Inr J Rudrur,on On 43°C. The average of the monitored intratumoral temperatures for all treatments (Tave) was 43.2”C, the average of the monitored intratumoral minimal temperatures for all treatments (Tmin) was 40.1 “C, and the average of all monitored intratumoral maximum temperatures (Tmax) was 46.7”C. In comparison with temperatures obtained in 277 superficially located tumors of other histologies, Tmax was significantly higher in Hodgkin’s disease lesions (p = 0.007). The difference in Tave approached significance (p = 0.058). These initial results support the role of radiation therapy and hyperthermia for palliation of isolated superficial recurrences in patients with Hodgkin’s disease who have failed conventional therapies. In addition, this approach may aid in cytoreduction prior to bone marrow transplant in patients with superficially located bulky recurrent disease. Hyperthermia may also be considered in combination with chemotherapeutic agents for palliative treatment of recurrences. Hyperthermia,

Hodgkin’s

Disease,

Thermometry,

Low-dose

radiation

therapy.

rent tumors (16,25). Little has been reported however on the use of HT for the treatment of recurrent HD (11). Due to the presence of fibrotic bands which may have more limited perfusion, it would be anticipated that superficially located recurrences of nodular sclerosing Hodgkin’s disease (HD) would be readily heatable (34). We report our experiences in the retreatment of localized recurrences of HD with hyperthermia and low to moderate doses of radiation.

INTRODUCTION

Patients who have failed primary and secondary therapy for Hodgkin’s disease (HD) have usually been treated with a wide variety of chemotherapeutic agents and radiation therapy. Those who fail initial radiotherapy (XRT) can frequently be cured with combination chemotherapy with or without additional radiotherapy (28, 30, 3 1). Patients who fail primary chemotherapy can often be retreated with alternative combination chemotherapy or, for selected patients, radiotherapy (5, 32, 35). Those who have failed after multiple chemotherapeutic regimens and radiotherapy often are drug resistant and have minimal bone marrow reserve and yet still may require some form of palliative treatment for localized symptomatic disease. Hyperthermia (HT) in conjunction with low-dose radiation therapy has been successfully employed in the treatment of a wide variety of superficially located recur-

METHODS

AND

MATERIALS

Putient matrrial Between October 1983 and June 1987 five patients with seven superficially located sites of recurrent HD were treated at Stanford University Medical Center for palliation with combination XRT and HT. Four of these pa-

Presented in part at the 9th Annual Meeting of the North American Hyperthermia Group and supported by NC1 grant CA-44665. Reprint requests to: Daniel S. Kapp, Ph.D., M.D. AcknoM,led~ments-The authors would like to acknowledge the

technical assistance of Allen Lohrbach and the statistical analysis by Richard Cox. In addition, we would like to thank Saul A. Rosenberg for reviewing this manuscript and Sharon Clarke for her work in preparing the manuscript. Accepted for publication 12 September 1989. 603

I. J. Radiation Oncology 0 Biology 0 Physics

604

tients had received all their previous therapy at Stanford. All patients had their original pathology reviewed and documented as nodular sclerosing HD under the Rye classification (22, 23). Patients were initially staged using the Ann Arbor staging system (3). A summary of the patients’ characteristics is given in Table 1. All patients received multiagent chemotherapy for primary and/or secondary therapy. In addition all had received previous radiation to the field of retreatment. Patient 1 had tumor growth beneath the pericardial block. This was demonstrated by reconstruction of his mantle field at the time of his palliative therapy (see Fig. 1). Patient 2 apparently had a marginal recurrence in his inguinal region. All other recurrences were in previously irradiated peripheral nodal sites. Five ofthe seven fields treated with HT and XRT had initially received XRT at a time when no gross disease was noted in the field. Two of the retreatments were in fields which had received XRT for gross disease. All of the recurrences treated with HT and XRT were symptomatic.

Table I. Patient characteristics

of seven local-regional

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Rudiution therupy XRT was delivered in 150-200 cGy per fraction using anterior posterior opposed fields for the neck treatments, tangential fields for the chestwall lesions, oblique fields to the posterior auricular area, and a direct anterior field for the two inguinal regions. Patients were treated using 4 or 6 MV photons except for Patient 5 whose inguinal region was treated with 16 MeV electrons. The total XRT dose utilized was based on the extent of prior XRT and the location of the region being retreated.

