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Annals of Surgical Oncology 8:347-353 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Five-Year Survival Following Hepatic Resection After Neoadjuvant Therapy for Nonresectable Colorectal [Liver] Metastases

R. Adam, MD, PhD, E. Avisar, MD, A. Ariche, MD, S. Giachetti, MD, D. Azoulay, MD, PhD, D. Castaing, MD, F. Kunstlinger, MD, F. Levi, MD and F. Bismuth, MD

From the Centre Hépato-Biliaire (RA, EA, AA, DA, DC, FK, HB), and Centre de Chronothérapie (SG, FL), Service de Cancérologie Hopital Paul Brousse, Villejuif, France.

Correspondence: Address correspondence and reprint requests to: Pr. Rene Adam, Centre Hepato-Biliaire, Hopital Paul Brousse, 12, Av. Paul Vaillant Couturier, BP 200 - 94804 VILLEJUIF Cedex, France; Fax: 01-45-59-38-57; E-mail: rene.adam{at}pbr.ap-hop-paris.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Surgical resection is the most effective treatment for colorectal liver metastases but only a minority of patients are candidates for a potentially curative resection. Our experience with neoadjuvant chemotherapy followed by resection and five years survival analysis of the patients treated is presented.

Methods: Between February of 1988 and September of 1996, 701 patients with unresectable colorectal liver metastases were treated with neoadjuvant chemotherapy. Four categories of nonresectable disease were defined: large size, ill location, multinodularity, and extrahepatic disease. Liver resection was performed in those patients whose disease became resectable. After resection, the patients were followed up every 3 months. A 5-year survival analysis by the different categories described was performed.

Results: Ninety-five patients (13.5%) were found to be resectable on reevaluation and underwent a potentially curative resection. There was no perioperative mortality, and the complication rate was 23%. As of December of 1999, 87 patients have completed 5 years of follow-up. The overall 5-year survival is 35% from the time of resection and 39% from the onset of chemotherapy. Respective 5-year survival rates are 60% for large tumors, 49% for ill-located lesions, 34% for multinodular disease, and 18% for liver metastases with extrahepatic disease. In this latter category, however, a 35% 5-year survival was found when all the patients with extrahepatic disease were analyzed rather than only those for whom extrahepatic disease was the main cause of nonresectability.

Conclusions: Neoadjuvant chemotherapy enables liver resection in some patients with initially unresectable colorectal metastases. Long-term survival is similar to that reported for a priori surgical candidates.

Key Words: Neoadjuvant therapy • Chronotherapy • Colorectal liver metastases • Nonresectable hepatic metastases


