In!. J Radrarmn Oncology Rio/ Phys, Vol. Pnnted in the U..C.A All rights reserved.

22. PP.

1009-1014

0360.3016192 $5.00 + .Xl Copyright c 1992 Pergamon Press Ltd.

??Hyperthermia Original Contribution

REGIONAL HYPERTHERMIA COMBINED WITH RADIOTHERAPY IN THE TREATMENT OF LUNG CANCERS MASAHIRO HIRAOKA, M.D.,’ SHIN-ICHIRO MASUNAGA, M.D.,’ YASUMASA NISHIMURA, M.D.,’ YASUSHI NAGATA, M.D.,’ SHIKEN Jo, M.D.,’ KEIZO AKUTA, M.D.,’ Yu PING Lr, M.D.,’ MASAJI TAKAHASHI, M.D.2 AND MITSUYUKI ABE, M.D.’ ‘Departmentof Radiology,Facultyof Medicine;and 2ChestDiseaseResearchInstitute,Kyoto University,Japan Twentylocallyadvanced lung cancers were treated by hyperthermia in combination with radiotherapy between November 1980 and January 1990. All tumors selected had invaded or were in contact with the chest wall, so that transcutaneous insertion of thermal probes into the tumor was possible. Using an 8 or 13.56 MHZ RF capacitive heating device, hyperthermia was given once or twice a week after irradiation for 30-60 min per session (l-12 sessions in total). Radiotherapy was delivered at dose of 13.6-70 Gy. The thermal parameters analyzed were a) maximum, average, and minimum intratumor temperatures (Tmax, Tav, and Tmin), which were recorded at the termination of each treatment, and b) the percentages of the intratumor points that exceeded 41 C (%T r 41 C). The mean + SD for Tmax, Tav, Tmin, and %T 2 41 C was 42.9 + 1.7 C, 41.6 + 1.2 C, 39.7 + 1.1 C, and 56.2 f 25.8, respectively. Larger tumors showed higher thermal parameters than the smaller tumors. Of the 12 tumors treated by definitive therapy, 2 (17%) achieved CR, 7 (58%) PR, and 3 (25%) NR. Four of 10 tumors that did not achieve CR showed large httratumor low density areas on post-treatment CT, reflecting massive coagulation necrosis. Higher thermal parameters were closely related to the appearance of low-density areas but not to changes in tumor sire. Four tumors treated preoperatively were successfully resected 2 weeks after thermoradiotherapy, whereas four palliatively-treated tumors showed no regression. The side effects associated with hyperthermia were pain in 12 patients (60%) and dyspnea in 3 (15%), all of which resolved after termination of treatment. A skin abscess and a pneumothorax attributed to thermal probe insertion were observed in one patient each. These results indicate that regional RF capacitive hyperthermia is clinically feasible for local treatment of selected lung cancers. Hyperthermia,

Lung cancer, Radiation therapy, Radiofrequency.

INTRODUCIION

METHODS

AND

MATERIALS

Lung cancers are the leadingcause of cancer-relateddeath in many countries. The local control rate of lung cancers by radiotherapy or surgery is still low, particularly in the case of locally advanced cancers. During the past decade, hyperthermia in combination with radiotherapy has proven to be an effective treatment modality for superficial tumors (7, 17). The application of this new treatment modality to lung cancers, however, had been very limited, mostly because of the physical difficulties associated with the delivery of heat and the measurement of temperature (3). Previously we have demonstrated that a radiofrequency (RF) capacitive heating device developed by our group can heat various deep-seated tumors to a therapeutic range (1, 10). We herein present our clinical experiences with RF hyperthermia for locally advanced lung cancers with special reference to its clinical feasibility.

From November 1980 through January 1990, 20 patients with locally advanced lung cancers were treated with a combination of irradiation and hypertharmia at Kyoto University Hospital. The patients were 16 males and 4 females whose ages ranged from 46 to 81 years with a median age of 66 years. Table 1 shows the characteristics of the 20 patients. Tumors selected for this trial were those that had invaded or were in contact with the chest wall so that a transcutaneous insertion of thermal probes into tumors was possible. The three mutually orthogonal diameters of the tumors ranged from 4-9.5 cm with a mean of 6.8 cm. Histologic types were seven squamous cell carcinomas, six adenocarcinomas, four large cell carcinomas, two small cell carcinomas, and one non-small cell carcinoma. With regard to the clinical stage, nine were Stage IIIA, two Stage IIIB, and four Stage IV. The remaining

Reprintrequeststo: MasahiroHiraoka,M.D., Department of Radiology, Facultyof Medicine,KyotoUniversity, 54 Shogoin

Supportedin part by a grant-in-aidfor scientificresearch (0 10 10042) fromtheMinistryof Education,Science and Culture,

Kawahara-cho, Sakyo-ku, Kyoto 606, Japan. Accepted for publication 5 September 199 1.

