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1 Department of Ultrasound, Chinese PLA General Hospital, 28 Fuxing Rd.,
Beijing, 100853 China.
2 Chinese PLA Medical Library, 5 Fengtai Rd., Beijing, 100039 China.
Received April 1, 2003;
accepted after revision May 14, 2003.
Address correspondence to P. Liang.
Abstract
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SUBJECTS AND METHODS. From July 1995 to March 2002, 74 patients with 149 hepatic metastases were treated with percutaneous microwave coagulation therapy under sonographic guidance. The largest metastasis in each patient ranged from 0.7 to 6.8 cm (mean, 3.12 cm; SD, 1.81 cm). Survival rates and influencing factors were analyzed.
RESULTS. The cumulative survival rates of all 74 patients were 91.4% at 1 year, 59.5% at 2 years, 46.4% at 3 years, 29% at 4 years, and 29% at 5 years. Patient age (p = 0.46) and sex (p = 0.12) and site of primary malignancies (p = 0.58) were not related to prognosis, whereas tumor grade (p = 0.01), number of metastases (p = 0.00), tumor size (p = 0.03), and local recurrence or new metastasis (p = 0.00) significantly affected survival as single independent factors. Multivariate analysis revealed that tumor grade (p = 0.03), number of metastases (p = 0.025), and local recurrence or new metastasis (p = 0.04) each had a significant effect on survival. No severe complications occurred.
CONCLUSION. The probability of long-term survival for patients with one or two metastases, well-differentiated tumors, and without recurrence or new metastasis may be significantly higher than for other patients.
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Clinicians use surgical resection as the initial treatment for some hepatic metastases. Unfortunately, surgical resection is not an option for more than two thirds of patients with colorectal liver metastases, and the survival rates are 25–40% at 5 years [4–6]. Moreover, the high rate of recurrence in the liver, affecting 53–68% of patients, would require repeated resection, which can be tolerated by only a minority of patients [3].
Percutaneous in situ tumor ablation with a thermal energy source, such as a radiofrequency, microwave, or laser, is receiving increased attention as a promising technique for the treatment of focal malignant disease in the liver [7–18]. Potential benefits of this procedure using these various techniques are the treatment of nonsurgical candidates, reduced morbidity compared with surgery, ease with which the treatment can be repeated for recurrent or new lesions, and improved quality of life.
Thermal ablation of hepatic metastases from colorectal cancers reportedly results in 1-, 2-, and 3-year survival rates of 57–94%, 42–69%, and 14–42%, respectively [19–22]. The survival rates and mean survival times for patients who undergo hepatectomy seem to be similar for those who are treated with microwave ablation [21] or radiofrequency ablation [19]. An evaluation of the literature yielded the preoperative factors that might predict long-term survival after liver resection. Factors that have been proposed as predictors of survival include the number of liver metastases [4], tumor size, timing of appearance of metastatic disease [23], patient age [24], and patient sex [25]. To our knowledge, no variable analysis of therapeutic results of microwave coagulation therapy has been reported. We performed a single institution study of 74 consecutive patients undergoing microwave coagulation therapy of liver metastases in which a number of factors were examined and their relationship to outcome was assessed to determine whether any of these factors' effect on survival might be used to predict the prognosis for patients who undergo microwave coagulation therapy for the treatment of liver metastases.
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Patients
In this study, 74 patients with 149 nodules were recruited and underwent
percutaneous microwave coagulation therapy between July 1995 and March 2002
and were then followed up continuously until August 2002. The study group was
composed of 44 men and 30 women who ranged in age from 27 to 81 years. The
largest metastasis in each patient ranged from 0.7 to 6.8 cm (mean, 3.12 cm;
SD, 1.81 cm; median, 3.0 cm). The distribution of tumor size and number of
nodules are shown in Table
1.
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Primary tumors included colorectal adenocarcinoma in 28 patients, gastric or cardiac adenocarcinoma in 12 patients, breast carcinoma in 11 patients, lung cancer in 12 patients, pancreatic adenocarcinoma in one patient, gallbladder adenocarcinoma in two patients, renal cell carcinoma in five patients, ocular melanoma in one patient, and leiomyosarcoma of the small bowel in two patients. All patients had undergone resection of the primary tumors 5–74 months before undergoing microwave coagulation therapy.
