Abstract
Previous in vitro and in vivo experiments had demonstrated dose‐dependent anti‐cancer effects of clinical plasma colchicine concentrations on hepatocellular carcinoma (HCC) cells. This phase IIa trial was to evaluate the potential efficiency and safety of our novel colchicine dosage schedule for the palliative treatment of advanced HCC. The dosage schedule started from oral intake of 1 mg colchicine three times per day for 4 days and discontinuation in the following 3 days (one cycle). The treatment cycle was repeated and the dosage was adjusted ranging from 3 to 1.5 mg/day according to the condition of the participant. The control group was originated from chart review of 86 HCC patients treated by sorafenib for more than 2 months. Fifteen participants signed the inform consent. Two participants were excluded due to screening failure in one and less than four treatment cycles in another. For severe adverse events, the colchicine group demonstrated higher incidence of biliary tract obstruction (p = 0.0184) than the sorafenib group. Comparison grade 1 or 2 adverse events between two groups, the colchicine group had higher incidence of diarrhea (p = 0) and the sorafenib group had higher incidence of palmar‐plantar erythrodysesthesia syndrome (p = 0.0045). There was no significant difference in mortality, median survival, and overall survival between two groups (all p > 0.2). In conclusion, our novel colchicine dosage schedule is clinically feasible and has the potential to be applied in the palliative treatment of advanced HCC especially based on the cost‐effectiveness consideration.
Keywords: colchicine, hepatocellular carcinoma, immunotherapy, sorafenib, target therapy
1. INTRODUCTION
Sorafenib is the first approved oral multi‐kinase molecular inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Despite the successful approval and extensive application of sorafenib in the treatment of advanced HCC, only a limited number of patients have experienced a real and long‐term benefit. 1 , 2 , 3 Several new target or immunotherapy drugs have subsequently been approved for the treatment of advanced HCC. However, the efficiencies of these new drugs are also modest. 1 , 2 , 3 Moreover, target or immunotherapy drugs are very expensive and may have non‐negligible side effects. Therefore, searching a cheap and easily tolerable drug with at least non‐inferiority in efficiency for the treatment of advanced HCC as compared with current target or immunotherapy drugs is mandatory.
Colchicine is a very cheap tricyclic alkaloid that has been used in medicine for very long time. 4 , 5 , 6 Colchicine at high concentration is a microtubule destabilizer with very strong binding capacity to tubulin to perturb the assembly dynamics of microtubules. 7 , 8 , 9 , 10 , 11 , 12 , 13 It also can increase cellular free tubulin to limit mitochondrial metabolism in cancer cells through inhibition of the voltage‐dependent anion channels of the mitochondrial membrane. 11 The clinical application of colchicine as an anti‐cancer agent has not been accepted due to its toxicity and very narrow therapeutic range. 12 , 13 However, oral intake of colchicine is very safe when it is appropriately used and contraindications have been excluded. 4 , 5 , 6 The peak plasma concentrations after oral administration of 0.6–1 mg colchicine range from approximately 2 to 6 ng/ml. 14 , 15 , 16 Previous in vitro and in vivo experiments had shown that the clinical plasma colchicine concentrations had dose‐dependent anti‐cancer effects on HCC cells, 17 cancer‐associated fibroblasts, 17 gastric cancer cells, 18 and cholangiocarcinoma cells. 19 The anti‐cancer effects of colchicine on HCC cells originate not only from the well‐known direct colchicine‐tubulin interaction 7 , 8 , 9 , 10 , 11 , 12 , 13 but also from colchicine‐induced differential expressions of several antiproliferative genes. 17 The anti‐proliferative effects of 6 ng/ml colchicine on HCC cells were the same as 1 μg/ml epirubicin 17 which is near the maximum plasma concentration of epirubicin obtained by intravenous bolus of 75 mg/m2 body surface epirubicin in patients. 20 These findings indicate that oral intake of colchicine under careful administration has potential to be applied as an anti‐cancer drug for the palliative treatment of HCC. This phase IIa trial was to evaluate the potential efficiency and safety of our novel colchicine dosage schedule using clinically acceptable doses for the palliative treatment of advanced HCC. Since complete obliteration of HCC is not the proposed treatment goal for colchicine and current HCC target or immunotherapy drugs, tumor progression with time can be expected as a final treatment result. Time to tumor progression (TTP) and tumor progression‐free survival (PFS) are frequently applied in developing a new drug in oncology. An advantage of measuring TTP or PFS over measuring overall survival (OS) is that TTP or PFS takes much shorter duration of trial than OS. However, PFS or TTP improvements do not always result in corresponding improvements in OS. 21 , 22 , 23 In clinical practice, the duration of survival and the quality of life rather than TTP or PFS are the main concerns for the patients. Therefore, median survival and OS were applied to evaluate the potential efficiency of colchicine in HCC.
