Liver Resection for Primarily Unresectable Colorectal Metastases Downsized by Chemotherapy

This study was performed prospectively to assess the effect of systemic chemotherapy (FOLFIRI protocol) in patients with initially unresectable colorectal liver metastases (CRLM) and, after performing liver resection in patients with downsized metastases, to compare the postoperative and long-term results with those of patients with primarily resectable CRLM. Records from a prospective database including all consecutive admissions for CRLM between June 2000 and June 2004 were reviewed. The analysis addressed all patients who underwent hepatectomy for primarily resectable CRLM (Group A), or underwent chemotherapy for primarily unresectable CRLM and among these, particularly the patients who were finally resected after downsizing of CRLM (Group B). There were 60 primarily resected patients (Group A). Forty-two other patients underwent chemotherapy; after an average of nine courses, 18 of them (42.8%) with significantly downsized lesions were explored and 15 (35.7%, Group B) were resected, whereas three had peritoneal metastases. Group B differed from Group A for a significantly higher rate of synchronous CRLM upon diagnosis of colorectal cancer, a larger size of CRLM upon evaluation in our center, and a lower rate of major hepatectomies (20.0% vs. 51.6 %) at surgery. No patient in Group B had positive margins of resection. Operative mortality was nil and morbidity was 20.0% in both groups. In Group B vs. Group A median survival after hepatectomy was 46 vs. 47 months (n.s), 3-year survival rate was 73% vs. 71% (n.s.), disease-free survival rate was 31% vs. 58% (p = 0.04) and, at a median follow-up of 34 months, tumor recurrence rate was 53.3% vs. 28.3% (n.s.). Four out of the eight Group B patients with recurrence underwent a re-resection, and were alive at 9 to 67 months after the first resection. These results show that in about one-third of the patients with primarily unresectable CRLM, downsizing of the lesions by chemotherapy (FOLFIRI protocol) permitted a subsequent curative resection. In these patients, operative risk and survival did not differ from the figures observed in primarily resectable patients and, in spite of a lower disease-free survival with more frequent recurrence, re-resection still represented a valid option to continue treatment. Presented at the 2005 Surgical Spring Week AHPBA Meeting (April 14–17, 2005, Fort Lauderdale, Florida).     

Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival

OBJECTIVE: To evaluate the long-term survival of patients resected for primarily unresectable colorectal liver metastases (CRLM) downstaged by systemic chemotherapy and to use prognostic factors of outcome for a model predictive of survival on a preoperative setting. SUMMARY BACKGROUND DATA: Surgery of primarily unresectable CRLM after downstaging chemotherapy is still questioned, and prognostic factors of outcome are lacking. METHODS: From a consecutive series of 1439 patients with CRLM managed in a single institution during an 11-year period (1988-1999), 1104 (77%) initially unresectable (NR) patients were treated by chemotherapy and 335 (23%) resectable were treated by primary liver resection. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined to oxaliplatin (70%), irinotecan (7%), or both (4%) given as chronomodulated infusion (87%). NR patients were routinely reassessed every 4 courses. Surgery was reconsidered every time a documented response to chemotherapy was observed. Among 1104 NR patients, 138 "good responders" (12.5%) underwent secondary hepatic resection after an average of 10 courses of chemotherapy. At time of diagnosis, mean number of metastases was 4.4 (1-14) and mean maximum size was 5.2 cm (1-25). Extrahepatic tumor was present in 52 patients (38%). Multinodularity or extrahepatic tumor was the main cause of initial unresectability. All factors likely to be predictive of survival after liver resection were evaluated by uni- and multivariate analysis. Estimation of survival was adjusted on risk factors available preoperatively. RESULTS: Seventy-five percent of procedures were major hepatectomies (> or =3 segments) and 93% were potentially curative. Liver surgery was combined to portal embolization, to ablative treatment, or to a second-stage hepatectomy in 42 patients (30%) and to resection of extrahepatic tumor in 41 patients (30%). Operative mortality within 2 months was 0.7%, and postoperative morbidity was 28%. After a mean follow-up of 48.7 months, 111 of the 138 patients (80%) developed tumor recurrence, 40 of which were hepatic (29%), 12 extrahepatic (9%), and 59 both hepatic and extrahepatic (43%). Recurrence was treated in 52 patients by repeat hepatectomy (71 procedures) and in 42 patients by extrahepatic resection (77 procedures). Survival was 33% and 23% at 5 and 10 years with a disease-free survival of 22% and 17%, respectively. It was decreased as compared with that of patients primarily resected within the same period (48% and 30% respectively, P = 0.01). At the last follow-up, 99 patients had died (72%) and 39 (28%) were alive; 25 were disease free (18%) and 14 had recurrence (10%). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, > or =3 metastases, maximum tumor size >10 cm, and CA 19-9 >100 UI/L. Mean adjusted 5-year survival according to the presence of 0, 1, 2, 3, or 4 factors was 59%, 30%, 7%, 0%, and 0%. CONCLUSIONS: Modern chemotherapy allows 12.5% of patients with unresectable CRLM to be rescued by liver surgery. Despite a high rate of recurrence, 5-year survival is 33% overall, with a wide use of repeat hepatectomies and extrahepatic resections. Four preoperative risk factors could select the patients most likely to benefit from this strategy.     

