Important prognostic factors influencing outcome of combined radiation and hyperthermia

Phys

0360-3016/H $3.00 + .oO Copyright 0 1988 Pergamon Press plc

hr. J. Radialron Oncology Biol. Vol. 15, pp. 959-972 Printed in the U.S.A. All rights reserved.

??Original Contribution

IMPORTANT PROGNOSTIC FACI-ORS INFLUENCING OUTCOME COMBINED RADIATION AND HYPERTHERMIA RICCARDO VALDAGNI,

M.D., FEI-FEI LIU, M.D.,

F.R.C.P.(C)

OF

AND DANIEL S. KAPP, PH.D.,

M.D.

Department of Therapeutic Radiology, Stanford University Medical Center, Stanford, CA 94305 Clinical experience with combined local-regional hyperthermla and radiation therapy has been rapidly accumulating over the past few decades. Its superior efficacy to the use of radiation alone has been demonstrated in several retrospective and prospective reports in the literature. It is evident now that there are several important factors that will influence the final outcome of the treated patients. The parameters that will be discussed in this paper include: I. Pretreatments factors: 1. tumor dimension 2. tumor histology 3. tumor site. II. Treatment factors: 1. radiation therapy dose 2. hyperthermia parameters: (a) thermal variables (b) number of heat treatments (c) sequence of hyperthermia and radiation treatments (d) hyperthermic device. Finally, evaluation of response and complications will also be discussed. The importance of abiding by an accepted reporting system will be emphasized, and clarification of times at which response assessments were made will also be discussed. With the availability of longer term follow-up, use of an actuarial method of reporting becomes more important. The future of hyperthermia and radiation remains very promising but a lot of questions still need to be answered by well-conducted and reported clinical trials. Hyperthermia, Prognostic factors, Radiation therapy. INTRODUCTION

METHODS

AND

MATERIALS

Over the past few decades, there has been extensive clinical experience in the use of radiation therapy (XRT) in conjunction with hyperthermia (Ht) in the treatment of malignant neoplasms. Results from both retrospective and prospective trials point consistently to the superior efficacy of the combined approach over XRT alone.3,4*‘6,‘7.24.44.63*70.7’ The most important end-point is the rate of local control of tumors to this combined modality. Interpretation and comparison of different trials’ results are difficult due to a lack of standard reporting methods. In addition, it is apparent that there are a number of different, but inter-related factors that can influence the response of neoplastic lesions to the combined effects of ionizing radiation and hyperthermia. All these variables need to be considered when assessing the role of hyperthermia as an adjunct to radiation therapy. This paper will attempt to review the currently important parameters that may influence the response of tumors to this combined modality.

Pre-treatment parameters Tumor dimension. Tumor size bears a complex relation to local control by radiation and hyperthermia. With a bulky tumor, it is more likely to have necrotic regions, poorer vascularity, and a lower pH. All these factors would render it more susceptible to the tumoricidal effects of hyperthermia. I9 Clinical experience, however, has shown that it is actually easier to control a smaller tumor with combined XRT and Ht. Dewhirst et al.” demonstrated a statistically significant inverse relation between tumor volume and complete response rate in the palliative management of 92 evaluable lesions in pet animals. This trend is reflected in the majority of work outlined in Table 1 %II,l7,21.29,30,35&3.59,70,7 I Valdagni et al.” in 1986 had demonstrated a statistically significant adverse effect of maximum tumor diameter on complete response rate in their prospective study. When the analysis was repeated however, with the inclusion of only patients treated with radical intent, tumor size no longer

Presented in part at the IXth Meeting of the European Society for Hyperthermic Oncology, July 14-16, 1987 Cardiff,

logico, Istituti Ospedalieri, 38 100 Trento, Italy.

Reprint requests to: Riccardo Valdagni, M.D., Centro Onco-

U.K.

Acknowledgments-The authors wish to thank Dr. George Hahn for kindly reviewing the manuscript and Dr. Stavros Pri-

Dr. Liu is a recipient of the Gordon E. Richards Fellowship, The Princess Margaret Hospital, 500 Sherboume St., Toronto, Canada M4X 1K9. Dr. Valdagni is supported in part by Fondazione per la Ricerca sul Cancro L. Pete, by Provincia Autonoma di Trento; and Dr. Kapp is supported in part by National Cancer Institute Grant No. CA-40434.

onas for his helpful advice. Accepted for publication 2 1 April 1988.

959

960

1. J. Radiation Oncology 0 Biology 0 Physics

remained significant. In addition to the listed authors in Table 1, both Oleson et d4* and Hofman et ~1.~~had found tumor size to be a significant predictor of poor clinical control with p values of
Table 1. Tumor size as a prognostic factor

Author

Heating device

Kim et al.”

RF 13.56 MHz or 27 MHz RF 8 MHz or 13.56 MHz

Hiraoka et al. 21

Luk et a1.35

Dewhirst et al. ’’ Arcangeli et

MW 2450 MHzor915 MHz MW915MHz

MW 500 MHz

aL3 RF 4 MHz or MW 433 MHz MW 280-300 al.” MHz KAPP et a1.29 MW 434 MHz or US l-2 MHz Gonzalez Gonzalez et al.” Valdagni et

Seegenschmi edt et al.59 Perez et a1.48

Valdagni et

al.”

MW 915 MHz MW 915 MHz

MW 915 MHz or RFO.l-1 MHz (interstitial) MW 280-300 MHz

Tumor

Complete response

dimension

@)

< 10 CM3 >10CM3 <4 CM 4-10CM >lOCM <4 CM2 >4 CM2

73 65 100 59 0 70 48

<1 1.8CM3 11.8-54 CM3 >54 CM3 2-10 CM3 13-24 CM3 26-54 CM3 <3 CM 3-6 CM >6 CM <6 CM 6-8 CM <5 CM3 >5 CM3 <300 MM2 >300 MM2 <3 CM >3 CM <100CM2 >100CM2 <2 CM 2-4 CM >4 CM <4 CM r4 CM

77 32 23 100 60 69 89 80 75 75 36 81 25 88 25 75 30 93

<6 CM 6-7 CM <52 CM3 >52 CM3

::: 48 A: 35

83 80 82 83

October 1988, Volume 15,Number 4

same observation of a higher average maximum temperature in larger tumors was also noted by Oleson et uL4* If the thermal washout measurement were considered as an accurate reflection of relative blood flow rate, then based on the Stanford data reported by both Samulski et ~1.~’and Valdagni et al.,‘* the relative blood flow rate would be significantly higher at the tumor-normal tissue interface than at the center of the tumor. This clinical observation was corroborated by the in vivo work by Song6* and Endrich et al. I4 This scenario may be analogous to the Thomlinson and Gray model of anoxic, hypoxic and aerated cells of human bronchogenic carcinomas.66 It can be postulated that the interface region might contain the potentially clonogenic cells that may ultimately define failure of local control. It logically follows that the larger the tumor volume, the larger the interface area, and this may be one possible explanation for this apparently paradoxical relation between tumor size and complete response rate. It follows then, that instead of concentrating on the maximum tumor temperature obtained, the minimum tumor temperature might be a more important predictor for local control. This observation was first noted in murine tumors by Hahn,” and in human tumors by Oleson et ~21.~~ With the presently available technology, it is easier to heat smaller tumors homogeneously than larger tumors.3’ Kapp et al. 29 had demonstrated a lower minimum temperature for tumors >5 cm3. This may be a function of inferior heating at greater depths. Perez et uL4* demonstrated that 70% of tumors <4 cm in depth achieved temperatures >42.5”C, as opposed to less than 10% for tumors >4 cm in depth (using 9 15 MHz microwaves). Abe et al.,’ using the Thermotron RF-8, found a decreasing complete response rate with increasing depth of tumor location. The complete response rates for superficial (~3 cm), subsurface (3-6 cm), and deep (>6 cm) tumors were 68%, 54%, and 23% respectively. An historical analogy may be drawn from the experience with Hodgkin’s disease,26 whereby megavoltage has replaced orthovoltage radiation because of its skin-sparing property and improved depth dose distribution. Perhaps with future equipment improvement plus use of blood flow modifying agents, tumor size may no longer be an adverse prognostic factor. Therefore, when assessing the relation between tumor size and response rates, it is important to also examine the device utilized, the form of energy chosen, and the frequency of operation, since all these factors will affect the ease with which different tumors can attain homogeneous heating. This may be one explanation for Figure 1, whereby despite different methods to calculate tumor volumes, there is no obvious maximal volume above which tumor control cannot be achieved when inter-institutional comparisons are made. In summary, large tumor size is presently a significant adverse factor in the response of tumor lesions to Ht and

Outcome of combined radiation and hyperthermia 0 R. VALDACNI efal.