H~ywthermiu

treatment

All patients signed investigational study consent forms which had been approved by the Stanford Committee for the Protection of Human Subjects in Research. The patients received 1-4 HT treatments. with each HT treatment generally initiated within 45 minutes after the irradiation treatment. The HT was given with at least 3 days between treatments to minimize the influence of thermotolerance. Hyperthermia was administered using

sites of NSHD retreated

with radiation

and hyperthermia

Patient

1

Age Sex Initial surgical stage Original sites

Primary therapy Initial failure site(s) Time to initial failure (months) Salvage therapy

Previous radiation dose (cGy) Maximum diameter of recurrent disease (cm)

35 Male

2

3

4

5

40 Male

24 Female

36 Male

49 Male

lIIsA Medistinum/left neck/left axilla/ spleen TLI/Au’“’ Bilateral inguinal/ iliac

lIIsA Right axilla/spleen

IIlsA PA/Iliac/left SCV/ mediastinum/ spleen PAVe/ABVD

IIB

HA’

Bilateral neck/ mediastinum

Bilateral neck/ mediastinum

TLI

MOPP/STLI

PA/spleen

Bilateral inguina I

Left neck

3 TLI; B-CVPP; nitrogen mustard/ vincristine/ VP161 prednisone

27 MOP/ABVD

60 MOP; B-CAVe/ MOP; MOA/ ABV; CCNU: cytoxan; CCNU/ VPl6/MTX; procarbazine/ prednisone; chlorambucil

1

MOPP; ABVD: CCNU

2a

2b

15362

4000

j

4000

7.1

2.4

2.0

5.2

-

TLI Bone 31 MOP; MOPP/ ABVD

5a

5b

4400

4400

4400

7.0

6.0

6.8

’ Clinical stage. 2 Recurrence directly beneath pericardial block. 3 Marginal recurrence, see text. PA = Paraaortic; SCV = Supraclavicular: TLI = Total lymphoid irradiation; STLI = Subtotal lymphoid irradiation; ABV(D) = Adriamycin, bleomycin, velban, (DTIC); MOP(P) = Nitrogen mustard, vincristine, procarbazine, (prednisone); MOA = Nitrogen mustard, vincristine, adriamycin; CCNU = Lomustine; MTX = Methotrexate; B-CVPP = BCNU, cytoxan, velban, procarbazine, prednisone; B-CAVe = bleomycin, lumustine, adriamycin, velban.

Hyperthermia

and radiation

therapy

of HD 0 I. A. PETERSENAND D. S. KAPP

sensors. High resistance thermistors+ as well as fluoroptic systems’ were used for thermometry for the microwave treatments. Thermocouples were used in cases of ultrasound treatments. Intratumoral and surrounding subcutaneous tissue temperatures were manually mapped at 0.5-1.0 cm intervals at least two times during the treatment. HT treatment goals were to obtain intratumoral temperatures 2 43°C without exceeding 43.5”C in the surrounding normal subcutaneous and cutaneous tissues. Temperatures were raised rapidly to steady state values (3-6 minutes) and then were maintained at a steady state for 45 minutes. The hyperthermia treatments were characterized by the average, maximum, and minimum ofthe mapped intratumoral temperatures. In addition, the percentage of temperatures measured that were greater than or equal to an index temperature were determined as described previously ( 18). Average temperatures (Tave) were defined as the average of all intratumoral mapped temperatures made over all treatments. Average maximum temperature (Tmax) was defined as the average of the maximum intratumoral temperatures for all mapped temperatures for all treatments. Similarly the average minimum temperature (Tmin) was the average of all the minimum intratumoral temperatures for all treatment maps for all treatments. The treatment parameters for the five patients are summarized in Table 2. Thermal parameters were also characterized for all other patients with superficially located tumors of other histologies treated during the same time period. There were 277 such fields treated including 164 adenocarcinomas, 42 metastatic melanomas, 30 squamous cell carcinomas, 29 sarcomas, and 12 other histopathologies. The thermal parameters obtained in those 277 fields were compared to those for the seven HD lesions.

