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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 7  |  Page : 205-211

The significance of transarterial chemoembolization combined with systemic chemotherapy for patients with KRAS wild-type unresectable metachronous colorectal carcinoma with liver metastases


1 School of Medicine, Zhejiang University; Department of Hepatopancreatobiliary Surgery, Zhejiang Cancer Hospital, Hangzhou, China
2 Department of Nursing, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
3 Department of General Surgery, Zhejiang Hospital, Hangzhou, China
4 Department of Hepatopancreatobiliary Surgery, Zhejiang Cancer Hospital, Hangzhou, China

Date of Web Publication21-Feb-2017

Correspondence Address:
Xinbao Wang
Department of Hepatopancreatobiliary Surgery, Zhejiang Cancer Hospital, Hangzhou 310022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.200603

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 > Abstract 

Purpose: The purpose of this study was to assess the survival benefits of transarterial chemoembolization (TACE) combined with systemic chemotherapy as the first-line treatment for metachronous unresectable colorectal carcinoma with liver metastases (CLMs) and to identify prognostic determinants.
Patients and Methods: One hundred and fifty-four patients with KRAS wild-type metachronous unresectable CLMs were retrospectively collected from January 2006 to December 2014. Patients were divided into four groups according to treatment modality: 43 patients with chemotherapy alone (Group A), 39 patients with chemotherapy plus TACE (Group B), 38 patients with chemotherapy plus cetuximab (Group C), and 34 patients with chemotherapy plus TACE and cetuximab (Group D). We compared the rate of patients converted to resection for liver metastases (LMs), overall survival among these groups, and assessed prognostic factors.
Results: The median interval time from resection of primary tumor to the diagnosis of CMLs was 12.0 months. The 1-, 3-, and 5-year survival rates and median survival time (MST) for all patients were 83.1%, 24.7%, 5.8%, and 22.9 months, respectively. Survival rates were significantly different in four groups at 1 year, 3 years, and 5 years with the MST of 17.5, 28.4, 18.9, and 30.3 months, respectively (P < 0.0001). The R0 resection rates for LMs were 7.0% in Group A, 30.8% in Group B, 10.5% in Group C, and 32.4% in Group D, which were statistically significantly different (P = 0.004). Univariate analysis revealed that posttreatment carcinoembryonic antigen serum level, tumor node (TN) stage, resection of LMs, tumor response, and treatment group were the significant prognostic factors. After adjusting the covariates in multivariate analysis, TN stage (hazard ratio [HR] = 1.394, 95% confidence interval [CI] = 1.027–1.893,P = 0.033), tumor response (HR = 2.901, 95% CI = 2.105–3.999,P < 0.0001), and treatment group (HR = 0.726, 95% CI = 0.594–0.887,P= 0.002) remained independent prognostic determinants.
Conclusion: For patients with initially unresectable KRAS wild-type CLMs, chemotherapy plus TACE improved the resectability of LMs and survival compared with chemotherapy alone or chemotherapy plus cetuximab.

Keywords: Chemotherapy, colorectal carcinoma, liver metastases, transarterial chemoembolization


How to cite this article:
Yu Q, Zhang L, Fan S, Huang L, Wang X, Xindun C. The significance of transarterial chemoembolization combined with systemic chemotherapy for patients with KRAS wild-type unresectable metachronous colorectal carcinoma with liver metastases. J Can Res Ther 2016;12, Suppl S3:205-11

How to cite this URL:
Yu Q, Zhang L, Fan S, Huang L, Wang X, Xindun C. The significance of transarterial chemoembolization combined with systemic chemotherapy for patients with KRAS wild-type unresectable metachronous colorectal carcinoma with liver metastases. J Can Res Ther [serial online] 2016 [cited 2021 Mar 1];12:205-11. Available from: https://www.cancerjournal.net/text.asp?2016/12/7/205/200603