+--

Not Specified Valdagni 7o Valdagni70+_t--~

K.ppzg 80

-+-*

Dawh,rrt ”

?? -f;;;&O

Arcangela

.

.

Kim 3E__, 60

Arcangeli3

01 ’ 0

’

10

’

’

20

’

’ 30

’

’

’

40

TUMOR VOLUME

’ 50

’ ;o

‘40

(cc)

,IIT

Fig. 1. Complete response rates as a function of tumor volume. Inter-institutional comparison of local control and different tumor volumes indicates no volume above which control cannot be achieved.

XRT. There are however, other variables that may alter the relation between tumor size and response rate. In the design of future XRT and Ht clinical trials, tumor size should be considered as a stratification variable. Histology. Review of the relation between histology and local control reveals that there is no histologic subtype which is particularly sensitive to the effect of combined XRT and Ht. Definitive evaluation of this issue is hindered by other accompanying factors which may

961

influence the ultimate outcome. Histologic subtype may of course be a function of its site. For example, the histology of chest wall diseases is usually an adenocarcinoma from recurrent breast cancer. The tumor’s subsequent response may also be influenced by the type and shape of the applicator used. In addition, different regimens of radiation dose per fraction may be chosen for different histologies. Most melanoma lesions were not irradiated with conventional dose per fraction (180-200 cGy), which may subsequently alter the complete response rate of these tumors. As shown in Table 2, both squamous cell and adenocarcinoma lesions have complete response rates ranging from 30% to 100%.4.6.7,9,17,18,21,22,24.32,35,38,47,48,69 Kim et ~1.~’had suggested that melanoma lesions were more sensitive to the effects of combined XRT and Ht than other neoplasms, however the experience reported in the literature does not corroborate this. The complete response rates for melanoma range from 33%-79%, which is comparable to that of other histologies (Table 2). Experience with sarcoma is limited; this merely reflects the relative rarity of this neoplasm. Total number of patients in each report is less than 10, and there is a wide range in complete response rates which does not permit conclusions to be drawn about this histologic subtype. In addition, sarcomatous lesions can become quite large, and tend to spread along fascial planesSo such that their heating would be very limited by the use of superficial external applicators. Using univariate and multivariate analyses, Oleson et a1.42found no correlation between histology and com-

Table 2. Complete response as a function of histology Complete response (o/o) No. of

Author Bicher et a1.6 Cony et al9 Kim et al.32 Hiraoka et al.*’ Hofman et a1.22 Luk et al.35Sample Xb Sample Yb Matsuda et al.38 Richer et al.’ Gonzalez Gonzalez et al. ‘73’8 Arcangeli et aL4 Howard et a1.24,d Perez et a1.47.48 Valdagni and Amichetti69

patients or lesions 82 21 86 33 61 63 27 20 125 88 59 13 199 101

Lymphoma

Squamous cell carcinoma

100

37

-

81 -

100

-

50 83 61 46 83 49 79 100 58 50-78’

a Inoperable breast CA: CR = 30%; Chest wall recurrence: CR = 6 1%. b X: biweekly XRT + Ht Y: daily XRT + biweekly Ht. ’ Inoperable breast CA: CR = 100%; chest wall recurrence: CR = 50%. d Overall response. e Palliative XRT: CR = 50%; radical XRT: CR = 78%.

Melanoma 47 64 82 67 67 57

33 50 76 80 79 75

Adenocarcinema 73 57 90 43 30-6 la 40 86 64 64

50- 100’ 100 46 58

Sarcoma 0 100 40 3 33

-

43

962

I. J. Radiation Oncology 0 Biology 0 Physics

plete response rates. Van der Zee et a1.73also found no difference between response rate of adenocarcinoma lesions as compared to other histologies analyzed per Spearman ranks correlations. There have been only 2 groups that used combined XRT and Ht on patients with lymphoma;6,32 the latter group included patients with lymphoma cutis and mycosis fungoides. Both centers obtained respectable results ranging from 8 1%- 100% local control. In summary, the experience to date does not give any indication that different histologic subtypes would have differing responses to combined XRT and Ht. More experience with lymphoma may be warranted however, in view of the promising preliminary results of the two aforementioned reports. Site ofdisease. Evaluation of the site of disease as a prognostic factor cannot be performed without considering the device used to treat the tumor since this would obviously influence the attained intratumoral temperatures. In terms of superficial hyperthermia treatments, neither Bicher et al.’nor Oleson et aL4*found site of disease to be a prognostic parameter for local control. The only group that had analyzed site of disease in a univariate fashion and found it to be significant was Luk et aI.36 It was observed that head & neck or thoracic sites yielded a 56% response rate vs 32% for all other sites (p = 0.03). When a log-linear model was used for analysis however, site no longer ranked significantly. In regional hyperthermia, both Sapozink et a1.54355 and Issels et al.*’ using the annular phased array system (APAS),67 have reported higher complete response rates with pelvic tumors as opposed to abdominal lesions. In the University of Utah experience, patient tolerance was also superior when the target tissue was located in the pelvis. Systemic stress occurred in 43% of abdominal treatments as opposed to 25% for pelvic treatments.54.55 The same group reported a 26% complete response rate for pelvic tumors vs 0% for abdominal tumors.54.55 Issels et a1.25found that two-thirds of pelvic tumors attained >42S”C as compared to only 1 out of 5 for abdominal tumors. The Japanese experience with a radiofrequency (RF) capacitive heating equipment (Thermotron-RF8) appears to be different from that of APAS heating (vide supra). The thickness of subcutaneous fat, tumor site, and tumor size are all more important factors determining heating efficacy than systemic stress. In theory, one would predict that subcutaneous fat, due to its high resistivity, would be very easy to heat. This is indeed borne out by clinical experience whereby the limiting thickness of subcutaneous fat is apparently 1.5 cm. It is also evident that rectal cancer and some liver neoplasms achieve higher intratumoral temperatures more readily than pancreatic or uterine cervical cancers. The poorer heating in the latter two tumors may be attributable to the surrounding bowel gas which may interfere with RF pen-

October 1988, Volume 15, Number 4

etration (M. Hiroaka, written communication, July, 1987). In summary, for superficial therapy, site of disease is probably not a significant factor. For deep-seated tumors however, site is apparently important. Using the APA device, pelvic tumors achieve a higher complete response rate than abdominal tumors. Pelvic heating is better tolerated than abdominal heating, with the former achieving higher intratumoral temperatures than the latter. For Thermotron-RF8 heating however, different locations of tumors within either the abdomen or the pelvis appear to influence the ultimate outcome. Treatment parameters Radiation therapy. The administered radiation dose is obviously extremely important in the response of neoplastic lesions to the combined effects of XRT and Ht. There are 2 aspects of radiation dose that will be discussed in this paper. One is the prescribed total tumor dose and the other, dose per fraction. Total treatment time is not discussed in this paper since its effect is usually determined by the other two variables. How these 2 aspects of radiation dose influence the ultimate response of tumor to therapy is difficult to ascertain. Total radiation dose is a function of both dose per fraction and total number of fractions. The prescribed dose per fraction is also related to histology and tumor site. Most high dose per fraction regimens are prescribed for melanoma lesions due to the belief most radiation oncologists hold of the high reparative capacity of melanoma tumors. This was examined and recently reviewed by 0vergaard.45 The site of disease to be treated with combined therapy is also important in that it will dictate how much more radiation the normal surrounding tissues will tolerate on a repeat treatment, and the dose per fraction chosen. As illustrated in Table 3, there definitely appears to be a trend towards higher local control with higher total radiation dose.7,28,36,49,65,70,73 Oleson et a1.,42van der Zee et a1.,73and Luk et al.36all found that total radiation dose was a statistically significant influence on complete response rates. One confounding factor in these analyses was the non-uniformity of patients in terms of previous radiation exposure, which would influence the subsequent total dose prescribed. In addition, a previously irradiated tumor bed has likely sustained damage to its vascularity, and thus may not respond the same way as un-irradiated tissue. Luk et aZ.36actually found recurrent disease status to be a significantly favorable factor in tumor response. Despite the above issues, when Dewhirst et al. analyzed the control rate on 115 large animal lesions treated with palliative intent, a positive correlation between total radiation dose and disease control was still found (p < O.Ol).” The influence of dose per fraction is not as consistent as that shown for total radiation dose. Table 4 contains

