|Year : 2018 | Volume
| Issue : 10 | Page : 761-766
A randomized phase III study of hepatic arterial infusion chemotherapy with 5-fluorouracil and subsequent systemic chemotherapy versus systemic chemotherapy alone for colorectal cancer patients with curatively resected liver metastases (Japanese Foundation for Multidisciplinary Treatment of Cancer 32)
Mitsuo Kusano1, Toru Aoyama2, Koji Okabayashi3, Koichi Hirata4, Yasushige Tsuji5, Shoji Nakamori6, Toshimasa Asahara7, Yasuo Ohashi8, Takaki Yoshikawa2, Junichi Sakamoto9, Koji Oba10, Shigetoyo Saji11
1 Kushiro Rosai Hospital, Kushiro, Japan
2 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
3 Department of Surgery, Keio University School of Medicine, Tokyo, Japan
4 Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
5 Hijirigaoka Hospital, Date, Japan
6 Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
7 Hiroshima University, Hiroshima, Japan
8 Department of Biostatistics, School of Public Health, The University of Tokyo, Tokyo, Japan
9 Tokai Central Hospital, Kakamigahara, Japan
10 Translational Research and Clinical Trial Center, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
11 Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan
|Date of Web Publication||24-Sep-2018|
Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 1-1-2 Nakao, Asahi-Ku, Yokohama 241-0815
Source of Support: None, Conflict of Interest: None
Aim: This randomized phase III trial compared hepatic arterial infusion (HAI) chemotherapy with 5-fluorouracil (5-FU) followed by uracil/tegafur (UFT) and leucovorin (LV) versus UFT/LV alone for patients with curatively resected liver metastases from colorectal cancer (CRC).
Methods: The study was designed to include 280 patients to be randomized to receive either HAI with 5-FU followed by UFT/LV (Arm A) or UFT/LV alone (Arm B) to assess whether HAI chemotherapy improved disease-free survival (DFS).
Results: Forty-four patients were randomized. Three-year DFS was relatively worse in the experimental arm although this difference was not statistically significant (43.5% in Arm A vs. 58% in Arm B; hazard ratio [HR], 1.304; P = 0.534). The experimental arm also tended to have a worse 3-year overall survival rate (80.2% in Arm A vs. 85.2% in Arm B; HR, 2.255; P = 0.192). There was no significant difference in the frequency of Grade 3 or higher toxicities between the two arms.
Conclusion: Although this study was limited by a small sample size after early study termination, our analysis found that HAI with 5-FU followed by UFT/LV did not improve the DFS of patients with curatively resected liver metastases from CRC compared with UFT/LV alone. The future studies are necessary to evaluate the survival benefit of HAI in combination with newer systemic chemotherapeutic agents for patients with resectable liver metastases from CRC.
Keywords: Colorectal cancer, hepatic arterial infusion chemotherapy, liver metastases, randomized phase III study
|How to cite this article:|
Kusano M, Aoyama T, Okabayashi K, Hirata K, Tsuji Y, Nakamori S, Asahara T, Ohashi Y, Yoshikawa T, Sakamoto J, Oba K, Saji S. A randomized phase III study of hepatic arterial infusion chemotherapy with 5-fluorouracil and subsequent systemic chemotherapy versus systemic chemotherapy alone for colorectal cancer patients with curatively resected liver metastases (Japanese Foundation for Multidisciplinary Treatment of Cancer 32). J Can Res Ther 2018;14, Suppl S3:761-6
|How to cite this URL:|
Kusano M, Aoyama T, Okabayashi K, Hirata K, Tsuji Y, Nakamori S, Asahara T, Ohashi Y, Yoshikawa T, Sakamoto J, Oba K, Saji S. A randomized phase III study of hepatic arterial infusion chemotherapy with 5-fluorouracil and subsequent systemic chemotherapy versus systemic chemotherapy alone for colorectal cancer patients with curatively resected liver metastases (Japanese Foundation for Multidisciplinary Treatment of Cancer 32). J Can Res Ther [serial online] 2018 [cited 2020 Oct 26];14:761-6. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/761/179188
| > Introduction|| |
Colorectal cancer (CRC) is one of the most common malignant diseases worldwide. Approximately, 15% of CRC patients have liver metastases at diagnosis, and 60% of the patients with metastatic disease develop liver metastases. Patients with hepatic metastases from CRC who undergo complete liver resection have a 5-year survival rate of 30–50%; however, up to 70% of these patients will have disease recurrence, mainly in remnant liver.,, Therefore, it is very important to establish an effective adjuvant chemotherapy regimen to be administered after liver resection.