Japan. 1009

1010

I. J. Radiation Oncology 0 Biology 0 Physics Table 1. Clinical summary

No. case Age, sex

Tumor size (cm) histology

1 76, M 2 72 M 3 63, M 4 81, M 5 72, M 6 76, M 7 63, M 8 46, M 9 66, M 10 79, F 11 60, M 12 69, M 13 64, M 14 75, F 15 70, M 16 57, F 17 73, F 18 66, M

8X7 ADC I1 x 8.2 LCC 5 x 3.5 ADC 6.5 X 6.5 ADC 10 x 8 SQCC 7X6 ADC 4x4 ADC 10x 8 SQCC 6X5 LCC 12 x 10 SMCC 8X7 LCC 10x 8 SQCC 6X4 ADC 7x7 LCC 4x3 NSLC 8X7 SQCC 6X5 SQCC 7X6 SQCC

of 20 patients

treated with thermora Hyperthermia

TNM stage T3NOMO IRA T2NOM 1 IV T3NOMO IIIA T3N2MO IIIA T4NOM 1 IV T3N2MO IIIA T2N2M 1 IV T4NOM 1 IV Recurrence

Irradiation (Gy) Total/fraction

42.7 6012 43.0 6012 41.0 66.6/l .8, 2 41.6 6012 44.1 66.611.8 44.8 61/1.6,

1.8 40.9

50.4/1.8 41.4 3214 42.3

T3N3MO IIIB Recurrence

13.611.7

T3NOMO IIIA Recurrence

4814

47.8 5214

7012 41.9

T4NOMO IIIB Recurrence

2012

Recurrence

2812

3812 43.9

43.7 T3NOMO IIIA T3NOMO IIIA

3012 42.8 3012

Heating method and thermometry The heating devices used and the method for temperature measurement were described previously (9, 10). Two types of RF capacitive heating devices operating at 13.56 or 8 MHz were used. Nineteen of the 20 tumors were treated by the 8 MHz device.* The size of a pair of electrodes was determined according to the size and location of the tumor. A pair of electrodes either 21 and 25 cm, or 18 and 25 cm in diameter were applied in most cases. The smaller electrode was placed on the chest wall close to the tumor so that the high temperature area was shifted to the tumor side. An electrode was covered with a water pad and a temperature-controlled salt solution was per-

RF 8, Yamamoto

Tmax.

7012

five tumors were recurrence following operation (three tumors) or radiation therapy (two tumors).

* Thermotron Japan.

Volume 22, Number 5, 1992

Vinyter

Co., Ltd. Osaka,

42.1

-

Tav. 2/W, 41.7 l/W, 42.4 l/W, 40.1 l/W, 40.5 1JW, 42.9 l/W, 42.8 l/W, 39.7 l/W, 41.0 l/W, 41.5 1JW, 43.6 2/W, 41.2 2/W, 44.0 1JW, 40.6 l/W, 42.6 l/W, 41.4 l/W, 42.5 l/W, 41.4 l/W, 41.6

Tmin. 5 sessions 39.6 6 sessions 41.6 4 sessions 39.5 5 sessions 39.4 6 sessions 41.6 4 sessions 40.3 4 sessions 38.7 6 sessions 39.7 4 sessions 40.7 2 sessions 40.5 10 sessions

T>41C

75% 83% 36% 43% 100% 75% 8% 42% 56% 83%

12 sessions 7 sessions 38.9 2 sessions 40.6 3 sessions 1 session 40 3 sessions 39.5 3 sessions 40.1

40% 90%

75% 58% 51%

fused into the water pad to avoid excessive heating of the skin and subcutaneous fat. The temperature of the salt solution was raised to 35-40 C when the tumor had invaded the subcutaneous tissue. Temperature was measured using a thin, Teflon-coated microthermocouple+ that was inserted into the tumor through 2 l- or 19-gauge angiocatheters. The angiocatheter was inserted into tissues transcutaneously with the aid of ultrasound, fluoroscopy, or CT scans. The location of an angiocatheter was confirmed by the same methods. We inserted an angiocatheter as deeply into a tumor as possible and monitored the temperature of the deepest point. Thermal distributions within a tumor and the surrounding normal tissues were mostly obtained by moving a thermocouple by l-cm step immediately after termination of hyperthermic treatment. A multipoint ther-

+ Sensortek

Inc. Type IT-18, NJ, U.S.A.