Fig. I. Prior mantle field indicating location of pericardial block which was placed after 1500 cGy (solid lines). The outline of the recurrent tumor (dashed line) is superimposed on the mantle field lines.

microwave or ultrasound applicators as described in detail elsewhere ( 18). The majority of the treatments used either scanning single or double spiral microstrip antennas at a frequency of approximately 430 MHz (range: 395-460 MHz). One patient was treated with a single horn applicator* at a frequency of 405 MHz. Ultrasound treatments used a 6 cm diameter planar ultrasound transducer at a frequency of 2 MHz. Thcrmometry All HT treatments intratumoral sensor

were monitored using at least one and multiple surface temperature

Table 2. Treatment

parameters

for seven local-regional

605

failure sites of NSHD retreated

with radiation

and hyperthermia

Patient 1 Treatment Radiation

site dose

(CGY) No. of HT treatments Applicator(s) used” %T 2 43”C* Tave (‘C)* Tmin (“(I)*

Tmax (“C)*

2a

2b

3

Ant. chestwall 3060

Sup. inguinal 1730

Inf. inguinal 4109

Lt. post. cervical 2944

Rt. post. auricular 2880

Rt. SCV 1947

Rt. inguinal 3800

1

4

4

3

2

3

3

SP: Sing scan

US-06/SP: Sing scan 45.0 42.5 39.4 45.4

US-06/SP: Sing scan 41.7 42.4 40.5 44.6

MA-20 1

SP: Sing scan

SP: Sing scan

SP: Doub scan

45.0 42.7 38.7 46.2

22.9 42.5 40.8 44.5

56.5 43.7 40. I 47.6

58.3 43.5 40.5 47.7

55.6 44.3 40.9 48.7

* See text for definition

of thermal

4

5a

parameters.

Ant. = Anterior: Inf. = Inferior; Rt. = Right; Sup. = Superior; Lt. = Left: SCV = Supraclavicular; antenna;

SP = Doub scan: scanning

5b

double spiral microstrip

antenna;

* Single horn, MA 20 1, BSD Medical Corporation, Salt Lake City, UT 84108. + Bowman thermistors, BSD Corporation, Salt Lake City, UT 84108.

SP = Sing scan: scanning US-06 = 6 cm planar ultrasound transducer.

t Fhroroptic 94043.

3000 system, Luxtron,

single spiral microstrip

Inc., Mountain

View, CA

606

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Representative cu.se.s Case #4. This white male presented at age of 20 with nodular sclerosing HD (Stage I&A) with left cervical, supraclavicular, mediastinal and extensive splenic involvement (>5 nodules) ( 13). He received 4400 cGy total lymphoid irradiation and three injections of colloidal-Au 198 (36). He relapsed 5 years later and subsequently received multiple chemotherapeutic regimens as summarized in Table 1. Despite chemotherapy the patient had continued progression of a painful right posterior auricular mass and experienced some increased tearing of his right eye. Physical exam was remarkable for a 6 X 6 X 7 cm right posterior auricular node (Fig. 2A, B) and diminished sensation in right cranial nerve, V, and V2 distribution. The patient accepted treatment on our XRT-HT study and received 2880 cGy (6 Mv photons) in 35 elapsed days using opposed oblique fields to limit the dose to the spinal cord. His treatment required a 13 day break at 1800 cGy

March

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secondary to severe mucositis. Two hyperthermia (HT) treatments were given, 2 weeks apart, one before and one after his split from radiation. The treatments were administered with a scanning single spiral microstrip antenna operated at 454 MHz, using 75-105 watts (18). Representative time-temperature and spatial temperature distributions across the tumor are illustrated in Figure 3. The patient’s tumor regressed markedly over the course oftreatment (Fig. 2C) and a complete response continued throughout the remaining 9 months of the patient’s life. (hse #.5. This white male presented at age of 39 with nodular sclerosing HD (Stage III,A) with right axillary and minimal splenic involvement. He received 4400 cGy total lymphoid irradiation. He recurred initially at 31 months and was treated with chemotherapy as outlined in Table 1. Subsequently he developed a biopsy confirmed right supraclavicular recurrence and he was then treated with XRT-HT receiving 1947 cGy and 3 HT treatments

Fig. 2. (A and B) Right posterior auricular region I week prior to XRT and HT, demonstrating the 6 X 6 X 7 cm tumor mass. (C) Same area 6 months after completion of treatment showing complete resolution of mass.