Adjuvant systemic chemotherapy after liver resection has been evaluated in several studies. A meta-analysis of two small randomized trials showed a trend of improvement in disease-free survival (DFS) with the use of systemic 5-fluorouracil (5-FU) and leucovorin (LV) after adjustment for several prognostic factors. Although no definitive results of clinical trials for adjuvant chemotherapy after liver resection have been reported so far, several guidelines recommend adjuvant chemotherapy for patients with stage III colon cancer, a population that has been shown to benefit from adjuvant chemotherapy in several pivotal studies.,,,,,
Chemotherapy administered via hepatic arterial infusion (HAI) is reportedly effective for unresectable hepatic metastases in patients with CRC., HAI achieves a higher concentration of infused drugs in the liver compared to systemic chemotherapy, with fewer side effects. Liver metastases derive most of their blood supply from arterial circulation. Therefore, adjuvant HAI via arterial circulation is a promising strategy. HAI with or without systemic therapy significantly increased DFS when compared with systemic therapy alone (or with no further therapy) in two of three randomized studies in western countries.,, Our Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) group also conducted a randomized trial of HAI with weekly high-dose 5-FU versus systemic 5-FU after resection of hepatic metastases from CRC (JFMC 29-0003) in patients treated since July 2000. Although the JFMC 29-0003 trial was terminated in June 2003 because of low accrual, this study did confirm the feasibility of HAI after liver resection in a Japanese patient population. Therefore, we initiated another study to evaluate whether there was a survival benefit from HAI combined with uracil/tegafur (UFT) systemic chemotherapy and oral LV versus systemic chemotherapy with UFT/LV alone for patients with resected liver metastases from CRC (JFMC 32).
| > Methods|| |
To be enrolled in this study, patients had to meet all of the following criteria: (i) Presence of histologically confirmed colorectal adenocarcinoma with curatively resected liver metastases; (ii) no extrahepatic metastasis; (iii) Eastern Cooperative Oncology Group performance status 0 or 1; (iv) aged ≥20 years but <80 years; (v) adequate bone marrow reserve (leukocyte count ≥3000/mm3, hemoglobin level ≥9.0 g/dl, and platelet count ≥100,000/mm3); (vi) adequate hepatic function (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] <100 IU/L, and total bilirubin <1.5 mg/dl); (vii) adequate renal function (serum creatinine <1.5 mg/dl); (viii) sufficient oral intake.
Patients were excluded if they met any of the following criteria: (i) Previous history of chemotherapy and radiotherapy for liver metastasis (prior adjuvant chemotherapy for resection of a primary tumor was permitted if the last dose was given at least 3 months before study entry); (ii) other malignancy (within 5 years before study entry); (iii) serious comorbidities such as infection, history of stroke, myocardial infection, uncontrolled diabetes, severe liver cirrhosis, pulmonary fibrosis, and history of serious systemic illness. All patients provided written informed consent, and the appropriate Institutional Ethics Committees at each institution approved all study procedures.
Study design and treatment
This was a multi-institution, open-label, randomized phase III study to evaluate the benefit of HAI with 5-FU followed by systemic chemotherapy with UFT/LV for the treatment of patients with resected liver metastases from CRC.
For the experimental arm (Arm A), the infusion port system was implanted percutaneously. Two-vessel (celiac artery and superior mesenteric artery) angiography was carried out using the Seldinger method. Platinum coil embolization was carried out on the right gastric artery to prevent the influx of anti-tumor drugs into the gastrointestinal system. A side-hole catheter was inserted with the tip of the catheter placed in the gastroduodenal artery, common hepatic artery, or right and/or left hepatic artery. The proximal end of the catheter was connected with a port and implanted subcutaneously. Assessment of hepatic perfusion and confirmation of the absence of extrahepatic perfusion was performed by computed tomography angiography (CTA) via infusion port system before HAI and every 3 months during the treatment. The details of HAI treatment have been previously reported., Catheter replacement occurred when necessary, in cases of catheter dislocation, vascular occlusion, or inadequate drug distribution. Patients began HAI chemotherapy within 14 days after study enrollment. HAI with 1000 mg/m2 5-FU was infused in 5 h by pump flow rate. HAI administration continued weekly for a minimum of 3 months and a maximum of 6 months. After completion of HAI treatment, subsequent systemic chemotherapy with UFT/LV was initiated. Daily UFT 300 mg/m2 and LV 75 mg were divided into three separate doses administered every 8 h for 28 consecutive days in cycles that repeated every 35 days until 1- year after enrollment. In the control arm (Arm B), the oral UFT/LV treatment started within 14 days after enrollment and continued on the same schedule as Arm A until 1-year after enrollment.