963

Outcome of combined radiation and hypetthermia 0 R. VALDAGNI et al. Table 3. Tumor

response

Author/Histology

as

a function of total radiation dose

Radiation No. of dose patients or lesions (GY)

Table 4. Local control as a function of high dose per fraction Dose per

Complete response

No. of patients

@) Author/Histology

Perez et a1.49 Melanoma + adenocarcinoma Luk et a1.36 Various tumors Tan and Li65 Head and neck tumors Kapp et aI.” Various tumors van der Zee et al.” Various tumors Bicher et al.’ Various tumors Valdagni et al.” Neck lymph nodes (squamous carcinoma)

52 133 50 43 111 111

54

<20 20-32 32-40 <40 >40 <45 45-60 >60 <23.4 36-44 <39 r39 20 40 50-74 <60 260

36 50 76 32 75 33 50 66 50 71 27 62 42 65 69 50 78

a list of complete response rates for high dose per fraction regimens, that is, ~300 cGy/fraction.2,4,‘7.‘8.2’.24.3’.35*48.49~56 Interpretation on this issue is difficult due to the confounding influence of total dose. Luk et ~1.~~did not find a correlation between dose per fraction and response rate. If one examines however, the report from Gonzalez Gonzalez et ui.,” whereby 24 Gy was the total radiation dose administered to 25 patients with melanoma, the doubling of dose per fraction from 4 to 8 Gy resulted in a similar doubling in the complete response rate. Furthermore, an inter-institutional comparison of complete response rates and dose per fraction suggests that a positive relation may exist, though this has never been subject to a statistical analysis (Table 4). If one confined this analysis to melanoma, then a definite positive trend is observed with an improving complete response rate as the dose per fraction is increased (Fig. 2). This is not the same apparent effect observed with radiation alone for melanoma lesions. In Overgaard’s recent review, 45 there was no advantage to increasing the dose per fraction beyond 4 Gy per dose. This implies that with the addition of heat, the biologic behavior of melanoma, and their response to the tumoricidal effects of ionizing radiation may be altered. In summary, both total radiation dose and dose per fraction are very important factors in the treatment of tumors with combined XRT and Ht. Total radiation dose appears to be a treatment parameter which can significantly influence the complete response rate. The effect of dose per fraction is less clear, though adoption of a high dose per fraction regimen for melanoma seems to improve the final outcome.

Perez et aI.@ Melanoma

Head and neck Scott et ~1.‘~ Melanoma Hiraoka et a/.21 Variety Kim el cr/.” Melanoma Luk el al.” Variety Gonzalez Gonzalez et al.” Melanoma

Gonzalez Gonzalez et al. ‘s Breast recurrence Howard er a/ ” Variety Perez el crl ‘s Head and neck Alexander et al.’ Variety Amichetti and Valdagn? Melanoma Arcangeli et ul.‘,’ VarietyC Melanoma Melanoma Overgaard ef nl.’ Melanoma

or lesions

fraction (Gy)/No. of XRT per week

Complete Total dose (GY)

IO-20 20-32 32-40 20-32 32-40

Gy Gy Gy Gy Gy

response W)

61 83 70 25 58

22

4.0 GyJ2

35

4.0 Gy/2

I2

5.0 Gyl2

l5Gy

61

40’

4.0 GyJ2

32-60 Gy

53

27 23

4.0 Gy/2 6.6 Gy/ I

40 Gy 39.6 Gy

59 14

65b

3.0-4.0 Gy/2

17-44 Gy

52

I8 8 5 7

8.0Gy/l-2 6.0 Gy/ I-2 5.0 Gy/2 4.0 GyJ2

24Gy l8Gy 30 Gy 24 Gy

83 0 20 43

35

4.0 Gy/2

24 Gy

50

20’

4.0 Gy/2

24 Gy

45

99

4.0 GyJ2

20-45 Gy

46

37

4.0 Gy/2

40 Gy

35

4 20

5.0 Gy/2 6.0 Gy/2

30 Gy 30 Gy

100 80

25 13 8

5.0 Gy/2 5.0 Gy/2 6.0 Gy/2

40 Gy 40 Gy 30 Gy

72

21

8.0-9.0 Gy/3

24-27 Gy

90

71 75

’ 34 patients received outlined treatment. b 63 patients received outlined treatment. ’ I6 patients received outlined treatment. * unpublished data. ‘CR = 77% if Ht immediately followed XRT; CR = 67% if Ht followed XRT by 4 hrs. ‘Personal written communication.

RESULTS

Hyperthermia Thermal variables: One of the major difficulties encountered in the evaluation of hyperthermia treatments is the concept of thermal dose. There is no functional equivalence in hyperthermia to the absorbed energy per unit mass (Gray) used in radiation therapy. Attempts to quantitate thermal dose include the degree-minute concept, whereby the time-temperature integral above a specific temperature, for example, 4 1“C, is calculated. Sapareto and Dewey52 introduced the equivalent-minutes

964

1. J. Radiation Oncology 0 Biology 0 Physics

:

60-

October 1988, Volume 15,Number 4

??

x $3

o Arcangeli et al4

z

0

40 -

A Kim et a130 1 Perez et a14’

? w z! I 8

??Kim et a13’ D Gonzalez Gonzalez et alI7 20 -

D A

0. 0

I

I

200

1

I

400

I

D Amichetti & Valdagni* ??Overgaard + n

I

600

DOSE PER FRACTION

I

800 kGyl

Fig. 2. Complete response rate as a function of dose per fraction. Inter-institutional a positive correlation between these two variables. *See Table 4 for reference.

concept, which was based on the assumption of a biologic isoeffect relation of various combinations of timetemperature treatments. Both these concepts are limited by the exclusion of other important biologic parameters such as thermotolerance, interaction between radiation and hyperthermia, effect of sequencing, and variations in XRT-Ht fractionations. Different authors use different methods to report the thermal dose. Simple reporting of minimum, maximum or average tumor temperatures is also used and thus far, no one approach has proven to be superior to another. An alternate reason the thermal dose concept is difficult to define is due to limitations of existing thermometry systems. Presently, one cannot obtain a realtime 3-dimensional appreciation of the temperature distribution in the target tissue. Most centers use either a multi-point static thermometry system, or only 1 or 2 thermometry probes mapped through tumor tissue (as first suggested by Gibbs et al. 15),or a combination of the above. This only provides temperature information along 1 or 2 lines through the tumor, which may or may not be representative of the temperatures in the remainder of the target tissue. Despite the above constraints, attempts have been made to correlate measured temperatures to either response or complication rates (Table 5). 3,4.11-13,21,28,36.42.55.58.60,64,73.74 It is difficult to determine which thermal parameter was most predictive of local control, but several authors have found values representing minimum tumor temperatures to be most helpful. Dewhirst,1’-13 Luk,36 Oleson,42 Kap~,~* van der Zee,73 Storm,64 Seegenschmiedt59 and their co-workers, have all found that thermal parameters reflective of the lowest intratumoral temperatures were most useful in predicting response rates. In Dewhirst et d’s randomized trial of XRT vs XRT + Ht on spontaneous animal tumors,‘* it was concluded that the