Histologic diagnosis was confirmed using a sonographically guided biopsy system with an 18-gauge cutting-edge needle. Proof of malignancy for at least one metastasis was obtained in all 74 patients. Specimens were assessed by two pathologists independently who were unaware of medical history and diagnosis. The histologic grades of differentiation were defined as follows: well differentiated, corresponding to Edmondson's grade I or I–II; moderately differentiated, corresponding to Edmondson's grade II or II–III; or poorly differentiated, corresponding to Edmondson's grade III or III–IV. Histologic grading was obtained in all 74 patients: There were nine well-differentiated tumors (12.16%), 33 moderately differentiated tumors (44.60%), and 32 poorly differentiated tumors (43.24%).
Fifty-eight patients (78%) were not candidates for surgical metastasectomy because of multiple lesions located in different hepatic segments in 34 patients, prior hepatic metastasectomy in 10 patients, advanced age in seven, extrahepatic metastases in four, chronic renal disease in two, and cardiac disease in one. Although 16 patients (22%) in our study were candidates for resection, the patients refused surgical metastasectomy and preferred percutaneous microwave coagulation therapy. Fifty-seven (77%) of the 74 patients underwent systemic chemotherapy before and after microwave coagulation therapy, and the remaining 17 patients (23%) did not undergo any chemotherapy before or after microwave therapy.
Microwave Coagulation System
A delivery system (Ultrasound-Guided Microwave Coagulator-I [UMC-I], PLA
General Hospital and Institute 207 of the Aerospace Industry Company, Beijing,
China) with a microwave frequency of 2,450 MHz and a power output range of
10–80 W was used. The system was equipped with a needle electrode (1.4
mm in diameter). A 14-gauge percutaneous microwave coagulation therapy guiding
needle was used for puncture guidance. Iron-constantan thermocouples were
inserted and fixed into a 20-gauge needle sheath with exposed tips of 5 mm to
measure the temperature.
Preoperative Imaging Workup
Diagnostic workup before the treatment included both sonographic images and
contrast-enhanced multidetector CT (MDCT) scans in all patients. Sonographic
images (128XP/10 ART and Sequoia, Acuson, Mountain View, CA; or HDI 5000, ATL,
Bothell, WA) were obtained with 3.5-MHz convex probes equipped with
attachments for biopsy and electrode insertion. MDCT scans (Tomoscan SR 7000,
Philips Medical Systems, Best, The Netherlands) were obtained with a section
thickness of 5–10 mm, a collimation of 10 mm, a 1:1 pitch, a table speed
of 10 mm/sec, 120 kV, and 250 mA. Dualphase enhanced MDCT scans were obtained:
a power injector administered 100 mL of a 60% contrast agent (Ultravist 300
[iopromide], Schering, Berlin, Germany) at a rate of 3–4 mL/sec.
Microwave Ablation Technique
Therapeutic principle.—Coagulation volume should extend 10
mm beyond the borders of the tumor. A single- or multiple-puncture
simultaneous-emission technique was used depending on the size of the tumors.
Because the maximum transverse diameter of the coagulated area was 34 mm in a
previous study [26], for
tumors less than 14 mm in diameter, the single-puncture simultaneous-emission
technique was used. For tumors 14 mm or larger, a multiple-puncture
simultaneous-emission technique was required. The maximal distance between two
electrodes was set through computer simulation with a goal of maximizing the
total coagulated area while simultaneously merging the two areas into one
bigger area that attains an integrated shape, leaving no tumor tissue
untreated [26]. Indeed, a
tumor of 1.5–2.5 cm requires three to four overlapping ablations.
Microwave irradiation was stopped when the temperature 10 mm outside the tumor
border reached 60°C or continuously maintained a level of 54°C for 1
min.
Ablative procedures.—Treatment was performed with the use of IV anesthesia in all patients. Because the duration of each procedure was only 10–20 min, short-acting anesthesia was used; propofol (Diprivan, Zeneca Pharmaceuticals, Wilmington, DE) combined with ketamine hydrochloride was IV administered by an anesthesiologist. The loading dosage of propofol was given in a dose of 2.5 mg/kg. Maintained dosage was administered according to blood pressure, respiration, pulse, oxygenation, and ECG, which were monitored continuously.
With sonographic guidance, the electrode was inserted into the tumor through the guide needle. Thermometers placed 10 mm outside the tumor margin monitored the temperature. An average of 2.6 punctures and an average of 4.6 emissions per tumor were used for this technique. Follow-up color-flow Doppler sonography was performed at 1-month intervals. Routine contrast-enhanced MDCT was repeated at 1 and 3 months and then at 3-month intervals after microwave treatment (Fig. 1A, 1B). If colorflow Doppler sonography showed round hypoechoic areas with arterial blood flow signal, incomplete necrosis or local recurrence was highly suspected, and MDCT was performed immediately.
