Oxaliplatin is the third-generation platinum-based anticancer drug and is a useful drug in colorectal cancer therapy. Especially, oxaliplatin combined with 5-fluorouracil(5FU)/leucovorin (FOLFOX) has emerged as the standard of care in adjuvant treatment and in first-line and second-line therapy of advanced-stage colorectal cancer [
Oxaliplatin-induced neurotoxicity can be divided into two distinct syndromes. The first one is a unique syndrome of acute, transient peripheral nerve hyperexcitability, which is unique among the platinum complexes studied to date [
Several strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity, such as gabapentin, calcium-magnesium infusions, antiepileptic drugs like carbamazepine, amifostine, and glutathione. However, there were no randomized trials which had demonstrated a prophylactic or therapeutic effect of these agents on oxaliplatin cumulative neurotoxicity. Guilongtongluofang, a traditional Chinese medicine, is composed of ramulus cinnamomi, radix astragali, earthworm, safflower, radix angelicae sinensis, ligusticum, spatholobus, radix paeoniae alba, rhizoma curcumae, and licorice. All the herbs added increased the function of warming and activating yang to promote blood circulation to relieve from symptoms such as numbness and cold sensation in patients.
We hypothesized that Guilongtongluofang might have effect on the prevention of oxaliplatin-induced neurotoxicity. This study was therefore designed to determine the preventive effects of Guilongtongluofang on peripheral neurotoxicity induced by oxaliplatin in patients with colorectal tumor.
The plant material was purchased from the Beijing Medicinal Material Company (Beijing, China). Guilongtongluofang was composed of ramulus cinnamomi 9 g, earthworm 12 g, radix astragali 30 g, safflower 10 g, radix angelicae sinensis 12 g, ligusticum 12 g, spatholobus 30 g, radix paeoniae alba 30 g, rhizoma curcumae 9 g, and licorice 6 g. The aqueous extract was prepared by the following processes: each dose of the dried herbs was twice decocted in water to 100 mL, and then the 200 mL was mixed and divided into two potions to be taken twice daily.
Consecutive patients with colon or rectum cancer were enrolled in this prospective study from the chemotherapy department of Weifang Hospital of Traditional Chinese Medicine during the period from May 2007 to May 2011. Criteria for enrollment include (1) ≥18 years of age; (2) Eastern Cooperative Oncology Group performance status of 0 to 2; (3) normal bone marrow function (leukocyte count > 4,000/L, platelet count > 100,000/L), liver function (serum bilirubin < 1.5 mg/dL), renal function (creatinine < 1.5 mg/dL), and cardiac function (stable heart rhythm, no active angina, and no clinical evidence of congestive heart failure); (4) life expectancy ≥ 6 months; (5) no preexisting peripheral neurotoxicity from any cause. Pregnant or nursing women were not eligible for this study. Patients with diabetic neuropathy were also excluded. Concomitant use of anticoagulants, platelet aggregation inhibitors, opioids, anticonvulsants, tricyclic antidepressants, and other neuropathic pain medication agents was also prohibited. Informed consent was obtained from all participants, and this study was approved by the local ethics committee.
Using a prospective, randomized, placebo-controlled, double-blind design, 120 patients were randomly assigned into the trial group (60 patients) and the control group (60 patients). There are 83 males and 37 females, with a median age of 52.5 years. Group assignment for all subjects was determined using a random table prior to initiation of the study. The sequence of assignments was unknown to any of the investigators. Each assignment was kept in a sealed envelope, and the order in numeric number was shown on the outside of the envelope. Thus, the orders could not be changed. Envelopes were arranged in order. The principal investigator generated this random selection a few months before recruiting the first subject. No significant differences in gender, age, physical condition, and clinical stage of disease between the two groups were found.
All of the patients were given FOLFOX4 chemotherapy for six cycles. The chemotherapeutic regimen consisted of oxaliplatin 85 mg/m2 on day 1, given as a 3-hour infusion in 250 mL of dextrose 5%, concurrent with 6-S-stereoisomer of leucovorin 200 mg/m2 as a 2-hour infusion followed by fluorouracil 400 mg/m2 and 24-hour infusion of fluorouracil 2400 mg/m2/d for 2 consecutive days. Then, two weeks later, the patients were given the same chemotherapeutic regimen for 2 consecutive days again. Patients who finished twice chemotherapeutic regimen were defined as one cycle.