2. PATIENTS AND METHODS
This trial started from June 1, 2013 to May 31, 2019 with a total period of 72 months. All participants collected from one medical center. All participants signed the informed consent after explanation before screening. This study was approved by the institutional review board of the hospital, and all patients signed the informed consent (ClinicalTrials.gov: NCT01935700).
3. SELECTION CRITERIA
The inclusive criteria were the American Joint Committee on Cancer TNM stage IIIB to IVB HCC patients proven by cytological or pathological findings, and/or serum alpha‐fetoprotein level >400 ng/ml with typical HCC findings on contrast‐enhanced computed tomography or magnetic resonance imaging. The hepatic reserved function should be in Child class A.
The exclusive criteria at screening included (1) life‐threatening hemorrhage or infection, (2) serum creatinine level >1.5 mg/dl, (3) unable to stop or reduce the dose of statin or fibrates drugs, (4) white blood cell count <1500/μl, platelet count <30,000/μl or hemoglobin <9.0 g/dl after medication, (5) pregnant woman or planning to pregnancy, (6) history of severe side effects or allergy to colchicine, (7) systemic chemotherapy within 2 months before enrollment or planning to receive systemic chemotherapy in the future, (8) receiving or planning to receive target drugs, immunotherapy or other clinical trial testing drugs, (9) severe malfunction of vital organs justified by the research team, (10) receiving or planning to receive Chinese traditional medicine or herb drugs. Patient fitted any one of the above exclusive criteria was excluded.
4. DOSAGE SCHEDULE
The dosage schedule started from oral intake of 1 mg colchicine three times per day after meal (3 mg/day) for 4 days and discontinuation in the following 3 days (one cycle). The treatment cycle was repeated till the participant was unable to take the colchicine.
5. ADJUSTMENT OF COLCHICINE DOSAGE DURING STUDY
Total daily doses were reduced to 2.5 mg (1 mg morning, 0.5 mg afternoon, 1 mg night) when the hepatic reserved function of the participant changed from Child class A to B.
Colchicine cycle was stopped in participant with Child class C.
Colchicine cycle was temporarily stopped in participant suffering from severe diarrhea. The treatment cycle was started again with reduced total daily dose of 0.5 mg after improvement of the symptom. The definition of severe diarrhea was defined as more than three times of watery or not‐formed stool passages per day over baseline.
Colchicine cycle was temporarily stopped when the participant fitted any one of the exclusive criteria during the study. The treatment cycle was started again after the fitted exclusive criterion was eliminated.
Colchicine cycle was temporarily stopped 1 day before transcatheter arterial chemoembolization till the participant showed no fever, same hepatic reserved function as before, and serum creatinine level <1.5 mg/dl after embolization.
6. FOLLOW‐UP PROCEDURES
All participants received contrasted‐enhanced computed tomography or magnetic resonance imaging at an interval of 3–4 months. Serum alpha‐fetoprotein level was determined at least one session every 2–3 months. The hepatic and renal function were evaluated at least one session per month. The participants are asked to visit our outpatient clinic at least one session per month.
7. CRITERIA TO WITHDRAW OR TERMINATE
Participant suffered from systemic itching, nausea, vomiting, abdominal pain, fever, or skin rash after colchicine administration.
Participant was unable to tolerate 1.5 mg total daily colchicine dose for at least 4 cycles.
8. CONCOMITANT TREATMENT
This study allowed the participant to receive local abrasion, radiation therapy or transcatheter arterial chemoembolization. Systemic chemotherapy, target therapy, immunotherapy, other clinical trial testing drugs, Chinese traditional medicine or herb drugs were not permitted.
9. CONTROL GROUP
The control group was originated from chart review of HCC patients (from January 1, 2014 to May 31, 2019) with the same condition as the trial selected participants and treated by sorafenib for more than 2 months.
