOROS, PH.D.* *Radiation Oncology Center, Mallinckrodt Institute of Radiology, WashingtonUniversity School of Medicine, St. Louis, MO, ‘Radiation Therapy Oncology Group, Philadelphia,PA, *Albert EinsteinUniversity, Philadelphia,PA, qUniversity of California San Francisco,San Francisco,CA, %niversity of RochesterMedical Center, Rochester,NY. #Fox ChaseCancerCenter, Philadelphia,PA, * *Montefiore Medical Center, Bronx, NY Purpose: The objectives of this randomized trial were to determine if interstitial thermoradlotherapy (ITRT) improves tumor regression/control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the skin and soft tissue complications with either modality. Methods and Materials: From January 1986 to June 1992,184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstltlal radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG). One hundred seventythree cases were analyzed (87 patients in the IRT group and 86 in the ITRT arm). The two arms were well balanced regarding stratification criteria. Most tumors were in the head and neck (40% in the IRT group and 46% in the ITRT group,) and pelvis (42% and 43%, respectively). Eighty-four percent of patients in both arms had prior radiation therapy (2 40 Gy); 50% and 40%, respectively, had prior surgery, and 34% in each arm had prior chemotherapy. The dose of radiation therapy admhdstered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy. Hyperthermla was delivered in one or two sessions, either before or before and after interstitial implant. The intended goal of the hyperthermia was to maintain a mlnlmal tumor temperature of 425°C for 30 to 60 min. Results: There was no dllerence in any of the study end points between the two arms. Complete response (CR) was 53% and 55% in both arms. Two-year survival was 34% and 35%, respectively. Complete response rate for persistent lesions was 69% and 63% in the two treatment arms as compared with 40% and 48% for recurrent lesions. A set of minimal adequacy criteria for the delivery of hyperthermla was developed. When these criteria were applied, only one patient had an adequate hyperthermla session. Acute Grade 3 and 4 toxicities were 12% for IRT and 22% for ITRT. Late Grade 3 and 4 toxicities were 15% for IRT and 20% for ITRT. The difference was not significant. Conclusions: Interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone. Delivery of hyperthermia remains a major obstacle (since only one patient met the basic minimum adequacy criteria as defined in this study). The benefit of hypertherrmla in addition to radiaton therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved. Interstitial
hyperthermia,
Interstitial
radiotherapy,
Brachytherapy.
INTRODUCTION Hyperthermia in conjunction with radiation therapy has been used in the treatment of recurrent or persistent tu-
mors during the last 2 decades. Numerous single-institution clinical trials have demonstrated promising results (1, 2, 23, 25, 30). Most clinical experience reported in
Reprint requeststo: BahmanEmami,M.D., RadiationOncology Center,4939 Children’sPlace, Suite 5500, St. Louis,
MO 63110. Accepted for publication 11 September1995. 1097
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1. J. Radiation Oncology 0 Biology 0 Physics
Table
1. Pretreatment
characteristics
Pretreatment characteristics Lesion size Lesion type Lesion site
Histology
Prior radiation Prior surgery Prior chemotherapy Sex KPSf *IRT = Interstitial
t4 cm 24 cm Recurrent Persistent Head & neck Breast Abdomen Pelvis Extremities Back Other Adenocarcinoma Squamous cell Melanoma Other Unknown <4OGy >40Gy Female Male 90-100 60-80
by protocol
treatment
IRT* (n = 88)
ITRT’ (n = 88)
31 (35%) 57 (65%) 49 (56%) 39(44%) 35 (40%) 3(4%) 2(2%) 37(42%) 1 (1%) 2(2%) 8(9%) 28 (31%) 53 (63%) 4(5%) 2(2%) 1 (1%) 14 (16%) 74 (84%) 44 (50%) 31 (35%) 57 (65%) 31 (35%) 50(57%) 38 (43%)
30 (34%) 58 (66%) 48 (55%) 40 (45%) 40(46%) 6(7%)
3 (i%) 1 (1%) 22(25%) 64(73%) 0 2(2%) 0 15 (17%) 73 (83%) 36(41%) 31 (35%) 48(55%) 40(45%) 55 (62%) 33(38%)
radiotherapy.
