Secondary Liver Resection Research Articles

Hepatic Arterial Infusion Chemotherapy With Folfirinox or Oxaliplatin Alone in Metastatic Colorectal Cancer.

BackgroundHepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox.MethodsPatients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers.ResultsData were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox (n = 52) or HAI-Ox (n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15–32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4–34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9–10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0–7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox (p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20–0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6–9.0; p = 0.002).ConclusionHepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC.

Survival after secondary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (CELIM, FIRE-3).

e15025 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term overall survival (OS) and potential cure after complete hepatic metastasectomy. The appropriate postoperative treatment strategy is still controversial. L-BLP25 as antigen-specific cancer vaccine targeting mucin 1 (MUC1) was recently evaluated as adjuvant therapy in mCRC pts after R0/R1 LLD resection (LICC trial, NCT01462513). Here we compared the LICC surveillance program and efficacy results for secondarily resected LLD pts versus historical controls, i.e. the CELIM trial (Folprecht et al, Ann Oncol 2014) of potentially resectable LLD mCRC pts and a FIRE-3-LLD subgroup (Holch et al, Int J Cancer 2018). Methods: LICC, CELIM and FIRE-3-LLD subgroup pts with stage IV mCRC limited to liver metastases who underwent hepatic resection (R0 or R1) were compared regarding pts characteristics, surveillance and efficacy outcome. LICC pts received adjuvant L-BLP25 or placebo after secondary LLD resection as 8 weekly doses, followed by 6 week maintenance intervals and tight surveillance until recurrence or a maximum of 2 years. Results: In LICC, 41 /121 pts (33.9%) were secondarily resected, and R0 resection was achieved in 31 pts (75.6%). In CELIM, 36/106 pts (34%) with primary unresectable LLD were secondarily R0 resected. In FIRE-3-LLD, secondary resection was feasible for 29/133 pts (21.8%). After R0 resection, median recurrence free survival (mRFS) was 8.9 months in LICC, 9.9 months in CELIM and 11.5/ 12.4 months in FIRE-3-LLD in either treatment arm. In the LICC trial, median overall survival (mOS) in secondarily resected pts was 65.1 months, with 38.3 months for the R1 and is not yet reached for the R0 subgroup. In CELIM, mOS was 53.9 months for R0 resected pts. In FIRE-3-LLD, after secondary resection mOS was 56.2 months. Median age was about 5 years less in LICC. Further details will be presented. Conclusions: Secondary resected pts of LICC, CELIM and FIRE-3 showed impressive median OS with better OS for LICC and a younger patient cohort. The established tight LICC surveillance program after surgery might have had a positive impact on survival. Clinical trial information: LICC: NCT01462513; FIRE-3: NCT00433927; CELIM: NCT00153998.

Survival after secondary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (CELIM, FIRE-3).

571 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term overall survival (OS) and potential cure after complete hepatic metastasectomy. The appropriate postoperative treatment strategy is still controversial. L-BLP25 as antigen-specific cancer vaccine targeting mucin 1 (MUC1) was recently evaluated as adjuvant therapy in mCRC pts after R0/R1 LLD resection (LICC trial, NCT01462513). Here we compared the LICC surveillance program and efficacy results for secondarily resected LLD pts versus historical controls, i.e. the CELIM trial (Folprecht et al, Ann Oncol 2014) of potentially resectable LLD mCRC pts and a FIRE-3-LLD subgroup (Holch et al, Int J Cancer 2018). Methods: LICC, CELIM and FIRE-3-LLD subgroup pts with stage IV mCRC limited to liver metastases who underwent hepatic resection (R0 or R1) were compared regarding pts characteristics, surveillance and efficacy outcome. LICC pts received adjuvant L-BLP25 or placebo after secondary LLD resection as 8 weekly doses, followed by 6 week maintenance intervals and tight surveillance until recurrence or a maximum of 2 years. Results: In LICC, 41/121 pts (33.9%) were secondarily resected, and R0 resection was achieved in 31 pts (75.6%). In CELIM, 36/106 pts (34%) with primary unresectable LLD were secondarily R0 resected. In FIRE-3-LLD, secondary resection was feasible for 29/133 pts (21.8%). After R0 resection, median recurrence free survival (mRFS) was 8.9 months in LICC, 9.9 months in CELIM and 11.5/12.4 months in FIRE-3-LLD in either treatment arm. In the LICC trial, median overall survival (mOS) in secondarily resected pts was 65.1 months, with 38.3 months for the R1 and is not yet reached for the R0 subgroup. In CELIM, mOS was 53.9 months for R0 resected pts. In FIRE-3-LLD, after secondary resection mOS was 56.2 months. Median age was about 5 years less in LICC. Further details will be presented. Conclusions: Secondary resected pts of LICC, CELIM and FIRE-3 showed impressive median OS with better OS for LICC and a younger patient cohort. The established tight LICC surveillance program after surgery might have had a positive impact on survival. Clinical trial information: LICC: NCT01462513; FIRE-3: NCT00433927; CELIM: NCT00153998.

Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer

AimsLong-term survival has been demonstrated for patients with irresectable colorectal liver metastases who are brought to resection by chemotherapy. However, it remains unclear whether improved long-term outcome seen with modern therapies translates to increased rates of secondary resection and whether response rates correlate with rates of secondary liver resection. MethodsA systematic review of literature published between January 1998 and September 2013 was performed. Phase II/III trials were included if they reported the rate of objective response and the rate of secondary resection of initially irresectable metastases. For the phase III trials, the ratio between response and resection rates within the trials was investigated as well as the correlation for both parameters in all trials. ResultsTwenty-five studies were identified. Response rate demonstrated a strong correlation with rates of secondary resection (R2=0.44, p=0.008). Ratios of response/resection between both arms of 10 randomised control trials (RCTs) were calculated to control for selection bias, and showed that in a randomised setting response rates correlate with increased rates of secondary resection in an intra-trial comparison (R2=0.87, p=0.002). Linear regression analysis demonstrated a significant difference between studies where criteria for resectability were defined (median 39.5%), and those where it was not (median 11%) (p=0.006). ConclusionThere is a clear correlation between radiological response and rates of secondary resection, with studies that define resectability achieving much higher rates. All trials investigating first line treatment in patients with metastatic colorectal cancer should have criteria for resection, with conversion to secondary resection as a defined study end-point.

Defining resectability of colorectal liver metastases: how and why?

SUMMARY Treatment outcome in metastatic colorectal carcinoma has improved because of advancements in medical therapy and increased use of liver resections. In primary nonresectable disease, prognosis improves when a secondary resection is performed after successful downsizing by neoadjuvant systemic therapy. Which patient groups may profit from a secondary liver resection and which neoadjuvant systemic therapy has the optimal chance of conversion to resectability has not been defined because various patient groups were selected in different studies and there is a lack of consensus on resectability. This invalidates cross-study comparisons of resection rates and survival rates. Prospective trials in which secondary resection rate is a predefined end point are needed and will allow more insight into this topic.

Treatment of unresectable cholangiocarcinoma

Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine. Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with cTACE using 15 mg mitomycin-C mixed with 5-10 ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria. iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n=7), hepatic abscess (n=1), pleural empyema due to biliary leakage (n=1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks. This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDEB-TACE is safe in patients with normal liver function, and results in a prolongation of PFS and OS. Local tumor control, PFS and OS seem similar to systemic ChT with oxaliplatin and gemcitabine, but superior to cTACE.

Serum matrilysin (MMP7) levels are associated with progression, in curatively resected colorectal cancer (CRC) patients

4124 Background: Matrilysin (MMP7) has been shown to be over-expressed in CRC, specially in liver metastases. Additionally MMP7 over-expression in primary tumor, predict metastatic potential in early-stage disease (Gut 12:1751;2005). As the activated pro-domain, could be detected in serum by ELISA method, we search if it could also identify a subgroup of non-metastatic CRC patients with a higher risk of relapse. Methods: Serum MMP7 (S-MMP7) was measured by commercially available ELISA, in 92 healthy controls and 175 consecutive patients before undergoing laparoscopy-assisted or open curative resection for CRC, between July 2003 to December 2004. Clinic- pathologic variables were tested for their effect on disease-free survival (DFS) in univariate and multivariate Cox regression analysis. Results: S-MMP7 levels were significantly higher in CRC patients than in controls (p=0.02). Mean age in CRC patients was 71 years (range 31–90). Median nodal retrieval was 14 (range 0–47). The median S-MMP7 (4.9 ng/ml) was chosen for cut-off value. After a median follow- up of 26 months, the rate of DFS was 72%. Univariate analysis identified high S-MMP7 levels, CEA concentration, age, extent of primary tumor and lymph-node metastases as variables associated with DFS. Multivariate analysis identified lymph-node metastases (OR.1,88, p=0.046) and S-MMP7 (OR.1,103, p=0.039) as independent prognostics factors. Conclusions: With a short follow-up, S-MMP7 levels predict recurrence in curatively resected CRC. As a subset of these patients could be managed with secondary liver resection, S-MMP7 determination would be particularly warranted for more intensive surveillance strategies. No significant financial relationships to disclose.

Repeat hepatectomy for cancer.