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is estimated that 15–20% of colorectal cancer patients present with synchronous liver metastases,1 and approximately half of the patients with colorectal tumors will fail in the liver at some point during the course of their disease.2 In almost one third of the cases, the liver was shown at autopsy to be the only site of cancer spread.3 This is in accordance with the 20% to 45% five-year survival4–9 obtained with surgical resection of hepatic metastases. Unfortunately, however, only 10% to 20% of patients presenting with liver metastases are amenable to curative resection.10–12 Palliative and symptomatic treatment is commonly offered to the rest of the patients, and the median survival does not exceed 15 months. Over the past 8 years, we have managed these patients in a protocol of neoadjuvant chemotherapy. Using a multidisciplinary approach, liver resection has been routinely reconsidered in all the cases of objective response to the treatment. This article summarizes our results with this approach.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Treatment
All the patients with colorectal liver metastases who presented to Paul Brousse Hospital from February of 1988 to September of 1996 were entered into a prospective nonrandomized study. Upon initial evaluation, the patients were divided in two groups according to the resectability of the liver disease. Patients with resectable disease were scheduled for surgery. The nonresectable group was treated with a neoadjuvant chemotherapy protocol. As previously published,10 we classified the nonresectable lesions into four categories, namely, large size, ill location, multinodularity, and extrahepatic disease. The great majority of those patients were treated with intravenous chronomodulated chemotherapy with 5-FU (700–1200 mg/m2 per day), folinic acid (300 mg/m2 per day), and oxaliplatin (25 mg/m2 per day). Every course lasted 4–5 days with intervals of 2–3 weeks between the courses. The treatment was administered in an ambulatory setting by means of a time/dose multichannel pump (Intelliject, Aguettant, Lyon, France). The rationale of this technique, which has been described in a prior publication,13 is to optimize dose intensities and tolerance of the drugs by a treatment that is modulated in a sinusoidal manner along a 24-hour period with peak flow rates at 4:00 AM for 5-FU and folinic acid and at 4:00 PMfor oxaliplatin (Fig. 1). Evaluation by ultrasound for objective response was performed every three treatments by the same radiology team. Partial response was defined as a 50% or more, decrease in tumor surface. Complete response was defined as no measurable mass, usually with a residual ultrasonic scar. Biochemical criteria of response included decreased CEA and CA 19–9 levels. Reconsideration for resection followed each evaluation. The criteria for surgery consisted in the feasibility of a curative resection, be it in one or two stages, coupled with a plateau in the response to chemotherapy. Different surgical techniques were used to enable the resection. These techniques included portal vein embolization to hypertrophy the remaining liver as described elsewhere;14 two-stage resections when all the lesions could not be resected by a single procedure; and cryotherapy, usually combined with surgery, to allow for a complete treatment of tumors, in patients otherwise unresectable. All the surgically treated patients after neoadjuvant chemotherapy, received additional chemotherapy according to the same protocol for 6 months after the resection. The treatment was then discontinued in stable patients with no evidence of disease. Follow-up was performed every 3 months with physical examination, ultrasound, CEA, and CA19–9. In addition, a CT scan of the chest and abdomen was performed every 6 months. Recurrent disease was treated according to the same protocol again, with reoperation when feasible or chemotherapy. All the demographic, clinical, surgical, radiologic, and biochemical patient information was entered in a database, which served to assess the results of our treatment.



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  		FIG. 1. Chronomodulated chemotherapy schedule.

 
Survival Analysis
Survival curves from surgery, were calculated according to Kaplan Meier actuarial survival technique. True 5-year survival curves were also calculated for those patients who completed 5 years of follow-up. To maintain uniformity with the oncologic literature when examining cancer patients outcome, the 5-year survival was calculated from presentation rather than from surgery. In addition, for this analysis, specific attention was given to lesions that fit in two categories. When prospectively entered in the database, those lesions were classified according to the main reason of unresectability; however, in the retrospective outcome analysis by categories, those lesions were classified by the one carrying the worse prognosis according to our previous results,10 in the following order: extrahepatic disease, multinodularity, location, and size. This classification should have a higher prognostic significance when evaluating the different treatment alternatives before and during surgery.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Resectability Rate
Eight hundred seventy-two patients were entered in this study. One hundred seventy-one (19.6%) had a curative resection; the remaining 701 were considered nonresectable and were treated with our protocol of neoadjuvant chemotherapy. Ninety-five of these patients (13.6%) achieved a measurable response to the neoadjuvant treatment and subsequently underwent a potential curative resection (Fig. 2). The main causes of nonresectability are shown on Figure 3.



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  		FIG. 2. Colorectal liver metastases, 1988–1988; n = 872.

 


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  		FIG. 3. Main cause of nonresectability. Ninety-five patients were resected after chemotherapy.

 
Duration and Effect of Neoadjuvant Chemotherapy
These patients received 3 to 29 courses of chemotherapy (mean = 10) during 3 to 29 months (mean = 10.6). An objective reduction in tumor size after chemotherapy was observed in all patients subsequently submitted to liver resection. A significant reduction of tumor markers was also demonstrated (mean CEA levels from 190 [1-4225] to 47 ng/ml [1-1243] and CA 19–9 levels from 4477 [22-228000] to 219 IU/ml [2-5900]). Five patients had a two-stage resection, and portal vein embolization or ligation was performed in nine patients. All visible extrahepatic disease was resected at the same time or during a second operation. Cryotherapy was used in 11 patients.