the literature deals with the treatment of superficial, accessible tumors with external microwave applicators ( 1, 25, 30). There have been significant problems with this type of hyperthermia, most importantly, the inability of external applicators to deliver heat to any target volume with a thickness beyond 2 to 3 cm (7, 24). Indeed, a recently reported phase III trial from a Radiation Therapy Oncology Group (RTOG) study (81-04) did not demonstrate an advantage of superficial hyperthermia plus irradiation over radiatiotherapy alone except in tumors less than 3 cm in size (24). It has been postulated that there is an advantage to interstitial hyperthermia over treatment with external waveguide applicators (9, 15 ) as a result of (a) better uniformity of heat within the target (implanted) volume; (b) adequate and more reliable thermometry; (c) better sparing of surrounding normal tissue; and (d) Table 2. Example of intratumoral temperatures as recorded in the hyperthermia treatment flowsheets of heat 10 20 30 40 50 60
Table 3. Percentage of intratumorai temperatures at and above a certain index temperature for the data given in Table 1 --~Temperature index (T,nrJC 38.0 38.5 39.0 39.5 40.0 40.5 41.0 41.5 42.0
38 (403%)
+ITRT = Interstitial thermoradiotherapy. * KPS = Kamofsky performance score.
Minutes
Volume 34, Number 5. 1996
#1
#2
#3
#4
38.4 38.6 39.2 40.2 39.9 39.7
39.9 41.3 41.9 41.9 41.9 42.7
41.8 43.2 43.6 43.1 43.4 42.9
40.9 42.4 42.4 42.8 43.1 43.0
(24/24) 100.0 (23124) 95.8 (22124) 91.7 (21/24) 87.5 (18/24) 75.0 (17/24) 70.8 (16/24) 66.7 (14/24) 58.3 111124) 45.8
suitability for both superficial and deep-seated tumors. Several institutional clinical trials, which have been published during the last 2 decades, have suggested promising results (3, 4, 8, 9, 14, 15, 19, 27, 29, 31, 32). Clearly, to demonstrate any advantages of combined heat and irradiation over interstitial radiation therapy alone require a direct comparison in a randomized clinical trial. To test whether interstitial thermoradiotherapy (ITRT) improves tumor regression or control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the complications of either regimen, the RTOG initiated a phase III, randomized trial in 1986. This ttial was completed in June 1992. We report here the results of this study. METHODS
AND MATERIALS
A total of 184 patients with recurrent or persistent epithelial tumors (not responding to conventional radiation therapy) were accessioned to this protocol. Tumors of any primary site were eligible. Eleven patients were excluded from analysis, mostly because they did not receive protocol treatment. One hundred seventy-three cases were evaluable: 87 patients in the IRT arm and 86 in the ITRT arm. All patients have a minimum of 1 year of followup. All tumors had to be measurable in at least in two perpendicular dimensions, and the entire tumor volume with margin had to be encompassed within the brachyTable 4. Best primary
response by protocol
Best primary response
IRT* (n = 87)
Complete Partial Stable Progression Inevaluable Unknown
47 (54%) 21(24%) 16(18%) 0 k&4%)
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy.
treatment
ITRT+ (n = 87) 50(57%) L2(14%) 16(18%) 4(5%) 4(5%) ICI%)
Phase III study of interstitial therrnoradiotherapyl E. EMAMI
1099
et al.