Hyperthemia

for lung cancer 0 M.

mocouple probe was occasionally used to obtain thermal distributions. The thermometry parameters used were as follows. These parameters were averaged over the entire course of heat treatments. Tmin.: the minimum intratumor temperature in a thermal distribution recorded at termination of treatment; Tmax.: the maximum intratumor temperature in a thermal distribution recorded at termination of treatment; Tav.: the mean of all intratumor temperatures in a thermal distribution recorded at termination of treatment; and %T 2 41 C: the percentage of intratumor points that exceeded 41 C. The microthermocouples used were calibrated against a standard mercury thermometer. Temperatures were measured after switching off the RF in an early study. We could thereafter continuously measure temperatures during RF heating by using an electrically isolated, RF filtered thermometry circuit. The accuracy of the thermometry was within to.2 C. Hyperthermia Hyperthermia was applied regionally once a week for a total of l-7 treatments in 17 patients, or twice a week for a total of 5-12 treatments in 3 patients. We administered hyperthermia after irradiation for 30-60 min from power on to power off. None of the patients were given sedatives or any analgesic before or during the treatment. The blood pressure and pulse rate were monitored. Radiation therapy Seventeen patients received a conventional fractionation scheme, 160 to 200 cGy per day, 5 days per week. A total dose of 50.4-70 Gy was delivered to 9 of the 17 patients as definitive radiotherapy, whereas in 4 patients a total of 28-40 Gy was given as preoperative radiotherapy. Palliative doses of 13.6-38 Gy were delivered to the remaining 4 patients. In three other patients, a total dose of 32-52 Gy were irradiated in fractions of 400 cGy, two times per week. Evaluation sf tumor and normal tissue response Tumor regression was graded as complete regression (CR), partial regression (PRa or PRb), or no regression (NR). PRa and PRb indicated 80- 100% and 50-80% tumor regression, respectively. Changes in tumor size were determined by cross-sectional area on CT scan taken l8 weeks after the treatment in 14 patients, whereas in 6 patients the response was assessed by chest X ray. Since the intratumor low density area developed in posttreatment CT scan was demonstrated to be a useful parameter for assessing the tumor response to thermoradiotherapy (2, 1 l), the presence of the low density area was also assessed as a treatment effect. The low density area was classified into three types according to its percent area in the tumor: less than 50% as type I, 50-80% as type II, and more than 80% as type III. Treatment sites were carefully inspected during each treatment. All patients had complete blood counts, serum

101I

HIRAOKA et al.

chemistries, and coagulation tests every 1 or 2 weeks during treatment. RESULTS

Temperature measurement Thermal distributions within the tumor and surrounding normal tissues were measured at the termination of treatment in 17 tumors. The number of intratumor temperature measurement points ranged from 3.5-8 with a mean of 5.1. Three to 8 seconds were required for temperature measurement at each point when thermal distributions were obtained by thermal probe pull back method. This pull back procedure was accomplished mostly in 20-40 seconds. A multipoint thermocouple probe was used in two patients and thermal washout curves were obtained. The decrease in intratumor temperatures 60 seconds after power off ranged from 0.40.7”C (average: 0.5) and 0.6-l. 1 C (0.8) respectively. Thermal parameters such as Tmax., Tmin., Tav., and %T 2 41 C obtained in the patients are shown in Table 1. Tmax. was over 4 1 C in 16 tumors (94%) and over 43 C in 7 tumors (41%), whereas Tmin. was raised to over 41 C only in 2 tumors (12%). With regard to %T 2 4 1 C, 4 (24%) and 10 tumors (59%) exceeded 80 and 50, respectively. The mean f SD of Tmax., Tav., Tmin., and %T 2 41 C in the 17 tumors were 42.9 ? 1.7,41.6 -t 1.2, 39.7 ? 1.1 C, and 56.2 +- 25.8, respectively. Thermal distributions in three patients are shown in Figure 1. Thermal parameters obtained were analyzed according to variables of tumors such as tumor size, histological type, and tumor site. Since the thickness of subcutaneous fat in the treatment region was less than 1.5 cm in all patients except for one, this variable was not analyzed in this study. Tumors larger than 7 cm in mean diameter showed significantly higher Tav. and %T > 41 C than smaller tumors (p < 0.025). Tumors located posteriorly tended to be more effectively heated than tumors located anteriorly. The other variables did not appear to be major determining factors for intratumor temperature elevation. Single point measurement of tumor temperature was performed in three tumors. The average of tumor temperature in each tumor at the end of each treatment over several heat treatments (2, 10, 12 treatments) was 41.2, 4 1.4, and 44.0 C in each tumor, respectively. Tumor response Of the 12 tumors treated with as definitive radiotherapy, 2 ( 17%) achieved CR and 7 (58%) PR. Four tumors treated with preoperative radiotherapy were graded as 3 PRb and 1 NR. All of them were successfully resected 2 weeks after thermoradiotherapy. One tumor that was heated over 43 C in Tmax. and over 42 C in Tav. demonstrated massive coagulation necrosis and severe vascular damage. Tumor cells, however, survived in the tumor periphery and sometimes around the undamaged blood vessels. T min.

