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10.1245/s10434-007-9400-1
Annals of Surgical Oncology 14:2078-2087 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Recurrence and Survival Outcomes after Hepatic Resection with or without Cryotherapy for Liver Metastases from Colorectal Carcinoma

Rui Niu, BSc (Med)1, Tristan D. Yan, BSc (Med), MBBS1, Jacqui C. Zhu, BSc(Med)1, Deborah Black, BSc, DipEd, MStat, PhD2, Francis Chu, MBBS1 and David L. Morris, MD, PhD1

1 Department of Surgery, University of New South Wales, St George Hospital, Sydney, NSW 2217, Australia
2 School of Public Health and Community Medicine, Sydney, Australia

Correspondence: Address correspondence and reprint requests to: David L. Morris, MD, PhD; E-mail: David.Morris{at}unsw.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Some reports support resection combined with cryotherapy for patients with multiple bilobar colorectal liver metastases (CRLM) that would otherwise be ineligible for curative treatments. This series demonstrates long-term results of 415 patients with CRLM who underwent resection with or without cryotherapy.

Methods: Between April 1990 and January 2006, 291 patients were treated with resection only and 124 patients with combined resection and cryotherapy. Recurrence and survival outcomes were compared. Kaplan-Meier and Cox-regression analyses were used to identify significant prognostic indicators for survival.

Results: Median length of follow-up was 25 months (range 1–124 months). The 30-day perioperative mortality rate was 3.1%. Overall median survival was 32 months (range 1–124 months), with 1-, 3- and 5-year survival values of 85%, 45% and 29%, respectively. The overall recurrence rates were 66% and 78% for resection and resection/cryotherapy groups, respectively. For the resection group, the median survival was 34 months, with 1-, 3- and 5- year survival values of 88%, 47% and 32%, respectively. The median survival for the resection/cryotherapy group was 29 months, with 1-, 3- and 5-year survival values of 84%, 43% and 24%, respectively (P = 0.206). Five factors were independently associated with an improved survival: absence of extrahepatic disease at diagnosis, well- or moderately-differentiated colorectal cancer, largest lesion size being 4 cm or less, a postoperative CEA of 5 ng/ml or less and absence of liver recurrence.

Conclusions: Long-term survival results of resection combined with cryotherapy for multiple bilobar CRLM are comparable to that of resection alone in selected patients.

Key Words: Hepatic cryotherapy • Hepatectomy • Liver resection • Colorectal liver metastases


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatic resection has been regarded as the only curative treatment for patients with colorectal liver metastases (CRLM), achieving 5-year survival values of 30–50% and a median survival of 20–40 months in selected patients.1–4 However, the great majority of patients with CRLM present with unresectable disease. Without treatment, the long-term survival is limited. Presence of extra-hepatic metastases, extent of hepatic involvement, ability to obtain a tumor-free margin and the need to preserve sufficient functional parenchyma limit the usage of curative resection. Recent strategies, including the use of positron emission tomography (PET) in selection of surgical patients, neoadjuvant chemotherapy for tumor downstaging, preoperative portal vein embolization to induce hypertrophy of the liver remnant and additional ablative techniques for marginal non-surgical candidates may allow complete resection in patients that in years past would have been considered unresectable. Over the past decade, there has been a gradual evolution of treatment strategies involving a multi-modality approach for patients who do not conform to the traditional resection criteria.