I

1000 3127

comparison

of data suggests

average minimum Eq43 time on the first heat treatment was the most important predictor for both complete response rate (p < 0.00 1) and response duration (p < 0.05). In the human experience, Oleson et d4* performed a Phase I study of combined XRT with Ht, and found in a univariate analysis that the average minimum temperature for all hyperthermia techniques was statistically significant for response prediction (p c 0.0005). In a multivariate analysis however, this variable no longer remained significant because of the greater influences of treatment technique (p = 0.01 I), radiation dose (p = 0.019), and tumor volume (p = 0.001). The Stanford group28 found several thermal parameters from both the first and the overall treatments that were significant predictors for either complete response rates or duration of response. Van der Zee et al.,73after an exhaustive statistical analysis, also found that all thermal parameters pertaining to the minimum tumor temperature correlated with the overall response rate (p < 0.025). The correlation between minimum temperature parameters and local control makes biologic sense, because the tumor cells that were exposed to the lowest temperature are likely the ones that will ultimately dictate failure. Following the above reasoning, it is important to consider both the intratumoral and peri-tumoral temperatures since the tumor periphery, with its high vascularity, may well be the region still containing potentially viable and clonogenic cells at the conclusion of hyperthermia treatments. Two authors have correlated the maximum temperature measured with complications rates in the human experience. Luk et a1.37found that once tumor temperature exceeded 44”C, this was associated with a 56% probability of burns and a 33% likelihood of blister formation. More recently, Seegenschmiedt et ~1.~’ found that the total or mean T,,, 43 equivalent minutes correlated posi-

965

Outcome of combined radiation and hyperthennia ??R. VALDAGNI et al. Table 5. Thermal parameters that correlate with response rate

Author/Type

of tumor

Dewhirst et al. l3 Variety animal tumors Dewhirst and Sim” Variety animal tumors Hiraoka et al.*’ Variety Luk et al.36 Variety Oleson et aL4* Variety Sim et aLm Variety animal and human tumors Van der Zee et all4 Breast Arcangeli et aL3 Neck nodes Kapp et a12’ Breast

Dewhirst et al. ” Variety Sapozink et aLi Pelvis Van der Zee et all3 Variety

Arcangeli et aL4 Melanoma Storm et a1.64 Variety Seegenschmiedt et a15* Breast

tively with their complication

No. of lesions 59 116 40

Thermal parameter Minimum

Eq43 at first treatment

Average minimum

Eq43

Average tumour center temperature

133

Lowest daily average temperature

161

Minimum

109

Estimated treated volume (ETV) obtaining >42.5”C.

82 38 31

115 43 112

38 100

21

tumor temperature

averaged over all treatments

Mean temperature Mean of maximum temperature Average overall Eq42.5 % temperature % temperature

< 4O.o”C 2 42.5”C

Minimum temperature Average temperature % temperature I 4O.o”C % temperature 2 42.5”C Minimum Eq43

First treatment

Average all treatments

Number of treatments with any tumor temperature

242°C at sometime

Mean minimum Tmean Mean minimum Tmax Total minimum DMEqT43 Total minimum EqT43 EQ42.5 Lowest tumor temperature1st treatment Eq43-first treatment Cumulative Eq43 for all treatments Total/mean minimum Eq43

rate. In Valdagni et d’s randomized trial of radical XRT vs XRT + Ht for neck nodes, some tumor core temperatures reached 59°C but no difference in acute complications was demonstrated between the two arms of the study.” One major difference that may explain the discrepant results between the experiences of Luk et aL3’ and Valdagni et al.” is that the majority of lesions in the former study arose from the chest wall, as opposed to neck nodes for the latter trial. It is much easier to attain a high tumor temperature in a bulky neck node without deleterious effect on the surrounding normal tissues than attempting the same on a diffusely infiltrating lesion on a flat chest wall. The duration of each heat treatment in excess of 30 minutes does not appear to be critically significant. Different time periods of 30 minutes,3,42,70 45 minutes3’*’ or 60 minutes7*48*63*73 all result in similar response rates. As the discussion has thus far demonstrated, there are so many other prognostic factors that

once 30 minutes of selective tumor heating is achieved, perhaps longer durations are not really necessary, though this has never yet been a subject of a clinical trial. The device chosen to treat a tumor would obviously have significant impact on the resultant thermal variables and the subsequent response rate. Oleson et CZ~.,~* reporting their experience with regional, superficial and interstitial hyperthermia between 1977- 1982, found technique to be a significant factor for both response rate (p = 0.11) and mean maximum (Tmax) and mean minimum (T,& temperatures. Interstitial hyperthermia achieved both the highest T,,, and Tmin of 44.2”C and 4 1.2”C respectively. In a later study involving treatment of pelvic tumors, Oleson et ~1.~’found that the APA device6’ achieved higher intratumoral temperatures than the magnetic induction device (p < 0.001).40 Finally, Sim et al., in an update on the University of Arizona experience, found that the complete response rates varied significantly with the technique used.6’ The rate of com-

966

I. J. Radiation Oncology 0 Biology 0 Physics

plete responses for interstitial, external microwave heating, and magnetic induction coils were: 39%, 30%, and 5% respectively (p < 0.0005). In contrast, Perez et ~1.~~found no difference in response rates of recurrent head and neck tumors treated with either interstitial microwave or radiofrequency antennae combined with XRT. Additional information on the device issue will be available once the results from the NC1 Contract on Evaluation of Equipment for Hyperthermia Treatments of Cancer are published in toto. This work comprised of the evaluation of 50 different Ht devices, utilized on >800 patient sites, during 4800 Ht sessions.53 The devices were evaluated on the basis of thermal parameters achieved and resulting toxicities. Theoretically, one would expect that the type of device used would influence ultimate control of the disease. An ideal heating device would satisfy the following criteria: 1. Provide uniform heating: 2. Be sufficiently versatile to be utilizable on different body sites; 3. Allow for patient contour variation; 4. Heating unhampered by different tissue types; 5. Cause minimal discomfort to the patient.

Such an ideal heating device would be expected to achieve superior tumor control than one that did not satisfy the above criteria. In summary, no one method of temperature reporting is superior to any others in terms of correlating with response rates. The majority of reported experience to date does suggest that measurements reflective of the minimum tumor temperature appear to best predict for response rates, and in some instances, also the response

October 1988, Volume 15, Number 4

duration. It also appears to be important to control the maximum temperature for superficial heating since it may correlate with the acute complications of hyperthermia treatments. Total and weekly number ofhyperthermia sessions. To date, the optimal total number of heat treatments necessary for combined XRT and Ht therapy and in association, the number of heat treatments per week are not known. Table 6 contains a summary ofboth randomized and non-randomized studies comparing different hyperthermia schedules.2~4~5,2’*29~3’*70*7’ It is apparent that no one schedule provides superior control compared to another. If the preliminary results of the 3 randomized trials by Alexander et aL2 Kapp et a1.,29and Valdagni et a1.,68are examined, there is no evidence that more treatments are necessarily better. In fact, Kim et aZ.‘$’ nonrandomized and Alexander et aZ.‘s2 randomized study both suggest slightly superior control for patients treated with fewer total number of heat treatments, administered once a week. One possible biologic explanation for this observation may be the phenomenon of thermotolerance. Thermotolerance has been defined as any heat-induced transient increase in heat resistance.” Thermotolerance kinetics are extremely complex and clearly depend on the basal temperature, rate of heating, temperature attained, duration of heating, and the presence of step-down heating.” In vitro” and in vivo34data have indicated that thermotolerance may start to decay by 30-72 hours. Data on the kinetics of thermotolerance in human tissue is not yet available. Perhaps the reason that increasing the total number of heat treatments, or administering it more than once a week, does not offer any therapeutic advantage is due to the development and persistence of ther-

Table 6. Resnonse as a function of number of total and weekly heat treatments

Author1 Histology

Randomized study

No. of patients or lesions

Total no. ofHt

No. of weekly Ht treatments

Complete response (%)

Arcangeli et al.5 Variety Hiraoka et al.” Variety Kim et aL3’ Melanoma Valdagni et al.” Neck nodes

No

23

No

40

No

50

No

19b

Yes

48

No

21

Yes

38”

Yes

17

5 10 2-7 8-12 6 10 <6 6 >6 4 8 5 8 2 6 2 6

1 2 2 2 1 2 2or3 2or3 2 or 3 1 2 2 2 1 2 2 2

64 78 50 53 74 59 83 50 71 42 21 75 77 68 63 85 80

Alexander et al.2 Variety Arcangeli et a1.4 Melanoma Kapp et a1.29 Variety Valdagni et al.703b Neck nodes a 1 lesion per treatment field. b radical XRT + Ht.

