|Year : 2018 | Volume
| Issue : 7 | Page : 1600-1605
Comparison of treatment efficacy between adjuvant intravenous chemotherapy and intravenous chemotherapy combined with intraperitoneal perfusion chemotherapy to treat postresection colon cancer
Tao Jiang1, Rui Feng2, Zhangchi Pan2, Qian Xu1, Wenyu Gao3, Sheng Yang1, Qiang Chen4
1 Department of Medical Oncology, Fujian Medical University Union Hospital; Teaching and Researching Department of Oncology, Union Clinical Medical College of Fujian Medical University, Fujian, China
2 Department of Medical Oncology, Fujian Medical University Union Hospital, Fujian, China
3 Department of Digestive, Fujian Medical University Union Hospital, Fujian, China
4 Department of Medical Oncology, Fujian Medical University Union Hospital; Teaching and Researching Department of Oncology, Union Clinical Medical College of Fujian Medical University; Department of Digestive, Fujian Key Laboratory of Translational Cancer Medicine; Department of Digestive, Fujian Medical University Stem Cell Research Institute, Fujian, China
|Date of Web Publication||19-Dec-2018|
Department of Medical Oncology, Fujian Medical University Union Hospital, Fujian; Teaching and Researching Department of Oncology, Union Clinical Medical College of Fujian Medical University, Fujian; Fujian Key Laboratory of Translational Cancer Medicine, Fujian; Fujian Medical University Stem Cell Research Institute, Fujian
Department of Medical Oncology, Fujian Medical University Union Hospital, Fujian; Teaching and Researching Department of Oncology, Union Clinical Medical College of Fujian Medical University, Fujian
Source of Support: None, Conflict of Interest: None
Background: Surgery has been the definitive treatment for locoregional colon cancer. But approximately 40% of patients died from peritoneal seeding and tumor recurrence. To prevent peritoneal recurrence, the eradication of intraperitoneal cancer cells has been critical for improving postoperative survival. This study focused on the role of IPC in postoperative treatment of colon cancer.
Patients and Methods: Seventy colon cancer patients who underwent radical resection from September 2009 to September 2012 received adjuvant therapy. Specifically, 39 individuals received intravenous chemotherapy (IVC), and 31 received combined IVC and intraperitoneal perfusion chemotherapy (IVC + IPC). Disease-free survival (DFS) for those received IVC (20.71 months) was shorter than those received IVC + IPC (25.71 months). DFS in IVC group was also shorter than that in the IVC + IPC group, for patients with Stage III pathological tumor staging, T4 invasion depth, N2 lymph node metastasis, and low to undifferentiated tumor tissue. Peritoneal metastasis in the IVC + IPC group was less, but the toxicity was similar. No significant difference was observed among IPC treatment groups using three drugs. In the IVC + IPC group, DFS of patients received >5 or 3–5 times of IPC was longer than those received <3 times of treatment. No significant difference was observed in DFS between patients who received >5 times or 3–5 times of IPC.
Conclusion: After radical resection, patients who received IVC + IPC showed prolonged DFS than those received IVC, as well as fewer peritoneal metastasis. Compared to IPC, no significantly increased side effects or complications were occurred after IVC + IPC. More work should be performed to confirm that IVC + IPC was superior to IVC for treating postresection colon cancer.
Keywords: Clinical efficacy, colon cancer, intraperitoneal chemoperfusion, intravenous chemotherapy
|How to cite this article:|
Jiang T, Feng R, Pan Z, Xu Q, Gao W, Yang S, Chen Q. Comparison of treatment efficacy between adjuvant intravenous chemotherapy and intravenous chemotherapy combined with intraperitoneal perfusion chemotherapy to treat postresection colon cancer. J Can Res Ther 2018;14:1600-5
|How to cite this URL:|
Jiang T, Feng R, Pan Z, Xu Q, Gao W, Yang S, Chen Q. Comparison of treatment efficacy between adjuvant intravenous chemotherapy and intravenous chemotherapy combined with intraperitoneal perfusion chemotherapy to treat postresection colon cancer. J Can Res Ther [serial online] 2018 [cited 2019 Mar 22];14:1600-5. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1600/247726
| > Introduction|| |
Malignant tumors are the major causes of global morbidity and mortality. In 2012, 694,000 people died from colorectal cancer, making it the fourth most common worldwide cause of death due to the malignancy. In 2012, colon cancer was the fifth and fourth most common cancer among Chinese males and females, respectively. Surgery has been the definitive treatment for locoregional colon cancer. Recurrence has generally resulted from the occult micro-metastases present at the time of surgery. Approximately 40% of patients died from peritoneal seeding and tumor recurrence after radical resection for colon cancer. To prevent peritoneal recurrence, the eradication of intraperitoneal cancer cells has been critical for improving postoperative survival. Intraperitoneal perfusion chemotherapy (IPC) has been selective regional chemotherapy that was more effective than chemotherapy and immunotherapy. IPC could make a good effect on ovarian cancer and a certain effect on digestive tract tumors., Studies indicated that postoperative IPC was good for controlling disease and improving patients' quality of life., We randomly selected 70 patients with colon cancer who were undergoing radical surgery in Fujian Medical University Union Hospital between September 2009 and September 2012, who also received adjuvant therapy. Disease-free survival (DFS), local recurrence, metastasis, side effects, and complications after adjuvant therapy were monitored and assessed for factors affecting treatment efficacy.