Hepatic cryotherapy has been suggested as a treatment option for patients with unresectable CRLM, either in combination or as a stand-alone treatment.5–12 A median survival of 30 months and 2-year survival of 60% have been reported.13,14 However, the long-term survival data on the role of the combined resection/cryotherapy approach is still lacking. The primary aim of this study was to compare the long-term results of resection combined with cryotherapy with resection alone. The secondary aim was to identify possible prognostic factors that would facilitate better selection of patients likely to benefit from surgical treatments of CRLM.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Between April 1990 and January 2006, 415 patients who underwent resection with or without cryotherapy for CRLM were identified from a prospective database. Of these patients, 291 (70%) were treated by hepatic resection only and 124 (30%) were treated by combined hepatic resection and cryotherapy. All patients were managed by the same liver team, at the St George Hospital, Sydney. At our institution, resection with curative-intent was pursued aggressively and was performed in the absence of extrahepatic disease whenever technically possible. Lesions were considered unresectable if resection of disease with a clear surgical margin and preservation of sufficient functional hepatic parenchyma were not feasible. Cryotherapy was used to ablate remaining contralobar lesions after the resection. Following the principal of intention-to-treat, chemotherapy through the hepatic arterial catheter (HAC) was offered to patients with more than two hepatic lesions. Patients with extrahepatic involvement were managed with systemic chemotherapy, with or without surgery.

Pre-Operative Management
All patients underwent standard preoperative investigations that included liver biochemistry, pre-operative carcino-embryonic antigen (CEA), and computed tomography (CT) of the chest, abdomen and pelvis. Bone scan was also performed. If surgery was planned, abdominal angio-CT (CT portography) was performed to assess the extent of hepatic disease (number, volume and location) and resectability. PET was not routinely performed due to restricted government funding. When performed, it was either self-funded or at subsidized rates for apparently isolated liver or pulmonary metastases following previous therapy for colorectal carcinoma. All patient details, tumor biology and operative particulars were recorded prospectively. Synchronous disease was diagnosis of liver metastasis either at the same time or within 3 months of diagnosis of colorectal primary cancer. An optimal surgical margin of greater than 1 cm was considered.

Intra-Operative Techniques
An initial laparotomy through a right sub-costal incision was made for all patients. Exploration and palpation of the liver, hilar region and the abdominal cavity were performed to exclude extrahepatic disease. Any suspicious lymph nodes or peritoneal nodules were biopsied and sent for frozen section histology. The number, size and location of hepatic disease were confirmed by means of intra-operative ultrasound. When surgery was considered feasible, the incision was extended to bilateral sub-costal or tri-radiate incision and the liver was then fully mobilized. For liver parenchymal transection, an ultrasonic dissector (Sumisonic ME-2210; Sumitomo Bakelite Co., Japan or Selector Spembly UK) was used, with Pringle maneuver in selected cases to minimize blood loss or to maximize the efficacy of cryotherapy.15

Cryotherapy was performed using the L.C.S. 3000 liquid nitrogen system (Spembly, Andover, UK) or the Erbe system (Tubingen Germany). For larger lesions, greater than 3 cm in diameter, two or more cryoprobes were used simultaneously to ensure a total clearance. Due to the relationship between cryo-volume and the cryo-shock phenomenon, resection was used preferentially for large tumors, while remaining smaller metastases in the contralateral lobe were treated with cryotherapy.8,16 For superficial lesions, a spike probe was inserted into the center of the lesion under direct vision. For the deeper intra-parenchymal lesions, a Seldinger-type technique was used by placing an ultrasonographic-guided spinal needle in the tumor, followed by insertion of cryoprobe(s).8 Intra-operative ultrasound was used to monitor ice-ball formation to ensure tumor clearance in all planes by a margin of at least 1 cm, and the freezing process was continued for at least 5 min. When the liver tumor was close to a major portal sheath or hepatic vein, the Pringle maneuver was performed during cryotherapy to reduce the "heat sink" effect.15 Complete thawing and re-freezing could be time consuming and, more importantly, is associated causally with cryo-shock phenomenon.17 In most patients, after a partial thawing of the outer rim of the ice ball by approximately 1 cm, a second freeze cycle was used to optimize tumor ablation.18 After thawing, the probe was withdrawn gently and gelfoam was packed in the cryo-probe track to minimize bleeding. Cryo-lesions may crack and any subsequent bleeding was managed by suturing. HAC was inserted routinely in patients with more than two lesions; details of the technique are described elsewhere.19

Post-Operative Management
Adjuvant HAC was usually initiated within 1 month of surgery according to our hospital protocol – 1 g of 5-fluorouracil (5-FU) every 24 h for 4 days every 2 weeks. A minority of patients received no HAC because of catheter blockage or mal-perfusion to the duodenum. Systemic chemotherapy was given when recurrence developed. The main systemic chemotherapeutic agent was 5-FU based and, more recently, irinotecan and/or oxaloplatin were supplemented.