Hyperthermia

and radiation

therapy

of HD 0 1. A.

PETERSEN

AND

D.

S.

KAPP

607

44 G e

43

z 2 z

42

iz

41

E I-”

40

I

10

20

30

40

50

.

60

Time(min)

0

1

2

3

4

Distance along Lesion(cm)

Fig. 3. (A) Representative time-temperature curve during hyperthermia treatment of right posterior auricular lymph node (Patient 4). Bowman thermistors #l and 2 were used to monitor skin surface temperatures overlying the tumor (5 additional thermistors were used to monitor skin temperatures but results are not shown here). Tracing #3 illustrates intratumoral temperatures within a 19 gauge closed end catheter, traversing 3.5 cm of tumorous tissue. Arrows designate start of mechanical pull through mappings performed at 7 and 37 minutes. (B) Temperature distributions for the maps during treatment shown in (A). Temperature was measured at 0.5 cm intervals.

to his right supraclavicular fossa. All HT treatments to the supraclavicular mass were delivered using a scanning single spiral microstrip microwave antenna at 425 MHz using 74- 106 watts. Marked reduction and softening of the right supraclavicular mass was noted during the treatment course and a complete response was obtained. Four months later the patient developed a right groin mass which was verified on CT scan (Fig. 4A). He then received 3800 cGy with concurrent HT treatments. HT treatments were given three times, 1 week apart over the first 3 weeks of treatment. The scanning double spiral microstrip microwave antenna (18) was used at 430 MHz at a power of 142- 198 watts. Mapped intratumoral and surface temperatures are shown in Figure 5. The groin mass responded well with greater than 50% reduction in volume at the

end of treatment and complete response noted at time of follow-up. Subsequent to his HT and XRT he received CCNU for 6 months for possible pulmonary parenchymal involvement and right axillary adenopathy. His groin area became indurated and fibrotic and remains so with followup CT (at 17 months) showing no adenopathy (Fig. 4B). RESULTS

All patients tolerated the HT treatments well with mild to moderate discomfort in the treatment field during the treatment. No patient experienced treatment limiting pain, thermal burns or blisters. The majority of the patients had fibrosis in the treatment area on follow-up several months after completing therapy. However, none of

Fig. 4. (A) CT scan of pelvis of Patient 5 prior to treatment demonstrating 6.8 X 5 cm right inguinal adenopathy. (B) CT scan of same region 17 months after completion of treatment to inguinal nodes showing complete response.

1. J. Radiation

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20

Oncology

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0 Biology 0 Physics

40

50

March

1990, Volume

0

e

1

18, Number

2

3

3

Distance Along

Time(min)

4

5

6

Lesion(cm)

Fig. 5. (A) Representative time-temperature curve during hyperthermia treatment of right inguinal adenopathy. Patient 5. Bowman thermistors # 1 and 2 were used to monitor skin surface temperatures overlying the tumor (12 additional skin temperature probes were used but are not shown here). Tracing #3 represents intratumoral temperatures within a closed ended catheter. traversing 0.5 cm of normal tissue. 4.5 cm of tumorous tissue and then 1.0 cm of normal tissue. Arrows indicate start of mechanical mapping at 9 and 28 minutes. (B) Temperature distributions for the maps during treatment shown in (A). Temperature was measured at 0.5 cm intervals.

apy was not successful and two of these patients succumbed to their disease. Thermal parameters obtained in the seven fields of superficially located recurrent HD were compared with all superficial tumors of other histologies. The HD lesions obtained a significantly higher Tmax (Table 4). Tave was also higher. approaching significance (p = 0.058). Tmin was not statistically different from the other histologies that were heated.

the patients were symptomatic from this fibrosis. Given the high total doses of XRT used, it is difficult to delineate what role, if any, the HT played in potentiating normal tissue reaction. Local control was obtained in each of the treatment fields (Table 3). All patients had achieved a partial response (>50% reduction in tumor volume) by the end of treatment and subsequent complete response was noted on further follow-up. One patient had her node excised at I month after completion of therapy. Pathology revealed foci of necrosis surrounded by giant cells and chronic inflammatory cells with small foci of atypical lymphoid tissue. The margins of resection were suspicious for possible residual lymphoma, but no local recurrence was subsequently documented. Three patients had subsequent chemotherapy for active disease outside of the radiation therapy-hyperthermia field. However, this ther-

