Introduction
============

Colorectal cancer is the most common malignant tumor of the digestive tract, more common in people over 45 years old and more in male than female, as one of the main causes of human death ([@b1-ol-0-0-9574],[@b2-ol-0-0-9574]). With changes in people\'s eating habits and lack of physical exercise, the incidence of colorectal cancer has been increasing year by year, with nearly 1,000,000 new patients each year worldwide ([@b3-ol-0-0-9574],[@b4-ol-0-0-9574]). Approximately 81% of its sites are near the anal sphincter. Surgical resection is a very effective treatment method for malignant tumors. However, for most colorectal cancer patients, the preservation of anus and its function is a difficult problem to be treated by surgical treatment, and the most controversial disease in surgical treatment ([@b5-ol-0-0-9574],[@b6-ol-0-0-9574]).

Chemotherapy has always been one of the basic treatment methods for colorectal cancer patients, but as it continues, it becomes unbearable for patients due to its toxic side effects, and decreased efficacy over time. For decades, there has been no new breakthrough in the treatment for colorectal cancer ([@b7-ol-0-0-9574],[@b8-ol-0-0-9574]). FOLFIRI chemotherapy regimen is currently the main chemotherapy drug regimen in middle and advanced colon cancer ([@b9-ol-0-0-9574]), and some scholars have been trying to improve it. High frequency hyperthermia is a physical therapy, and the energy transmitted is absorbed by cells through the high frequency electromagnetic field. Due to its characteristics of rapid growth, the tumor tissue has disordered structure and abnormal blood vessel growth, which is often squeezed together, with slow heat dissipation. The sustained energy absorption of tumor cells causes a rapid rise in temperature, ultimately resulting in their irreversible damage and death, thereby treating tumors ([@b10-ol-0-0-9574],[@b11-ol-0-0-9574]). However, worldwide there have been few studies related to high frequency hyperthermia combined with chemotherapy.

Therefore, in this study, the clinical effects of high frequency hyperthermia-assisted irinotecan chemotherapy on patients with middle and advanced colorectal cancer were investigated, to analyze the application of high frequency hyperthermia in patients with middle and advanced colorectal cancer.

Materials and methods
=====================

### Clinical information

A retrospective analysis was performed on the medical records of 103 patients with middle and advanced colorectal cancer treated in Cancer Center of Guangzhou Medical University (Guangzhou, China) from May 2011 to June 2015, including 48 patients receiving irinotecan plus conventional treatment (irinotecan group) and 55 patients receiving high frequency hyperthermia-assisted irinotecan plus conventional treatment (combination group). All patients were diagnosed with middle and advanced colorectal cancer by pathology combined with imaging in Cancer Center of Guangzhou Medical University. Patients without abnormal leucocyte and lymphocyte counts were eligible for chemotherapy; without drug allergy history and contraindications; without organ dysfunction such as the heart and kidney before operation; without abnormal bleeding or coagulation dysfunction before operation; without portal hypertension, gastrointestinal diseases and past history of tumors; receiving a series of examinations and treatments in the Cancer Center of Guangzhou Medical University after diagnosis; willing to cooperate with medical staff in the Cancer Center of Guangzhou Medical University; and with complete medical records. Patients with a preoperative simple intelligence scale MMSE score of \<24 points were excluded; with incomplete medical records; with a history of hepatitis; with mental or learning dysfunction; with excessive diameter of the tumor; with other cardiovascular and cerebrovascular diseases; with other respiratory tract diseases; with other digestive tract diseases; transferred to other hospitals halfway; and taking antibiotics prescribed by other hospitals or with rehabilitation treatment arranged by other hospitals during treatment. The study was approved by the Ethics Committee of Cancer Center of Guangzhou Medical University, Guangzhou, China. Patients or their families signed an informed consent form.