Patients were followed up with clinical examination and CEA measurements at 1 and 3 months after surgery, and half-yearly thereafter. CT of the chest, abdomen and pelvis were performed selectively in patients with elevation of CEA to confirm recurrence. Recurrence was identified by hospital radiologists after comparison with previous CT scans. All patients were followed until January 2006 or death.

Statistical Analysis
The differences in baseline characteristics of patients who underwent resection and combined resection/cryotherapy were compared. Patients who died during the 30-day postoperative period were excluded from survival and recurrence analyses. Survival and disease-free interval analyses were performed using the Kaplan-Meier method and compared using the log-rank test. For univariate analysis, the Pearson chi-square (or Fisher’s exact) test was used for categorical factors. For multivariate analysis, a Cox-regression (Cox proportional hazards model) with forward stepwise selection of covariates and with enter and remove limits of P < 0.10 and P > 0.05 was used. All statistical analysis was performed using SPSS for Windows (version 11.5; SPSS GmbH, Munich, Germany). A statistical difference was assumed for P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
A total of 415 patients with CRLM underwent liver resection with or without cryotherapy. The median follow-up period was 25 months (range 1–124 months). There were 239 men (58%) and 176 women (42%), with a mean age of 62 ± 11 years. The mean number of lesions was 2.9 ± 2.3. The mean size of the largest liver metastasis was 5.0 ± 3.8 cm.

Of the patients, 291 underwent resection only (resection group) and 124 underwent resection combined with cryotherapy (combined group). The distribution of patients’ characteristics between the resection and combined groups are shown in Table 1Go. The differences in clinicopathological factors between the groups reflect the fact that patients in the combined group had more advanced disease, in that a significantly higher proportion of patients had bilateral disease (P < 0.001), a greater number of liver metastases (P < 0.001) and larger size lesions (P < 0.001). The 30-day perioperative mortality rate was 3.1% (n = 13). Eight patients were from the resection group (2.7%) and five patients were from the combined group (4.0%).


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  		TABLE 1. The baseline characteristics of 291 patients who underwent resection (resection group) versus those of 124 patients who underwent resection and cryotherapy (combined group) for colorectal liver metastases
 
Recurrence Results
At the final time of contact, some form of recurrence was observed in 289 patients (70%). Liver recurrence occurred in 195 patients (49%) and extra-hepatic recurrence in 166 patients (41%); this included pulmonary recurrence (n = 141, 35%), bone recurrence (n = 29, 7%) and abdominal recurrence (n = 17, 4%). The distribution of recurrence in the resection and resection with cryotherapy groups is shown in Table 2Go. The combined group is associated with a higher rate of overall recurrence (P = 0.005), liver recurrence (P = 0.004), overall extrahepatic recurrence (P = 0.004) and pulmonary recurrence (P = 0.005).


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  		TABLE 2. Patterns of recurrence in 283 patients who underwent resection (resection group) compared with those of 119 patients who underwent resection and cryotherapy (combined group) for colorectal liver metastases
 
Survival Results
A total of 174 patients (43%) remained alive at the final time of contact. The overall median survival was 32 months (range 1–124 months), with 1-, 2-, 3-, 4-and 5-year survival rates of 85%, 62%, 45%, 33% and 29%, respectively. For the resection group, the median survival was 34 months (range 1–124 months), with 1-, 2-, 3-, 4- and 5-year survival rates of 88%, 64%, 47%, 36% and 32%, respectively. For the combined group, the median survival was 29 months (range 1–117 months), with respective 1-, 2-, 3-, 4-and 5-year survival rates of 84%, 61%, 43%, 28% and 24%. There was no significant statistical difference between the resection and combined group (P = 0.206, Fig. 1Go).


