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Further Experience With Regional Radiofrequency Hyperthermia and Cytotoxic Chemotherapy for Unresectable Hepatic Neoplasia

FREDERICK L. MOFFAT, MD, FRCS (C), TOMAS GILAS, MD, FRCS (C), KEVIN CALHOUN, MD, MICHAEL FALK, RICHARD DALFEN, BSC, LOFINE E. ROTSTEIN, MD, FRCS (C), LEONARD MAKOWKA, MD, PHD, VICTORIA HOWARD, RN, DAVID LAING, DAVID VENTURI, BSC, JACOB C. I.ANGER, MD, JUDITH A. FALK, BSC, AND RUDOLF E. FALK, MD, FRCS (C) The authors report on 178 patients with unresectable hepatic tumors who have been treated with 1 to 25 (median, 6) courses of radiofrequency hyperthermia (RFHT) nad chemotherapy. In 137 patients, the hepatic tumors consisted of metastases from colorectal adenocarcinoms. For patients who had no previous therapy and who had olorec~al metastases with no extrahepatic disease, cumulative survival at 52 weeks follow-up was 80.5% and partial tumor regression was seen in 78.4%. Among the 69 patients who previously had conventional treatment for their h~patic disease, partial regression was aecu in 43.5%. We are no longer monitoring tumor core temperature routinely, as the invasive methods currently in use yield irreproducibie results; the risks to the patient cannot be justified in view of the questionable relevance of the data obtained. A prospective ramiomized study of systemic chemotherapy with or without RFHT in patients with colorectal hepatic metastases is in progress. CAmcer 55:1291-1295, 1985.

have U ominous prognosis irrespective of the type of


NRESECTABLE HEPATIC MALIGNANCIES an

therapy used. Systemic chemotherapy produces objective tumor responses in 7% to 45% of patients thus treated.~.2 Although the response rate is higher with hepatic artery infusional (HAl) chemotherapy, this is an invasive technique and its effect on survival is as yet unclear.~-~ External or interstitial radiotherapy to the fiver may provide some palliation for patients with symptomatic hepatic neoplasia, but it has no effect on survival or objective response and can cause serious morbidityf-6.~ Interruption of the hepatic arterial circulation is of questionable benefit)~ A Phase II clinical study of regional capacitive radiofmquency hyperthermia (RFHT) in combination with cytotoxic chemotherapy has been in progress at the Toronto General Hospital since August 1981. The literature is replete with reports of the antineoplastic effect of thermotherapy both in vitro and in vivo.8-~ Furthermore, locally and regionally applied hyperthermia using
Pre=nted at the Joint Meeting of the Society of Surgical Oncoiogy and the Society of Head and Neck Surgeons. New York, New York, May 13-17, 1984. From the Toronto General Hospital, Toronto, Ontario. Address for reprints: R. E. Fatk, MD, FRCS, 1-046 Mulock Larkin Wing, Toronto General Hospital, 101 College Street, Toronto, Ontario, MSG IL7. Accepted for publication August 9, 1984.

noninvasive technology produces only infrequent adverse effects in humans when employed with chemotherapy.~6"~8-23 Our preliminary results with chemotherapy and FlIT in the treatment of hepatic neoplasia have been published previouslY-|9 Our experience with this regimen in patients with unresectable liver tumors is updated in this report.
Patients and Methods To date, 847 patients with tumors of various types have been treated with RFHT and chemotherapy at this center. Of 291 patients treated for hepatic neoplasia, 113 were excluded from this analysis: 59 were moribund when initially seen (anticipated survival less than 2 weeks), 35 have been lost to follow-up, and 19 did not complete even a tingle treatment course. The remairfing 178 patients included 99 men and 79 women ranging in age from 28 to 80 years (median, 57 years). Sites of origin of hepatic neoplasia in these patients are summarized in Table 1. The apparatus and treatment protocol used have been described in detail elsewhere,t9 Briefly, the capacitive RFHT machines in use at this center produce radiofrequency energ3, of 13.56 MHz through three channels with up to 500 W of power per channel. One or all channels may be employed in the treatment of a single patient as described by LeVeen et al.~ The output from

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TABLE i. Primary Tumors in 178 Patienls Treated With RFHT and Chemotherapy for Unrer~ctable Hepatic Neoplasia No. of I~tients

Adenoea_~noma Colorectal Bl~aSt


Pancrc, as

Gallbladder

Slomach
Unknown primary Esophagus Duodenum Malignant melanoma Cutaneous

137 6 5 5 4 4 2 l I ! 3 2 I I 3 I I 178

Ocular
Malignant gastrinoma (pancreatic) Malignant carcinoid (small bowel) Primary