Additive Chemotherapie bei Lebermalignomen zur Verbesserung der Operabilität

Complete tumor resection is the only curative option for patients with colorectal liver metastases. Hepatic resection is frequently not possible for technical reasons: because of large tumors, multiple or bilateral metastases, or tumors that are too close to vessels. In these cases chemotherapy might downstage the tumor volume and facilitate secondary curative resection in patients initially not eligible for curative surgery. Treatment with fluorouracil (5-Fu) alone has resulted in disappointing response rates of about 10-20% in patients with colorectal liver metastases, which make these protocols useless in the neoadjuvant setting. Because regional chemotherapy into the hepatic arteria results in significantly higher response rates (40-50%), some studies have documented some success in secondary curative surgery after regional chemotherapy of initially unresectable colorectal liver metastases. However, regional chemotherapy is invasive and therefore not standard therapy for every patient with colorectal liver metastases. Recently new exciting treatment options have become available for colorectal cancer. Combinations of chemotherapy consisting of irinotecan and 5-Fu/FA or oxaliplatin and 5-Fu/FA result in response rates of 50% and can be considered a new standard first-line chemotherapy for patients with metastatic colorectal cancer. Recently, two encouraging retrospective studies have been published with chronomodulated chemotherapy of oxaliplatin and 5-Fu/FA in the setting of neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases. With this multidisciplinary approach, antitumor activity of chemotherapy appears to be translated into a long-term survival benefit and some patients with initially unresectable colorectal liver metastases can potentially be cured. As a consequence, on the premises of close cooperation between surgeons and internists, more patients with metastatic colorectal cancer will be cured in the future.     

Liver resection after downstaging with neoadjuvant chemotherapy for "unresectable" colorectal metastases

Hepatic resection is the only treatment that offers a chance of long-term survival in patients with metastases from colorectal cancer. Nevertheless, a curative resection can be performed in only 10-20 per cent of patients: multiple bilobar metastases or "unresectable" disease are the greatest obstacles to surgical radicality. Techniques such as preoperative portal embolisation, preoperative portal ligation, two-stage hepatectomy, and neoadjuvant chemotherapy, have extended the possibility of liver surgery to patients with advanced metastatic colorectal cancer. The outcomes of two patients treated successfully with neoadjuvant chemotherapy (one case with FOL-F-OX, and one with FOL-F-IRI) followed by liver resection were analyzed. In both patients neoadjuvant chemotherapy enabled a curative liver resection to be performed without significant complications. In some patients, neoadjuvant chemotherapy permits the "downsizing" of metastatic disease to such an extent that a surgical approach proves feasible. This advance can dramatically improve the prognosis of patients with multiple or unresectable liver metastases from colorectal cancer.     

Regional hepatic therapies: an important component in the management of colorectal cancer liver metastases

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.Key Words: Colorectal, liver metastases, tumor ablation     

Colorectal liver metastases: Resect,ablate, or embolize

The management of colorectal liver metastases (CRLM) is complex and should be individualized to each patient. Resectable CRLM benefit from surgical resection, preferably minimally invasive and parenchymal sparing, when feasible. Ablation is a viable alternative. Chemotherapy in this setting is potentially indicated in select patients, however, it has a clear role in unresectable CRLM. Newer locoregional therapies may benefit some unresectable CRLM with resistance to chemotherapy. Liver transplantation, a new therapy on the horizon for unresectable disease, has encouraging preliminary long-term survival outcomes for carefully selected patients.     