10. OBJECTIVES
The objective for non‐inferiority in efficacy was to compare the median survival and OS between participants receiving colchicine for more than eight cycles and the control group. The safety objective was to observe the side effects of colchicine. The grading of adverse event was based on the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 24
11. STATISTICAL ANALYSIS
Fisher exact test or chi‐squared test was applied to compare proportions between two groups. The log‐rank test was applied to compare the OS and the Mann–Whitney U test was applied to compare the median survival. The safety analysis was performed by collection of adverse events.
12. RESULTS
Fifteen participants signed the inform consent. All participant had been received HCC treatment before screening. Among them, 13 participants had been treated by sorafenib (Table 1). One participant (C014) was excluded due to life‐threatening gastrointestinal hemorrhage during screening period. The other one participant (C002) was withdrawn from the study due to less than four treatment cycles. The colchicine treatment cycles for the remaining 13 participants at the end of this trial ranged from 5 to 143 cycles with the median of 14 cycles (Table 2). The reasons for 12 participants to stop colchicine included tumor progression in eight participants, life‐threatening cholangitis in two participants (C005, C007) and inform consent withdrawn in two participants (C006, C015). The causes of death in these 12 participants included tumor progression in 11 participants and cholangitis in one participant (C005). For C005 participant, there was no evidence of HCC recurrence examined by the follow‐up contrast‐enhanced magnetic resonance imaging and serum alpha‐fetoprotein examination. One participant (C013) is still alive for more than 1548 days calculated from the first dose of colchicine till November 30, 2020. This participant continues to receive colchicine provided by the research team after the end of the trial due to good benefit of colchicine in this participant.
TABLE 1.
Characteristics of participants at baseline
| Code | Age (year) | Sex | Etiology | LC | Body weight (kg) | TNM staging a | Previous sorafenib treatment | Previous HCC treatment |
|---|---|---|---|---|---|---|---|---|
| C001 | 61 | F | HBV | No | 62.5 | IVA | No | OP, TACE |
| C002 | 66 | M | unknown | No | 78 | IVB | 30 days (TP) | OP, TACE |
| C003 | 65 | M | HBV | No | 50.2 | IVB | 7 days (ISE) | OP |
| C004 | 53 | M | HBV | No | 45 | IVB | 7 days (ISE) | TACE |
| C005 | 59 | M | HBV | No | 63.1 | IIIB | 60 days (TP) | RT, TACE |
| C006 | 43 | M | HBV | Yes | 87.8 | IIIB | 60 days (TP) | RT, TACE |
| C007 | 53 | M | alcohol b | Yes | 55.7 | IIIB | 90 days (TP) | RT, RFA, TACE |
| C008 | 58 | M | HCV | Yes | 64 | IVB | no | RT, TACE |
| C009 | 54 | M | HBV | Yes | 55.8 | IVB | 60 days (TP) | RT, TACE |
| C010 | 77 | M | unknown | Yes | 79 | IVB | 28 days (ISE) | RT, TACE |
| C011 | 71 | M | HBV | Yes | 70.6 | IVB | 60 days (TP) | TACE |
| C012 | 74 | M | unknown | No | 58.6 | IIIB | 60 days (TP) | RT, OP, TACE |
| C013 | 59 | M | HCV | Yes | 64.2 | IVB | 14 days (ISE) | TACE |
| C014 | 71 | M | unknown | No | 57.5 | IVB | 60 days (TP) | OP |
| C015 | 77 | M | HCV | Yes | 51.9 | IVB | 21 days (ISE) | OP |
Note: Parentheses indicate the reason for the discontinuation of sorafenib treatment.
The tumor stage was determined on enrollment based on the American Joint Committee on Cancer TNM staging system 7th or 8th edition.
Consumption for more than 120 g alcohol per day for more than 10 years. F, female; HBV, hepatitis B virus; HCV, hepatitis C virus; ISE, intolerable side effects; LC, liver cirrhosis; M, male; OP, operation; RFA, radiofrequency ablation; RT, radiation therapy; TACE, transcatheter arterial chemoembolization; TP, tumor progression.
TABLE 2.