### Treatment methods

Irinotecan group was treated with irinotecan plus conventional treatment, and combination group with high frequency hyperthermia-assisted irinotecan plus conventional treatment. Both groups of patients were treated with FOLFIRI chemotherapy regimen, with irinotecan (guoyaozhunzi: H20020687, manufacturer: Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China) 180 mg/m^2^ and calcium folinate (guoyaozhunzi: H33020913, Zhejiang Wansheng Pharmaceutical Co., Ltd., Zhejiang, China) 400 mg/m^2^ intravenously infused for 2 h at the same time. 5-fluorouracil (guoyaozhunzi: 05501H201, Xi\'an Haixin Pharmaceutical Co., Ltd., Xi\'an, China) 400 mg/m^2^ was intravenously injected, and then 5-fluorouracil 2,400-3,000 mg/m^2^ was pumped within 46 h. Based on this, combination group was treated with high frequency hyperthermia (NRL-004 endogenous field tumor hyperthermia system, Jilin Maida Medical Equipment Co., Ltd., Jilin, China). The height of the electrode plate was adjusted, to lower the upper electrode plate to 5--7 cm on the skin surface corresponding to the lesion, with a working frequency of 13.56 MHz and a treatment power of 1,300-1,400 W. The computer fitting temperature was adjusted to 41--43°C according to the patient\'s condition and tolerance, each treatment time for 40--60 min, 2--3 times a week. All treatment methods were every 2 weeks for one course, for a total of 4 courses.

### Observation indicators

The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ([@b12-ol-0-0-9574]) was used to evaluate treatment effects on the two groups of patients after 4 courses of treatment. Complete remission: Τhe target lesion disappears, and the short diameter of the lymph node does not exceed 10 mm. Partial remission: Τhe sum of the measurement results of the target lesion diameter is reduced by no less than 30% compared to baseline measurements. Stable disease: Τhe measurement results of the target lesion after treatment are between those of partial remission and disease progression. Disease progression: Τhe sum of the measurement results of target lesion diameter is increased by no less than 20% compared to baseline measurements, and the absolute increase is no less than 5 mm. The objective remission rate is the ratio of the sum of patients with complete remission and partial remission in the total number of patients. The CTCAE version 4.0 ([@b13-ol-0-0-9574]) was used to evaluate the severity of adverse reactions in the two groups of patients, divided into 1--5 grades. The higher the grade is, the more severe the adverse reactions are. The incidence of adverse reactions in the two groups of patients was recorded (neutrophil deficiency and leukopenia), and the treatment safety was evaluated. The QLQ-C30 scale was used to evaluate the quality of life (emotional, role, cognitive, physiological and social function) in the two groups of patients before and after treatment. The higher the score is, the higher the quality of life is.

### Statistical analysis

SPSS 19.0 (IBM Corp., Armonk, NY, USA) was used. Count data were expressed as n (%). χ^2^ test was used for the comparison of ratio. Measurement data were expressed as mean ± SD. Α t-test was used for comparison between the two groups, paired t-test for comparison before and after treatment, K-M survival curve for analyzing the 3-year survival rate of the two groups of patients. P\<0.05, indicates a statistically significant difference.

Results
=======

### General information

Altogether 48 patients were in irinotecan group, including 26 male and 22 female patients, aged 53.76±9.48 years, with a BMI of 23.42±3.47 kg/m^2^. Fifty-five patients were in combination group, including 30 male and 25 female patients, aged 54.13±11.29 years, with a BMI of 24.25±3.14 kg/m^2^. There was no statistically significant difference in sex, age and BMI between the two groups of patients (all P\>0.05), and in tumor pathological type, metastasis, site, α-fetoprotein level, hemoglobin level, smoking history, drinking history, education status and place of residence (all P\>0.05) ([Table I](#tI-ol-0-0-9574){ref-type="table"}).

### Analysis of treatment effects on two groups of patients

After 4 courses of treatment, there was no statistically significant difference in the proportions of patients with complete remission, stable disease and disease progression between the two groups of patients (all P\>0.05), but there were statistically significant differences in the proportions of patients with partial remission and objective remission, with those in combination group higher than those in irinotecan group (both P\<0.05) ([Table II](#tII-ol-0-0-9574){ref-type="table"}).

### Safety assessment of two treatment methods

After 4 courses of treatment, no patient died. There was no statistically significant difference in the severity of adverse reactions between the two groups of patients (P\>0.05). The results of the statistical analysis of the incidence of complications in the two groups of patients showed that there was no statistically significant difference in the proportions of patients with neutrophil deficiency, leukopenia, nausea and vomiting, diarrhea, scald, anemia and fatigue between the two groups of patients (all P\>0.05) ([Tables III](#tIII-ol-0-0-9574){ref-type="table"} and [IV](#tIV-ol-0-0-9574){ref-type="table"}).