The trial group was given Guilongtongluofang from 3 days prior every chemotherapy and the herb treatment was administered for consecutive 10 days. One dose of Guilongtongluofang was taken every day. The control group was given placebo seen as Guilongtongluofang in the same way.
The primary study endpoint was efficient measurement which included oxaliplatin-induced neurotoxicity and tumor response.
Oxaliplatin-induced neurotoxicity was assessed after every two cycles using the National Cancer Institute’s (NCI) common toxicity criteria (CTC) as follows: grade 1: paresthesia and/or dysesthesia (induced by cold) with complete regression within one week; grade 2: paresthesia and/or dysesthesia with complete regression within 14 days; grade 3: paresthesia and/or dysesthesia with incomplete regression at day 14; grade 4: paresthesia and/or dysesthesia with functional consequences [
Treatment response was assessed according to World Health Organization criteria based on a CT scan 2 months after the completion of treatment. A complete response was defined as the disappearance of all known disease for at least 4 weeks. A partial response required a reduction of at least 50% in the size of the tumor for at least 4 weeks. Progressive disease was defined as an increase of 25% or more in the size of the tumor, and stable disease was defined as no change or less than 50% reduction or more than 25% increase.
The secondary endpoint was safety, and the number of participants discontinued to treatment. All patients underwent followup office visits every two weeks until 2 months after the completion of treatment. At each followup, blood routine, transaminases, blood urea nitrogen (BUN), and creatinine were measured, and the incidence and severity of various side effects (i.e., diarrhea, nausea, vomiting, headache, dizziness and abdominal pain, etc.) which may be associated with treatment were monitored.
With the published event rates for our primary endpoint, we estimated the number of subjects required for the study to have >80% power (
Patient characteristics are shown in Table
Basic characteristics of study population.
Characteristics | Trial group ( |
Control group ( |
|
---|---|---|---|
Age (years) | |||
≥50 | 10 (16.7) | 7 (11.7) | 0.83 |
<50 | 50 (83.3) | 53 (88.3) | |
Gender | |||
Male | 43 (71.7) | 40 (66.7) | 0.55 |
Female | 17 (28.3) | 20 (33.3) | |
Performance status | |||
0 | 34 (56.7) | 29 (48.3) | 0.36 |
1,2 | 26 (43.3) | 31 (51.7) | |
Location of primary tumor | |||
Colon | 32 (53.3) | 34 (56.7) | 0.74 |
Rectum | 28 (46.7) | 26 (43.3) | |
Histological differentiation | |||
Well/moderately | 45 (75.0) | 41 (68.3) | 0.41 |
Poorly/unknown | 15 (25.0) | 19 (31.7) | |
Sites of distant metastasis | |||
Liver | 12 (20.0) | 10 (16.7) | 0.74 |
Lung | 8 (13.3) | 8 (13.3) | |
Liver and lung | 4 (6.7) | 3 (5.0) | |
Others | 0 | 1 (1.7) |
As shown in Table
Incidence of oxaliplatin-induced neurotoxicity in the trial group and the control group.
Neurotoxicity | Trial group ( |
Control group ( |
|
---|---|---|---|
After two cycles | |||
Grade 0 | 52 (86.7) | 48 (80.0) | 0.04 |
Grades 1-2 | 8 (13.3) | 11 (18.3) | |
Grades 3-4 | 0 (0.0) | 1 (1.7) | |
After four cycles | |||
Grade 0 | 43 (71.7) | 34 (56.7) | 0.05 |
Grades 1-2 | 14 (23.3) | 18 (30.0) | |
Grades 3-4 | 3 (5.0) | 8 (13.3) | |
After six cycles | |||
Grade 0 | 29 (48.3) | 18 (30.0) | 0.04 |
Grades 1-2 | 24 (40.0) | 23 (38.3) | |
Grades 3-4 | 7 (11.7) | 19 (31.7) |
In addition, the onset of grade 1 or more sensory neurotoxicity was much later in patients who received Guilongtongluofang. Data regarding the time to grade 1+ sensory neurotoxicity are illustrated in Figure
Time to grade 1 or more sensory neurotoxicity in patients treated with or without Guilongtongluofang.