Figure 1
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  		FIG. 1. Survival in patients who underwent liver resection lesions (resection group) versus that in those who underwent resection/cryotherapy (combined group) (P = 0.206).

 
Univariate Analysis of 19 Potentially Prognostic Factors Affecting Survival
We analyzed 19 identified potential prognostic variables for their significance in survival (Table 3Go). Univariate analysis suggested that a favorable prognosis was associated with the following 11 variables: well- or moderately differentiated colorectal cancer (P = 0.047), absence of extrahepatic disease at diagnosis (P < 0.001), fewer than four lesions (P = 0.018), largest size of lesions being 4 cm or less (P < 0.001), preoperative CEA of 5 ng/ml or less (P = 0.005), surgical margin greater than 1 cm (P = 0.006), postoperative CEA of 5 ng/ml or less (P < 0.001), lack of post-operative HAC (P = 0.041) and an absence of disease recurrence at the following sites: overall (P < 0.001), liver (P < 0.001) and extrahepatic sites (P = 0.015). However, the remaining nine variables did not demonstrate any significant impact on overall survival.


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  		TABLE 3. Univariate analysis of 19 potentially prognostic variables affecting survival (n = 402). P value was calculated using log-rank test; N/A - median disease-free interval has not been reached
 
Multivariate Analysis of Potential Prognostic Factors Affecting Survival
Of the 11 variables that were significant from the univariate analysis, 10 were entered into a Cox-regression model for multivariate analysis. Overall recurrence was excluded from this analysis because it was not independent of the other two recurrence variables, namely liver recurrence and extrahepatic recurrence. Five factors were found independently associated with a favorable outcome: well- or moderately-differentiated colorectal cancer (P = 0.029), absence of extrahepatic disease at diagnosis (P = 0.026), liver lesions of 4 cm or less (P = 0.003), postoperative CEA of 5 ng/ml or less (P = 0.005) and absence of liver recurrence (P = 0.003) (Table 4Go).


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  		TABLE 4. Multivariate analysis of the factors affecting survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Patients who are not eligible for hepatic resection may benefit from combined resection/cryotherapy. At our institution, resection with a curative intent has been pursued aggressively and performed in the absence of extrahepatic disease whenever technically possible. Factors such as number and size of lesions alone have not restricted the patient selection. Lesions were considered unresectable only if resection of disease with a clear margin and preservation of sufficient functional hepatic parenchyma were not feasible. In these situations, resection combined with cryotherapy to obtain an adequate surgical margin was utilized. In the present study, the median survival was 29 months, with 5-year survival rates of 24% in patients who underwent combined resection/cryotherapy. These results are not significantly different from a median survival of 34 months and 5-year survival of 32% in the resection patients. Considering that these patients were intrinsically different in terms of their baseline characteristics, in that the former group was associated with more extensive disease, the aggressive surgical approach for patients with multiple bilobar disease is promising. Finlay et al. reported similar results from a series of 107 patients.13 More recent series have also reported on the efficacy of cryotherapy in conjunction with hepatic resection.5,6,8,10,20

In the multivariate analysis, primary tumor differentiation, extrahepatic disease at diagnosis, size of lesion, postoperative CEA and liver recurrence were independent prognostic predictors. These findings are consistent with that reported in the literature.21,22 It was interesting to note that the number of lesions was not significant in the Cox-regression model (P = 0.182). There has been much disagreement with the prognostic value of the number of metastases in predicting survival outcomes.23 Early series from Taylor et al. regarded the number of lesions as the most reliable long-term predictor of poor survival, with a 5-year survival of 47% reported for solitary lesions compared with only 17% for multiple lesions.24 This was later substantiated by Fong et al. who incorporated numbers of metastases and surgical margins as predictors of poor prognosis in a seven independent parameter prognostic scoring system.25 Recently, this view has been challenged by investigators such as Moroz et al., who reported that a 5-year survival of 39% for patients undergoing resection of four to seven metastases was not significantly different from that of patients undergoing resection of one to three metastases (5-year survival = 30%).6,26

