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Experimental Studies |
1 From the Departments of Radiology (S.N.G., J.C.H., J.B.K.), Surgical Oncology (P.F.S.), Medical Oncology (K.E.S.), and Pathology (T.J.), Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215; and Department of Radiology, Massachusetts General Hospital, Boston, (G.S.G.). Received October 5, 2000; revision requested November 16; final revision received February 9, 2001; accepted March 1. Supported in part by grants from Radionics. Address correspondence to S.N.G. (e-mail: sgoldber@caregroup.harvard.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.2–1.5-cm- diameter nodules (n = 110) were implanted subcutaneously in 84 female Fischer rats. For initial experiments (n = 46), tumors were treated with (a) conventional, monopolar RF (250 mA ± 25 [SD] at 70°C ± 1 for 5 minutes) ablation alone; (b) direct intratumoral doxorubicin injection (volume, 250 µL; total dose, 0.5 mg) alone; (c) combined therapy (doxorubicin injection immediately followed by RF ablation); (d) RF ablation and injection of 250 µL of distilled water; or (e) no treatment. In subsequent experiments, amount of doxorubicin (0.02–2.50 mg; n = 40 additional tumors) and timing of doxorubicin administration (2 days before to 2 days after RF ablation; n = 24 more tumors) were varied. Pathologic examination, including staining for mitochondrial enzyme activity and perfusion, was performed, and the resultant tumor destruction from each treatment was evaluated.
RESULTS: Coagulation diameter was 6.7 mm ± 0.6 for tumors treated with RF ablation alone and 6.9 mm ± 0.7 for those treated with RF ablation and water (P = .52), while intratumoral doxorubicin injection alone produced only 2.0–3.0 mm of coagulation (P < .001). Increased coagulation was observed only with combined doxorubicin injection and RF therapy (P < .001). Coagulation was dependent on concentration and timing of doxorubicin administration, with greatest coagulation (11.5 mm ± 1.1) observed for doxorubicin administered within 30 minutes of RF ablation.
CONCLUSION: Adjuvant intratumoral doxorubicin injection increases coagulation in solid tumors compared with RF ablation alone. Increased tumor destruction is also seen when doxorubicin is administered after RF ablation, which suggests that RF ablation may sensitize tumors to chemotherapy. Such combination therapies may, therefore, offer improved methods for ablating solid tumors.
Index terms: Breast neoplasms, therapy, 00.32 • Chemotherapy • Hyperthermia • Radiofrequency (RF) ablation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Prior efforts at increasing local tumor control have been based on maximizing thermally mediated tissue coagulation by increasing the amount of thermal energy deposited during ablation. This has been accomplished largely by increasing generator output with modified RF application (ie, pulsed RF techniques or other algorithms [14]) or electrode modification (ie, arrays of hooked conventional electrodes [3,8], or internally cooled electrodes [4,9,15,16]) to deposit greater amounts of heat within the tissue. Such strategies have met with some success, since coagulation diameters of 3.5–5.0 cm can be obtained with a single RF application. However, the application of high-current energy has not been without increased patient risk from complications, such as burns from the grounding pad (17). Thus, alternative complementary strategies to increase coagulation that do not rely on further increases in energy deposition would be highly desirable.
We postulate that combining thermal ablation with other tumoricidal therapies, such as chemotherapy, may be beneficial in increasing the amount of focal tumor destruction and in reducing the local rate of tumor recurrence (ie, treatment failure). The purpose of this study was to determine whether a combination of intratumoral doxorubicin injection and RF ablation increases tumor destruction compared with RF ablation alone in an animal tumor model.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Experiments were performed by using a well-characterized (18,19) established R3230 mammary adenocarcinoma cell line (Ralph Weissleder, MD, PhD, Center for Molecular Imaging Research, Massachusetts General Hospital, Boston). Fresh tumor (approximately 1.0 cm in diameter) was initially harvested from a live carrier. Within 1 hour of this tumor explantation, the tumor was homogenized with a tissue grinder (model 23; Kontes Glass, Vineland, NJ) by using an aseptic technique and was suspended in 7 mL of medium (RPMI 1640; INC Biomedicals, Aurora, Ill). Investigators in prior control experiments have documented that this produces a concentration of approximately 1 x 107 tumor cells per 0.1 mL, with greater than 95% cellular viability.