Hepatocarcinoma Cholangiocarcinoma
Angiosarcoma

with comfort for each patient. This ranged from 58 to 360 W (median, 145 W). Medications administered during thermotherapy included mild sedatives or analgesics as necessary, metronidazole and cytotoxic chemotherapy. Metronidazole, three oral or intravenous doses of 500 rag per daily RFHT session, has been administered routinely since April 1982. This drug appears to facilitate tumor heating by RFHT)s Chemotherapy was administered concomitantly to all but three patients (Table 2). Forty-nine patients received HAl chemotherapy following a standan protocol,~ 83 patients received systemic (intravenous) chemotherapy, and the remaining 43 patients received cytotoxic agents by both routes during different course. of RFHT. Of those receiving HAl chemotherapy, laparotomies performed for various unrelated indications in 22 patients provided an opportunity for insertion of an indwelling silastic hepatic artery catheter with a subcutaneous injection port (Port-A-Cath, Pharmacia, Piscataway, N J). These patients were treated thereafter on an outpatient basis.

RFHT: radiofrequency hypcnhermia.

Results
each channel is delivered to the patient through two flexible planar electrodes placed on the body surface opposite and facing one another so that the tumor lies between them. For the last 15 months we have been treating patients using only one machine channel, as we have found that this is the best method of treatment with the electrodes currently in use. Tumor core temperature was monitored in 38 selected patients with hepatic tumors in the early months of the RFHT program. Twenty-seven of these are among the 178 patients analyzed here. Two electronic thermometry systems were used, both of which require percutaneous insertion of a wire thermistor or fluoroptic heat-sensitive probe into the tumor mass being treated,m9 Systemic temperature was measured orally or rectally before and at the end of each days RFHT treatment. Informed consent was obtained from all patients before admission to the RFHT program, and the provisions of the Hlsinki Declaration (1975) were observed. Treatments were given on an outpatient basis except for patients undergoing hepatic artery infusion (HAI) chemotherapy via transfemoral angiographic catheter or requiring admission to hospital for other reasons. To date, patients have received 1 to 25 treatment courses (median, 6 courses) of RFI-IT and chemotherapy. Each treatment course consisted of one to five consecutive daily sessions of 75 to 120 minutes of thermotherapy. Total time on RFHT in each treatment course ranged from 80 to 565 minutes (median, 271 minutes). Machine power was set at the maximum level compatible The results of tumor core temperature measurement in the 38 monitored patients have been published previously)9 Systemic temperature in all 178 patients increased by only 0.6 _.+ 0.3C during thermotherapy, a clinically negligible increment. Patient Groups For analysis, the patients were stratified by extent of disease and previous therapy into four groups. Group I: Group I comprised 51 patients with advanced disease whose expected survival was less than 8 weeks. Group II: Group II comprised 69 patients whose expected survival was greater than 8 weeks and who had failed to respond to the best available chemotherapy for their tumors before coming to hyperthermia. Group II1: Group III comprised 58 patients with newly diagnosed and as yet untreated hepatic neoplasia, some of whom had extrahepatic disease. Group IV: Group IV comprised 37 patients from Group III with colorectal adenocarcinoma metastatic to the liver, but with no extrahepatic disease.

Survival and Response


As of April 1984, 86 patients have died, having survived 3 to 76 weeks (median, 26 weeks) from the date of initial treatment with RFHT. The other 92 patients have been followed for 3 to 107 weeks (median, 36.5 weeks). Survival and follow-up by patient group are summarized in Table 3.

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TABLE 2. Concomitant C~otoxic C"l~moth~mpy in 178 Paticnt~ Treated With RFHT for Unres~ble Hepatic Neoplasia Chemotherapy Syslemlc Priimaw tumors (n = 178) Adenoca~notr~s Colorc~tum (n = 137) Breast (n = 6) Pancreas (n = 5) Gallbladder (n = 5) Stomach (n = 4) Unknown I" (n = 4) Lun$ (n = 2 Esophagus (n = 1) Ovary (n = 1) Duodenum (n = I) Melanoma (n -- 5) Gaslrinoma (n = I) Carcinoid (n = I) Hepatocarcinoma (n = 3) Cholangiocaminoma (n = !) Angiosarcoma (n ffi I) To~! 5-FU 86 3 l 2 3 2 2 ! ! i I 2 I 106 ! MTX 12 1 ! ! l 2 MITO 93 3 2 5 3 2 2 i l 1 2 I 2 1 119 CCNU 31 2 2 I I i 4 l ! 44 3 3 VCR VBL 44 i 2 4 I I I I 1 I 2 I I ! 62 3 I I PCB DOX HAl