 > Introduction Top


Colorectal carcinoma (CRC) is one of the most frequent cancers worldwide, and at the time of the first diagnosis of CRC, 20%–50% of all patients already present with synchronous liver metastases (LMs).[1] LMs are the most common cause of death of patients with CRC.[2] Without treatment, the median survival of patients with carcinoma with LMs (CLMs) is 6–12 months.[3] Resection of metastases is the only potentially curative treatment option for patients with CLMs; however, <20% of the patients with LMs are candidates for surgical resection.[4] Therefore, the major goal of the current therapeutic strategies is to optimize the response and downsize metastatic disease to resectability.[5] Currently, the standard first-line treatment for patients with unresectable CLMs is palliative chemotherapy, and the option of chemotherapy is a combination of infusional 5-fluorouracil (5-FU) and folinic acid with either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). Other treatment methods include hepatic arterial infusion (HAI) of chemotherapy, transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and target therapy.

For patients with unresectable CLMs, TACE was recommended as one of the effective treatment options, and TACE is defined as an intra-arterial administration of chemotherapeutic drugs usually combined with selective embolizing of the feeding arteries of the LMs.[6] Liver tumors receive most of their blood supply from the hepatic artery while the normal parenchyma has the main venous supply from the portal vein.[7] Embolization of tumor arteries promotes penetration of chemotherapeutic drugs into the tumor. Target therapy such as cetuximab has increased the median survival of patients with metastatic CRC (mCRC) from about 6 months to 2 years.

Cetuximab is a high-cost treatment not approved for reimbursement in China. Only patients who have better economic circumstances can be treated with additional cetuximab, and the financial burden leads to treatment discontinuation and discourages patients who want to receive cetuximab, which might result in unsatisfied effect. In this study, we compared the first-line chemotherapy plus TACE with chemotherapy plus cetuximab in Chinese patients with initially unresectable metachronous KRAS wild-type CLMs. The principal goal was to evaluate the radical resectability of LM, tumor response, overall survival (OS), and progression-free survival (PFS).


 > Patients and Methods Top


Patients

From January 2006 to December 2014, a total of 154 consecutive patients were diagnosed with KRAS wild-type metachronous unresectable CLMs in our hospital. All patients had underwent resection of primary tumor, and the diagnosis of LM was made based on the pathological evaluation of the aspiration biopsy or by imaging studies (enhanced computed tomography [CT] or magnetic resonance imaging). This study was reviewed retrospectively. The primary tumor was located in the rectum in 32.5% (n = 50) of the patients and in the colon in 67.5% (n = 104) of the patients.

All patients were assessed by physical examination, serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), chest radiography, abdominal ultrasonography, CT imaging, and colonoscopy. LM resectability was determined using four criteria: (i) ability to obtain a complete resection (negative margins); (ii) preservation of two contiguous hepatic segments; (iii) preservation of adequate vascular inflow and outflow as well as biliary drainage; and (iv) ability to retain a sufficient liver remnant (>20% in healthy liver). Unresectability was defined as not meeting any of these criteria. All the patients were categorized into four groups according to the treatment modality performed: 43 patients with chemotherapy alone (Group A), 39 patients with chemotherapy plus TACE (Group B), 38 patients with chemotherapy plus cetuximab (Group C), and 34 patients with chemotherapy plus TACE and cetuximab (Group D). The clinicopathological characteristics of the 154 patients are shown in [Table 1]. In the four groups of patients, gender, age, postoperative recurrence time, the size of the lesion, the number of lesions, Child-Pugh score of liver function, and other general information were not statistically significantly different.
Table 1: Clinical characteristics of 154 patients with KRAS wild - type metachronous unresectable CLMs

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In this study, patients were eligible for inclusion if they met all the following criteria: (i) their primary tumors had been resected and histologically confirmed as wild-type KRAS colorectal adenocarcinoma; (ii) their Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and life expectancy of at least 3 months; (iii) the interval between resection of the primary tumor and the diagnosis of CLMs was at least 6 months; (iv) patients with the liver function of Child-Pugh A or B; and (v) patients who can tolerate conventional chemotherapy and interventional therapy.