Table 5. Best primary response before additional nonprotocol therapy for recurrent and persistent lesion types Persistent
Recurrent Best primary response
IRT* (n = 48)
ITRT’ (n = 47)
IRT* (n = 39)
ITRT’ (n = 40)
Complete response Partiai response
19 (40%) 17 (33%)
24 (51%) 8 (17%)
28 (72%) 4 (10%)
26 (63%) 4 (13%)
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy.
therapy volume. Eligibility
criteria included: (a) histological proof of malignancy; (b) no chemotherapy for 2 weeks prior to or during the course of protocol treatment; (c) age over 18 years; (d) Karnofsky’s score of at least 60; and (e) life expectancy of at least 6 months. All patients were informed of the investigational nature of this protocol and signed a special consent form. Patients were stratified according to size of the lesion (< 4 cm vs. 2 4 cm), prior irradiation ( < 40 Gy vs. 2 40 Gy), and Kamofsky performance score (KPS of 90-100 vs. 60-80). The two arms were well balanced according to stratification criteria. Patient characteristics are shown in Table 1.
Treatment Radiation therapy. Radiation therapy (RT) was identical in both arms. The dose of RT was dependent on the prior course of therapy, according to the following formula: previous RT (external and interstitial) dose to the study lesion + protocol interstitial tumor dose 5 100 Gy. The dose was considered to be the minimum tumor dose to a volume encompassing the target volume. Dose delivery was at the rate of 10 Gy & 10% per day (dose rate in the range of 0.40 to 0.50 Gy per h). Coverage of the entire palpable gross tumor with some margin (i.e., 0.5 to 1 cm) by the volume implant was a protocol requirement. Dose inhomogeneity in the range of 15% within the volume encompassed by the minimum tumor dose was suggested. Only afterloading techniques using “*Ir seeds or wires were used. The implantation procedure was left to the common practice of the participating institution.
Hyperthermia.
For hyperthermia
(HT) , electromag-
netic fields from coaxial microwave antennas or radiofrequency (RF) electric currents were used. The general frequency required was 300 to 2450 MHz for microwaves and 0.1 to 1.0 MHz for RF currents. The HT regimen consisted of either one or two sessions, each with a 43°C minimum measured tumor temperature for 60 min. The interval between heating sessions should have been at least 72 h. The heating session could be performed before or before and after interstitial implant (in the case of two hyperthermia sessions). The interval between the RT and HT treatments was not to exceed 60 min. Thermometry. Nonconducting temperature probes (e.g., Bowman, and Gal As, Luckstron probe) that are not perturbed by microwave fields were used. Satisfactory characterization of the thermal state of the heated tissue required that temperatures be monitored at a number of points throughout the volume receiving interstitial HT. The actual number of catheter tracks (and, therefore, thermometers) used to monitor and document interstitial thermometry administered to a given patient depended on the volume being heated. Protocol recommendations included at least one thermometer to be placed in the central region of the volume bounded by four antennas and extra thermometry points at the periphery. Therefore, temperature measurements in microwave interstitial HT using 12 antennas should have been carried out along at least three and perhaps as many as five tracks (for two rows of six antennas). Later in the course of this study, detailed specific recommendations were devised (7). Response assessment Tumor response was assessed as CR (complete disappearance of treated lesion) ; PR (over 50% regression of
Table 6. Best primary response before additional nonprotocol therapy for head and neck and pelvic sites Pelvis
Head and neck Response
IRT* (n = 35)
ITRT’ (n = 40)
IRT* (n = 37)
ITRT+ (n = 38)
Complete response Partial regression
18 (52%) 13 (37%)
24 (62%) 4 (10%)
21 (57%) 3 (8%)
23 (60%) 4 (10%)
* IRT = Interstitial radiotherapy. + ITRT = Interstitial thermoradiotherapy.