| > Materials and Methods|| |
Seventy colon cancer patients treated with adjuvant therapy after radical surgery in Fujian Medical University Union Hospital from September 2009 to September 2012 were randomly selected and the clinical data was collected. The TNM staging was determined according to the 7th Edition AJCC Cancer Staging Manual.
Thirty-nine cases (20 males and 19 females, age range: 31–72 years) received intravenous chemotherapy (IVC), and 31 (20 males and 11 females, age range: 26–73 years) received IVC and IPC (IVC + IPC). Adjuvant systemic chemotherapy in IVC and IVC + IPC groups after radical colon cancer resection consisted of dual-drug regimens containing oxaliplatin, 5-fluorouracil (5-Fu), and capecitabine. Patients in the IVC group only received IVC, while patients in IVC + IPC group received both IVC and IPC during 3–4 weeks postoperatively. IPC involved single-, dual-, or triple-drug combination regimen(s) containing tegafur, mitomycin, and platinum-based drug. Patients in both IVC and IVC + IPC groups did not receive radiotherapy or targeted therapy.
DFS, local recurrence, abdomen and liver metastases, side effects and complications of intraperitoneal perfusion, and perfusion dosage and cycle were collected and included in the outcome measures.
All cases received at least one follow-up. The day of radical resection was defined as the starting date of the follow-up for each patient; September 2013 or the date of death was defined as the endpoint of the follow-up. Until September 31, 2013, three subjects were lost of follow-up (follow-up success rate of 95.7%). Follow-up duration for all subjects ranged from 2 to 42 months (median of follow-up: 24.1 months).
A retrospective analysis was conducted. The statistical analysis and data processing were performed with SPSS 19.0 software (SPSS, Chicago, IL, USA). Count data were analyzed with the Chi-square test (χ2-test) or a Fisher's exact test. The comparison of measurement data means was analyzed with ANOVA. The survival of patients was analyzed with the Kaplan–Meier method and plating survival curves. Survival rates of patients in different groups were compared with a log-rank test. A Cox proportional hazard regression analysis was applied to identify factors that affected survival. The forward stepwise (Wald) method was applied, with the inclusion criteria of 0.05 and exclusion criteria of 0.10. Dependent variables in this study were overall survival and DFS. Independent variables of this study were gender, age, pathological staging, depth of tumor invasion, lymph node metastasis, and tissue differentiation. P < 0.05 was considered statistically significant (significance level of α = 0.05).
| > Results|| |
Clinical data for treatment groups
The comparability of gender, age, tumor differentiation, pathological staging, depth of tumor invasion, and lymph node metastasis between treatment groups were confirmed with a χ2-test (P > 0.05). DFS of patients in IVC + IPC group was better than that of in IVC group [Figure 1]. A Kaplan–Meier assessment showed that DFS was only affected by pathological staging and tissue differentiation and a Cox multivariate model (forward stepwise, Wald, regression analysis) showed that pathological staging, tumor differentiation, and IPC were the three independent prognostic factors that affected DFS [Table 1] and [Table 2]. The stratified analysis was performed on patient variables that affected survival [Table 3]. The anastomotic recurrence, peritoneal metastasis, and liver metastasis were compared for both groups [Table 4].
|Figure 1: The disease-free survival between IVC + IPC and IVC group. IVC = Intravenous chemotherapy, IVC + IPC = IVC combined intraperitoneal perfusion chemotherapy|
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|Table 1: Univariate analysis on factors associated with patients' disease-free survival|
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|Table 2: Multivariate analysis on factors associated with patients' disease-free survival|
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|Table 3: Stratification analysis of variables on factors which affected patients' disease-free survival|
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Toxicity (third and fourth grade) for treatments involved gastrointestinal reactions, hand-foot syndrome, peripheral neuropathy, bone marrow suppression, side effects, and complications; however, all these symptoms were not statistically significant.