5 2 2 I I

73 3 2 i 3 1

2 ! ! 2

19

92

RFHT: radiofrequency hyperthermia: 5-FU: 5-fluorouracil: MTX: methotmxaze: MITO: mitomycin C; CLNU: cis-chloroni~rosourca: VCR:

vincristine: VBL: vinblastin~ PCB: procarbazine; IX)X: doxorubicin; HAl: hepatic artery infusional.

Cumulative survival is shown in Figure 1. It is apparent r~ctively, and the median duration of these responses that patients as yet untreated for their hepatic disease was 32 weeks. Even in patients who had previously those who previously had failed conventional therapy occurred in 43.5% (median duration, 26 weeks).

(Groups III and IV) have fared substantially better than failed chemotherapy (Group II), partial tumor regression
There were no differences in survival or objective tumor response between patients who received chemo(Group I). In particular, Group IV patients have done therapy by hepatic artery infusion and those treated very well: 11 patients have been followed for 52 weeks systemically. or longer. Cumulative survival at 52 weeks is 80.5% for Group IV. Toxicity Objective response was assessed using the criteria The adverse effects related to tumor core temperature outlined by Moertel.24 In all cases the assessment was monitoring have been reported previously,t9 Briefly, two made by at least one of the following methods: hepatic patients developed local peritonitis and fever as a result angiography, computerized transaxial tomography, abof thermistors being inserted into the iive~, both comdominal ultrasonography and/or scintigraphic hepatic plications were managed conservatively. In one other scan. Response rate and duration are given for each patient, a thermistor broke off and was retained in 4he group in Table 4. In Groups lit and IV, partial tumor liver with no ill effect. regression wasseen in 67.2% and 78.4% of patients,

(Group II) or patients with far advanced hepatic neoplasia

TABLE 3. Follow-Up and Survival by Group: April, 1984 Mortalities Patients


No.

Cur~ntly living Survival (wk) Patients No. 14 36 42 32 Percent (27.5%) (52.2%) (72.4%) (86.5%) Follow-up (wk) Median 14 23 35 36 (Ranse) (4-39) (3-74) (3-107) (3-107)

Percent (72.5%) (47.8%) (27.6%) (13.5%)

M_~l_ian 20 35 40 39

(Range) (3-37) (9-73i (13-76) (10-64)

Group ! (n = 51) Group II (n = 69) Group I11 (n = 58) G~oup IV (n = 37)