Outcome of combined radiation and hyperthermia 0 R. VALDAGNI etal.

motolerance. With further progress in dansyl lysine staining technique75 and quantification of HSP 70,* both of which can potentially predict for thermotolerance, it may be possible in the future to utilize these assays clinically to determine the optimal hyperthermia fractionation regimen. In summary, none of the presently reported XRT and Ht regimens have demonstrated superior local control results. It can be concluded however, that the administration of a large number of hyperthermia sessions, several times a week, appears unjustified. Further clinical work in clarifying this issue is crucial to the future of clinical hyperthermia. In a milieu of limited medical resources, it becomes very important to determine the optimal Ht and XRT regimen so that needless treatments to patients, and unnecessary expense to the system may be obviated. Sequence of Ht and XR T One of the major goals in combined XRT and Ht treatments is to optimize the thermal enhancement ratio (TER), which can be radiobiologically defined as the ratio of radiation dose needed without, and with hyperthermia to achieve the same biologic end-point on the target tissue. According to Overgaard’s in vivo work on mouse mammary tumors, maximal TER is obtained with simultaneous administration of Ht and XRT.43 This is presently impossible to accomplish in human patients. Most centers administer heat following XRT for logistic reasons to minimize the interval between the two treatments. The rationale for this is derived from the same study by Overgaard where it was demonstrated that as the time interval between Ht and XRT increased, the TER for tumor decreased.43 Table 7 contains reports whereby Ht did not routinely follow XRT.k%l0.31,33,46 If one compares the results from groups which administered Ht following XRT,2’,35*48,56.70,7’ their reported local control rates are not significantly different from that of the Ht-XRT sequences. Both Arcangeli et al.’and Overgaard & 0vergaard46 have tested XRT followed by immediate heat (within 30 min-

967

utes), vs XRT followed by delayed heat (3-4 hr). Both prescribed unconventional dose per fraction of 500 cGy and 400 cGy respectively. An interesting finding from both groups was that the therapeutic gain was greater for the patients treated with the delayed regimen. The TER of normal surrounding tissue is just as important as the TER for tumor since there is no ultimate benefit if Ht equally enhances damage to normal structures. The ratio of the TER of tumor vs TER of normal tissue is the therapeutic gain factor (TGF). Overgaard & Overgaard46 found a TGF of 1.3 after delayed treatment vs 1 for immediate treatment. Similarly, Arcangeli et al.’ found a TGF of 1.4 for the former, and 1.2 for the latter treatment sequences. These clinical findings are in agreement with murine tumor studies by 0vergaard43 and Hill & Denekamp” which suggest that TER of the tumor remains > 1 for up to 24 hours between XRT and Ht. In normal tissues however, TER returns to 1 within 4 hours. Thus, if both tumor and normal tissues were treated to the same extent, therapeutic gain would be best achieved by a 4 hour interval between XRT and Ht. Both Overgaard & Overgaard46 and Arcangeli et al.’however, recommend that if one can selectively heat the tumor without heating the surrounding normal tissue, for example, a well-defined neck node, Ht immediately following XRT would be the optimal sequence. In summary, there is no apparent optimal sequence for combined XRT and Ht treatments, except that the interval between the two treatments should be kept to a minimum to maximize the TER for tumor tissue. If one can finely adjust and carefully monitor the target tissue temperature so as to minimize acute normal tissue damage, then perhaps the delay between XRT and Ht may not be absolutely necessary even when selective heating is not easily achievable. DISCUSSION

Evaluation of results The most important end-point used in the evaluation of clinical trials is the final outcome of patients undergo-

Table 7. XRT + Ht clinical trials: “Unconventional” sequence of Ht + XRT No. of lesions

Authors

Cony et ~21.~ Kim et aL3’

Overgaard and Overgaard46

21 28 22 13 12 65

Lauche et a1.33 Cosset et al. lo

22 57

Arcangeli et al.’

’ TER: Thermal enhancement

Sequence Ht-XRT Ht-XRT XRT-Ht XRT-Ht XRT-Ht XRT-Ht XRT-Ht Ht-XRT Ht-XRT

ratio based on 50% tumor control dose.

(immediate) (4 hours’ delay) (immediate) (3-4 hours’ delay) (interstitial)

Complete response (%) 62 64 68 77 67 TER = 1.5” TER = 1.3’ 41 79

I. J. Radiation Oncology 0 Biology 0 Physics

968

ing a particular therapeutic regimen. Almost all the authors in the clinical hyperthermia literature abide by the WHO definition of complete response (CR), partial response (PR), no response (NR), and disease progression.39 One difficult issue that remains to be clarified is the time at which response was assessed. Obviously it is also important to state the beginning of the time period, that is, whether counting started at the initiation or at the completion of therapy. “Early” response is usually defined at the completion of therapy or shortly thereafter. Tumor response is a dynamic phenomenon, thus “early” response may not necessarily represent maximal response. As demonstrated by the work from Scott et als7 and Hofman et ai.,22 maximal complete response rates were not attained till the 4th to 6th months’ follow-up. Long-term follow-up in the majority of patients selected for combined XRT and Ht treatments is not readily obtainable, since most patients either die from disseminated disease, or are subject to subsequent systemic therapy which preclude further evaluation of the results of local therapy. Nevertheless, more experience is accumulating with the use of combined radical XRT and Ht as definitive initial therapy, which will permit longer follow-up time on these patients. It then behooves the authors not only to report the times of response evaluation, but also to report these results using an actuarial method to account for patients lost to follow-up, or who have died from either systemic cancer or other causes, but with continued local control.

October 1988, Volume 15,Number 4

Review of some of the reported results in the literature (Table 8) indicates that “early” response for breast carcinomas and head & neck metastatic lymph nodes, do translate into a durable control in 62-9 1% of instances. 4V’*V22*23,27,47,57 A common difficulty shared by combined XRT and Ht trials is the advanced disease status of the study patients which obviously compromises long-term follow-up. For Scott et al’s data on head & neck tumors,57 the maximal complete response rate of 78% occurred at 6 months. At the 1 and 2 year followup time, there were only 5 and 1 patients respectively available for evaluation, all of whom achieved local control. Similarly, for chest wall lesions, maximal complete response occurred at 6 months (94%).57 At 12, 18, and 24 months’ time intervals, 11, 8, and 5 patients were respectively available for follow-up, the vast majority of whom were complete responders. In their experience with neck nodes, Arcangeli et al. found that once the Eq42.5 time exceeded 305 minutes, the complete response rate increased from 58% to 92% at 2 years.4 Melanoma however, according to data from Arcangeli et aL4 Perez et a1.,47and Hofman et a1.23may have a more durable remission in that 70- 100% of controlled lesions remained so up to 36 months’ follow-up. The North American, European, and Asian literature to date has not demonstrated any survival benefit from the use of Ht with XRT. One reason may be related to the patient population chosen for these treatments such that a survival benefit is unlikely to be demonstrated. Another reason lies in the intent of presently adminis-

Table 8. “Early” and “durable” control rates

Author I. Breast carcinoma Scott et al.57

Early response %

Follow-up (months)/contorl

rates (%)

16

7-12

12-18

24

29

94

*

*

*

89 94 94

89 88 93

77 56 68

62 56

58

100 50

-

-

66

-

-

-

(45)

46

-

-

-

(34)

33 45 79

78 73

* 69

60

* 36 58

100

87 76 -

70 -

70 -

-

Hofman et a1.22,2” Previously non-irradiated recurrence Previously irradiated chest wall Breast primary Gonzalez Gonzalez et al. ‘* Breast primary Previousfy irradiated chest wall Kapp et al. Previously irradiated chest wall Perez et a1.47 Previously irradiated chest wall II. Squamous cell carcinoma neck nodes Scott et al. ” Perez et a1.47 Arcangeli et ai.4 III. Melanoma Hofman et a1.23 Arcangeli et aL4 Perez et aL4’ ( ): If only range of follow-up is specified. * See text.