I. J. Radiation Oncology 0 Biology 0
I 100
Physics
Table 7. Complete response according to tumor size, KPS and prior radiation dose Complete response Factor Tumor size <4 cm 24 cm KPS’ 90- 100 60-80 Prior RT dose <40 Gy 240 Gy
IRT:‘;
ITRTf
58% 52%
74% 49%
59% 47%
67% 42%
46% 55%
66% 56%
* IRT = Interstitial radiotherapy. ’ ITRT = Interstitial thermoradiotherapy. ? KPS = Kamofsky Performance score. the treated tumor as measured in two or three dimensions); and NR (which is less than 50% regression). Tumor control was considered if treated lesion remained in complete response until the patient’s death or last follow-up. Toxicity was divided into acute (within 90 days of completion of treatment) or late (after 90 days of completion of treatment) and graded according to the RTOG toxicity score. Calculation of T,, Recently the parameter TW has been used as a prognostic variable ( 18). Therefore, this parameter was used to characterize the spatial-temporal temperature distributions induced in the lesions receiving two hyperthermia treatments in this protocol. TgO was calculated from the intratumoral temperature information given in the treatment flowsheets of the protocol forms. Table 2 shows an example of the temperature data from intratumoral probes (tumor center and periphery) recorded during a typical HT treatment. TgO for each treatment was the minimum temperature for 90% of the recorded temperatures during the treatment course. It was calculated from all of the available intratumoral temperature measurement locations and for times between 10 and 60 min after initiation of the hyperthermia treatment. The calculation was performed in the following manner: the percentage of data points equal to or greater than a specified temperature index ( Tindex) was calculated for Tin+x ranging from 38” to 42°C. The results of this calculation based on the treatment data shown in Table 2 were tabulated in Table 3. From tables such as this, T,,, was obtained by linear interpolation. For the data shown in Table 3, Tgo is equal to 39.2”C. Notice that this parameter was calculated from a limited number of data points (24 data points in this example ) . Statistical analysis Primary response was taken to be the best tumor response observed in follow-up prior to any subsequent
Volume
34.
Number
5. 1996
treatment. Tests for differences in response rates were examined using the Fisher’s exact test (5). Patients who did not achieve a complete response were considered a failure at day I for local-regional control. Estimates t’o~ time-adjusted local control rates were obtained with the cumulative incidence method ( 12). Differences between treatment arms for local-regional control were analyzed using Gray’s test ( 13). Overall survival was measured from the date of randomization and estimated using the product-limit method ( 16). Tests for differences in survival were performed with the log-rank test ( 26 ).
RESULTS The best primary response between the IRT and ITRT arms is shown in Table 4. The complete response rate for IRT was 54% compared with 57% for ITRT. There was no statistically significant difference between the two XtllS.
At 2 years, the local control rate for IRT was 37% compared with 43% for ITRT. The results are not signiticantly different (p = 0.64). The response rate according to the type of lesion (recurrent or persistent) in the two arms are shown in Table 5. Overall, persistent lesions had better CR and PR as compared to recurrent lesions, although the difference was not statistically significant. Most patients accrued in this protocol had either primary head and neck or pelvic tumors. The results of the analysis for these primary sites are shown in Table 6. Again, the difference was not statistically significant. There were too few patients in sites other than head and neck and pelvis for analysis. The complete tumor response rates for lesions less than 4 cm for IRT and ITRT were 58% and 74%, respectively. The difference was not statistically significant (p = 0.11 ) . Complete response rates for lesions 2 4 cm for IRT and ITRT were 52% and 49%, respectively (Table 7 ). Complete response rate according to Karnofsky’s per8419
- HYPEffTHERMlA
SURVIVAL
CURVE
1 -
-0
3
6
9
12 nMEmMwTlf9
IRT (n E 87) ITRT (n = 86)
15
18
21
Fig. I. Survival by protocol treatment group.
24
Phase III study of interstitial thermoradiotherapy 0 E. EMAMI et nl. Table 8. A. I. Criteria for an AdeQuateTreatment: 1. The ratio (VR) of the-implanted volume to the lesion volume plus Margin Volume must be greater than or ecmal to 1.0 (VR 2 l.O), Implanted volume where VR = Lesion volume + Margin volume For a given margin this ratio can be written as alblcI VR = (aL + Ml b. + Ml (CL + M) where a,, b,, c,, a,., b,. and c,. are the orthogonal dimensions of the Implanted and LesionVolumes, respectively. For 1 cm margin, M = 1. 2. The numberof intramuraltemperaturesensors(NTI) must
be greaterthan or equal to that recommendedby RTOG guidelines,and 3. The minimumintratumoral temperature(TI,J (center or periphery of tumor, whichever is lower) between 10 and 60 min of treatmentmustbe 2 41.5”C for 30 min or more (TI,,, 2 41S”C for t 2 30 min), and 4. The temporalaverageintratumoral temperature(TI,,,)
(averageof all center and periphery sensorsor measurement
locations)
for the entire treatment must be
greaterthan or equal to 41.YC), and 5. The maximum temporal intratumoral temperature
(TI,,,) (center or periphery of tumor, whichever is higher) between 10 and 60 min of treatment must be equal to or larger than 43.5”C (TI,,,, 2 43.5”(Z), and
6. Typical spacingbetweenheat sources(S) must be less
than or equalto 2.0 (S 5 2.0).