Mortality and Morbidity
There was no perioperative mortality during the first 20 days after surgery. Twenty-two (23%) complications were recorded: two postoperative hemorrhages requiring a laparotomy, four infected and eight sterile fluid collections treated nonoperatively, four transient biliary fistulas, and four systemic complications (Table 1).


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  		TABLE 1. Complications for 22 of 95 (23%) patients
 
Survival
The actuarial 5-year survival for the post neoadjuvant resection group is 34% (Fig. 4). When divided by the different categories of nonresectability, 5-year survival is 60% for large lesions, 49% for ill located tumors, 34% for multinodular disease, and 18% for extra hepatic disease (Fig. 5).



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  		FIG. 4. Actuarial survival of liver resection after systemic chronotherapy. Data include all 95 patients.

 


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  		FIG. 5. Actuarial survival of liver resection after systemic chronotherapy for the different categories of nonresectability.

 
Eighty-seven patients have completed 5 years of follow-up. Thirty four patients are alive (39%) (Fig. 6). Nineteen of these patients have no evidence of disease (22%) (Fig. 7).



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  		FIG. 6. Resection of nonresectable liver metastases after neoadjuvant chemotherapy: True 5-year survival for patients who completed 5 years of followup; n = 87.

 


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  		FIG. 7. Five-year survival. AWD, alive with disease; ANED, alive with no evidence of disease.

 
After reclassification of the 5-year survivors whose lesions fit in two categories according to prognosis, we had 37 patients with multinodular tumors, 31 with extrahepatic disease, 10 with ill-located lesions, and 9 patients with large tumors (Fig. 8). Five-year survival for the different categories is 35% for multinodular disease and for extrahepatic disease, 50% for ill located tumors, and 56% for large lesions (Fig. 9).



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  		FIG. 8. Prognostic classification of nonresectability.

 


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  		FIG. 9. Resection of nonresectable liver metastases after neoadjuvant chemotherapy: 5-year survival according to the initial cause of non-resectability by prognostic category.

 
Regarding extrahepatic disease, a marked difference in survival was found for different extrahepatic locations. Although solid organ resectable disease is associated with a 36% 5-year survival rate, lymph nodes disease carries a dismal prognosis (Table 2).


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  		TABLE 2. Extrahepatic disease by site
 
A complete clinical response was present in four patients as assessed by preoperative ultrasound; however, the clinical response did not correlate with the pathologic response, and there was no difference in survival between partial and complete clinical responders.

A complete pathologic response was found in 6 of 95 patients (6.3%). Five of these patients (83%) are alive at a mean follow-up of 5.7 years (range, 4.7–7.9 years). Three patients (50%) have no evidence of disease (Table 3).


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  		TABLE 3. Complete pathologic response for 6 of 95 (6.3%) patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Surgical resection is the only effective treatment for hepatic metastases of colorectal cancer. However, this option is available only to a minority of patients. For the majority, for whom surgery is not a curative option, palliative therapy only is available resulting in no long-term survivors. The reasons for unresectability can be divided into two categories: diffuse extrahepatic disease, which would not be controlled by treatment of the liver disease; and intrahepatic disease, which would endanger the patients life if resected. No available form of systemic therapy can effectively eradicate diffuse metastatic disease, but a partial response to chemotherapy could be used to downstage the liver disease, which would then be amenable to a surgical resection. Preliminary results with this strategy were reported after systemic15 or hepatic artery chemotherapy.16 In a selected number of patients, the same logic can be applied to a limited amount of extrahepatic disease that could also be resected after initial chemotherapy. The combination of 5-FU, folinic acid, and oxaliplatin has been shown recently to have a response rate of 59%.17 Oxaliplatin is a recently developed derivative of the platinum agents with no nephrotoxicity and a good activity against colorectal tumors.18 Chronomodulation of the therapy enables the delivery of higher concentrations of these agents with a higher tolerance rate and fewer complications.19–21 The most significant decrease in complications is with the occurrence of severe stomatitis, which was shown in a randomized trial to drop from 89% to 18%.22 In another recent multicenter trial, chronotherapy reduced 5-fold the rate of severe mucosal toxicity, halved the incidence of functional impairment from peripheral sensory neuropathy, and increased the response rate from 29% to 51%.23