The incidence of grade 1 or more sensory neurotoxicity increased with the increasing cumulative dose of oxaliplatin (Figure
Probability of sensory neurotoxicity by cumulative dose of oxaliplatin in patients treated with or without Guilongtongluofang.
All patients completed six cycles of treatment, and the overall response rates (complete response and partial response) were 43.3% in the trial group and 35.0% in the control group, respectively. Two patients in the trial group and two patients in the control group had a complete response, respectively. No significant differences of tumor response rate were found between the two groups (Table
Objective tumor response in the trial group and the control group.
Group |
|
CR (%) | PR (%) | SD (%) | PG (%) |
|
---|---|---|---|---|---|---|
Trial group | 60 | 2 (3.3) | 24 (40.0) | 28 (46.7) | 6 (10) | 0.72 |
Control group | 60 | 2 (3.3) | 19 (31.7) | 32 (53.3) | 7 (11.7) |
CR: complete response; PR: partial response; SD: stable disease; PG: progression.
Nonneurologic adverse events which may be associated with the treatment are listed in Table
Adverse events in the trial group and the control group.
Adverse events | Trial group ( |
Control group ( |
|
---|---|---|---|
Anemia | |||
Grades 1-2 | 7 (11.7) | 8 (13.3) | 0.78 |
Grades 3-4 | 0 | 0 | |
Neutropenia | |||
Grades 1-2 | 14 (23.3) | 13 (21.7) | 0.92 |
Grades 3-4 | 7 (11.7) | 6 (10.0) | |
Thrombocytopenia | |||
Grades 1-2 | 10 (16.7) | 9 (15.0) | 0.80 |
Grades 3-4 | 0 | 0 | |
Nausea | |||
Grades 1-2 | 18 (30.0) | 20 (33.3) | 0.69 |
Grades 3-4 | 0 | 0 | |
Vomiting | |||
Grades 1-2 | 14 (23.3) | 16 (26.7) | 0.67 |
Grades 3-4 | 0 | 0 | |
Diarrhea | |||
Grades 1-2 | 12 (20.0) | 13 (21.7) | 0.56 |
Grades 3-4 | 1 (1.7) | 3 (5.0) | |
Stomatitis | |||
Grades 1-2 | 12 (20.0) | 11 (18.3) | 0.81 |
Grades 3-4 | 0 | 0 |
Oxaliplatin has become an integral component of chemotherapeutic regimens for the treatment of colon or rectum cancer [
The main target organ of platinum-based preparations with peripheral neurotoxicity is the dorsal root ganglion, which is consistent with the platinum accumulation studies [
In this study, we also proved the effects of Guilongtongluofang on preventing acute and chronic oxaliplatin-induced neurotoxicity. 8 patients in the trial group and 11 patients in the control group appeared grades 1-2 neurotoxicity after two cycles of chemotherapy. After four cycles, and especially six cycles oxaliplatin-induced neurotoxicity gradually increased with increasing dose. It showed that the neurotoxicity was dose-dependent. After four cycles, 14 patients (23.3%) in the trial group and 18 patients (30.0%) in the control group experienced grades 1-2 sensory neurotoxicity. The difference of the incidence of neurotoxicity between the two groups was significantly different after six cycles of treatment. As for tumor response, the response rate was 43.3% in the trial group and 35.0% in the control group, no significant difference was found between the two groups.
Most scholars considered [
According to the modern pharmacological research, the main component of
There are some limitations in our study. First, all patients underwent follow-up office visits every two weeks until 2 months after the completion of treatment, and hence a long-term study is obviously needed to further confirm our results. Second, clinical findings were used as the endpoints in our study, whereas a hard clinical endpoint such as mortality should be used in a large sample of patients in a future study.
In summary, the application of FOLFOX4 treatment with Guilongtongluofang in advanced colorectal cancer cannot only reduce the incidence of neurotoxicity but also improve the quality of life in patients. It does not reduce the efficacy of the treatment or increase the toxicity of chemotherapy.
Guilongtongluofang can safely decrease the incidence of severe neurotoxicity induced by FOLFOX4 regimen, without reducing the efficacy of the treatment or increasing the side effects. Therefore, Guilongtongluofang is useful in preventing oxaliplatin-induced neurotoxicity in patients with colorectal cancer.
There is no conflict of interests regarding the publication of this paper.
This study was supported by Grants from the National Natural Science Foundation of China (nos. 81172596, 81173427).