76 79

-

(50)

-

76 63

Outcome of combined radiation and hyperthermia 0 R. VALDAGNI et al.

tered XRT and Ht, which aims for optimal loco-regional control, thus the anticipated impact on survival would be quite small. However, if one were to extrapolate from Overgaard’s experience with radiation treatment only for melanoma,45 whereby a superior survival was achieved by the group with persistent local control, then perhaps with careful patient and tumor selection, a survival advantage to the combined modality of XRT and Ht might be demonstrable. At the present time, there is not yet a standardized scheme for reporting hyperthermia complications. Acute and subacute toxicities may be reported by using a modified version of the WHO system,39 but long-term complications need continual careful surveillance since information in this area is still being accumulated. In summary, it is important to attempt standardization of response reporting, both in terms of the qualitative assessment, and times of their determination. Definition of response as outlined by WHO should be followed.39 Response evaluation should be performed initially at 3 months after completion of therapy. Further follow-up is obviously essential, but local control rates should be reported in an actuarial fashion to allow accurate interpretation of results. Finally, a grading system for acute and subacute hyperthermia complications should be established at the present time. Late complications of hyperthermia treatments are still undergoing continued observation and establishing a grading system at the present time may be premature. CONCLUSION This paper has attempted to summarize and discuss some of the factors that have prognostic influence on the outcome of malignant tumors treated with combined XRT and Ht. Among the pre-treatment parameters, tumor size at the present time would appear to negatively correlate with complete response rate. Perhaps with future improvement in hyperthermia equipment, tumor size may have less prognostic influence. Histology does not seem to be that important, and site is important only for regional hyperthermia. In the category of treatment parameters, total radiation dose is important for final

969

outcome. The effect of dose per fraction is less clear, but may be positively correlated, especially for melanoma le-

sions. Among the thermal variables studied, no one method of temperature reporting appears superior to another. Nevertheless, measurements reflective of minimal tumor temperature seem to predict for response. Similarly, maximal temperatures for superficial tumors need to be carefully monitored since they may correlate with acute complications, and possibly also influence late complications. The hyperthermia device used influences both the thermal and response results, but presently available literature does not permit a definite conclusion on this issue. There is no clear regimen for hyperthermia in terms of total number of treatments, number of treatments per week, or sequence of XRT and Ht that will result in a superior control rate. It is apparent however, that excessive number of heat treatments, several times a week, is presently unjustified. One important point to be noted is that the end-point used by most authors is the rate of complete response. To date, only a few groups have examined the duration of response as another end-point.12.28 If more analyses were consistently performed accounting for all the aforementioned variables for response duration, the significance of these currently identified prognostic indicators may be subsequently altered. Reporting of response according to a recognized system is important. The time of assessment also needs to be clearly stated. With availability of longer follow-up, adopting an actuarial method of response reporting becomes more important in order to permit intelligent interpretation of control rates. Acute and subacute complications should be reported according to a standard scheme, and continued surveillance of delayed complication is obviously still necessary. The future of hyperthermia treatments in combination with radiation is very exciting. There still remains a number of challenging questions that can only be answered by well-conducted and reported clinical trials. By designing trials in a thoughtful manner, and with cautious interpretation of their results, the definitive role of hyperthermia and radiation may soon be defined in cancer therapy.

REFERENCES Abe, M., Hiroaka, M., Takahashi, M., Egawa, 8, Matsuda, C., Onoyama, Y., Morita, K., Kakehi, M., Sugahara, T.: Multi-institutional studies on hyperthexmia using an 8MHz radiofrequency capacitive heating device (Thermotron RF-8) in combination with radiation for cancer therapy. Cuncer58: 1589-1595, 1986. 2. Alexander, G.A., Moylan, D.J., III, Waterman, F.M., Nerlinger, R.E., Leeper, D.B.: Randomized trial of 1 vs. 2 adjuvant hyperthermia treatments in patients with superlicial metastases (Abstr.). Presented at the Thirty-fifth Annual Meeting of the Radiation Research Society, February 21-26, 1987, Atlanta, GA, pp. 18.

Arcangeli, G., Arcangeli, G.C., Guerra, A., Lovisolo, G., Cividalli, A., Marino, C., Mauro, F.: Tumour response to heat and radiation: prognostic variables in the treatment of neck node metastases from head and neck cancer. Int. J. Hyperthermia l(3): 207-217, 1985. Arcangeli, G., Benassi, M., Cividalli, A., Lovisolo, G.A., Mauro, F.: Radiotherapy and hyperthermia: Analysis of clinical results and identification of prognostic variables. Cancer60:

950-956,1987.

Arcangeli, G., Nervi, C., Cividalli, A., Lovisolo, G.A.: Problem of sequence and fractionation in the clinical ap-

970

6. 7.

8.

9.

I. J. Radiation Oncology 0 Biology 0 Physics

plication of combined heat and radiation. Cancer Rex 44(Suppl.): 4857s-4863s 1984. Bicher, HI., Sandhu, T.S., Hetzel, F. W.: Clinical Thermoradiotherapy. Henry Ford Hosp. Med. J. 29: lo- 15, 198 1. Bicher, HI., Wolfstein, R.S., Lewinsky, B.S., Frey, H.S., Fingerhut, A.G.: Microwave hyperthermia as an adjunct to radiation therapy: Summary experience of 256 multifraction treatment cases. Int. J. Radiat. Oncol. Biol. Phys. 12: 1667-1671, 1986. Birck, E.M., Mak, J.Y., Li, G.C.: Possibility of using HSP 70 as a predictor of thermal response in tumors during fractionated hyperthermia (Abstr.). Thirty-fifth Annual Meeting of the Radiation Research Society, February 2 l25, 1987, Atlanta, GA pp. 47. Cony, P.M., Spanos, W.J., Tilchen, E.J., Barlogie, B., Barkley, H.T., Armour, E.P.: Combined ultrasound and radiation therapy treatment of human superficial tumors. Radiology145:

165-169,

1982.

10. Cosset, J.M., Gerard, J.P., Janoray, P., Haie, C., De Laroche, G., Horiot, J.C., Dutreix, J.: Advances in interstitial thermoradiotherapy (Abstr.). Eighth Meeting of the European Society for Hyperthermic Oncology, September 2225, Tiberias, Israel. Int. J. Hyperther. 2(4): 396, 1986. 11. Dewhirst, M., Lindley, J., Vaguine, V.: Variables influencing the palliative treatment of malignant lesions with hyperthermia and radiation (Abstr.). Thirty-third Annual Meeting of the Radiation Research Society, May 5-9, Los Angeles, CA, 1985, pp. 27. 12. Dewhirst, M.W., Sim, D.A.: The utility of thermal dose as a predictor of tumor and normal tissue responses to Cancer Res. combined radiation and hypetthermia. 44(Suppl.): 4772s-478Os,

October 1988, Volume 15, Number 4

hyperthermia combined with radiation in the treatment of radioresistant cancers. Cancer 54: 2898-2904, 1984. 22. Hofman, P., Lagendijk, J.J.W., Schipper, J.: Thecombination of radiotherapy with hyperthermia in protocolized clinical studies. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis, 1984, pp. 379-382. 23. Hofman, P., Lagendijk, J.J.W., Schipper, J.: Long-term control of inoperable breast tumours (Abstr.). Eighth Meeting of the European Society for Hyperthermic Oncology, September 22-25, 1986, Tiberias, Israel. Znt. J. Hyperther. 2(2): 400, 1986. 24. Howard, G.C.W., Sathiaseelan,

V., Freedman, L., Bleehart, N.M.: Hyperthermia and radiation in the treatment of superficial malignancy: An analysis of treatment parameters, response and toxicity. Znt. J. Hyperther. 3(l): 1-8,

1987. 25. Issels, R.D., Wadepohl, M., Tiling, K., Mueller, M., Wil-

26.