Chemotherapy (HAI with 5-FU or UFT/LV) was delayed until recovery in patients with a white blood cell count <3000/mm3, platelet count <75,000/mm3, AST >100 IU/L, ALT >100 IU/L, or any significant and persistent nonhematologic toxicity. If patients experienced Grade 3 or higher toxicities, the dose of 5-FU or UFT was reduced by approximately 25% (i.e., reduction to 750 mg/m2 and then 500 mg/m2 for 5-FU, and reduction to 250 mg/m2 and then 200 mg/m2 for UFT). Treatment was discontinued before completion if the tumor recurred, severe toxicity occurred, or if requested by the patient.
The data center confirmed patient eligibility, and treatment was randomly assigned in a 1:1 ratio with minimization according to stratifying factors for eligible patients. The following four variables were used for stratification: Primary tumor site (colon vs. rectum), disease status (synchronous liver metastasis vs. metachronous liver metastasis without adjuvant chemotherapy after surgery for primary tumor vs. metachronous liver metastasis with adjuvant chemotherapy after surgery for primary tumor), number of liver metastases (1 vs. 2 or more), and institution. Enrolled patients were randomly assigned to receive experimental treatment (Arm A) or standard treatment (Arm B).
End points and assessments
The primary endpoint of this study was 3-year DFS. DFS was measured from the date of study entry to the date of disease recurrence or death. DFS analysis was based on the Kaplan–Meier product-limit method. Secondary endpoints included overall survival (OS), liver-specific DFS, extra-liver DFS, adverse events, and quality of life (QOL) score. OS was measured from the date of study entry to the time of death from any cause. Liver-specific DFS was measured from the date of study entry to the time of recurrence in remnant liver. Extra-liver DFS was measured from the date of study entry to the time of recurrence in any location other than the liver. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 3.0 was provided from National Cancer Institute. QOL score was calculated based on daily activity, physical function, psychological status, social activity, visual analog scale and face scale, and intention to continue treatment. Patients were evaluated using the QOL questionnaire for cancer patients treated with anticancer drugs 1, 3, 6, 12, and 18 months after the initiation of treatment.
All patients were evaluated every month for the 1st year after study enrollment and every 3 months for the next 3 years. The evaluation included a physical examination, complete blood count, blood chemical tests, and serum tumor markers. Chest, abdominal, and pelvic computed tomography scans were performed every month for 3 months, every 3 months until the end of the 2nd year, and then every 6 months.
The sample size was calculated by the method of Schoenfeld and Richter. The study was designed to detect a hazard ratio (HR) for relapse or death of 0.57 in the experimental arm compared to the control group with 80% power at a two-sided α-level of 0.05. Assuming a 3-year DFS rate of 35% in the control arm (50% expected in experimental arm), a 3-year accrual period, and a 3-year follow-up, the target sample size was calculated to be 140 patients per arm (280 patients total). Interim analysis for safety was planned 1-year after trial initiation. Interim analysis for efficacy was planned after one-third or two-third of expected events were observed.
The full analysis set (FAS) for efficacy analysis was defined as all eligible patients. Patients who were judged to be ineligible after study registration and who experienced other new malignancies within 1-year after surgery were excluded from analysis. The safety analysis included patients who received any study treatment. The exploratory analysis cohort excluded patients who discontinued treatment after a short period (HAI within 3 months or UFT/LV within two courses) and patients with suspected insufficient distribution of chemotherapeutics by CTA.