Dosing regimens were applied in IVC + IPC subgroups. Comparisons were performed between any two subgroups, and there was no significant difference in DFS (P > 0.05 in subgroup 1 versus subgroup 2; subgroup 2 versus subgroup 3; subgroup 1 versus subgroup 3).
An average of 4.4 IPC cycles was applied (median: 4 cycles). According to IPC times (i.e., >5, 3–5, and <3 cycles), the patients in the IVC + IPC group were divided into three subgroups (1: N = 11; 2: N = 10; 3: N = 8) and there were significant differences in DFS among subgroups [P < 0.05, [Table 5]. The two subgroups were compared with a log-rank test, which confirmed significantly different DFS between subgroups 1 and 3; subgroups 2 and 3 (P < 0.05). There was no significant difference in DFS between subgroups 1 and 2 [P > 0.05, [Table 6].
| > Discussion|| |
Approximately 40% of patients with colon cancer die from local recurrence or metastasis after radical surgery. Local recurrence was often observed in the abdominal cavity or peritoneum, near the primary site. Recurrence may be explained by the “seed-soil” theory and tumor cell entrapment hypothesis proposed by Sugarbaker et al.
IPC is a topical treatment based on the anatomical characteristics of the abdominal cavity combined with the pharmacokinetics of regional chemotherapy. After administration, the plasma concentration of IPC-delivered drugs can be increased to 2.5–8 folds of the concentration within first a few hours. The concentration of anticancer-drug would be relatively low once in the systemic circulation. The IPC-administrated anticancer drugs could be sufficiently contacted with free cancer cells, which eliminated intraperitoneal-free cancer cells. The intraperitoneal drugs would be absorbed mainly via the portal vein and then transferred to the tumor thrombus. Thus, there would be a strong therapeutic effect on hepatic cancer cells. Chemotherapy drugs damaged intraperitoneal inflammatory cells and platelets, reduced the release of growth factor, and blocked their roles in promoting tumor cells proliferation. Therefore, IPC might prevent and treat local intraperitoneal tumor recurrence and distant metastasis after colon cancer radical resection.
Effect of intraperitoneal perfusion chemotherapy on survival after colon cancer radical resection
In 2009, Elias et al. reported that, after treatment with IVC + IPC, the 2- and 5-year survival for 48 postresection colon cancer patients was 81.5% and 51%, respectively. This survival was longer than those treated with IVC, with 2- and 5-year survival of 65% and 13%, respectively. Median survival for patients treated with IVC + IPC and IVC was 62.7 and 23.9 months, respectively, and the difference was statistically significant (P < 0.05). Chua et al. conducted a retrospective analysis of 19 treatment involving 2492 patients with advanced and metastatic colon cancer between 1995 and 2009. Patients who received combined cytoreductive surgery (CS) and IPC showed a median survival of 33 months, which was significantly prolonged compared to those received single CS or systemic chemotherapy (median survival of 12.5 months) (P < 0.05). In this study, DFS was also improved with adjuvant IVC and IPC after radical resection.
The results of our stratified analysis suggested that DFS after IPC could be extended, for patients with low-undifferentiated tumor, Stage III pathological tumor staging, T4 invasion depth, and N2 lymph node metastasis. High malignancy, poor prognosis, and moderate-to-advanced pathological tumor staging were the risk factors for peritoneal metastasis after radical resection. Extended DFS after IPC may result from the elimination of peritoneal-free cancer cells, cancer cells in the portal vein, and hepatic micrometastases, as well as the suppression of tumor cell proliferation. Compared to patients with better biological behaviors, adjuvant IPC made no significant effect for preventing peritoneal colon cancer recurrence and metastasis.
Effect of intraperitoneal perfusion chemotherapy on recurrence and metastasis after radical resection
Vaillant et al. reported that recurrence and metastasis for patients treated with IVC + IPC (24.8%) were significantly lower than those treated with IVC (31.3%), suggesting that peritoneal local recurrence and liver metastasis could be controlled by postoperative IPC. Some studies in China indicated that liver metastasis and local recurrence were significantly less after IPC treatment, compared to those treated with IVC. In the current study, peritoneal colon cancer metastasis was significantly reduced with postoperative IPC; however, no significant difference in anastomotic recurrence and liver metastasis was found between the two treatment groups. The result was inconsistent with those reported in previous studies. Theoretically, anastomotic recurrence and liver metastasis after radical resection should also be reduced with IPC, and this difference may be explained by the limitations in medical records collection in this study.