37 33 16 ~

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resolved when the drugs were withheld. As reported previously, two patients treated with HAl chemotherapy via transfemoral catheters developed fevers and a third became septicemic. The patients recovered a~er removal of their catheters and treatment with antibiotics)9 Discussion We have been imp~ssed by the low incidence of toxicity associated with RFHT. The adverse effects seen consist only of minor self-limited thermal injuries to subcutaneous tissues and skin. When used in combination with chemotherapy, RFHT provides good palliation for patients with incurable hepatic cancer, particularly patients with newly diagnosed hepatic metastases from colorectal adenocarcinoma. FIG. !. Cumulative survival for 178 patients mated with RFHT In a review of the therapeutic options currently availand chemotherapy for unresectable hepatic cancer. Patients hav~ been able for colorectal hepatic metastases the incidence of s~ratified by extent of disease and previous therapy into four groups (l-IV) as described in text. tumor response to systemic chemotherapy was found to range from 7% to 21% in patients treated with a single There have been no mortalities or systemic effects drug. and from 30% to 43% when multiple agents are attributable to RFHT. Superficial partial thickness burnsused) Hepatic artery infusional chemotherapy produces to the skin underlying the electrodes occurred in 6 tumor regression in 40% to 60% of treated patients.2 patients (3.4%) and subcutaneous fat necrosis was seen Balch et al., reporting on 81 patients who underwent in 18 patients (10.1%). All thermal injuries healed continuous 5-fluorodeoxyuridine (FUDR) infusion into quickly and uneventfully. In patients with fat necrosis, the hepatic artery using an implantable infusion pump local induration persisted indefinitely but was of no device, found that 88% of patients had a reduction of ~onsequence.19 33% or more in their serum carcinoembryonic antigen There were no adverse effects related to the adminis(CEA) levels. Survival was substantially improved over tration of metronidazole. Chemotherapeutic toxicity that of 129 matched historical controls treated wi~h consisted of thrombocytopaenia in three patients which systemic chemotherapy.2~ We have shown that when chemotherapy administered TABLE 4. Objective Response to RFHT and Chemotherapy in 178 by either route is combined with RFI-IT, the response Patients With Hepatic Neoplasia rate in patients with previously untreated colorectal Patients Duration (wk) metastases confined to the liver is over 75%. Although our results do not permit conclusions to be drawn Median (Range) No. (Percent) concerning the influence of RFHT and chemotherapy Group I (n = 51) on survival, the data from patients in Groups HI and Partial regression $ (15.7~) 15 02-28) IV suggest that ihere may be a substantial positive effect. Stable 3 (5.9%) ( I 1-37) The quality of life in patients who respond to therapy Proton 37 (72.5%) Indeterminate* 3 is excellent; in almost all cases these patients are more Group I1 (n = 69) functional than they had been before entering the RFHT Pa~Jal regression 30 (43.5%) 26 programme. Dramatic reduction in pain and fatiguability Stable 9 (13.0%) 17 Progression 24 (34.S%) was reported by all patients responding to treatment Indeterminate 6 and by most of those whose tumors were stabilized by Group ii! (n ffi 58) this regimen. In patients whose tumors did not respond Partial regression 39 (67.2%) 32 (~-~)) ~able 3 (5.2%) 14 (18-19) to RFHT, the quality of life was not compromised by Priori 14 (24. 1%) the treatment protocol. lndelt~mina~ 2 We abandoned tumor temperature monitoring as a Group IV (n = 37) part~ regression 29 (78.4%) 32 routine procedure in the early stages of the RFHT 14 Stable 3 (8.1%) program for several reasons. As reported previOusly, w~ Progression 4 00.8%) found that tumor temperature measurements in patients Indeterminate I with hepatic cancers were irreproducible from one days These patients have been followed for less ~han 10 weeks~ all are RFHT treatment session to the next. We also found [~trrently alive. that the tumor temperatures recorded had no relationship RFHT: radiofrequency hyl~rthermi&

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RFHT AND ~-IEMOTHERAPY FOR HEPATIC NEOPLASMS

Moffat et ai.
REFERENCES

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to the machine power used or to the objective tumor responses observed.~ These findings are not surprisins in view of the methods currently available for measming temperature ~ deeply situated tumors and the difficulty in placing one or more thermistors or probes in exactly the ~ame positions in a tumor over several successive RFHT treatments. The architecture of a malignant neoplasm is very heterogeneous: areas with excellent blood supply are interspersed with areas of poor tissue perfusion and regions of frank necrosis. The distribution of heat within a tumor undergoing RFHT is therefore very uneven and probably changes over time as the lesions size and architecture change. Therefore, it is unreasonable to suggest that measurements obtained with a single probe inserted at the start of each RFH session would have much relevance with t~et to the efficacy of therapy. The use of multiple probes would only yield a larger quantity of data of equally dubious significance. Furthermore, the insertion of temperature probes into deeply situated tumors is associated with potentially serious complications, as our experience demonstrates. The use of multiple probes can only increase the risk of serious mishap to the patient. Although there have been claims that multiple probes can be inserted with impunity into tumors of the pancreas, liver or pelvis, we suggest that this practice will eventually result in major morbidity or even mortality. We contend that the routine use of invasive tumor temperature monitoring in patients undergoing thermotherapy is unjtistifmble given the questionable quality of the information obtained and the real potential for serious misadventure with these methods. Invasive mon~ing should be largely confined to the animal laboratory currently. When noninvasive technology for measuring temperature in deep tumors becomes available, the current methods could justifiably be used in selected low-risk patients in an attempt to corroborate the results obtained with the newer systems. In view of the shortcomings and risks of invasive tumor temperature monitoring~ the efficacy of RFHT as a treatment m0dality for malignant neoplasia must be determined by carefully designed Phase lIl efinical trials. Since February 1983 we have been entering patients with eolorectal hepatic metastases into a proSleeve randomized study of RFHT and systemic chemotherapy. Patients are treated with systemic chemotherapy alone (5-fluorouracil and mitomycin C) or systemic chemotherapy plus FLIT. Patients who fail therapy are put on the HAl chemotherapeutic regimen3 with or without RFHT as determined by the initial randomization. We hope to complete this trial within the next 18 to 24 months.

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