A log-rank test was used to compare DFS between treatment arms. Cox proportional hazard models were used to calculate HRs. OS was analyzed using the same method as the DFS analysis. Fisher's exact tests or Chi-square tests were used to explore the relationships between dichotomous variables. The frequency of adverse events was also calculated and compared using Fisher's exact tests or Chi-square tests, as appropriate, for the worst adverse events (all grades and Grade 3 or higher) observed in each patient during the study treatment.
| > Results|| |
The trial was prematurely discontinued due to low accrual after 44 patients from 21 institutions had been randomized from February 2005 to December 2007 [Figure 1]. All patients were eligible by our criteria. Therefore, the FAS included 22 patients in Arm A and 22 patients in Arm B. One patient in each arm could not receive any study treatment, so the safety analysis included 21 patients in Arm A and 21 patients in Arm B. The exploratory cohort included 12 patients (54.5%) in Arm A and 19 patients (86.4%) in Arm B. Patient and disease characteristics were well-balanced between the two arms [Table 1].
|Figure 1: CONSORT flowchart showing the disposition of enrolled patients at the time of data cut-off. Forty-four patients were randomized before study termination. All patients were eligible. Therefore, the efficacy analysis included 22 patients in Arm A and 22 patients in Arm B. One patient in each arm could not receive any study treatment; therefore, the safety analysis included 21 patients in Arm A and 21 patients in Arm B. One patient in Arm A started uracil/tegafur + leucovorin without hepatic arterial infusion because the catheter could not be inserted|
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In the experimental arm (Arm A), HAI with 5-FU was initiated in 20 patients. HAI was administered for 3 months in 17 patients (85%) and for 6 months in six patients (30%), with a median duration of HAI treatment of 4.0 months (range, 1–6 months). One patient could not receive any treatment, and one patient started UFT/LV without treatment with HAI because the catheter for HAI could not be inserted. Drug distribution was considered to be appropriate in all patients by CTA. Among the 20 patients who received HAI, three patients discontinued HAI because of disease recurrence, and two patients discontinued HAI because of toxicity or a technical problem. The dose of 5-FU was reduced in five patients (25%), mainly because of nonhematological toxicities.
UFT/LV therapy was initiated in 17 patients in Arm A and 21 patients in Arm B. The median number of courses of UFT/LV was 5 in Arm A (range, 1–8 courses) and 9 in Arm B (range, 1–11 courses). Nine of 17 patients in Arm A and 11 of 21 patients in Arm B completed UFT/LV therapy. Three patients in Arm A and four patients in Arm B stopped receiving UFT/LV because of disease recurrence. The dose of UFT was reduced in four patients in Arm A (23.5%) and six patients in Arm B (28.6%), mainly because of nonhematological toxicities.
At the time of analysis, all eligible patients were evaluated for efficacy. The median follow-up time was 3.5 years (range, 1–5.1 years). Disease recurrence was identified in 12 patients in Arm A (55%) and 10 patients in Arm B (46%). Of the patients with recurrence, seven patients (32%) in Arm A and seven patients (32%) in Arm B developed liver metastases. Extrahepatic recurrence was more frequent in Arm A (n = 11, 50%) than in Arm B (n = 6, 27%). Three-year DFS was relatively worse in the experimental arm, although this difference was not statistically significant (43.5% in Arm A vs. 58% in Arm B; HR, 1.304; P = 0.534); [Figure 2]a. No difference in DFS was observed in the exploratory analysis cohorts (56.3% in Arm A and 51% in Arm B; P = 0.477). Arm A patients tended to have a worse 3-year OS rate (80.2% in Arm A vs. 85.2% in Arm B; HR, 2.255; P = 0.192) [Figure 2]b. The experimental arm tended to have a worse liver-specific DFS rate at 3 years (62.8% in Arm A vs. 76.8% in Arm B; HR, 1.416; P = 0.491) and extrahepatic DFS rate at 3 years (48% in Arm A vs. 60.9% in Arm B; HR, 1.678; P = 0.253). Surgery for recurrence was performed in four patients (18.2%) in Arm A and five patients (22.7%) in Arm B.
|Figure 2: Kaplan–Meier plots of (a) disease-free survival and (b) overall survival|
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Adverse events and quality of life evaluation
The frequency of adverse events during all treatment courses in the safety population is summarized in [Table 2]. Most of the adverse events were Grade 1 or 2; only a few patients experienced Grade 3 or higher toxicities. Elevated ALT was experienced by more patients in Arm A (n = 16; 76%) than in Arm B (n = 8; 38%) although only one patient (5%) in Arm A experienced Grade 3 toxicity. Similarly, anorexia of any grade was more commonly seen in Arm A (n = 13, 62%) than in Arm B (n = 7; 33%). One patient in Arm A and two patients in Arm B experienced Grade 3 anorexia. In contrast, stomatitis was more common in Arm B (n = 4; 19%) than in Arm A (n = 1, 5%) with one patient in Arm B experiencing Grade 3 toxicity.