In a series of 279 hepatectomies performed for cancer between June 1984 and March 1992, 46 were repeat operations, for metastases in 41 patients. The primary tumour was in the colon and rectum (28 patients), APUDoma (five) and miscellaneous (eight). Repeat hepatectomies were performed in 26 per cent of patients who had recurrence after the first liver resection and in 40 per cent of those who had liver recurrence. An unsuspected extrahepatic recurrence was discovered and resected in eight instances and in two other cases a known extrahepatic recurrence was resected during the second hepatectomy. The hospital mortality rate was 2 per cent (one patient); the death was from nosocomial pneumonia. The total morbidity rate including minor complications was 32 per cent, with a higher frequency of haemorrhagic problems after secondary liver resection (12 per cent) than after primary hepatectomy (5 per cent). The rate of postoperative complications after repeat hepatectomy was related significantly to operative blood loss greater than 1500 ml (P = 0.04). The technical problems of repeat hepatectomy were: (1) re-exposure of the liver, considered to be difficult in 67 per cent of second liver resections and 80 per cent of third procedures; (2) the liver parenchyma, which often had histological modifications between first and second resections and was more difficult to 'work' as shown by the mean duration of clamping of the hepatic pedicle (54 min for secondary versus 36 min for primary liver resection); and (3) modification of the intraparenchymal vasculobiliary anatomy following liver regeneration after major hepatectomy. Intraoperative ultrasonography was of great benefit. Rates of crude and recurrence-free survival were relatively encouraging at 47 and 33 per cent 3 years after the second liver resection for the whole group. These values were lower for colorectal cancer (37 and 21 per cent 3 years after the second hepatectomy). These figures do not, however, convey the complete picture of the outcome for these patients. During the same follow-up period, 143 recurrences were detected and a mean of 2.9 resections per patient were performed. The indications for repeat hepatectomy are still to be clarified, although the surgical technique is safe.

Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer

3593 Background: Although surgical resection remains the treatment of choice for liver metastases from colorectal cancer, only a minority of pts are suitable for surgery. Preoperative chemotherapy allows secondary liver resection and subsequent long-term survival in some patients (pts)with unresectable CCR liver metastases Methods: The aim of this study was to evaluate the safety and efficacy of oxaliplatin 120 mg/m2 day 1, CPT-11 150 mg/m2 day 1 and 14, fluorouracil 2600 mg/m2 days 1 and 14 and folinic acid 500 mg/m2 days 1 and 14, every four weeks, in metastasic liver CCR patients either technically unresectable or with known poor prognostic factors for long term survival after surgery. Results: 39 pts (M/F: 30/9), median age 55 (28–77), median ECOG 1 (0–2) were included. Mean number of liver nodes and mean size were 6.7 and 6.1 cm, respectively. 22 pts (56.4%) were initially unresectable while 17 (43.6%) had poor prognostic factors including large tumor size (52.9%), multinodular (23.5%), ill-located (23.5) and/or bilobar metastases (35.3%).Overall response rate to induction chemotherapy was 64%, 3 pts (7.7%) progressed while on-therapy. 23 pts underwent secondary surgery, including hepatectomy (52.2%) and wedge resections (47.8%), with (n=10) or without radiofrequency. An R0 resection was achieved in 84 % of pts, with margins <1cm in 60.9% of them. Pathological complete response rate was 17.4%. After neoadyuvant chemotherapy, 11 out of 22 initially unresectable CCR pts underwent surgery with curative intent, including 9 of then with a R0 resection. After a median follow up of 15 months (4–40), median progression-free survival and overall survival have not been reached. Main grade 3–4 toxicity included anemia (7.7%), leucopenia (13.9%), neutropenia (30.8%), plaquetopenia (5.1%), vomiting (5.1%) and diarrhea (23%) 1 pt died due to postoperative complications. Conclusions: Induction therapy with this triplet regimen achieves a high resectability and pathological complete response rates. No significant financial relationships to disclose.

Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer

3593 Background: Although surgical resection remains the treatment of choice for liver metastases from colorectal cancer, only a minority of pts are suitable for surgery. Preoperative chemotherapy allows secondary liver resection and subsequent long-term survival in some patients (pts)with unresectable CCR liver metastases Methods: The aim of this study was to evaluate the safety and efficacy of oxaliplatin 120 mg/m2 day 1, CPT-11 150 mg/m2 day 1 and 14, fluorouracil 2600 mg/m2 days 1 and 14 and folinic acid 500 mg/m2 days 1 and 14, every four weeks, in metastasic liver CCR patients either technically unresectable or with known poor prognostic factors for long term survival after surgery. Results: 39 pts (M/F: 30/9), median age 55 (28–77), median ECOG 1 (0–2) were included. Mean number of liver nodes and mean size were 6.7 and 6.1 cm, respectively. 22 pts (56.4%) were initially unresectable while 17 (43.6%) had poor prognostic factors including large tumor size (52.9%), multinodular (23.5%), ill-located (...