DISCUSSION Local or marginal recurrences in HD are not infrequent in patients treated with XRT alone. These occur more frequently in regions following doses < 3000 rad (I 5. 36) and are more frequent in sites of bulky disease (6, 42). Similarly patients treated with chemotherapy alone recur

Table 3. Outcome of sites of HD retreated

with radiation

and hyperthermia

Patient

I

2a

2b

4

3

5a

5b

Follow-up (months) Local control Subsequent therapy

6

5

5

27

9

23

16

Yes Cytoxan

Yes Prednisone

Yes CCNU

Yes CCNU

DOD

Yes CCNU, PAVe. Prednisone DOD

Yes* none

Disease status

Yes CCNU, PAVe. Prednisone DOD

D

DOD

AWD

AWD

* Partially excised node, see text. PAVe = Melphalan, velban, procarbazinc: = Alive with disease.

CCNU

= Lomustine;

DOD = Dead of disease: D = Dead unknown

etiology: AWD

Hyperthermia and radiation therapy of HD 0 1. A. Table 4. Thermal parameters in patients with superficially located tumors: NSHD compared with all other histolopathologies treated with radiation and hyperthermia

NSHD Number of fields Tmax (“C)* Tave (“C)* Tmin (“c)*

7 46.7 43.2 40.1

All other histopathologies 277 44.8 42.4 40.0

p-values

0.007 0.058 0.897

* See Kapp et cd. (18). most frequently in sites of extensive disease (6, 42). At Stanford University Medical Center freedom from relapse for Stages 1 and 11 HD is 78% at 10 years. This drops to 69% for Stage Ill and 52% for Stage IV, with relapse rates, therefore, of 22-48% as a function of stage (12). At the time of first relapse after XRT or chemotherapy several treatment options exist. MOP(P) retreatment in first relapse patients can be effective in achieving a complete remission in 59% (19/32 patients) as described by Fisher et a/. (5). The median duration of these remissions was 21 months with 53% (10 patients) of the complete responders subsequently failing. This was especially effective retreatment in patients with disease limited to nodal sites and with a long disease-free interval. Conversely a subset of patients who failed initial chemotherapy may also be treated for cure with radiation (32). Combination chemotherapy and low-dose radiation may also be effective in a high percentage of patients relapsing after XRT alone (30, 31). Alternative chemotherapy regimens for MOPP failure include (but are not limited to) ABVD, B-CAVe (bleomycin, CCNU, adriamycin. velban), B-DOPA (bleomycin, DTIC, vincristine, prednisone, adriamycin), and SCAB (streptozotocin, CCNU, adriamycin, bleomycin) (9, 20, 21, 29, 33, 35). Third-line therapy for refractory HD patients who have failed multiagent chemotherapy and XRT has varied widely. The Milan group reported up to 40% complete response with 17-month median duration in patients who received CEP (CCNU, etoposide, prednimustine) (2). Other regimens which have been utilized include CEM (CCNU, VP- 16, methotrexate), CAD (CCNU, melphalan, vindesine), and MIME (methyl-GAG, ifosfamide, methotrexate, VP- 16) all with complete response rates below 25% (8, 38, 40). Use of single agent therapy in patients with end-stage HD has been reported to give palliative remission or stabilization of disease for 6 months or longer (24). Bone marrow transplantation has been utilized in patients with advanced resistant HD with up to 50% complete response (4, 14). Patients who responded best in this situation were ones who had less than two failures to different drug regimens before undergoing transplant. As demonstrated in the present study, patients with symptomatic superficially located recurrences, who have failed other forms of therapy, may benefit from treatment with low to moderate dose XRT in combination with