Patients who met any of the following criteria were excluded from the study: (i) any other noncurative factors, such as tumor infiltrating to adjacent organs, para-aortic lymph node metastasis, or distant metastasis; (ii) ECOG PS of 2 or more at initial diagnosis; (iii) other concurrently active malignancy or history of malignancies other than CRC; (iv) patients with the liver function of Child-Pugh C; (v) any prior targeted therapy, chemotherapy, radiation therapy, or intervention therapy for CLMs. (vi) age younger than 18 or older than 85 years old; and (vii) LM occupying more than 75% of liver parenchyma determined by CT scan.

Methods

Treatments were planned to commence at 2 weeks after the diagnosis of CLMs. For Group A, 43 patients underwent chemotherapy alone; for Group B, 39 patients underwent chemotherapy and TACE, TACE was performed by selectively cannulating hepatic arteries. Equal amounts of an emulsion of 10 ml lipiodol, 1500 mg 5-FU, and 15 mg of leucovorin were deployed selectively to the main arteries of the tumor, once a month for three times from the beginning of the diagnosis of CLMs. For Group C, 38 patients underwent chemotherapy plus cetuximab, patients received cetuximab once every 2 weeks (500 mg/m 2 on day 1) followed after 1 h by chemotherapy for 24 weeks. And for Group D, 34 patients underwent chemotherapy plus TACE and cetuximab. The use of chemotherapy compounds was similar among the four groups, with most patients receiving either mFOLFOX6 (day 1: oxaliplatin 85 mg/m 2, folinic acid 400 mg/m 2, and FU 400 mg/m 2 intravenous bolus, then 2400 mg/m 2 over 46 h continuous infusion) or FOLFIRI (day 1: irinotecan 180 mg/m 2 and folinic acid and FU, administered as with mFOLFOX6). The mean time of adjuvant chemotherapy was equally administered in all groups which was at least more than eight cycles. Treatments were continued until tumor response indicated suitability for surgery for LM or until disease progression or unacceptable toxicity.

Enhanced CT scan was performed for all patients at baseline and after each TACE to assess the response of tumor. Biochemical laboratory tests were performed both 1 week before and 1 week after chemotherapy to assess the damage to liver. The criteria used to evaluate the objective response were according to the Response Evaluation Criteria In Solid Tumors criteria. A complete response was defined as the total disappearance of all the known lesion(s) confirmed at 4 weeks. Partial response was defined as a reduction of at least 50% of all the known lesion(s) confirmed at 4 weeks. Stable disease was defined as neither partial response nor progressive disease criteria met. Progressive disease was defined as an increase of at least 25% of the overall measurable lesion or the appearance of a new neoplastic lesion. OS was defined as the interval time from the date of diagnosis of LM to the date of death from any cause or the last follow-up. PFS was defined as the period between the date of diagnosis and the first recorded instance of disease progression, death from any cause, or the last follow-up.

The primary end point was the conversion rate to radical resection for LM; for patients whose LMs were assessed resectable, resection was scheduled to be performed within 2–3 weeks of the last treatment cycle. After resection, patients were advised to continue the same therapeutic regimen.

Follow-up

Patients' information was obtained from outpatient clinical records or by direct telephone interview with the patients or next of kin. All patients were followed up at 1st month and then for every 3 months for the first 2 years, and then for every 6 months thereafter. The median follow-up after diagnosis for patients with CLMs was 22.9 months.

Statistical analysis

All statistical analyses were performed using the SPSS 17.0 (IBM Corp., Armonk, NY, USA) software, and 1-, 3-, and 5-year OS and PFS curves were estimated by Kaplan–Meier method and compared using the log-rank test. Multivariate Cox's regression analysis was performed to identify prognostic factors for survival by adjusting potential confounding factors. Variables achieving P < 0.05 in the univariate analysis were subsequently introduced into the multivariate analysis. P < 0.05 was considered statistically significant.