Our results with neoadjuvant chemotherapy for colorectal liver metastases were previously published for a smaller number of patients and a shorter follow-up.10 In this series, we have shown a 13.6% rate of conversion from unresectability to resectability with a curative potential. If calculated for the whole group of 872 patients, neoadjuvant chemotherapy was able to increase the tumor resectability from 20% to 30%. This increased number of curative resection was accompanied by a "reasonable" complication rate and a 5-year survival that is in the range of the survival rates with initially resectable lesions.

In this study, we also included patients who failed first line chemotherapy and entered the protocol as a second or third line of treatment. This group of patients has a more limited chance of having their tumors become resectable after the neoadjuvant treatment. It seems logical to assume that the resectability rate after treatment would have been higher if only patients treated for the first time would have been included.

As expected by the nature of the disease, patients with multinodular lesions had a worse prognosis and were more likely to require more than one operation and additional procedures such as portal vein embolization or cryotherapy.

The actuarial survival curves after surgery and the true survival curves from presentation are very similar for most categories, despite an average of 10 months neoadjuvant treatment. This is in agreement with the flattening of the survival curves after 3–4 years indicating a plateau pattern in long-term survival.

The only figure differing significantly is the true survival of patients with extrahepatic disease. Inclusion of more patients in the extrahepatic category led to a marked improvement in survival from 18% to 36%. This finding is probably related to a group of patients with minimal extrahepatic disease that was not considered as the main cause of unresectability or that was discovered only in the operating room, suggesting an inverse correlation between the amount of extrahepatic disease and the long term prognosis.

Extrahepatic disease has commonly been a reason for a nihilistic approach. Some reports, however, were able to demonstrate a reasonable 5-year survival for concomitant hepatic and pulmonary involvement, provided that the disease is resectable.24,25 Our results concur with these findings showing a survival of 36% in those patients with resectable extrahepatic disease to solid organs. The use of neoadjuvant therapy may help to define those tumors that will benefit from an attempt to eradicate the disease. On the other hand, our findings do not support an aggressive approach in trying to resect lymphatic disease.

This series suffers from the limitations of a nonrandomized prospective study; however, it would have been unethical to prevent the potential benefit of the neoadjuvant chemotherapy from a control arm.

Only six patients were found to have a complete pathologic response, but those patients had an excellent survival rate. The clinical response assessment by ultrasound was not able to accurately predict the pathologic responders due to residual scarring and fibrosis at the site of the lesions, which is not echographically different than viable tumor. On the other hand, complete ultrasound resolution of the lesions, when it rarely occurred, did not correlate with viable cancer cells disappearance.

In conclusion, major hepatic resections after tumor response to chemotherapy can provide a significant hope for long-term survival. Further analysis is required to better define the subset of patients that is most likely to benefit from a neoadjuvant approach, and new protocols need to be developed to increase the cure rate of metastatic colorectal cancer.


   Footnotes
 
Dr. Avisar is currently at the Division of Surgical Oncology, University of Pittsburgh Medical Center, Pittsburgh Pennsylvania.