PETERSENAND D. S. KAPP

609

HT. Our report suggests that these patients can be safely and effectively retreated using these two modalities with essentially no significant toxicity except for the additional scarring/fibrosis. For all ofthe patients with complete follow-up the disease in the heated field has remained locally controlled, although 4 of 5 patients subsequently recurred elsewhere. One patient had possible minimal residual disease after XRT-HT in a partially excised lymph node but remained without evidence of local failure for 27 months until the time of her death from uncertain causes. The duration of survival or time to last follow-up has been 527 months in these patients. There has been little previously reported on the retreatment of lymphoma with combined XRT and HT. Kim et ul. noted a complete response in 5/6 patients with lymphoma cutis treated with XRT and HT compared to 2/ 6 patients receiving identical doses of radiation alone ( 19). For mycosis fungoides, 12/l 5 patients had a complete response to XRT plus HT compared with 3/12 patients receiving radiation alone. XRT doses, fractionation, and thermal distributions obtained were not described in detail and toxicities were not delineated in this study. Bicher et al. reported a complete response in all eight fields in patients with lymphoma treated with combined XRT and HT (1). HT (goal: 4 fractions of 45 +- 0.5”C for 90 min) was administered every 72 hr. After 1 week rest the patient received combined XRT and HT using four fractions of 4 Gy per fraction given twice a week, with each radiation treatment followed within 20 minutes by HT (goal: 42 -t 0.5”C for 90 min). This report is not specific as to whether any of these lymphoma patients recurred in the treatment field. Complications from the HT included local skin burns which subsequently healed and some enhanced skin reactions especially in patients with scarred or grafted skin. Specific histologies of the lymphomas were not reported. Neither Kim et al. or Bicher et al. noted whether further therapy was given in any of these patients after their combined local therapy. Holt was the first to report specifically on treatment of recurrent HD using combination XRT-HT therapy (11). XRT and 434 MHz microwave treatments were used in 1 1 patients. Initial histologic subtypes of HD were lymphocytic predominant, nodular sclerosing, mixed cellularity, and lymphocytic depletion in 2,4,4, and 1 patient, respectively. Disease recurrence was pathologically verified and sites identified by radiographs. The recurrences treated were located in both visceral and nodal sites. XRT doses ranged from 3-20 Gy, “followed by four or more doses of 434 MHz over the following 2 hours.” No thermal parameters were provided and HT treatment itself was defined only in terms of power administered. Complete responses were documented in all patients with durations of 7-50 months. It is difficult to further analyze Holt’s study due to the lack of thermal parameters. Our report suggests that patients with HD achieve excellent intratumoral temperatures with minima1 patient discomfort and toxicity. The Tmax was significantly

610

I. J. Radiation Oncology 0 Biology 0 Physics

higher than for superficially located tumors of other histologies treated at our institution during this time period and the increase in Tave was of borderline significance. The high intratumoral temperatures obtained may be attributed in part to the sclerotic bands throughout the tumor, which may have lower perfusion and therefore selectively retain heat (34). However. additional studies comparing the extent of sclerotic bands in the tumors with the thermal distributions obtained need to be performed to confirm this hypothesis. Furthermore, the excellent results reported by Holt (I I) with other histologic subtypes of HD suggest that all subtypes of HD may respond well to combined XRT-HT treatment. As seen with primary XRT or chemotherapy. tumor regression in our study was rapid though a complete response was not attained in all cases by the end oftherapy. The optimal number of HT treatments needed when used with low to moderate dose XRT remains to be defined, though preliminary data suggest that excellent results are obtained with either two or six treatments for superficial lesions less than 3 cm in maximum diameter (I 7). For nonlymphomatous histopathologies poor results have been reported for larger lesions (>3 cm) using up to eight HT treatments in conjunction with XRT (26). Complete response rates of 27%) were obtained for patients with a range of tumor types treated with XRT alone or in combination with HT. Our excellent responses were noted despite 5/7 (7 1%) of the lesions treated being larger than 5 cm in diameter. XRT doses employed in our study varied but were less than standard dose used at our institution for the definitive treatment of large lymph nodes in HD. Schewe (J/ cl/. presented data suggesting doses > 40 Gy for larger volume lesions did not add to local control and that for all fields including those with subclinical disease. local control was