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Statistical Analysis
Cumulative survival rates were calculated using the Kaplan-Meier method.
Statistical comparisons of the effect of each of the potential predictive
factors on survival rates were first performed using the log-rank test.
Predictive factors included patient age, patient sex, the location of the
primary tumor, level of tumor differentiation, number of metastases, size of
metastases, changes in tumor size before and 3 months after microwave
treatment, and local recurrence or new metastasis after microwave treatment. A
p value of less than 0.05 was considered a statistically significant
difference. A multivariate Cox proportional hazards model was used to
determine the covariants and their risk, with the dependent variable
survival.
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Univariate Analysis
The results (Table 2)
revealed that there were statistically significant differences in survival
rates depending on the number of metastases (
2 = 19.21,
p = 0.00) (Fig. 3),
the tumor size (2 = 7.31, p = 0.03)
(Fig. 4), the presence of tumor
recurrence or new metastasis (2 =13.59, p = 0.00)
(Fig. 5), and the degree of
tumor differentiation (2 = 9.12, p = 0.01)
(Fig. 6). Statistical results
also showed that the differences in survival rates attributable to patient sex
(2 = 2.46, p = 0.11), the age of the patient
(2 = 1.54, p = 0.46), or the location of the original
lesions (2 = 2.87, p = 0.58) were not significant.
The changes in the size of tumors before and 3 months after microwave
coagulation therapy were also not significant (2 = 2.92,
p = 0.23).
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The survival rate (Fig. 3) for patients with one or two metastatic lesions was significantly higher than the survival rate for those with three or more metastases. However, the difference in the survival rates of patients with a single metastatic lesion versus those with two metastases was not statistically significant.
In Figure 4, the results revealed that the survival curve for the patients with tumors 3 cm or smaller in diameter differed significantly from the survival curve for those with tumors larger than 3 cm and less than or equal to 5 cm; in addition, the difference in survival curves was statistically significant between the patients with tumors 3 cm or smaller and those with lesions larger than 5 cm. Survival rates for patients with tumors 3 cm or smaller were significantly higher than for survival rates for those with tumors larger than 3 cm and less than or equal to 5 cm and those with tumors larger than 5 cm. However, there were no statistical differences between the survival curve of patients with hepatic lesions larger than 3 cm and less than or equal to 5 cm and the survival curve of patients with hepatic lesions larger than 5 cm.
In comparing survival curves of patients with tumors of different histologic grades (Fig. 5), we found that the patients with well-differentiated tumors survived significantly longer than those with the moderately differentiated tumors, and those with moderately differentiated tumors, in turn, survived longer than those with poorly differentiated tumors.
No local recurrence or new metastasis occurred in 26 of the patients (35%) during the follow-up period. Forty-eight patients (65%) had local recurrence or new metastasis after microwave treatment. Ten patients (14%) had local regrowth of a microwave-treated lesion. New metastases occurred in the liver but apart from the original sites in 38 patients (51%). New lesions were found extrahepatically in six patients (13%), and new metastatic lesions were found in both intra- and extrahepatic locations in four patients (8%). The survival curves shown in Figure 6 reveal that patients without recurrence or new metastasis survived longer than those with recurrence or metastases. However, survival curves were not related to the location of any recurrence or new metastasis (p > 0.05).
Multivariate Analysis
The multivariable analysis (Table
3) showed there were relationships between survival rates and
number of tumors (t = 2.16, p = 0.03), survival rates and
tumor differentiation (t = –2.24, p = 0.02), and
survival rates and recurrence or new metastasis (t = 1.98, p
= 0.04). Tumor size appeared to be a significant risk factor using univariate
analysis; however, the survival rates were not significantly related to tumor
size by the Cox proportional hazards model (t = 0.83, p =
0.408). The risk of death for patients with recurrence or metastases was 3.6
times higher than for those without recurrence or metastases. The hazard ratio
of death in the group with multiple metastases was 1.9 times higher than that
in the group with only a single nodule. The better differentiated the tumor,
the lower the hazard ratio of death was. Factors that were not useful in
predicting survival were age at diagnosis, patient sex, the location of
different original lesions, size of tumors, and changes in tumor size before
and 3 months after percutaneous microwave coagulation therapy.
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Complications
No severe complications were observed. Sixty-seven patients (90.54%)
experienced local pain. Minor to medium pleural effusion developed in seven
patients whose nodules were located near the liver dome. Two patients had
slight subcapsular bleeding observed on sonography during the microwave
procedures but did not require transfusion because the hemoglobin and blood
pressure of the patients stabilized at normal levels without intervention.