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尽管已经有一些随机对照研究,但结直肠癌肝转移的诊治还存在很多争议。并非所有可切除病人都能从新辅助化疗中获益,应该选择高危病人进行新辅助化疗;对不可切除病人,除了全身化疗,肝动脉灌注(HAI)有望成为重要的转化手段;对于无法达到根治性切除(R0切除)的病人,如果能行R1切除也是有意义的;合并不可切除肺转移灶不再是肝转移灶切除的绝对禁忌;联合肝脏分隔和门静脉结扎的二步肝切除(ALPPS)由于其高并发症发生率和高病死率,应该客观看待。     

Borderline resectable for colorectal liver metastases: Present status and future perspective

Surgical resection for colorectal liver metastases (CRLM) may offer the best opportunity to improve prognosis. However, only about 20% of CRLM cases are indicated for resection at the time of diagnosis (initially resectable), and the remaining cases are treated as unresectable (initially unresectable). Thanks to recent remarkable developments in chemotherapy, interventional radiology, and surgical techniques, the resectability of CRLM is expanding. However, some metastases are technically resectable but oncologically questionable for upfront surgery. In pancreatic cancer, such cases are categorized as “borderline resectable”, and their definition and treatment strategies are explicit. However, in CRLM, although various poor prognosis factors have been identified in previous reports, no clear definition or treatment strategy for borderline resectable has yet been established. Since the efficacy of hepatectomy for CRLM was reported in the 1970s, multidisciplinary treatment for unresectable cases has improved resectability and prognosis, and clarifying the definition and treatment strategy of borderline resectable CRLM should yield further improvement in prognosis. This review outlines the present status and the future perspective for borderline resectable CRLM, based on previous studies.     

Chance of Cure Following Liver Resection for Initially Unresectable Colorectal Metastases: Analysis of Actual 5-Year Survival

Background

Survival with long-term follow-up following liver resection for unresectable colorectal liver metastases (CRLM) downsized by chemotherapy has rarely been reported. The aim of this study was to determine the chance of cure following liver resection for initially unresectable CRLM.

Methods

Between January 2000 and December 2009, 61 patients underwent hepatectomy for unresectable liver-only CRLM downsized after chemotherapy. Cure was defined as a recurrence-free interval of at least 5 years after primary hepatectomy.

Results

Resectability of CRLM was achieved after a mean number of 11 courses, and 42.6 % of patients underwent liver resection after ≥10 courses. Postoperative mortality was nil, and morbidity rate was 19.7 %. The 5- and 10-year actuarial overall survival rates were 42.6 and 16.0 %. Of 30 patients with a follow-up ≥5 years, 11 were alive, yielding a 5-year actual overall survival rate of 36.7 %, and 7 (23.3 %) were considered cured because they are alive without recurrence. On multivariate analysis, response to chemotherapy was the only independent predictor of both overall and disease-free survival.

Conclusions

Cure can be achieved in about 23 % of patients resected for initially unresectable CRLM downsized by chemotherapy. Liver resection can be safely performed in selected patients even after multiple courses of chemotherapy.     

结直肠癌肝转移诊治中焦点问题

尽管已经有一些随机对照研究,但结直肠癌肝转移的诊治还存在很多争议。并非所有可切除病人都能从新辅助化疗中获益,应该选择高危病人进行新辅助化疗;对不可切除病人,除了全身化疗,肝动脉灌注（HAI）有望成为重要的转化手段;对于无法达到根治性切除（R0切除）的病人,如果能行R1切除也是有意义的;合并不可切除肺转移灶不再是肝转移灶切除的绝对禁忌;联合肝脏分隔和门静脉结扎的二步肝切除（ALPPS）由于其高并发症发生率和高病死率,应该客观看待。     

Neoadjuvant chemotherapy as a treatment strategy for multiple bilobar liver metastases from colorectal carcinoma