With direct visualization, an 18-gauge needle was used to slowly inject 0.2–0.3 mL of the tumor suspension into the mammary fat pad of 84 female Fischer 344 rats (Taconic, Germantown, NY), the strain of animals from which this tumor was initially derived. One tumor was implanted within the mammary fat pad on each side of the abdomen in each animal, for a total of 168 tumor implantations. Tumors were grown for 10–20 days until the desired size was achieved. Animals were monitored every 3–4 days to measure tumor growth. Solid 12–15-mm-diameter nonnecrotic tumors (as determined with ultrasonography [US]) were used for ablation studies. In total, 110 tumors were used for this study. The remaining 58 tumors were not used because they were too small (<12 mm in diameter) to meet entrance criteria for this study (ie, there was a greater than 3-mm difference in tumor growth rate) or because they had developed central cystic cavitary necrosis.
Overall Experimental Design
The study was performed in three phases. In the first phase, the effect of combined doxorubicin injection and RF ablation was explored. In the second phase, the effect of doxorubicin concentration and volume in tumors also being treated with RF ablation was studied. In the third phase, the effect of altering the interval between doxorubicin administration and RF ablation was explored.
Phase 1.—In the first phase, we examined a total of 46 tumors. Eight tumors were randomly assigned to each of five groups (n = 40). These included (a) RF ablation alone, (b) doxorubicin injection alone, (c) doxorubicin injection followed by RF ablation 48 hours later, (d) injection of 250 µL of distilled water followed by RF ablation 48 hours later, and (e) no therapy. For these first experiments, a total of 250 µL of doxorubicin hydrochloride injection (Adriamycin RDF; Pharmacia & Upjohn, Kalamazoo, Mich), pH 3.0, diluted in distilled water was administered at a concentration of 2.00 mg/mL for a total dose of 0.5 mg. Doxorubicin or distilled water was injected slowly during 30 seconds into the center of the tumor with a 27-gauge needle; this procedure was performed without moving the needle to increase the likelihood of maximally uniform diffusion.
Four of the control tumors that were not treated were obtained from animals in which the contralateral tumor was treated with RF ablation alone, and four were obtained from animals in which the contralateral tumor was treated with an intratumoral injection of doxorubicin. This additional internal control helped to verify that the injected intratumoral doxorubicin did not induce substantial tumor necrosis in the noninjected contralateral tumor. Additionally, to minimize the potential effect of systemic doxorubicin, tumors in treatment groups 1 and 4 were from animals that were not treated with an intratumoral injection of doxorubicin.
Animals were sacrificed 48 hours after the last intervention. Tumors were excised and were examined pathologically, as described later. To determine whether the effects of combined therapy could be seen immediately, the remaining six of the 46 tumors in this first phase were treated with a combination of doxorubicin injection followed by RF ablation 48 hours later, and specimens were examined at pathologic study immediately (within 15 minutes) after RF application.
Phase 2.—In the second phase of the study, the effects of doxorubicin concentration and volume were assessed (n = 48). For the concentration experiments, a total of 250 µL of doxorubicin solution was directly injected into the tumor immediately before RF ablation. The total amount of doxorubicin was varied from 0.02 to 2.50 mg by altering the drug concentration dilution in distilled water. Eight tumors each were treated with 0.02, 0.10, 0.50, 2.00, and 2.50 mg of doxorubicin (total, n = 40; including eight tumors from phase 1). To assess the effects of increased doxorubicin volume, an additional eight tumors were treated with a larger volume (1,000 µL, or 1 mL) of doxorubicin (2.00-mg total dose) at a concentration of 2.00 mg/mL. The results obtained with treatment of these tumors were directly compared with those obtained with the injection of 250 µL at 8.00 mg/mL (ie, an equivalent 2.00-mg total dose). For this phase, pathologic analysis was performed 48 hours after RF application.
Phase 3.—In the third phase, the time of administration of doxorubicin was varied in relation to the RF application from 2 days before to 2 days after RF ablation (total n = 40). In addition to the previously studied doxorubicin injections at 48 hours and immediately before RF ablation (n = 16, eight each from phases 1 and 2), eight tumors each were treated with intratumoral injection 20–30 minutes, 6 hours, or 48 hours after the standardized course of RF therapy (n = 24). In these experiments, 0.50 mg of doxorubicin was administered in 250 µL of distilled water. In the 15 rats with both tumors ablated, identical timing and spacing of the RF and doxorubicin treatments were maintained for both tumors. This eliminated the possibility that long-term doxorubicin exposure would affect the results in the second tumor. Pathologic study was performed 48 hours after the last intervention.