Skin burns occurred in three patients because the lesions protruded beyond the
liver capsule.
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Statistical results showed that the survival rates were not significantly influenced by patient age or patient sex, which corresponds to the results of several surgical series [4, 30–32]. Moreover, the survival rates were not attributable to the location of the original lesions. This result is inconsistent with results of previously reported radiofrequency studies [3, 33] but comparable to a laser study [34]. Livraghi et al. [33] reported that the high control rate observed in breast cancer metastases in comparison with colorectal cancer suggested that the occult invasion of surrounding liver tissue may be absent or less pronounced with breast metastases. Alternatively, different histologic tumor types have different thermophysical properties; therefore, their responses to thermal injury differ. In our experience, a safety margin around the tumor was needed to accomplish complete necrosis of the liver tumor during the thermal ablation. For the treatment of liver metastases, the area of complete coagulation necrosis should encompass not only the tumoral nodule, but also a margin of 10 mm of peritumoral liver tissue to necrotize infiltrating tumor cells and reduce the risk of recurrence. In addition, temperature was an objective criterion to evaluate coagulated necrosis. Complete tumor necrosis can be obtained when the temperature reaches 60°C. These factors may explain why the same control rate was obtained in patients in whom the original lesions were in different locations and why survival was not related to the location of the original lesion. In this study, the patient population was not sufficiently homogeneous, the numbers were small for each type of tumor, and the follow-up was limited. The different outcomes for small numbers of each category of patient may not be able to reveal actual statistical significance. For future studies, researchers need to increase the number of each category of patient, prolong the follow-up time, and perform strictly comparative studies for different histologic tumor types.
In this study, four of the variables were found to be important risk factors that affect survival rate in univariable analysis (Table 2). However, in the multivariate analysis, the only factors with a significant effect on survival were recurrence or new metastasis, number of tumors, and degree of tumor differentiation. Tumor size appeared to be a significant risk factor using univariate analysis, but was not significant when reviewed by Cox proportional hazards model. The result seemed to be inconsistent with that of prior investigators of radiofrequency ablation. Sica et al. [2] reported that radiofrequency ablation was most efficacious for the treatment of tumors less than 2.5 cm in diameter; early detection and accurate staging provided the opportunity for treatment, which may result in prolonged survival and improved chance for cure. Lencioni et al. [35] revealed that the indication for radiofrequency treatment of liver tumors should be that they are smaller than 3–4 cm in maximal diameter. In our experience, small tumors were more easily destroyed than large tumors during microwave ablation. Local tumor control was influenced by tumor size. However, although multiple variables were compared and analyzed, survival was more strongly influenced by other factors and was not significantly related to tumor size. This opinion is also shared by Solbiati et al. [19] and other groups of researchers [4, 30].
Our data from multivariate analysis indicated that recurrence or new metastasis was the most important determinant of survival. The risk of death in a patient with recurrence or new metastasis compared with a patient without recurrence or metastasis was four times greater. In fact, treatment failure was mainly due to recurrence or new (intra- or extrahepatic) metastasis, especially extrahepatic metastasis that are indicative of the end stage of malignancy and may directly affect survival. Four patients with extrahepatic metastases before microwave ablation had died by the end of this study. This result has been confirmed by that of surgical studies [30–32] and a radiofrequency ablative study [19]. A high local recurrence rate (14%) was found in this study. Local recurrence was mainly concentrated (8/10) in patients with tumors larger than 3.5 cm in diameter. Although computer simulation of thermal distribution and dynamic temperature measurement were applied for microwave therapy during the procedure, sometimes it was difficult to envelop the tumors completely in three dimensions for large tumors. It depended not only on the experience of the doctor performing the procedure in placing the electrodes to cover the entire tumor, but also on the position of the tumors; the ribs limited accurate puncture in some cases.
It is important to realize that microwave ablation of liver metastases will not cure most patients with hepatic metastases. The influences on survival rate depend not only on the presence of hepatic metastases, but also on the patient's general condition. Further studies are ongoing. Randomized, controlled trials are needed to establish the role of microwave ablation in comparison with resection. A larger study with a higher number of patients with hepatic metastases and a prolonged observation time is required to confirm which patients would benefit the most from microwave ablation.
In patients with metastases confined to the liver who are evaluated as candidates for microwave therapy, those with one or two hepatic metastases, with well-differentiated tumor or tumors, and without recurrence or new metastasis have a significantly higher probability of long-term survival than other patients.
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