Results of colchicine treatment
| Code | Combined treatment with colchicine | Total colchicine treatment courses | Cause to stop colchicine treatment | Treatment after colchicine | Cause of death | Survival (day) |
|---|---|---|---|---|---|---|
| C001 | No | 34 (3 mg 4, 2.5 mg 5, 2 mg 25) | TP | RT for abdominal lymph nodes | TP | 381 |
| C002 | No | 3 (3 mg) | TP | No | TP | 81 |
| C003 | No | 5 (2 mg) | TP | No | TP | 69 |
| C004 | No | 6 (3 mg 1, 2.5 mg 2, 2 mg 3) | TP | No | TP | 84 |
| C005 | No | 38 (3 mg) | Cholangitis | No | cholangitis | 333 |
| C006 | No | 7 (3 mg 2, 2.5 mg 5) | Participant withdrew | TACE twice | TP | 131 |
| C007 | TACE twice | 49 (3 mg 47, 2.5 mg 2) | cholangitis | TACE once | TP | 468 |
| C008 | No | 12 (3 mg 7, 2.5 mg 5) | TP | No | TP | 218 |
| C009 | No | 14 (3 mg) | TP | No | TP | 123 |
| C010 | TACE 4 sessions, PEI 4 sessions | 70 (3 mg 48, 2 mg 22) | TP | No | TP | 788 |
| C011 | No | 8 (2 mg) | TP | No | TP | 67 |
| C012 | TACE once | 24 (3 mg) | TP | No | TP | 226 |
| C013 a | TACE, RT twice for pulmonary lesions | 143 (3 mg 4, 2 mg 114, 1.5 mg 1, 1 mg 24) b | N/A | N/A | N/A | 1000 |
| C014 | N/A | N/A | Screening failure | N/A | TP | 60 |
| C015 | No | 11 (2 mg) | Participant withdrew | No | TP | 255 |
The data were calculated at the end of this trial.
The colchicine dose was reduced to 1 mg/day during treatment of chronic hepatitis C by direct‐acting antiviral drugs for 24 weeks and the treatment result was sustained virologic response. N/A, not applicable; PEI, percutaneous ethanol injection; RT, radiation therapy; TACE, transcatheter arterial chemoembolization; TP, tumor progression.
To evaluate the potential efficacy of colchicine treatment, nine participants (9/13, 69.2%) receiving colchicine for more than eight cycles were compared with the control group (Table 3, Figure 1). The control group showed significantly higher ratio of combined HCC treatment during and/or after sorafenib medication than the colchicine group (p = 0.0002). However, there was no significant difference in mortality (p > 0.4), median survival (p > 0.4), and OS (p = 0.3290) between two groups. Furthermore, there was also no significant difference in mortality (p > 0.5), median survival (p = 0.2722), and OS (p = 0.8488) between all included participants in colchicine group and the sorafenib group.
TABLE 3.
Characteristics and survival of patients receiving either colchicine or sorafenib for more than 2 months
| Colchicine group (n = 9) | Sorafenib group (n = 86) | p‐Value | |
|---|---|---|---|
| Age (years) | 53–77 (median 59) | 26–83 (median 62) | |
| Sex (male/female) | 8/1 | 67/19 | >0.05 |
| LC (+/−) | 6/3 | 59/27 | >0.05 |
| Etiology | |||
| HBV | 3 | 42 | |
| HCV | 3 | 26 | |
| HBV + HCV | 1 | ||
| Alcohol a | 1 | 1 | |
| Unknown | 2 | 16 | |
| TNM staging b (IIIB/IVA/IVB) | 3/1/5 | 37/16/33 | >0.05 |
| Combined treatment during and/or after colchicine or sorafenib medication (yes/no) c | 5/4 | 85/1 | 0.0002 |
| Colchicine or sorafenib treatment duration (week) d | 11–143 (median 34) | 10–168 (median 16) | >0.1 |
| Mortality d | 8/9 (88.9%) | 81/86 (94.19%) | >0.4 |
| Survival (days) d | 123–1000 (median 333) | 74–1560 (median 290) | >0.4 |
Note: Data for continuous variables are expressed as range and median.
Consumption for more than 120 g alcohol per day for more than 10 years.
The tumor stage was determined on enrollment based on the American Joint Committee on Cancer TNM staging system 7th or 8th edition.
Combined treatment included immunotherapy, percutaneous ethanol injection, radiation therapy, radiofrequency ablation, systemic chemotherapy, target therapy (regorafenib or lenvatinib) or transcatheter arterial chemoembolization according to the condition of the patient. The detail information for combined therapy in colchicine group was shown in Table 2.
The data were calculated at the end of this trial. HBV, hepatitis B virus; HCV, hepatitis C virus; LC, liver cirrhosis. Fisher exact test, chi‐squared test or Mann–Whitney U test was applied for statistical calculation.
FIGURE 1.