 > Results Top


Patients were followed up until death or April 15, 2016. There are 103 males and 51 females, with a median age of 57 (range, 34–82) years. A comparison of all patients revealed no significant difference in gender, age, pre-/post-treatment CEA/CA 19-9 serum level, the number or location of LMs, primary tumor location, tumor node (TN) stage, and treatments after primary tumor resection.

The median interval time from resection of primary tumor to the diagnosis of CMLs was 12.0 months (6.1–115.8 months). Fifty-two percent (80/154) of the patients progressed into LM in 1 year after the resection of primary colorectal cancer. The TN stage had nothing to do with the time of LM. However, for 54 patients who had not received adjuvant chemotherapy, the median interval time was 8.4 months, which was statistically significantly shorter than those whose received chemotherapy after the resection of primary tumor (14.5 months, P < 0.0001).

The 1-, 3-, and 5-year OS rate and median survival time (MST) for all patients were 83.1%, 24.7%, 5.8%, and 22.9 months (5.17–86.8 months), respectively. During the follow-up, 42 (97.7%) patients in Group A, 30 (76.9%) patients in Group B, 32 (84.2%) patients in Group C, and 24 (70.6%) patients in Group D died of cancer or complications associated with liver disease by the data cutoff date. Survival rates were significantly different in four groups at 1 year (76.7%, 94.9%, 86.3%, 100%), 3 years (9.6%, 47.5%, 30.9%, 59.5%), and 5 years (0, 33.6%, 13.3%, 37.5%), with the MST of 17.5, 28.4, 18.9, and 30.3 months, respectively (P < 0.0001) [Figure 1]a.
Figure 1: (a) Overall survival curve calculated by Kaplan-Meier method for all patients comparing treatment modality. (b) Overall survival curve for all patients comparing different stages of primary tumor. (c) Overall survival curve for all patients comparing with or without resection of liver metastases. (d) The overall survival for all patients with carcinoembryonic antigen >7 μg/L or not. (e) Overall survival curve for all patients compared with different response due to treatments

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The median PFS rates were 9.37, 21.63, 13.97, and 23.72 months in the four groups, respectively, with the 5-year PFS rates at 2.5%, 22.3%, 7.6%, and 20.3%, respectively (P < 0.0001). The PFS rates were similar in Group A and Group D, which were significantly higher than that of Group B or C.

The R0 resection rates for LMs were 7.0% (3 of 43 patients) in Group A, 30.8% (12 of 39 patients) in Group B, 10.5% (4 of 38 patients) in Group C, and 32.4% (11 of 34 patients) in Group D, which were statistically significantly different (P = 0.004). In addition, all patients, those who had resection of LMs, had a significantly improved MST compared with those who did not undergo surgery (31.9 vs. 19.8 months, P = 0.013). There were no serious complications during the perioperative period except for mild abnormalities of liver function in six patients.

No complete tumor response was observed in any of the 154 patients. Partial tumor response was observed in 51 of 154 patients (33.1%). Fifty-nine patients (38.3%) exhibited a minor response or disease stabilization for a period after the regimen. The remaining 44 (28.6%) patients had disease progression without tumor response during the period of treatments. The median interval free of disease progression was 14.2 months (range, 2.3–86.8 months). The rate of partial objective tumor response of the four groups was 11.6%, 46.2%, 34.2%, and 44.1%, respectively (P = 0.001), as shown in [Table 2]. Extrahepatic progression developed in 55 patients, including 13 cases of abdominal carcinomatosis, 33 cases of lung metastasis, 7 cases of bone metastasis, and 2 cases of brain metastasis. Most of the patients (73/128) died of liver failure.
Table 2: The effects in the near future of 4 groups