I. J. Radiation Oncology 0 Biology 0 Physics

1012

42 G e e 40

.

Volume 22, Number 5, 1992

. .

??

0

$ 42

t

E 41 F t 40 t

36 t ?? I

0123456

Distance

from

skin

(cm)

0

I8 0

I

1

I

1

2

4

6

8

Distance

from

skin (cm)

Fig. 1A. Thermal distributions and CT scans showing the location of agiocatheters which were inserted into the tumors (case # 10).

of this tumor was 39.9 C. Neither massive necrosis nor severe vascular damage were demonstrated in the other three tumors in the post-operative specimens. Four tumors in which palliative treatment was given showed no regression. Post-treatment CT scans were performed in 14 patients. Remarkable intratumor low density areas appeared in 6 of 12 tumors that did not regress completely. According to the classification system of the low density areas, 1 tumor exhibited type III, 5 type II, and 6 type I. Table 2 shows the relationship between thermal parameters and tumor response, which is assessed by tumor size change and the appearance of low density areas. The thermal parameters were related to the appearance of low density areas but not to the tumor regression. Tmax. and Tav. were significantly higher in type III + II than in type I. Of 16 patients who complained of chest pain before thermoradiotherapy, 12 patients (75%) showed relief of pain with the treatment.

Fig. 1B. Thermal distributions and CT scans showing the location of agiocatheters which were inserted into the tumors (case #16).

second-degree skin burn nor subcutaneous fat necrosis was observed. Three patients whose lung functions had been impaired complained of dyspnea on hyperthermic

Toxicity

All patients complained of sweating and general fatigue at the termination of hyperthermic treatment. Twelve of the 20 patients (60%) experienced pain associated with the treatment. The pain disappeared in all of them immediately after the termination of hyperthermia. Neither

Fig. 1C. Thermal distributions and CT scans showing the location of agiocatheters which were inserted into the tumors (case # 13).

Hyperthermia for lung cancer 0 M. HIRAOKAet al.

1013

Table 2. Tumor response by thermal parameters Thermal parameters Response

No. of tumors

Tmax.

CR

I

PR NR Type III Type II Type I

6 3 1 3

41.0 42.4 + 1.4 42.8 + 1.2 44.1 43.6 + 1.1 I

6

41.7 + 0.8

Tmin.

Tav.

1

*

40.1 41.4 + 1.2 41.7 + 1.2 42.9 42.2 + 0.6

40.8 + 0.9

+

ST>41

C

39.5 39.9 + 1.0 40.4 + 1.4 41.6 39.9 + 0.4

36 54.3 + 28.6 65.3 + 31.1 100 68.7 + 11.0

39.4 + 1.2

38.2 + 26.8

* p < 0.025. +p < 0.05. all of which disappeared after treatment. Fever, possibly associated with an angiocatheter placement, developed in two patients, and resolved with a removal of the angiocatheter and administration of antibiotics. One patient developed a pneumothorax attributed to a thermal probe insertion. Changes in blood pressure and pulse rate before and after hyperthermic treatment were evaluated in 15 patients. The maximum blood pressure increased in 10 patients and decreased in the remaining 5 patients. The minimum blood pressure increased in 8 patients, unchanged in 1 patient and decreased in 6 patients. The changes in maximum and minimum blood pressure were 6.9 + 3.3 and 5.4 & 4.4 (mean + SD) millimeters of mercury, respectively. The pulse rate increased in 12 patients and the increase ranged from 3 to 32 with a mean of 18.4 +- 9.6. treatment,