Comparison the survival between patients treated by either colchicine (n = 9) or sorafenib (n = 86) for more than 2 months. The log–rank test was applied for statistical analysis; p = 0.3290
The severe adverse events for both colchicine and sorafenib groups were shown in Table 4. The colchicine group demonstrated significantly higher incidence of biliary tract obstruction than the sorafenib group (p = 0.0184). For two participants in colchicine group (C005 and C007) suffered from biliary tract obstruction, one (C005) previously treated by radiation therapy for HCC portal venous invasion at hepatic hilar area showed segmental stricture of common bile duct at hepatic hilar area. Another one was caused by direct HCC invasion into biliary tract. Grade 1 or 2 adverse events for both groups were shown in Table 5. Colchicine group had significantly higher incidence of diarrhea than the sorafenib group (p = 0). All participants in colchicine group suffered from diarrhea which usually noted from the 2nd day of the treatment cycle. On the contrary, sorafenib group had significantly higher incidence of palmar‐plantar erythrodysesthesia syndrome than the colchicine group (p = 0.0045).
TABLE 4.
Severe adverse events
| Event | Colchicine group (n = 14) | Sorafenib group (n = 86) | p‐Value for the incidence of involved patients | ||
|---|---|---|---|---|---|
| Number of episodes | Involved patients (%) | Number of episodes | Involved patients (%) | ||
| Pneumonia | 3 | 3 (21.43) | 5 | 4 (4.65) | 0.0552 |
| Biliary tract obstruction a | 3 | 2 (14.29) | 0 | 0 | 0.0184 |
| Cholangitisa | 3 | 2 (14.29) | 2 | 2 (2.33) | 0.0931 |
| Peritonitis | 2 | 2 (14.29) | 1 | 1 (1.16) | 0.0506 |
| Sepsis | 0 | 0 | 2 | 2 (2.33) | 1 |
| Diarrhea | 1 | 1 (7.14) | 4 | 4 (4.65) | 0.5374 |
| Anorexia | 1 | 1 (7.14) | 0 | 0 | 0.14 |
| Abdominal pain | 1 | 1 (7.14) | 3 | 3 (3.49) | 0.4584 |
| Skin rash | 0 | 0 | 1 | 1 (1.16) | 1 |
| Palmar‐plantar erythrodysesthesia syndrome | 0 | 0 | 5 | 4 (4.65) | 1 |
| Hypertension | 0 | 0 | 2 | 2 (2.33) | 1 |
| Hemorrhage b | 0 | 0 | 11 | 8 (9.30) | 0.5958 |
| Hypoglycemia | 1 | 1 (7.14) | 0 | 0 | 0.14 |
| Hyperglycemia | 0 | 0 | 1 | 1 (1.16) | 1 |
| Hypocalcemia | 0 | 0 | 1 | 1 (1.16) | 1 |
| Pleural effusion | 0 | 0 | 1 | 1 (1.16) | 1 |
Note: The definition of severe adverse event (grade ≥ 3) was based on the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) published at August 9, 2006.
Two participants in colchicine group concomitantly suffered from both biliary tract obstruction and cholangitis.
Eleven episodes of hemorrhage in sorafenib group included one episode of intracranial hemorrhage from one patient, one episode of hemoperitoneum from another one patient, and nine episodes of gastrointestinal hemorrhage from the remaining six patients.
TABLE 5.
Grade 1 or 2 adverse events with an incidence of more than 5% in either group
| Event | Colchicine group (n = 14) | Sorafenib group (n = 86) | p‐Value for the incidence of involved patients | ||
|---|---|---|---|---|---|
| Number of episodes | Involved patients (%) | Number of episodes | Involved patients (%) | ||
| Diarrhea | 40 | 14 (100) | 83 | 36 (41.86) | 0 |
| Palmar‐plantar erythrodysesthesia syndrome | 0 | 0 | 58 | 31 (36.05) | 0.0045 |
| Nausea/vomiting | 5 | 4 (28.57) | 28 | 15 (17.44) | 0.4604 |
| Hair loss | 1 | 1 (7.14) | 18 | 14 (16.28) | 0.6874 |
| Hypertension | 0 | 0 | 17 | 13 (15.12) | 0.2046 |
| Skin rash | 0 | 0 | 29 | 13 (15.12) | 0.2046 |
| Oral mucositis | 0 | 0 | 6 | 5 (5.81) | 1 |
Note: The definition of adverse event was based on the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) published at August 9, 2006.