27.

28.

1984.

13. Dewhirst, M.W., Sim, D.A., Sapareto, S., Connor, W.G.: Importance of minimum tumor temperature in determining early and long-term responses of spontaneous canine and feline tumors to heat and radiation. Cancer Rex 44: 43-50,

1984.

14. Endrich, B., Zweifach, B.W., Reinhold, H.S., Intaglietta, M.: Quantitative studies of microcirculatory function in malignant tissue: Influence of temperature on microvascular hemodynamics during the early growth of the BA 1112 rat sarcoma. Int. J. Radiat. Oncol. Biol. Phys. 5: 202 l2030,1979. 15. Gibbs, F.A.: “Thermal mapping” in experimental cancer treatment with hyperthermia: Description and use of a semiautomatic system. Int. J. Radiat. Oncol. Biol. Phys. 9:

29.

30.

1057-1063,1983.

16. Goldobenko, G.V., Durnov, L.A., Knysh, V.I., Amiraslanov, A.T., Kondrateva, A.P.: Experience with thermoradiotherapy of malignant tumors. Med. Radiol. (Mosk.) 32( 1): 36-38, 1987. 17. Gonzalez Gonzalez, D., van Dij k, J.D.P., Blank, L.E.C.M., Rumke, Ph.: Combined treatment with radiation and hyperthermia in metastatic malignant melanoma. Radiother. Oncol. 6: 105-l 13, 1986.

18. Gonzalez Gonzalez, D., van Dij k, J.D.P., Blank, L.E.C.M., Zum Vorde Sive Vording, P.: Combined treatment with radiation and heat in breast cancer (Abstr.). Eighth Meeting of the European Society for Hyperthermic Oncology, September 22-25, Tiberias, Israel, 1986. Int. J. Hyperther. 2(2): 399, 1986.

19. Hahn, G.M.: Hyperthermia and Cancer. New York, Plenum Press, 1982. 20. Hill, S.A., Denekamp, J.: The response of six mouse turnouts to combined heat and X-rays: implications for therapy. Brit. J. Radiol. 52: 209-2 18, 1979. 21. Hiraoka, M., Jo, S., Dodo, Y., Ono, K., Takahashi, M., Nishida, H., Abe, M.: Clinical results of radiofrequency

31.

32.

manns, W.: Regional hyperthermia combined with systemic chemotherapy for clinically advanced, deepseated malignancy: Preliminary results of a pilot study employing an annular phased array applicator (Abstr.). Hyperthermia Meeting ‘87-2nd European BSD Users’ Meeting, Munthen, W. Germany 1987, pp. 57. Kaplan, H.S.: Radiotherapy. In Hodgkin’s Disease. Cambridge-London, Harvard University Press. 1980, Chap 9, pp. 366-44 1. Kapp, D.S.: Chest wall treatments-Second recurrences. Presented at the Sixth Annual Hyperthermia BSD Users’ Conference. January 1 l- 13, 1987, Salt Lake City, Utah. Kapp, D.S., Bagshaw, M.A., Meyer, J.L., Samulski, T.V., Fessenden, P., Lee, E.R., Lohrbach, A.W.: Optimization of hyperthermia and low dose irradiation in the treatment of superficial tumors: A prospective randomized trial of 2 vs 6 heat treatments (Abstr.). Presented at the Thirty-third Annual Meeting of the Radiation Research Society, May 5-9, 1985, Los Angeles, CA, pp. 29. Kapp, D.S., Samulski, T.V., Fessenden, P., Bagshaw, M.A., Lee, E.R., Lohrbach, A.W., Cox, R.S.: Prognostic significance of tumor volume on response following localregional hyperthermia (HT) and radiation therapy (XRT) (Abstr.). Presented at the Thirty-fifth Annual Meeting of the Radiation Research Society, February 21-26, 1987, Atlanta, GA, pp. 17. Kim, J.H., Hahn, E.W., Ahmed, S.A.: Combination hyperthermia and radiation therapy for malignant melanoma. Cancer 50: 478-482, 1982. Kim, J.H., Hahn, E.W., Ahmed, S.A., Kim, Y.S.: Clinical study of the sequence of combined hyperthermia and radiation therapy of malignant melanoma. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. 1984, pp. 387-39 1. Kim, J.H., Hahn, E.W., Antick, P.P.: Radiofrequency hyperthermia for clinical cancer therapy. N.C.Z. Monog. 61:

339-342, 1982. 33. Lauche, H.M., Jung, G.M., Kotewicz, A., Hoen, J., Gauth-

erie, M.: Critical review of phase II-therapeutic trials of radiofrequency hyperthermia (13MHz) alone or combined with radiotherapy with special reference to head-and-neck tumors (Abstr.). VIIth Meeting of the European Society for Hyperthermic Oncology, September 16-18, 1985. Strahlentherapie 161: 541. 34. Law, M.P.: Thermotolerance

induced in the mouse ear by fractionated hyperthermia depends on the interval between fractions (Abstr.). VIIth Meeting of the European Society for Hyperthermic Oncology, September 16- 18, 1985 Paris, France. Strahlentherapie 161: 54 1. 35. Luk, K.H., Francis, M.E., Perez, C.A., Johnson, R.J.:

Outcome of combined radiation and hyperthermia 0 R. VALDAGNI et~1.

Combined

radiation and hyperthermia: Comparison of schedules based on data from a registry established by the radiation therapy oncology group (RTOG). Int. J. Radiat. Oncol. Biol. Phys. lO(6): 801-809, 1984. Luk, K.H., Pajak, T.F., Perez, C.A., Johnson, R.J., Conner, N., Dobbins, T.: Prognostic factors for tumor response after hyperthermia and radiation. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. 1984, pp. 353-356. Luk, K.H., Purser, P.R., Castro, J.R., Meyler, T.S., Phillips, T.L.: Clinical experiences with local microwave hyperthermia. Znt.J. Radiat. Oncol. Biol. Phys. 7: 615-619, 1981. Matsuda, T., Sugiyama, A., Nakata, Y.: Fundamental and clinical studies of radiofrequency hyperthermia and radiation therapy. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. 1984, pp. 349-352. Miller, A.B., Hoogstraten, G., Staquet, M., Winkler, A.: Reporting results of cancer treatment. Cancer 47: 207214, 1981. Oleson, J.R.: Hyperthermia by magnetic induction. I. Physical characteristics of the technique. Int. J. Radiat. Oncol. Biol. Phys. 8: 1747-1756, 1982. Oleson, J.R., Sim, D.A., Conrad, J., Fletcher, A.M., Gross, E.J.: Results of a Phase I regional hyperthermia device evaluation: Microwave annular array versus radiofrequency induction coil. Int. J. Hyperther. 2(4): 327-336, 1986. Oleson, J.R., Sim, D.A., Manning, M.R.: Analysis of prognostic variables in hyperthermia treatment of 16 1 patients. Int. J. Radiat. Oncol. Biol. Phys. 10:223 l-2239, 1984. 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.: Rationale and problems in the design of clinical studies. In Hyperthermic Oncology, 1984, Vol. 2, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. 1985, pp. 325-338. Overgaard, J.: The role of radiotherapy in recurrent and metastatic malignant melanoma: A clinical radiobiological study. Int. J. Radiat. Oncol. Biol. Phys. 12: 867-872, 1986. Overgaard, J., Overgaard, M.: A clinical trial evaluating the effect of simultaneous or sequential radiation and hyperthermia in the treatment of malignant melanoma. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Francis and Taylor. 1984, pp. 383386. Perez, C.A., Emami, B., Hederman, M.A., Straube, W., VonGerichten, D., Fox, S.: Clinical results of irradiation combined with local hyperthermia in superficial tumors (Abstr.). Thirty-fifth Annual Meeting of the Radiation Research Society, February 2 l-26, 1987, Atlanta GA, pp. 18. Perez, C.A., Emami, B., Scott, R.S., Homback, N.B., Gillespie, B.W., Hederman, M.A., VonGerichten, D.: Irradiation and hyperthermia in treatment of locally advanced and recurrent head and neck tumors. In Head and Neck Cancer: ScientiJic Perspectives in Management and Strategies fir Cure, Jacobs, J.R., Crissman, J., Valeriote, F.A., Al-Sarraf, M. (Eds.). New York, Elsevier Science. 1987, (In press). Perez, C.A., Nussbaum, G., Emami, B., vonGerichten, D.: Clinical results of irradiation combined with local hyperthermia. Cancer 52: 1597- 1603, 1983. Rosenberg, S.A., Suit, H.D., Baker, L.H.: Sarcomas of Soft