March 1990,Volume 18.Number 3

not significantly improved with doses over 30. I Gy (36). This suggests that for some of our patients the XRT dose may have been sufficient by itselfto control disease. However, Thar ~1 u/. reported that all three of their patients with HD and sites of disease more than 6 cm failed treatment at doses of 3 I-33 Gy (39). Both of our patients with disease 7.0 cm or greater obtained local control at doses of 2880 and 3060 cGy plus HT. Our results suggest two other potential uses of HT and low-dose XRT in the treatment of HD. Since most recurrences after bone marrow transplant develop in sites ofinitial pretransplant involvement (7.27). low-dose XRT with HT may aid in pretransplant cytoreduction. HT also potentiates many chemotherapeutic agents used in treating HD including alkylating agents. nitrosoureas, adriamycin, and the vinca alkaloids (10). In vitro studies on murinc cell cultures also indicate that tumors resistant to a given chemotherapeutic agent may be responsive to the same agent when used at elevated temperatures (4 I ). Local-regional HT may therefore be of potential value when used with chemotherapy in the treatment of recurrent disease. In summary, despite great advances in the treatment of HD over the last three decades a significant number of patients (20-25’s) remain resistant to standard primary and secondary therapies (5, 24). We report here excellent local control in seven symptomatic superficially located masses in five patients who had received previous irradiation and multiple chemotherapeutic regimens. Good temperature distributions have been obtained without signihcant toxicity. The use of HT in conjunction with XRT treatment for superficially recurrent HD may be beneficial either for palliative or cytoreductive purposes. Further studies utilizing HT combined with XRT or chemotherapy are felt warranted.

REFERENCES I. Bicher, H. I.; Sandhu, T. S.; Hetzel, F. W. Clinical thermoradiotherapy. Henry Ford Hospital Special Symposium ‘Clinical Hyperthermia Today.” June 2 I, 1980: I - 13. 2. Bonadonna. G.: Viviani, S.: Valagussa, P.: Bonfante. V.: Santoro. A. Third-line salvage chemotherapy in Hodgkin’s disease. Sem. Oncol. I2(Supp. 2):23-25: 1985. 3. Carbone, P. P.: Kaplan, H. S.: Mussholf, K.; Smithers. D. W.: Tubiana, M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 3 1: 1860- I86 1; 1971. 4. Carella. A. M.; Congiu, A. M.: Gaorza. E.: Mazra, P.; Ricci. P.: Visani, G.: Meloni. G.: Cimino. G.: Mangoni. L.: Coser, P.; Celto, G. L.: Cimino. R.: Alessandrino, E. P.: Brusamolino, E.; Santini, G.: Tura. S.: Mandelli. F.; Rizzoli. R.; Bernasconi, C.: Marmont. A. M. High-dose chemotherapy with autologous bone marrow transplantation in 50 advanced resistant Hodgkin’s disease patients: An Italian Group Report. J. Clin. Oncol. 6:14l I-1416: I9XX. 5. Fisher. I.: DeVita. V. T.: Hubbard, S. P.: Simon. R.: Young. R. C. Prolonged disease-free survival in Hodgkin’s disease with MOPP: reinduction after first relapse. Ann. Intern. Med. 90:76 l-763; 1979.

6. Frei. E.: Lute. J. K.; Gamble. J. F.: Coltman. C. A.: Constanzi, J. J.: Talley. R. W.: Monto, R. W.: Wilson, H. E.: Hewlett, J. S.: Delaney, F. C.: Gehan, E. A. Combination chemotherapy in advanced Hodgkin’s disease. Induction and maintenance of remission. Ann. Intern. Med. 79:3763x2; 1973. 7. Goldstone, A. H. EBMT experience of autologous bone marrow transplantation in non-Hodgkin’s lymphoma and Hodgkin’s disease. Bone Marrow Transplant. I(Supp. I): 289-292; 1986. 8. Hagemeister, F. B.; Tannir. N.; McLaughlin. P.; Salvador. P.: Riggs. S.; Velasquez. W. S.: Cabanillas. F. MIME chemotherapy (methyl-GAG. ifosfamide, methotrexate. etoposide) as treatment for recurrent Hodgkin’s disease. J. Clin. Oncol. 5:_556-561: 1987. Y. Harker. W. G.; Kushlan, P.; Rosenberg, S. A. Combination chemotherapy for advanced Hodgkin’s disease after failure of MOPP: ABVD and B-CAVe. Ann. Intern. Med. 101: 440-446; I YX4. IO. Herman. T. S.: Teicher. B. A.: Coleman, C. N. Rationale for use of local hyperthermia with radiation therapy and selected anticancer drugs in locally advanced human ma-

Hyperthermia and radiation therapy of HD 0 I.

1I.

12. 13.

14.

15. 16.

17.

18.

19.

20.

2 1.

22. 23. 24.

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