RF Application
Conventional, monopolar RF was applied by using a 500-kHz RF generator (model 3E; Radionics, Burlington, Mass) (Fig 1). To complete the RF circuit, the animal was placed on a standardized metallic grounding pad (Radionics). Contact was ensured by shaving the animal’s back and by liberally using electrolytic contact gel. Initially, the 1-cm tip of a 21-gauge electrically insulated electrode was placed at the center of the tumor with US guidance. The distal 1-cm tip of this needle was not insulated, to permit RF deposition. RF was applied for 5 minutes with the generator output titrated to maintain a tip temperature of 70°C ± 1 (90.4 mA ± 25.8; range, 48–160 mA). This standardized method of RF application has been previously demonstrated to provide reproducible coagulation volume of approximately 50% of the tumor diameter (19,20). A thermocouple at the tip of the RF electrode constantly measured the local ablation temperature, thereby enabling proper generator manipulation. Parameters of the RF ablation procedure, including tip temperature, tissue impedance, and applied current, were recorded at baseline and thereafter at 60-second intervals for the duration of RF application.
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Statistical Analysis
For all experiments, coagulation diameter was measured and results were compared by using routine statistical analysis. One-way analysis of variance was performed for the comparisons reported in phases 1 and 3. Pairwise t tests (
= .05; two-tailed test) based on the least square means were subsequently performed, if and only if the overall P values demonstrated statistically significant differences. Regression analysis was performed for the dosimetry data in phase 2.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The rationale of our study stems from the conventional, multidisciplinary approach used for the treatment of most solid cancers, which includes combined surgery, radiation therapy, and chemotherapy. In prior investigations, results of treatment with a combination of RF ablation and percutaneous ethanol instillation (19) and a combination of RF ablation and chemoembolization (22) have been reported. Additionally, we sought to exploit the known effect of hyperthermia (ie, the increased susceptibility of heated cells to cytotoxic agents), which occurs in tissues surrounding the zone of RF-induced coagulation. Our study findings demonstrate that use of a combination of RF ablation and direct intratumoral doxorubicin chemotherapy, compared with either therapy alone, markedly increases the extent of induced coagulation in an animal breast tumor model. This strategy may, therefore, offer an improved method for ablating chemosensitive breast, liver, or other focal neoplasms.
Pathologic analysis of tumors treated with RF ablation demonstrated a treatment pattern with findings characteristic of heat preservation or an electrocautery effect at histologic examination. Findings in prior studies have demonstrated that this histopathologic morphology after RF ablation corresponds to gross pathologic findings and is predictive of cellular death, since these cells also show absence of critical mitochondrial or cytosolic enzyme activity (lactate dehydrogenase) (21). Likewise, absent mitochondrial function, which has been previously reported to be correlated with gross and histopathologic findings (19), was confirmed by findings in our study as well. Furthermore, while the zone of RF-induced coagulation with this R3230 rat tumor model is known not to increase from immediately after RF ablation to 48 hours after therapy (19), further cell death during this time was observed with the addition of an intratumoral doxorubicin injection. In comparison with the pathologic findings with RF ablation alone, conclusive histopathologic coagulative necrosis was observed in the expanded treatment zone (pattern B). This difference in morphologic appearance, coupled with the increased time to observe changes compatible with cell death after therapy, suggests that the thermal damage from combined RF ablation and chemotherapy produces cytotoxic effects through mechanisms that are different from the mechanisms of the thermal damage from RF ablation alone.
Results of serial experiments in which the time of doxorubicin administration was varied in relation to the RF therapy provide insight into these mechanisms of improved tumor destruction with combination therapy. Identical amounts of coagulation were seen when doxorubicin was administered either immediately before or 20–30 minutes after RF ablation. This suggests that the process is not mediated by a direct increase in the effect of doxorubicin as a result of heat itself. Exposure of the tumor cells to doxorubicin for 2 days before RF ablation did not increase the sensitivity of cells to RF when compared with the increases in coagulation observed when doxorubicin was administered immediately before ablation. This suggests that the presence of doxorubicin is only required during a critical period of RF-induced cell damage.