DISCUSSION Carcinoma of lung is one of the most challenging sites of tumors for loco-regional hyperthermia in terms of both heating equipment and thermometry technique. A trial using an RF inductive heating device+ has been reported (16). However, since the authors reported limited data on thermometry, the effectiveness of this method for treating lung cancers is difficult to evaluate. An annular array applicator (AA) operated at 55-100 MHz,” one of the most widely distributed types of equipment for regional heating, has rarely been applied to patients with lung cancer because of the induced systemic stress (8). Several other clinical reports have also been published concerning the use of RF capacitive heating for lung cancers (4, 13, 14, 15). A problem of those reports is that little multipoint thermometry data were obtained. Therefore, the present study seems to be the first report to obtain more detailed thermal parameters in lung cancers heated with RF capacitive equipment. Tumors selected for this trial were those that had invaded or were in contact with the chest wall so that the thermal probe insertion into the tumor through the chest wall was possible. We obtained the thermal mapping data mostly by pullt Magnetrode, Henry Medical Electronics Inc., Los Angeles, CA. U.S.A.

ing back a thermocouple after power is turned off. Since the temperature in the tumors continue to decrease after power off, the thermometry data provided in the study are underestimates of the actual temperatures. Thermal washout curves investigated in two tumors indicated 0.5 and 0.8 C decrease, on the average in intratumor temperatures within 60 seconds after power off. These results suggest the magnitude of the underestimate is not marked since the thermometry was accomplished in 20-40 seconds in most cases. We used four thermal parameters, Tmax., Tmin., Tav., and %T r 41 C as parameters to assess the heating capability of the 8 MHz RF capacitive heating device. The thermal parameters obtained showed that this heating equipment is suitable for regional hyperthermia for lung cancers. However, some problems exist in the application of this equipment. The thermal parameters demonstrated were considerably inferior to those reported for superficial tumors (9). Also, the minimum tumor temperature, which is suggested to correlate best with treatment outcome (5, 6) was not high enough. This difficulty in raising the whole tumor volume to therapeutic temperatures has been shown in other types of heating equipment for deep-seated tumors and is apparently a common problem for regional deep heating. With regard to variables influencing the thermal parameters, tumor size may be important. Large tumors showed better parameters than small tumors in terms of Tav. and %T 2 4 1 C. Note, however, that Tmin. was not different by tumor size. The complications associated with hyperthermia were not generally serious. The systemic stress is likely to be less toxic in RF capacitive heating than in AA. The most common limiting factor for power elevation was pain. Since the patients treated did not have thick subcutaneous fat, the most probable reason for the pain was heating of the intercostal space induced by the concentrated RF current flow into the space. The number of patients studied here is too small to draw any definitive conclusions about the effect of the thermoradiotherapy. Note, however, that 6 of 12 tumors g BSD Medical Corp., Salt Lake City, UT, U.S.A.

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that didn’t regress completely showed remarkable intratumor low density areas as assessed by on post-treatment CT scans. The appearance of these low density areas was clearly related to the thermal parameters, and some histopathological examinations demonstrated that these areas correspond to coagulation necrosis associated with the hyperthermia. These findings are consistent with our previous reports on histological changes following thermoradiotherapy (11, 12). It has also been shown in our preliminary report that tumors assessed as having type III low density areas rarely regrow, whereas type II or I tumors

Volume 22, Number 5, 1992

regrow in high percentages (2). Because of the small number of patients evaluated and the short follow-up periods, the significance of this grading system of the intratumor low density areas in lung cancers is difficult to assess at the present. Probably the low incidence of type III responses in this present study indicates insufficient temperature elevation of the whole lung tumor volume. In conclusion, regional hyperthermia by an 8 MHz RF capacitive heating device is clinically feasible for local treatment of large lung cancers invading or in contact with the chest wall.

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T.; Onoyama, Y.; Morita, IL; Kakehi, M.; Sugahara, T. Multiinstitutional studies on hyperthermia using an ~-MHZ radio frequency capacitive heating device (Thermotron RF2.

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