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Numerous factors were assessed for their ability to predict OS, including age, gender, pre-/post-treatment CEA/CA 19-9 serum level, the number or location of LMs, primary tumor location, TN stage, and treatment after primary tumor resection. Univariate analysis revealed that posttreatment CEA serum level (P = 0.001), TN stage (P = 0.01), resection of LMs (P = 0.036), tumor response (P < 0.0001), and treatment group (P < 0.0001) were significant prognostic factors, as shown in [Figure 1]b,[Figure 1]c,[Figure 1]d,[Figure 1]e. After adjusting the covariates in multivariate analysis, TN stage (hazard ratio [HR] =1.394, 95% confidence interval [CI] =1.027–1.893, P = 0.033), tumor response (HR = 2.901, 95% CI = 2.105–3.999, P < 0.0001), and treatment group (HR = 0.726, 95% CI = 0.594–0.887, P = 0.002) remained independent prognostic determinants as shown in [Table 3].
Table 3: Univariate and multivariate analysis showing factors associated with overall survival in 154 patients

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 > Discussion Top


Patients with unresectable CLMs have a poor prognosis with 1- and 3-year survival rates of 31% and 2.6%, respectively.[8] At present, palliative chemotherapy is the only established treatment in patients with CLMs who are not eligible for surgery. The outcome of palliative chemotherapy for patients with unresectable liver lesions was relatively poor.[9] Alternative therapies include RFA, microwave therapy, percutaneous alcohol injection, HAI of chemotherapeutic drugs, target therapy, and TACE. Here, we describe the first study of comparing the effect of chemotherapy plus TACE with chemotherapy plus cetuximab conducted in a Chinese sample of CLMs patients. In the present study, the MST of the patients with CLMs was 22.9 months, significantly longer than that of patients who received palliative chemotherapy in previous reports. Patients who underwent chemotherapy plus TACE had a better survival than those who underwent chemotherapy plus cetuximab or chemotherapy alone.

TACE in patients with CLMs concentrates and prolongs the retention of the chemotherapeutic agent to the tumor with the use of the artery as a conduit to the tumor and reduce systemic levels.[10] Combining systemic chemotherapy with TACE in treating unresectable CLMs may be more effective because the mechanisms of these two treatments differ. Several studies performed to date have evaluated the effectiveness of TACE in patients with CLMs.[11] Albert et al.[12] have reported a 2% partial response, 41% stable disease, and 57% progressive disease after repeated TACE. In our study, we obtained a 46.2% partial response, 41.0% stable disease, and 12.8% progressive disease for patients with CLMs who received chemotherapy plus TACE. You et al.[13] evaluated the response of CLMs in combining systemic chemotherapy with TACE; in this study, the partial tumor response rate was 47.5% which is in accordance with our findings. In a review of studies done by Vogl et al.,[14] it was concluded that TACE increases the possibility of surgery, improves its outcome, and can be used when surgery is not possible or not successful.

Although traditional chemotherapeutic agents (FOLFIRI or mFOLFOX6) for CLMs have capacity to reduce tumor burden, the rate of metastasectomy remains poor (3.3%).[15] With the introduction of cetuximab, a higher rate of metastasectomy was achieved. For instance, in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill trial,[16] FOLFIRI plus cetuximab increased the resection rate from 4.5% to 9.8% in a subgroup of patients with CMLs. Similarly, in the OPUS study,[17] with FOLFOX plus cetuximab, the resection rate for LM doubled from 2.4% to 4.7%. As our data from patients in Group A demonstrate that chemotherapy alone yielded a low rate of metastasectomy (7.0%), when introduced cetuximab, the rate raised to 10.5%. However, when combined chemotherapy with TACE, the rate of metastasectomy was 30.8%, significantly higher than those who underwent chemotherapy plus cetuximab or chemotherapy alone.