The progressive decrease in coagulation when doxorubicin was given at 6 and 48 hours after RF ablation not only defines the very narrow optimal window for combining the therapies but also points to cellular viability, given active cellular recovery from the sublethal RF insult. For the regions that are damaged but not completely coagulated by using RF ablation, substantial reversal of the RF damage has likely occurred by 6 hours after ablation, with even greater recovery of cellular functioning at 48 hours. Nevertheless, some benefit of administering doxorubicin 48 hours after RF ablation was identified, suggesting incomplete recovery at this time. The less than maximal increase in coagulation observed when doxorubicin was administered 2 days before RF ablation is likely due to the intratumoral doxorubicin concentration, which likely decreases with time.
On the basis of these findings, we hypothesize that the improved treatment effect is due to RF-induced short-term, but reversible, thermal injury, which sensitizes the tumor to chemotherapy. The synergy between doxorubicin and hyperthermia (ie, mildly elevating tissue temperatures to 41°C–45°C during long periods of time) has been previously shown (23–25). One often proposed mechanism for hyperthermia has been that heat increases vascular permeability and, hence, improves intratumoral delivery of cytotoxic agents (26,27). Given the direct intratumoral injection strategy used for doxorubicin administration in our study, our results support the contention that the hyperthermic effect is, at least in part, due to other nonvascular mechanisms. Other proposed mechanisms include transient damage to cellular homeostatic mechanisms that permit increased cellular or nuclear membrane permeability to doxorubicin (28,29). In many tumor cell lines, doxorubicin is actively pumped out of cells by the action of the multidrug resistance membrane protein, which can be transiently damaged by heat (30,31). Alternatively, RF ablation has been shown to transiently reduce blood flow at 45°C–50°C, and cellular uptake of doxorubicin is known to increase with hypoxic conditions (32,33).
For clinicians performing thermal tumor ablation (ie, obtaining tissue coagulation by heating to greater than 50°C for a short time), the use of adjuvant therapies that increase the diameter of coagulation by taking advantage of the large zone of sublethal heating at the periphery of the focus of the ablation is particularly appealing. Prior investigators (20) have demonstrated a steep thermal gradient in tissues surrounding an RF electrode, with a threshold to induce coagulation of approximately 50°C. However, by decreasing the threshold for cell death by as few as 5°C (ie, to 45°C), the volume of coagulated tissue would be substantially increased. Although the exact temperature at which synergy between doxorubicin and typical ablation heating times (6–15 minutes) is unknown at this time, the 4-mm increase in coagulation diameter observed in this study, coupled with previously obtained remote thermometry data (20), suggests that the lower threshold to induce tumor destruction in this model is likely 45°C–48°C.
In our study, increased coagulation was seen in a range of increasing doxorubicin dosage to a near-maximum effect for this sigmoidal curve observed at 0.50 mg. However, greater doses of doxorubicin or increases in the volume of injection at a standard concentration of doxorubicin did not increase the diameter of coagulation. We attribute the lack of change to the fact that the smaller injection volume was adequate to cover the region of RF-induced abnormalities. Nevertheless, larger volumes of doxorubicin will undoubtedly be required for the treatment of larger tumor volumes when combined with RF techniques that create greater volumes of coagulation. However, investigators (34) have reported difficulty in achieving uniform diffusion of other percutaneously injected compounds, such as ethanol, greater than these larger volumes. Thus, the use of alternate delivery routes, such as intravenous or intraarterial routes for chemotherapy, may ultimately be required. Indeed, our results suggest that some of the improved effect, in prior studies (24) in which the findings demonstrate the benefit of chemoembolization combined with RF ablation, is likely due to the chemotherapy itself and not only to the reduced blood flow at the time of RF ablation. Targeted drug delivery vehicles may also be of benefit. One such agent, stealth liposome encapsulated doxorubicin, has already been shown to be of benefit for hyperthermia therapy (35).