Hepatic resection remains the only potentially curative therapy for patients with colorectal liver metastases. Because most have multiple bilobar liver metastases, surgical resection is possible in only 25-58% of patients with colorectal liver metastases. Currently, attention is focused on the potential for neoadjuvant chemotherapy to render formerly unresectable patients resectable. The availability of more efficacious chemotherapy agents and an inventive approach to delivery schedules have resulted in an increase in the number of candidates for hepatic resection after neoadjuvant chemotherapy. Although tumor response varies with regimen and/or route of chemotherapy for colorectal liver metastases, with 16-63% tumor response rates, hepatic resection for responders after neoadjuvant chemotherapy gives survival benefits, with 20-48% 5-year survival rates after surgery. Provided that neoadjuvant chemotherapy controls multiple bilobar liver metastases well, aggressive hepatic resection should be considered for patients with those lesions. As a treatment strategy for multiple bilobar liver metastases, neoadjuvant chemotherapy is a useful to increase resection rates and may contribute to the improvement of prognosis in patients with such lesions.     

Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.

OBJECTIVE: The authors discuss the technique and evaluate the results of an aggressive surgical approach in patients with primarily unresectable colorectal liver metastases that were downstaged by chronomodulated chemotherapy. BACKGROUND: Resection is the best treatment of colorectal liver metastases, but it may be achieved in only 10% of patients. In the remaining 90%, survival is poor, even after partial response to chemotherapy. Little is known about the results of curative hepatectomy in patients whose metastases are downstaged by chemotherapy. PATIENTS AND METHODS: Fifty-three patients with colorectal liver metastases initially unresectable because of ill located (8), large (8), multinodular (24) lesions, or because of extrahepatic disease (13) were downstaged by a systemic chronomodulated chemotherapy associating 5-fluorouracil, folinic acid and Oxaliplatin to the point that operation could be performed. This consisted of a major hepatectomy in 37 patients and a minor resection in 16. Associated procedures (including 5 two-stage hepatectomies and 3 pulmonary resections) were performed in 25 patients. RESULTS: There was no operative mortality. Complications occurred in 14 patients. The cumulative 3- and 5-year survival rates were 54% and 40% (according to the type of lesions: ill-located, 75% and 48%; large, 62% and 62%; multinodular, 54% and 40%; extrahepatic, 43% and 14%). Hepatic recurrence (34 patients, 64%) was amenable to repeat surgery in 15 cases. CONCLUSIONS: Liver resection may be achieved in some previously unresectable patients with the help of an effective chemotherapy. The benefit in survival seems comparable to that obtained with primary liver resection (40% at 5 years). This therapeutic strategy involves a multimodal approach, including repeat hepatectomies and extrahepatic surgery.     

Interval Period Tumor Progression: Does Delayed Hepatectomy Detect Occult Metastases in Synchronous Colorectal Liver Metastases?

Background  Rapid remnant liver recurrence in patients with synchronous colorectal liver metastases (CRLM) is occasionally experienced after simultaneous colorectal and liver resection. We evaluated the tumor progression during interval periods to determine whether delayed hepatic resection detects occult metastases. Methods  One hundred thirty-seven patients underwent hepatectomy for synchronous CRLM. Up to 2003, 116 patients underwent simultaneous colorectal and hepatic resection. From 2004 onward, we identified 21 patients undergoing delayed hepatectomy for synchronous CRLM. The tumor progression during interval was determined by a dynamic computed tomography scan. Results  Median/mean interval between the two evaluations prior to the first and second surgery was 2/2.4 months. The median/mean number of metastases detected at each evaluation was 2/3.3 and 3/4.6, respectively. Nine of the 21 (43%) patients had new detectable metastatic lesions after reevaluation. For 11 of the 21 patients, it was necessary to reconsider planned surgical procedure which was determined prior to colorectal surgery. Hepatic disease-free survival was significantly different between patients undergoing delayed and simultaneous hepatectomy. Multivariate analysis showed that the delayed hepatectomy was a significant independent prognostic factor in hepatic disease-free survival. Conclusion  Tumor progression was recognized and occult metastases were detected after the interval reevaluation. Delayed hepatectomy may be a useful approach to reduce rapid remnant liver recurrence in synchronous CRLM.     