Received for publication July 24, 2000. Accepted for publication November 20, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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J.-N. Vauthey and E. K. Abdalla
Unresectable Hepatic Colorectal Metastases: Need for New Surgical Strategies
Ann. Surg. Oncol., January 1, 2006; 13(1): 5 - 6.
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G. Masi, S. Cupini, L. Marcucci, E. Cerri, F. Loupakis, G. Allegrini, I. M. Brunetti, E. Pfanner, M. Viti, O. Goletti, et al.
Treatment with 5-Fluorouracil/Folinic Acid, Oxaliplatin, and Irinotecan Enables Surgical Resection of Metastases in Patients With Initially Unresectable Metastatic Colorectal Cancer
Ann. Surg. Oncol., January 1, 2006; 13(1): 58 - 65.
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S. R. Alberts, W. L. Horvath, W. C. Sternfeld, R. M. Goldberg, M. R. Mahoney, S. R. Dakhil, R. Levitt, K. Rowland, S. Nair, D. J. Sargent, et al.
Oxaliplatin, Fluorouracil, and Leucovorin for Patients With Unresectable Liver-Only Metastases From Colorectal Cancer: A North Central Cancer Treatment Group Phase II Study
J. Clin. Oncol., December 20, 2005; 23(36): 9243 - 9249.
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G. Chong and D. Cunningham
Improving Long-Term Outcomes for Patients With Liver Metastases From Colorectal Cancer
J. Clin. Oncol., December 20, 2005; 23(36): 9063 - 9066.
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G. J. Poston, R. Adam, S. Alberts, S. Curley, J. Figueras, D. Haller, F. Kunstlinger, G. Mentha, B. Nordlinger, Y. Patt, et al.
OncoSurge: A Strategy for Improving Resectability With Curative Intent in Metastatic Colorectal Cancer
J. Clin. Oncol., October 1, 2005; 23(28): 7125 - 7134.
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N. J. Petrelli, J. Abbruzzese, P. Mansfield, and B. Minsky
Hepatic Resection: The Last Surgical Frontier for Colorectal Cancer
J. Clin. Oncol., July 10, 2005; 23(20): 4475 - 4477.
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H. Kelly and R. M. Goldberg
Systemic Therapy for Metastatic Colorectal Cancer: Current Options, Current Evidence
J. Clin. Oncol., July 10, 2005; 23(20): 4553 - 4560.
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G. D. Leonard, B. Brenner, and N. E. Kemeny
Neoadjuvant Chemotherapy Before Liver Resection for Patients With Unresectable Liver Metastases From Colorectal Carcinoma
J. Clin. Oncol., March 20, 2005; 23(9): 2038 - 2048.
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G. J. Poston
Radiofrequency Ablation of Colorectal Liver Metastases: Where Are We Really Going?
J. Clin. Oncol., March 1, 2005; 23(7): 1342 - 1344.
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T. Delaunoit, S. R. Alberts, D. J. Sargent, E. Green, R. M. Goldberg, J. Krook, C. Fuchs, R. K. Ramanathan, S. K. Williamson, R. F. Morton, et al.
Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741
Ann. Onc., March 1, 2005; 16(3): 425 - 429.
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M. Sebagh, M. Plasse, F. Levi, and R. Adam
Severe hepatic sinusoidal obstruction and oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer: a real entity?
Ann. Onc., February 1, 2005; 16(2): 331 - 331.
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G. Masi, G. Allegrini, S. Cupini, L. Marcucci, E. Cerri, I. Brunetti, E. Fontana, S. Ricci, M. Andreuccetti, and A. Falcone
First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule
Ann. Onc., December 1, 2004; 15(12): 1766 - 1772.
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Z. Z. R. Hamady, A. Kotru, H. Nishio, and J. P. A. Lodge
Current techniques and results of liver resection for colorectal liver metastases
Br. Med. Bull., October 27, 2004; 70(1): 87 - 104.
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C. Pozzo, M. Basso, A. Cassano, M. Quirino, G. Schinzari, N. Trigila, M. Vellone, F. Giuliante, G. Nuzzo, and C. Barone
Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients
Ann. Onc., June 1, 2004; 15(6): 933 - 939.
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I. Chau, M. J. Allen, D. Cunningham, A. R. Norman, G. Brown, H. E.R. Ford, N. Tebbutt, D. Tait, M. Hill, P. J. Ross, et al.
The Value of Routine Serum Carcino-Embryonic Antigen Measurement and Computed Tomography in the Surveillance of Patients After Adjuvant Chemotherapy for Colorectal Cancer
J. Clin. Oncol., April 15, 2004; 22(8): 1420 - 1429.
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