With the aggressive multidisciplinary approach becoming more evident, the traditional criteria for resection are now less rigid than in the past. It is increasingly recognized that long-term survival is possible in the setting of adverse clinicopathological factors such as multiple bilobar disease and, therefore, they should not be regarded as absolute contraindications for surgery.27,28 Although complete agreement regarding selection criteria has not occurred, consensus for resection is evident. Currently, most liver surgeons support consideration of resection in patients, whereby a margin-negative resection is achievable, with preservation of two contiguous hepatic segments and more than 20% functional liver remnant, sufficient vascular supply and biliary drainage.29–31 This has reiterated a theoretical shift to define resectability by what will remain following resection instead of what is removed. This broadens the cohort of patients with multiple bilobar lesions, and adverse clinicopathological factors who would otherwise not have been treated with curative resection.32

Advances in neoadjuvant chemotherapy regimens for tumor downstaging have allowed curative resection in patients with previously unresectable lesions.33,34 Current data suggest that curative resection can follow neoadjuvant chemotherapy in approximately 8% of cases, but this conversion rate varies between 1% and 33% depending on patient selection.35–39 Bismuth et al. used 5-FU, folinic acid and oxaliplatin for tumor downstaging and demonstrated a 5-year survival of 40% after resection.40 A more recent series identified a 3-year disease-free survival rate of 21%, but with substantial recurrence rates of approximately two-thirds during the first two years.28,41 The present series supports combined resection/cryotherapy in the subset of patients with unresectable disease. The comparable survival outcome of combined resection/cryotherapy means that more patients can undergo curative surgery. The neoadjuvant chemotherapy approach has not been routinely adopted at our institution. In these 415 patients, only 25 patients received neoadjuvant systemic chemotherapy, and their median survival was 37 months and 5-year survival rate 13%. Their long-term survival did not seem to be as impressive as reported by others. This may be due to the fact that our threshold for unresectable disease is much higher, in that these 25 patients were not even considered immediate candidates for combined resection/cryotherapy.

This study also showed that the rates of overall recurrence, and that in the liver and lung, were significantly different between the two groups. This may be related to more extensive disease in the combined group and also that cryotherapy may not result in complete tumor ablation. However, these findings did not translate into significantly poorer survival results in the combined group. Hepatic cryotherapy was one of the most widely used ablative techniques in the past. Although radiofrequency ablation (RFA) has become more widely used as the ablative technique, cryotherapy has the advantage of being economical and the probes are reusable. In certain parts of the world, cryotherapy still has its place in the treatment of liver tumors. Data obtained from the present treatment cohort could potentially be correlated with RFA. There has been no comparative study demonstrating the efficacy of one versus the other. We believe that hepatic resection/cryotherapy has its place and is a mature treatment modality.

However, one of the drawbacks feared by many hepatic surgeons is cryotherapy-induced systemic inflammatory response—the cryo-shock effect. It has been shown that the complete double freeze-thaw cycle would produce more cytokine release, which might in turn cause the cryo-shock phenomenon.7,8,17,42 In order to avoid this, we have been using a partial double freeze-thaw cycle, where thawing of the outer rim of the ice-ball by approximately 1 cm is performed prior to re-freezing instead of complete thawing and re-freezing. In our experience with cryotherapy for primary and secondary hepatic tumors, we have not experienced any cryo-shock phenomenon.

The major limitation of the present study is that this is not a randomized controlled study. Although there is no statistically significant survival difference in the resection only and combined treatment groups, this may partly be due to the fact that the study is underpowered to identify the survival difference.

This study demonstrated acceptable long-term survival results after the combined treatment modality of resection and cryotherapy for CRLM. The survival outcomes achieved in a group of patients with advanced unresectable CRLM were not significantly different from outcomes in response to resection alone.

Received for publication November 6, 2006. Accepted for publication February 15, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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