The developing clinical problem of chemotherapy-induced hepatic injury

Chemotherapy is being administered to an increasing number of patients with colorectal liver metastases (CRLM), whether they have resectable disease or not. Although this may be appropriate to downstage patients with unresectable disease, and offers theoretical advantages to those who have resectable disease, there is a price to be paid in the development of chemotherapy-induced hepatic injuries (CIHI). These include chemotherapy-associated fatty liver diseases and sinusoidal injuries. The main chemotherapeutic agents currently used in the adjuvant setting for colorectal carcinoma, and the neoadjuvant treatment of CRLM include 5-flurouracil, oxaliplatin and irinotecan, and while there are non-specific and overlapping injury profiles, oxaliplatin does appear to be primarily associated with sinusoidal injury and irinotecan with steatohepatitis. In this review, the rationale for administering chemotherapy to patients with CRLM is presented, and the problems this brings are outlined. The specific injury patterns will be detailed, as well as the data correlating specific chemotherapy regimens to these injury patterns. Finally, the clinical outcomes of patients with CRLM who undergo neoadjuvant chemotherapy followed by hepatic resection will be considered. The need for methods to identify patients at risk of CIHI and to recognize established CIHI prior to surgery will be emphasized.     

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??Convertible therapy for unresectable colorectal liver metastases ZHU De-xiang, REN Li, XU Jian-min. Department of General Surgery, Zhongshan Hospital, Fudan University; Institute of General Surgery, Fudan University; Colorectal Cancer Research Center, Fudan University, Shanghai 200032, China
Corresponding author??XU Jian-min, E-mail??xujmin@aliyun.com
Abstract Surgery is the most effective and the only potentially curative treatment for colorectal liver metastases (CRLM). However, most patients with CRLM are not suitable for liver resection. In recent years, a variety of cytotoxic drugs and/or targeted drugs were used to shrink unresectable liver metastases, and some patients were converted to resectable. Thereby they might be cured following surgical resection. Therefore the purpose of convertible chemothrapy is to get the best response rate, not the maximum response rate. It should choose efficient convertible chemotherapy with short courses for preoperative chemotherapy. For KRAS wild-type patients, cetuximab combined with FOLFOX/FOLFIRI, in which 5-fluorouracil is continuous infused, is recommended, and for KRAS-mutant patients, bevacizumab combined with two-drug chemotherapy regimen or three-drug chemotherapy regimen is considered. They should be operated as soon as the metastases become resectable.     

OncoSurge: a strategy for long‐term survival in metastatic colorectal cancer

OncoSurge is a combined modality strategy for the management of colorectal cancer with hepatic metastases. It has emerged as a result of new and expanded patient selection criteria for resectability of metastases, coupled with more effective neoadjuvant and postoperative chemotherapy. By bringing together these developments in surgery and medical oncology, the new approach promises to increase significantly the resectability rate and long‐term survival in colorectal cancer patients with liver metastases. Surgery for colorectal liver metastases should now be considered across a range of clinical circumstances that would historically have been contraindications to resection. These contraindications include multiple or bilobar metastases, large tumour size, a Dukes stage C or poorly differentiated primary tumour, synchronous detection of metastases with the primary tumour, disease in elderly patients, or a resection margin of less than 1 cm. None of these criteria should necessarily exclude a patient from resection, because although they may be associated with a less favourable prognosis they do not exclude the possibility of long‐term survival. Non‐resectable extrahepatic disease and portal lymph node involvement, however, remain contraindications to resection in most circumstances. Retrospective studies of neoadjuvant therapy have indicated that a regimen based on low dose oxaliplatin, 5‐fluorourucil (5‐FU) and leucovorin increased the overall resectability rate of patients presenting with hepatic colorectal metastases from 20% to 30%, with 13.6% of patients with unresectable metastases becoming eligible for curative resection. More recently, studies using more potent oxaliplatin‐based regimens have reported significantly higher resectability rates of at least 40%, with 5‐year survival of 50% reported in one large study among patients whose liver metastases were resected after initial neoadjuvant therapy for unresectable tumours. Following resection, postoperative therapy based on a combination of hepatic artery infusion (HAI) and systemic chemotherapy reduces hepatic recurrence and increases survival, but more potent systemic therapy is required to reduce the rate of extrahepatic recurrence. Studies are now in progress combining HAI with oxaliplatin‐based systemic therapy to address this issue. By combining a more inclusive approach to surgery with more effective neoadjuvant and postoperative chemotherapy, the OncoSurge treatment model is likely to increase significantly the number of patients with hepatic colorectal metastases who can be treated with curative intent, and thus has the potential to improve overall patient survival.     

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

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.     