The combination regimen of FOLFOX and cetuximab was removed as a treatment option in the National Comprehensive Cancer Network (NCCN) guidelines (version 1.2012) for mCRC because of the recent European and US studies.[18],[19] COIN trial reported no OS (17.9 vs. 17.0 months; P = 0.67) or PFS benefit (8.6 months in both groups; P = 0.60) for patients with wild-type KRAS CMLs when cetuximab was added. Our study indicated possibly improved MST and PFS after adding cetuximab to chemotherapy, but the effect of chemotherapy plus TACE was more dramatic.

Prognostic factors and subgroup analysis can help select patients who might get benefit from treatments. At present, there are many extensive researches about factors influencing the prognosis of colorectal cancer after surgical resection. However, few studies lay emphasis on the prognostic factors of patients with unresectable CLMs. Metastasectomy, TN stage, CA 19-9/CEA serum level, and the number and size of LM were identified as significant prognostic factors in previous reports.[20],[21] In the present study, the prognostic factors associated with survival in patients with CLMs were analyzed. We found that posttreatment CEA serum level, TN stage, resection of LMs, tumor response, and treatment group were identified as significant prognostic factors in univariate analysis. Moreover, TN stage, tumor response, and treatment group remained independent prognostic determinants for survival in multivariate analysis. In contrast, gender, age, serum CA 19-9 level, the number or location of LMs, primary tumor location, and treatment after primary tumor resection were not useful predictors for indicating the prognosis of CLMs.

The NCCN guidelines (2015) have recommended that for those with resectable CMLs, resection of LM can improve survival according to some studies.[22],[23] In the present study, 1-, 3-, and 5-year survival rates for patients with CLMs who underwent metastasectomy were 100%, 51.4%, and 17.7%, respectively, similar to literature reports.[24],[25] As far as CEA is concerned, some experts believe that the CEA serum level is associated with disease progression and prognosis.[26],[27] In the present study, CEA serum level is also one of the prognostic predictors for LMs. The 5-year survival rate of patients with CEA negative was 32.4% with a MST of 25.5 months, significantly superior to those with CEA positive (5.6%, 22.1 months) though CEA serum level and resection of LM were not independent prognostic determinants.

There were several limitations in this study. First, because of the retrospective nature with a great heterogeneity, patient selection bias still could not be completely avoided. Second, the number of patients analyzed was small and limited. Moreover, toxicity or complications of treatments may affect the prognosis of patients with CLMs; Not mentioning the toxicity or complications in this study is another limitation.





Despite these drawbacks, it seems that the addition of TACE to FOLFIRI or mFOLFOX6 provides a viable option for Chinese patients with initially unresectable CLMs (wild-type KRAS) and can benefit their survival. Future prospective randomized trials are needed to confirm our findings and will be important in establishing standard treatment guidelines for patients with CLMs who cannot afford the exorbitant target therapy in China.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Martin RC, Robbins K, Tomalty D, O'Hara R, Bosnjakovic P, Padr R, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: An interim report. World J Surg Oncol 2009;7:80.  Back to cited text no. 11
    
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You YT, Changchien CR, Huang JS, Ng KK. Combining systemic chemotherapy with chemoembolization in the treatment of unresectable hepatic metastases from colorectal cancer. Int J Colorectal Dis 2006;21:33-7.  Back to cited text no. 13
    
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Vogl TJ, Zangos S, Eichler K, Yakoub D, Nabil M. Colorectal liver metastases: Regional chemotherapy via transarterial chemoembolization (TACE) and hepatic chemoperfusion: An update. Eur Radiol 2007;17:1025-34.  Back to cited text no. 14
    
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Delaunoit T, Alberts SR, Sargent DJ, Green E, Goldberg RM, Krook J, et al. Chemotherapy permits resection of metastatic colorectal cancer: Experience from Intergroup N9741. Ann Oncol 2005;16:425-9.  Back to cited text no. 15
    
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