Intraperitoneal perfusion chemotherapy dosing, treatment cycle, and timing
Currently, there has been no large-scale clinical study or data to describe IPC treatment for colon cancer and standard research protocols. Available IPC drugs were 5-FU, mitomycin (i.e., mitomycin C [MMC]) and platinum-based drugs (i.e., oxaliplatin). IPC regimens can be single-, dual-, or triple-drug administrations and some researchers reported the synergistic effects between 5-FU, MMC, and heat,, suggesting that IPC could be combined with hyperthermia during the treatment. Relevant studies indicated that tumor cells developed irreversible damage at 42.5°C. At 42°C–43°C, sensitivities of IPC with 5-FU and MMC were increased from 5.0% and 6.0% to 32.0% and 38.0%, respectively. Votanopoulos et al. analyzed 186 cases of colon cancer or appendix cancer. Of the 186 cases, 132 patients received MMC IPC and 55 patients received oxaliplatin IPC. Median survival for patients treated with MMC IPC and oxaliplatin IPC was 23.8 and 17.8 months, respectively, without statistically significant difference (P > 0.05). Prada-Villaverde et al. reported that the American Society of Peritoneal Surface Malignancies conducted a comparative analysis on treatment efficacy of MMC or oxaliplatin intraperitoneal hyperthermia chemoperfusion (IPHC) in 539 patients with intestinal cancer. Data showed that median survival after MMC IPC and oxaliplatin IPHC was 32.7 and 31.0 months, respectively, which was not significantly different (P > 0.05). In the current study, selective analyses of IPC regimens indicated that common IPC drugs, including 5-FU, MMC, and platinum-based drugs, provided not significantly different DFS in single-, dual-, and triple-drug regimens (P > 0.05). Given the side effects associated with chemotherapy, we recommended a single-drug regimen. Due to synergism among 5-FU, MMC, and heat in IHCP, a dual-drug regimen would also be worthwhile for colon cancer therapy. However, triple-drug regimens failed to significantly improve DFS in colon cancer patients and side effects included increased toxicity and complications. Due to sampling limitations, IHPC treatment efficacy was not evaluated in colon cancer patients.
The choice of IPC mainly depended on individual tolerances, as well as the assessment of regular treatment and treatment experience. In this study, IPC cycles were preliminarily evaluated, confirming that >3 cycles of IPC would be more efficacious.
IPC can be implemented before, during, or after radical resection for colon cancer. To date, intraoperative and postoperative IPC have been most common. A previous study reported that adjuvant IPC should be implemented as early as possible after radical resection. Due to tumor cells would be inevitably squeezed during resection, shedding, and free circulation of those tumor cells would lead to postoperative tumor cell seeding and tumor recurrence, mostly at the resection site and the resection-mediated peritoneal damage surface. The tumor burden was minimized after primary tumor resection. The tumor cell division and proliferation would be accelerated, leading to the sensitivity to the anticancer drug. During early postoperative stages, intraperitoneal adhesion has not been formed or to a small degree. Administration of anticancer drug(s) in highly recurrent regions such as the resection site and the peritoneal surface and the exposure to chemotherapy would be better thus preventing peritoneal tumor metastasis. In the current study, we included patients who received IPC 3–4 weeks after radical resection but not patients who received intraoperative IPC or IPC 2 weeks after radical resection. This was due to the difficulties with intraoperative IPC, and most patients could not tolerate IPC 2 weeks postoperatively.
Side effects and complications of intraperitoneal perfusion chemotherapy
IPC has considerable therapeutic effects for colon cancer, but there were also side effects during the implementation of IPC. However, the third and fourth grades of toxicities were compared in patients who received IVC and IVC + IPC, while no statistically significant difference was observed between the two treatment groups (P > 0.05). In addition, no disability, death, or other serious complications were reported. Therefore, side effects and complications of combined chemotherapies after radical resection for colon cancer were not significantly worse than those of single IVC after radical resection for colon cancer, suggesting that postoperative IVC + IPC was within tolerable limits for patients.
| > Conclusion|| |
Adjuvant IVC + IPC after radical resection for patients with colon cancer improved DFS and reduced peritoneal metastasis, compared to that of postoperative IVC. Pathological tumor staging and tumor differentiation were independent prognostic factors for DFS. The DFS after IPS was better for patients with Stage III pathological tumor staging, T4 invasion depth, N2 lymph node metastasis, and low-undifferentiated colon cancer. Moreover, patients who received >3 cycles of IPC showed extended DFS. No significant difference in DFS was found between single- and multiple-drug regimens for IPC. Adjuvant IVC + IPC after radical resection for patients with colon cancer extended DSF and reduced peritoneal metastasis, compared to that of single IVC. Toxicity or complication was not increased with postoperative IVC + IPC.
The present study was supported by the Special Program for the Development of Strategic Emerging Industries of Fujian Province, the Peoples' Republic of China (13YZ0201). Young Scientist Foundation of Fujian Provincial Commission of Health and Family Planning (2016-2-16). No author had a conflict of interest.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]