Surgical Therapy for Colorectal Metastases to the Liver

Colorectal cancer is the fourth most common type of cancer in the West and the second leading cause of cancer-related deaths in the United States. Approximately 35 to 55% of patients with colorectal cancer develop hepatic metastases during the course of their disease. Surgical resection of colorectal liver metastases represents the only chance at potential cure, and long-term survival can be achieved in 35 to 58% of patients after resection. The goal of hepatic resection should be to resect all metastases with negative histologic margins while preserving sufficient functional hepatic parenchyma. In patients with extensive metastatic disease who would otherwise be unresectable, ablative approaches can be used instead of or combined with hepatic resection. The use of portal vein embolization and preoperative chemotherapy may also expand the population of patients who are candidates for surgical treatment. Despite these advances, many patients still experience a recurrence after hepatic resection. More active systemic chemotherapy agents are now available and are being increasingly employed as adjuvant therapy either before or after surgery. Modern treatment of colorectal liver metastasis requires a multidisciplinary approach in an effort to increase the number of patients who may benefit from surgical treatment of colorectal cancer liver metastasis.     

Hepatic Arterial Infusion of Oxaliplatin and Intravenous LV5FU2 in Unresectable Liver Metastases from Colorectal Cancer after Systemic Chemotherapy Failure

Background We have previously shown promising activity of hepatic arterial infusion (HAI) oxaliplatin combined with intravenous (IV) 5-fluorouracil (5-FU) and leucovorin (LV) as first-line chemotherapy in patients with colorectal liver metastases (CRLM) (intent-to-treat [ITT] objective response rate [ORR], 64%; secondary resection rate, 18%; overall survival [OS], 27 months). Whether this regimen could be beneficial after systemic chemotherapy failure is unknown. Methods Patients with unresectable CRLM and history of systemic chemotherapy failure were treated bimonthly with HAI oxaliplatin (100 mg/m² 2 hours) combined with IV LV and IV bolus and infusional 5FU (modified LV5FU2 regimen). Results Forty-four consecutive patients (median age 56 years; median number of prior systemic chemotherapy regimens, 2 range 1–5) were included, of whom 43 (98%) had previously received oxaliplatin (n = 34), irinotecan (n = 37), or both (n = 28). Patients received a median of nine cycles of HAI oxaliplatin and IV modified LV5FU2 (range 0–25). Toxicity included grade 3–4 neutropenia (43%), grade 2–3 neuropathy (43%), and grade 3–4 abdominal pain (14%). We observed 24 partial ORs (62%) among the 39 assessable patients (ITT ORR, 55%; 95% CI, 40–69%), including 17, 12, and 12 patients who had failed to respond to prior systemic chemotherapy with FOLFIRI, FOLFOX, or both, respectively. Tumor response allowed further R0 surgical resection (n = 7) or radiofrequency ablation (n = 1) of initially unresectable CRLM in eight patients (18%). Median progression-free survival and OS were 7 and 16 months, respectively. Conclusions HAI oxaliplatin and IV LV5FU2 is feasible, safe, and shows promising activity after systemic chemotherapy failure, allowing surgical resection of initially unresectable CRLM in 18% of patients.     

A Critical Appraisal of the Role of Neoadjuvant Chemotherapy for Colorectal Liver Metastases: A Case-Controlled Study

Background The aim of this study was to analyze the outcome of patients that received neoadjuvant chemotherapy prior to resection for colorectal liver metastases (CRLM) and compare them with a matched cohort of patients that underwent resection followed by adjuvant chemotherapy. Methods 687 patients have undergone curative resection between January 1993 and January 2006. In this period, 84 patients received neo-adjuvant chemotherapy and 71 of this group went on to resection. A control group was chosen, matched with these patients, made up of patients who underwent resection followed by adjuvant chemotherapy. Results There was no difference in clinico-pathological features between the neoadjuvant and the control group. However patients in the control group had more-extended resections and longer hospital stays than those in the neoadjuvant group (p = 0.015). Patients in the control group had an increased incidence of early recurrences (p < 0.001). Despite this, there was no significant difference in either the cancer-specific or the disease-free survival between the two groups of patients. Conclusion Neoadjuvant chemotherapy has a role in the management of patients with disease that is considered initially unresectable as a down-sizing technique. In patients with resectable disease, the test-of-time approach that neoadjuvant therapy offers is yet to be proven.