Fourteen patients (63.6%) in both arms completed QOL questionnaires for 6 months, and seven patients in Arm A (31.8%) and eight patients in Arm B (36.4%) completed QOL questionnaires for 18 months. At 3 months, scores for social activity and intent to continue treatment were significantly lower for Arm A patients than for Arm B patients. There were no other apparent differences in the QOL assessments between the two arms.
| > Discussion|| |
This is the first Japanese study to evaluate the benefit of HAI with 5-FU in combination with systemic chemotherapy for resected liver metastases from CRC. Although this study was terminated early because of low accrual, the results of this study show that adjuvant HAI followed by UFT/LV after liver resection did not decrease the rate of recurrence compared to UFT/LV alone. Extrahepatic recurrence was more frequent in patients who received HAI. Furthermore, recurrence in the remnant liver was not decreased by HAI. These results are in agreement with our previous study (JFMC 29-0003), which compared HAI with 5-FU and systemic 5-FU in a similar patient population. The results from both studies suggest that systemic chemotherapy must be the standard backbone of adjuvant therapy for patients with resected liver metastases from CRC.
In contrast to our results, two previous randomized studies showed that HAI with floxuridine (FUDR) plus systemic chemotherapy improved OS, DFS, and liver-specific DFS compared to systemic chemotherapy alone or surgery alone., HAI with FUDR in combination with systemic chemotherapy (5-FU/LV) significantly improved the 2-year OS rate compared to 5-FU/LV alone (86% vs. 72%) and also improved the liver-specific 2-year DFS rate (90% vs. 60%). The most important difference between these past studies and this study may be the timing of HAI and systemic chemotherapy. HAI and systemic chemotherapy were administrated concurrently in these two studies with positive results whereas they were sequentially administrated in the current study. Furthermore, different agents were administered by HAI in these studies (FUDR vs. 5-FU). The hepatic extraction rate is reported to be as high as 94–99% for FUDR but is only 19–54% for 5-FU. Therefore, FUDR may be a more suitable agent for liver-specific treatment in combination with systemic chemotherapy., This hypothesis is supported by another randomized study in Germany that evaluated HAI with 5-FU after liver resection. This study was terminated because of lack of efficacy (survival was worse in the HAI arm). Recent trials of HAI with FUDR in combination with oxaliplatin-based systemic chemotherapy also showed promising results and acceptable feasibility.,, The efficacy of these new combinations should be evaluated in a phase III study with sufficient sample size.
Another promising strategy for resectable liver metastases is the neoadjuvant (or preoperative) approach. The Organization for Research and Treatment of Cancer intergroup trial 4098310 (EPOC) showed that the combination of perioperative chemotherapy (pre- and post-operative) with FOLFOX (folinic acid, 5-FU, and oxaliplatin), and surgery increased the progression-free survival compared to surgery alone for patients with liver-only metastases from CRC that were deemed resectable by preoperative imaging. The absolute difference in the proportion of patients alive and progression-free at 3 years was 7.3% (3-year progression-free survival, 28.1% in the surgery only group versus 35.4% in the perioperative chemotherapy group; HR, 0.79; P = 0.058) in all randomized patients. This result suggests that a perioperative approach is a promising strategy for resectable liver metastases of CRC. However, this study used both pre- and post-operative chemotherapy, which raises the question of which is more suitable (pre vs. post). A recent study using cetuximab, an anti-epidermal growth factor receptor monoclonal antibody, showed no benefit of cetuximab for perioperative chemotherapy in combination with FOLFOX, although the survival benefit of cetuximab has been confirmed in several randomized studies of unresectable CRC., Future clinical trials are necessary to determine the optimal treatment timing and to aid the selection of appropriate chemotherapeutic agents for patients with resectable liver metastases from CRC.
| > Conclusion|| |
This study was limited by early termination and the small sample size. This study found that HAI with 5-FU followed by UFT/LV did not improve DFS compared to UFT/LV alone in patients with curatively resected liver metastases from CRC. Future studies are necessary to evaluate the survival benefit of HAI in combination with newer systemic chemotherapeutic agents for patients with resectable liver metastases from CRC.
This work was supported, in part, by a nonprofit organization, the Epidemiological and Clinical Research Information Network.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]