formance score (KPS), for of patients with KPS of 90100, with IRT was 59% and for ITRT, 67%. For patients with KPS of 60-80, the complete responserates for IRT and ITRT were 47% and 42%, respectively (Table 7). There was no statistically significant difference between the IRT and ITRT arms whether the previous course of treatment was < 40 Gy or 2 40 Gy. For lesions previously receiving 2 40 Gy, the complete response rates for the two arms were 55% and 56%, respectively (Table 7 1. Overall survival for the two arms is shown in Fig. 1. At 2 years the survival rates for IRT and ITRT were 29% and 36%, respectively. Median survival for the two arms was 13.9 months and 12.9 months, respectively. Impact of quality of hyperthermia To assessthe quality of the hyperthermia sessionsand its impact on outcome, several criteria were listed that were, in part, based on RTOG quality assuranceguidelines for HT ( 10). Criteria for an “adequate HT treatment” are listed in Table 8. When the quality of HT sessionswas analyzed according to “adequacy of hyperthermia sessions” criteria, only one patient met the criteria for adequate HT sessions.Thus, it was impossible to assessthe response rate according to adequacy of the hyperthermia sessions.More detailed analysis of clinical results with physical parameters will be reported separately (21).
1101
Responseaccording to TsOand T9,, index Table 9 shows tumor responseaccording to the calculated TgOfor patients who received two HT treatments. For T9,, less than 40.5”C, the complete responserate was 53%, and for TgOequal to or greater than 40.5”C 68% (17 = 0.23, not statistically significant). Similar results were obtained for cutoff temperatures of 39.5” and 4O.o”C. Toxicity Acute and late toxicities for IRT and ITRT are listed in Tables 10 and 11. There was a slight increase in acute Grade IV toxicity with the addition of interstitial HT (3% vs. 10%). There was no difference in late toxicities between the two treatment arms.
DISCUSSION PhaseI/II of interstitial thermoradiotherapy trials from single institutions show CR rates of around 60% and PR rates of 30% to 35% (9-l 1, 17, 20). These studies usually had short follow-up with a smaller number of patients, except for a French multicenter report ( I 1) . When the results of these studies were compared with those of “historical controls” with apparently similar lesions who were treated with RT alone, superior results of ITRT over external and/or IRT were claimed. None of these studies were prospectively controlled randomized trials. Complete and partial responserates of 57% and 14%, respectively, for the ITRT arm of the present study are comparable to published series.However, when ITRT is compared directly with IRT alone, as it is done in the present study, there is no statistically significant difference between the two armsin tumor response,local tumor control. survival, acute or late toxicity. Grigsby et al. ( 14) reported on 69 patients treated with ITRT at Washington University with long-term follow-up. In their report CR rate was 53% and PR rate was 14%, comparable to those of the present study. They reported 35% long-term tumor control as compared to a 57% in the present study. Analysis of results from the literature does not show any correlation between tumor response and tumor site with the exception of a report by Shimm et al. (28 ), who found that CR demonstrated a significant univariate dependence on the site treated; 61% in head and neck tumors as compared to 29% for pelvic tumors, (p < 0.03 1) . The CR rate for the ITRT arm of this study for head and neck and pelvic sites was 62% and 60%, respec-
Table 9. Tumor response according to calculated T,,, and CR for patients that received two hyperthermia treatments (n = 63) T 90 <40.5”C ~4OS”C
CR
No CR
20/38 (53%) l7/25 (68%)
18138 (47%) 8/2S (32%)
I. J. Radiation Oncology l Biology 0 Physics