two treatment

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

971

Tissues, In Cancer, Principles & Practice of Oncology, 2nd edition, De Vita, V.T., Jr, Hellman, S., Rosenberg, S.A. (Eds.). Philadelphia, J.B. Lippincott Co. 1985, Chap. 36, pp. 1243-1291. Samulski, T.V., Fessenden, P., Valdagni, R., Kapp, D.S.: Correlations of thermal washout rate, steady state temperatures and tissue type in deep seated recurrent or metastatic tumors. Int. J. Radiat. Oncol. Biol. Phys. 13: 907916,1987. Sapareto, S.A., Dewey, W.C.: Thermal dose determination in cancer therapy. Int. J. Radiat. Oncol. Biol. Phys. 10: 787-800, 1984. Sapozink, M.D., Cony, P.M., Egger, M.A., Gibbs, Jr. F.A., Jabboury, K., Kantor, G., Kapp, D., Kong, J., Lele, P., Shimm, D., Shrivastava, P.: Report of the NC1 hyperthermia equipment evaluation contractors group (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 13(Suppl. 1): 138, 1987. Sapozink, M.D., Gibbs, F.A., Egger, M.J., Stewart, J.R.: Abdominal regional hyperthermia with an annular phased array. J. Clin. Oncol. 4: 775-783, 1986. Sapozink, M.D., Gibbs, F.A., Egger, M.J., Stewart, J.R.: Regional hyperthermia for clinically advanced deepseated pelvic malignancy. Am. J. Clin. Oncol. 9(2): 162169,1986. Scott, RX, 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. Radiat. Oncol. Biol. Phys. 9: 1327-1333,1983. Scott, R.S., Johnson, R.J.R., Story, K.V., Clay, L.: Local hyperthermia in combination with definitive radiotherapy: Increased tumor clearance, reduced recurrence rate in extended follow-up. Int. J. Radiat. Oncol. Biol. Phys. 10: 2119-2123,1984. Seegenschmiedt, M.H., Brady, L.W., Rossmeissl, G.: External microwave hyperthermia combined with radiation therapy for extensive superficial chestwall recurrences (Abstr.). Hyperthermia Meeting ‘87-2nd European BSD Users’ Meeting, April 2-4, 1987, Munchen, W. Germany, pp. 32. Seegenschmiedt, M.H., Brady, L.W., Tobin, R., Motyka, E.: Combining two or more microwave applicator fields for the treatment of widespread superficial chestwall recurrences (Abstr.). Presented at the Thirty-fifth Annual Meeting of the Radiation Research Society, February 21-26, 1987, Atlanta, GA, pp. 19. Sim, D.A., Dewhirst, M.W., Oleson, J.R., Grochowski, K.J.: Estimating the therapeutic advantage of adequate heat ($). In Hyperthermic Oncology, 1984, Vol. 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. pp. 359-362,1984. Sim, D.A., Oleson, J.R., Grochowski, K.J.: An update of the University of Arizona human clinical hyperthermia experience including estimates of therapeutic advantage. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Francis and Taylor. 1984, pp. 367-371. Song, C.W.: Effect oflocal hyperthermia on blood flow and microenvironment: A review. Cancer Rex 44(Suppl.): 4721s-473Os, 1984. Steeves, R.A., Severson, S.B., Paliwal, B.R., Anderson, S., Robins, H.I.: Matched-pair analysis of response to local hyperthermia and megavoltage electron therapy for superficial human tumors. Endocurie. Hypertherm. Oncol. 2: 163-170,1986. Storm, F., Roe, D., Drury, B., the Magnetrode Study Group: Analysis of thermaldose response to heat (Abstr.).

912

1.J. Radiation Oncology 0 Biology 0 Physics

Thirty-fifth Annual Meeting of the Radiation Research Society. February 21-26, 1987 pp. 16. 65. Tan, W., Li, Q.: Clinical effects of microwave combined with radiation in 50 headneck malignant tumor patients. In Hyperthermic Oncology, 1984. Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Taylor and Francis. 1984, pp. 351-358. 66. Thomlinson,

R.H., Gray, L.H.: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer9: 539-549, 1955. 67. Turner, P.F.: Regional hyperthermia with an annular phased array. IEEE Trans. Biomed. Eng. 31: 106-l 14, 1984. 68. Valdagni, R.: Two versus six hyperthermia treatments in combination with radical irradiation for fixed metastatic nodes: Progress Report. In Recent Results in Cancer Research. Berlin, Heidelberg, New York, Springer-Verlag (In press). 69. Valdagni, R., Amichetti, M., Pani, G.: Summary of recent clinical experience in hyperthermia combined with radiation (Abstr.). Hyperthermia meeting ‘87-2nd European BSD Users’ Meeting, April 2-4, 1987 Munchen, W Germany, pp. 25-26. 70. Valdagni, R., Amichetti, M., Pani, G.: Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: A prospective randomized clinical trial. Int. J. Radiat. Oncol. Biol. Phys. 15: 13-24, 1988.

October 1988, Volume 15, Number 4

7 1 Valdagni, R., Kapp, D.S., Valdagni, C.: N3 (TNM-UICC) metastatic neck nodes managed by combined radiation therapy and hyperthermia: clinical results and analysis of treatment parameters. Int. J. Hyperther. 2(2): 189-200, 1986. 72 Valdagni, R., Samulski, T.V., Cox, R.S., Kapp, D.S.: Local and regional hyperthermia treatment of superficial and deep tumors: Analyses of thermal washouts (Abstr.). Seventh Meeting of the European Society for Hyperthermic Oncology, Sept 16-18, 1985, Paris, France. Strahlentherapie 161: 552. 73. van der Zee, J., van Putten, W.L.J., van den Berg, A.P., van Rhoon, G.C., Wike-Hooley, J.L., Broekmeyer-Reurink, M.P., Reinhold, H.S.: Retrospective analysis ofthe response of tumours in patients treated with a combination of radiotherapy and hyperthermia. Int. J. Hyperther. 2: 337-349,1986. 74 van der Zee, J., van Rhoon, G.C., Wike-Hooley, J.L., van den Berg, A.P., Reinhold, H.S.: Thermal enhancement of radiotherapy in breast carcinoma. In Hyperthermic Oncology, 1984, Vol 1, Overgaard, J. (Ed.). London-Philadelphia, Francis and Taylor. 1984, pp. 345-349. 75. Woo, S.Y., Rice, G.C., Kapp, D.S., Hahn, G.M.: Predictive assay for human tumor cellular response to hyperthermia using Dansyl Lysine staining and flow cytometry. Znt. J. Radiat. Oncol. Biol. Phys. 14: 361-365, 1988.