The concept of increasing the extent of RF-induced tumor destruction by using other classes of injected adjuvant agents has been previously investigated. Several investigators (36,37) have injected saline before or during RF ablation therapy, with a resultant increase in tissue heating and coagulation. This increase was attributed to altered tissue conductivity, which permitted greater energy deposition in the tumor, or alternatively, to improved heat conduction by the spread of hot liquid. Goldberg et al (19) have also demonstrated that the injection of ethanol into rat tumors before but not after RF ablation increases the zone of coagulation. These results were attributed to improved heating from the decreased blood flow that was induced by the ethanol. Given that these previously studied agents increased coagulation with different mechanisms of action than those proposed for combined thermal ablation and chemotherapy, further study will be required to determine the optimal type of injection strategy and whether or not these types of injected agents can be combined to maximally improve RF ablation therapy.
Key limitations of this study include the limited generalization of results given the tumor model studied, the size of the ablated foci, the RF technique, and doxorubicin doses selected. Although this model was selected on the basis that it is a well-characterized adenocarcinoma (18,19), it is possible that results will vary with other tumor types (ie, hepatocellular carcinoma) and in other orthotopic tumor sites (ie, the liver). Furthermore, while the 70°C tip temperature for RF therapy was optimal in this model, since it permitted the demonstration of synergy between the two methods, the use of alternative thermal ablation protocols would have permitted the destruction of the entire 1.5-cm tumor without combined therapy. Hence, the size of our tumor model precluded the ability to detect differences with higher RF tip temperatures. Given these concerns, extrapolation to larger, more clinically relevant tumors must be made with caution. Within larger tumors, the greater volume or dose of doxorubicin that will likely be required, may prove to have undesired systemic toxic effects. It is also possible that the increased zone of ablation in larger tumors will not be proportional to the fivefold volumetric increases observed in this study and that only small increases in the coagulation zone (eg, the millimeter increases in diameter observed in the current study) will be noted. This is believed to be unlikely, given findings in prior thermometry studies that demonstrate a wide zone of elevated temperatures surrounding commonly used RF electrodes (14,15). Regardless, the additional coagulation induced by the use of combined therapy will likely be of marked importance near vessels or at tumor periphery, two of the sites reported to be most difficult to treat with thermal therapy due to perfusion-mediated tissue cooling (4,38,39).
Another limitation of this study is the potential for an error in quantitation of the drug-dose curve, which may have occurred as a result of our use of two tumors in many of the animals. Theoretically, some of the doxorubicin injected into one tumor could escape into the systemic circulation and be deposited into the contralateral tumor. However, we think that this is unlikely because we did not observe a statistical or meaningful difference in the extent of coagulation when we compared the results in animals in which a single tumor was treated with those in which both tumors were treated. Furthermore, even if a trace of doxorubicin cross-contamination were present, the validity of our primary finding, that a combination of doxorubicin injection and RF therapy improves ablation therapy in this model, would not be diminished. Nevertheless, we are currently studying both the effect of doxorubicin deposition into a contralateral tumor from intratumoral injection and the effects of systemic doxorubicin injection on the effectiveness of RF ablation.
Practical application: Findings in this study demonstrate that intratumoral injection of doxorubicin in conjunction with RF ablation increases coagulation in an animal tumor model. This effect is attributed to the combined effect of hyperthermia and chemotherapy. These methods may, therefore, prove useful in increasing the volume of RF-induced coagulation necrosis and, thus, may be useful in clinical applications, which might lead to the minimally invasive treatment of larger tumors. Additionally, improved tumoral cytotoxic effects might reduce the local recurrence rate of tumors treated with thermal ablation alone. Further research that optimizes the type of chemotherapeutic dosages and route by using clinically available technology is necessary in preparation for clinical trials of the use of this approach.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, S.N.G.; study concepts, S.N.G., P.F.S., G.S.G., J.B.K.; study design, S.N.G., K.E.S., J.B.K.; literature research, S.N.G., J.B.K.; experimental studies, S.N.G., J.C.H.; data acquisition, S.N.G., J.C.H., T.J., J.B.K.; data analysis/interpretation, S.N.G., G.S.G., T.J., J.B.K.; statistical analysis, S.N.G., G.S.G.; manuscript preparation, S.N.G., G.S.G., J.B.K.; manuscript definition of intellectual content, S.N.G., P.F.S., G.S.G., J.B.K.; manuscript editing, S.N.G., P.F.S., G.S.G., K.E.S., J.B.K.; manuscript revision/review and final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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