### Analysis of quality of life in two groups of patients

There was no statistically significant difference in emotional, role, cognitive, physiological and social function scores between the two groups of patients before treatment (all P\>0.05). After 4 courses of treatment, those that increased in different degrees (all P\<0.05), compared to those in combination group were significantly higher than those in irinotecan group (all P\<0.05) ([Table V](#tV-ol-0-0-9574){ref-type="table"}).

### Analysis of 3-year survival rate in two groups of patients

The 1-, 2- and 3-year survival rates of patients in irinotecan group were 31.25% (15 cases), 22.92% (11 cases) and 12.50% (6 cases), respectively. Those in combination group were 58.18% (32 cases), 29.09% (16 cases) and 16.36% (9 cases), respectively. The results of K-M survival curve analysis showed that there was no statistically significant difference in survival rate between the two groups of patients (P=0.05). ([Fig. 1](#f1-ol-0-0-9574){ref-type="fig"}).

Discussion
==========

Colorectal cancer is a type of malignant tumor with high incidence. In some studies, the proportion of colorectal cancer patients that can be found in the early stage is only approximately 2% of all colorectal cancer patients ([@b14-ol-0-0-9574]). The current chemotherapy regimens for patients with middle and advanced colorectal cancer are mainly FOLFIRI regimen containing irinotecan and FOLFOX regimen containing oxaliplatin. They effectively improve the survival and prognosis of patients, but adverse reactions caused by them in nervous, blood and digestive systems also increase with the increase of chemotherapy course ([@b15-ol-0-0-9574],[@b16-ol-0-0-9574]). In recent years, hyperthermia has been confirmed not to cause adverse reactions such as bone marrow suppression in patients, which has better killing effects on tumor cells ([@b17-ol-0-0-9574]). However, there are few studies on hyperthermia combined with chemotherapy for patients with middle and advanced colorectal cancer. In this study, the application effects of high frequency hyperthermia combined with FOLFIRI regimen containing irinotecan on patients with middle and advanced colorectal cancer were analyzed, to provide references for the clinical treatment of colorectal cancer.

In this study, the medical records of 103 patients with middle and advanced colorectal cancer were included in strict accordance with inclusion and exclusion criteria. There was no statistically significant difference in the basic data between the two groups of patients after grouping, suggesting that they are comparable in this study, and the results of the study are credible. The results of their efficacy analysis after 4 courses of treatment showed that the proportion of patients with partial remission was significantly higher in combination group than that in irinotecan group, and the objective remission rate was also higher in combination group than that in irinotecan group. It is indicated that high frequency hyperthermia can improve the treatment effects of irinotecan chemotherapy on patients with middle and advanced colorectal cancer.

In recent years, there have been some studies on hyperthermia combined with chemotherapy improving the treatment effects on tumors, which confirm the positive effects of hyperthermia as an adjunctive therapy for treating tumors ([@b18-ol-0-0-9574],[@b19-ol-0-0-9574]). Hyperthermia is one of the oldest cancer treatment methods. The tumor tissue is similar to heat storage due to its structure. Hyperthermia regulates the temperature to 39--45°C to selectively heat the tumor tissue, thereby killing tumor cells under high temperature. Recent advances based on its biological principles suggest that hyperthermia is an effective radiation sensitizer that is considered as a safe and effective supplementary method for treating tumors ([@b20-ol-0-0-9574],[@b21-ol-0-0-9574]). Adverse reactions caused by chemotherapy have always been one of the most important problems that clinicians want to overcome, seriously influencing the treatment effects on tumors and the use of drugs, which is one of the important reasons that hinder the improvement of chemotherapy regimens in recent decades ([@b22-ol-0-0-9574]). The results of this study showed that there was no statistically significant difference in the severity and incidence of adverse reactions between the two groups of patients, suggesting that high frequency hyperthermia as an adjunctive therapy does not change the safety of current chemotherapy regimens. However, there was one scalded patient in combination group, which should also be taken seriously.