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Volume 34, Number 5, 1996
Table 10. Acute and late toxicities (within 90 days)
ITRT (n = 86) grade
JRT (n = 87) grade Acute toxicity Skin and subcutaneous
tissue
Mucous membrane Bladder Urethra
Small intestine Vagina
Other Worst acute toxicity reported for each patient
1
2
3
17 1.5 3 2 1 0 5
16 10 2 1 1 1 5
20
26
4
1
2
3
4
3 5 0 0 0 1 0
27 12 3 4 4 4 1
9 11 2 0 2 2 3
3 4 1 0 1 0 2
7 3 0 0 1 1 0
8
24
16
10 (if%)
tively. We found no correlation between the tumor site and the CR rate, which is in agreement with the report of Grigsby et al. (14). Several reports have correlated the size of the tumor and the response rate, with better results obtained with ITRT for small tumors. The present study showed no such correlation. Although IRT alone resulted in a significantly lower CR rate for recurrent lesions (40%) compared to persistent lesions (72%)) no statistically significant difference between these two groups was noticed in the ITRT arm. Regardless of the choice of technique for delivery of hyperthermia, the quality of hyperthermia has been shown to be one of the most important factors in achieving tumor control (6, 8, 9, 22). When we set a series of factors for minimum adequacy of hyperthermia session, only 1 of 87 patients met the minimum criteria. Obviously, no analysis can be done in this regard. Proper controlled and variable (for QA) heat delivery continues to be a major obstacle. The thermal parameter T9,, was calculated for 63 lesions that received two hyperthermia treatments. In this analysis the TN relates a single temperature value to the spatialtemporal temperature distributions induced in the lesions during a hyperthermia treatment. For each intratumoral temperature probe there were six recorded temperatures
in the protocol forms. Consequently, the calculation of TPO was performed with a relatively small number of data points. An important point is that if the measurements recorded in the protocol forms were from locations of maximum temperature, the calculated values of Tw would represent overestimates. However, a higher value of TgO does, in general, indicate higher temperatures for longer durations. Bearing this in mind, it must be pointed out that the lesions with higher Tw showed a higher CR rate, although it was not statistically significant. Overall, the results of the present randomized study point to: (a) inadequacy of current hyperthermia technology to heat tumors commonly seen in radiation therapy clinics; (b) lack of familiarity and compliance with minimal quality assurance guidelines for hyperthermia; and (c) lack of rigid quality assurance guidelines for ITRT and its compliance. Most often the coverage of the target or the implanted volume is the subjective/objective opinion of the radiation oncologist who performed the procedure. At present, there is no quantitative criteria to evaluate the implant in a clear and consistent manner. Last, although this study did not show any difference between ITRT and IRT in any of the endpoints studied, it should be noted that in almost all patients the quality of the hyperthermia sessions was less than adequate. The question of whether or not adding hyperthermia confers addi-
Table 11. Late toxicities (after 90 days) IRT (n = 76) grade Toxicity Skin and subcutaneous
tissue
Mucous membrane Small/large Vagina Bladder Urethra Other
intestine
Worst acute toxicity reported for each patient
ITRT (n = 79) grade
1
2
3
4
4 3 2 2 0 1 4
5 1 1 3 0 0 1
2 2 1 1 0 0 1
15
8
4
1
2
3
4
3 2 1 3 1 0 1
4 :
3 2
2 31
2 1
2 0
3 0
i
02
0
(9k)
8
8
(li%)
Phase III study of interstitial thennoradiotherapy 0 E. EMAMI
tional benefit in terms of local control and/or survival was not satisfactorily answered by this study becausethe
et al.
1103
majority of patients failed to meet the minimum adequacy requirements of hyperthermia sessions.
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