It is necessary to pay close attention to changes in patients and make more detailed planning for temperature regulation in hyperthermia. Nevertheless, the effects of hyperthermia on the treatment safety have not been found in some hyperthermia-related reports ([@b23-ol-0-0-9574],[@b24-ol-0-0-9574]). Patients\' quality of life in the two groups was also analyzed. For patients with middle and advanced colorectal cancer, improving their quality of life is one of the most important goals of the treatment. The results of this study also showed that the quality of life scores of patients after treatment were higher in combination group than those in irinotecan group. This should be related to the treatment effects of the two methods. The better recovery of patients in combination group can effectively ςimprove their quality of life. Some studies ([@b25-ol-0-0-9574]) have reported that promoting blood circulation and enhancing immune function, hyperthermia can reduce muscle tone, thereby alleviating cancer pain, which should also be an important reason for patients\' higher quality of life in combination group. In this study, the results of the 3-year survival rate analysis showed that there was no statistically significant difference in it between the two groups of patients. In related reports, hyperthermia is also found to be able to reduce the risk of poor prognosis of patients, and no difference in the survival rate was found ([@b26-ol-0-0-9574],[@b27-ol-0-0-9574]). This is similar to our findings.

In summary, high frequency hyperthermia-assisted chemotherapy for patients with middle and advanced colorectal cancer can effectively improve its treatment effects and patients\' quality of life, with better treatment safety, worthy of clinical promotion.

Not applicable.

Funding
=======

No funding was received.

Availability of data and materials
==================================

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors\' contributions
=======================

ZL conceived and designed the study, collected and interpreted the data, and treated patients. The author read and approved the final manuscript.

Ethics approval and consent to participate
==========================================

The study was approved by the Ethics Committee of Cancer Center of Guangzhou Medical University (Guangzhou, China). Patients who participated in this research, signed the informed consent and had complete clinical data.

Patient consent for publication
===============================

Not applicable.

Competing interests
===================

The authors declare that they have no competing interests.

![Analysis of 3-year survival rate in two groups of patients. The 1-, 2- and 3-year survival rates of patients in irinotecan group were 31.25% (15 cases), 22.92% (11 cases) and 12.50% (6 cases), respectively. Those in combination group were 58.18% (32 cases), 29.09% (16 cases) and 16.36% (9 cases), respectively. The results of K-M survival curve analysis showed that there was no statistically significant difference in survival rate between the two groups of patients (P=0.05).](ol-17-01-0215-g00){#f1-ol-0-0-9574}

###### 

General information.

  Variables                      Irinotecan group (n=48)   Combination group (n=55)   χ^2^/t value   P-value
  ------------------------------ ------------------------- -------------------------- -------------- ---------
  Sex \[n (%)\]                                                                       0.001          0.969
    Male                         26 (54.17)                30 (54.55)                                
    Female                       22 (45.83)                25 (45.45)                                
  Age (years)                    53.76±9.48                  54.13±11.29              0.179          0.859
  BMI (kg/m^2^)                  23.42±3.47                24.25±3.14                 1.274          0.206
  Pathological type \[n (%)\]                                                         0.406          0.939
    Adenocarcinoma               32 (66.67)                34 (61.82)                                
    Squamous carcinoma           1 (2.08)                  2 (3.64)                                  
    Mucous carcinoma               6 (12.50)                 8 (14.55)                               
    Undifferentiated carcinoma     9 (18.75)               11 (20.00)                                
  α-fetoprotein (ng/ml)          19.42±3.25                19.58±3.64                 0.234          0.816
  Hemoglobin (g/l)               12.33±3.86                13.49±3.73                 1.549          0.125
  Metastasis \[n (%)\]                                                                1.334          0.248
    Yes                          40 (83.33)                50 (90.91)                                
    No                             8 (16.67)               5 (9.09)                                  
  Site \[n (%)\]                                                                      0.733          0.693
    Colon                        32 (66.67)                40 (72.73)                                
    Rectal                         9 (18.75)                 7 (12.73)                               
    Colon plus rectal              7 (14.58)                 8 (14.55)                               
  Smoking history \[n (%)\]                                                           0.149          0.699
    Yes                          28 (58.33)                30 (54.55)                                
    No                           20 (41.67)                25 (45.45)                                
  Drinking history \[n (%)\]                                                          1.258          0.262
    Yes                          19 (39.58)                16 (29.09)                                
    No                           29 (60.42)                39 (70.91)                                
  Education status \[n (%)\]                                                          1.324          0.250
    High school and below        21 (43.75)                18 (32.73)                                
    High school above            27 (56.25)                37 (67.27)                                
  Place of residence \[n (%)\]                                                        0.014          0.905
    Rural                        23 (47.92)                27 (49.09)                                
    Urban                        25 (52.08)                28 (50.91)                                

###### 

Analysis of treatment effects on two groups of patients.

  Variables             Irinotecan group (n=48)   Combination group (n=55)   χ^2^ value   P-value
  --------------------- ------------------------- -------------------------- ------------ ---------
  Complete remission    2 (4.17)                  5 (9.09)                   0.981        0.322
  Partial remission     15 (31.25)                29 (52.73)                 4.832        0.028
  Stable disease        23 (47.92)                17 (30.91)                 3.121        0.077
  Disease progression     8 (16.67)               4 (7.27)                   2.197        0.138
  Objective remission   17 (35.42)                34 (61.82)                 7.147        0.008

###### 

Assessment of severity of adverse reactions after 4 courses of treatment in two groups of patients.

      Groups                             
  --- ------------ ------------- ------- -------
  1   12 (25.00)   14 (25.45)    0.016   0.901
  2   20 (41.67)   22 (40.00)    0.029   0.864
  3   12 (25.00)   13 (23.64)    0.026   0.872
  4   4 (8.33)       6 (10.91)   0.194   0.660
  5   0 (0.00)     0 (0.00)              

###### 

Statistics on incidence of adverse reactions after 4 courses of treatment in two groups of patients.

  Variables               Irinotecan group (n=48)   Combination group (n=55)   χ^2^ value   P-value
  ----------------------- ------------------------- -------------------------- ------------ ---------
  Neutrophil deficiency   19 (39.58)                25 (45.45)                 0.361        0.548
  Leukopenia                9 (18.75)               10 (18.18)                 0.006        0.941
  Nausea and vomiting       9 (18.75)                 8 (14.55)                0.329        0.566
  Diarrhea                1 (2.08)                  2 (3.64)                   0.219        0.640
  Scald                   0 (0.00)                  1 (1.82)                                
  Anemia                  2 (4.17)                  2 (3.64)                   0.019        0.889
  Fatigue                   8 (16.67)                 7 (12.73)                0.320        0.572

###### 

Analysis of quality of life in two groups of patients before and after treatment.

  Variables                Irinotecan group (n=48)                                    Combination group (n=55)                                   t value   P-value
  ------------------------ ---------------------------------------------------------- ---------------------------------------------------------- --------- ---------
  Emotional function                                                                                                                                       
    Before treatment       50.69±11.47                                                51.33±11.24                                                0.286     0.776
    After treatment        59.72±11.05^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   64.38±11.67^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   2.072     0.041
  Role function                                                                                                                                            
    Before treatment       46.54±11.25                                                48.31±11.87                                                0.774     0.441
    After treatment        61.28±11.69^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   69.84±11.72^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   3.705     \<0.001
  Cognitive function                                                                                                                                       
    Before treatment       50.42±12.03                                                51.75±11.54                                                0.572     0.569
    After treatment        62.74±9.87^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^    74.59±10.66^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   5.825     \<0.001
  Physiological function                                                                                                                                   
    Before treatment       45.33±8.72                                                 44.96±9.28                                                 0.208     0.836
    After treatment        59.86±9.35^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^    67.33±10.24^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   3.845     \<0.001
  Social function                                                                                                                                          
    Before treatment       49.64±10.65                                                48.27±10.43                                                0.659     0.512
    After treatment        62.78±10.68^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   72.24±11.45^[a](#tfn1-ol-0-0-9574){ref-type="table-fn"}^   4.315     \<0.001

P\<0.05, compared to before treatment in the same group.