13. DISCUSSION
The treatment goal for current HCC target or immunotherapy drugs in advanced HCC is to slow down tumor progression and prolong survival rather than to cure the disease. This indicates that disease progression is an expected treatment result for these medications. Since target or immunotherapy drugs are quite expensive and usually have non‐negligible side effects, these medications are usually discontinued in patients with evidence of tumor progression based on the cost‐effectiveness and/or life quality consideration. However, discontinuation of these medications might have the risk to rapidly exacerbate HCC progression and shorten the survival due to completely loss the possible anti‐cancer effects originated from these medications. Continuation of target or immunotherapy drugs in patients with tumor progression is a theoretically acceptable treatment method if the side effects are tolerable and the cost‐effectiveness can be negligible. On the contrary, the cost of colchicine is extremely lower than the current target or immunotherapy drugs. The total cost of colchicine administration based on our novel dosage schedule for 1 year is still lower than the cost of sorafenib for just 2 days. This extremely low‐cost advantage allows us to long‐term prescription of this drug without causing any economic burden.
Colchicine is mainly metabolized by the liver, and liver cirrhosis will slow down its metabolism. 25 Since most patients with HCC also combine chronic hepatitis and/or cirrhosis, long‐term persistently administration of high colchicine doses will induce toxicity due to accumulation. To overcome this limitation, the present study established a novel dosage schedule based on previous colchicine pharmacokinetics reports. 14 , 15 , 16 This novel dosage schedule was designed to continuously administrate high clinically acceptable dose for 4 days followed by discontinuation for 3 days to eliminate the possible drug accumulation side effects as one treatment cycle. Since both colchicine and sorafenib are not highly efficient anti‐cancer drugs, administration of these drugs less than 2 months is hard to demonstrate their possible anti‐cancer benefits. Therefore, the potential efficacy of colchicine was to compare between participants and patients treated by either colchicine or sorafenib for more than 2 months. However, the baseline characters between two groups had bias. Previous real‐world evidence had revealed that combined sorafenib with transcatheter chemoembolization achieved improved survival vs. sorafenib alone. 26 In the present study, the sorafenib group had higher ratio of combined HCC treatment during and/or after sorafenib medication than the colchicine group. Moreover, current proven target therapy or immunotherapy was the first choice for the treatment of advanced HCC due to ethical consideration. Therefore, almost all included participants in colchicine group (11/13, 84.6%) were collected from patients with experiences of failure in sorafenib treatment. The colchicine group showed worse baseline situation in tumor progression than the sorafenib group. Nevertheless, the colchicine group did not show obvious inferiority in mortality, median survival, and OS as compared with the sorafenib group even when all included participants in colchicine group were applied for analysis. This suggests that colchicine may slow down HCC progression which can be supported by previous animal study. 17 Although this phase IIa trial is unable to make a definite conclusion about the anti‐cancer efficiency of colchicine on HCC due to small number of participants, our results support the potential of colchicine in the palliative treatment of HCC. For severe adverse events, there was higher incidence of grades 3–4 biliary tract obstruction in colchicine group than in sorafenib group. Since there is no evidence of HCC recurrence at C005, segmental stricture of common bile duct at hepatic hilar area in C005 can be explained by previously radiation therapy at hepatic hilar area. 27 The other one (C007) was caused by HCC biliary tract invasion. Although the severe adverse events of biliary tract obstruction were not considered as colchicine side effects, further study with large number of participants should be performed to clarify this issue. Diarrhea is the most well‐known side effect for colchicine treatment. All participants in the colchicine group suffered from this adverse event. This adverse event usually can be prevented and controlled by reducing colchicine dose and/or adding drugs such as dioctahedral smectite or loperamide during colchicine treatment days. Palmar‐plantar erythrodysesthesia syndrome is a well‐known sorafenib side effect. The control group also demonstrated higher incidence of this adverse event than the colchicine group. However, most of the patients in control group only showed grade 1 or 2 palmar‐plantar erythrodysesthesia syndrome and only few patients showed grade 3 event. This can be explained by that patients receiving sorafenib with severe adverse event of palmar‐plantar erythrodysesthesia syndrome were unable to continue for more than 2 months treatment and were excluded. Control group also did not show significantly higher incidence of well‐known sorafenib side effects such as hypertension, hemorrhage, and skin rash than the colchicine group. These can also be explained by pre‐exclusion of patients with severe sorafenib side effects from the trial. These results indicate that long‐term application of colchicine based on our novel dosage schedule is clinically feasible.
The number of participants in the present study was limited. The major reason for the patients to hesitate this trial was no confidence to colchicine because it is not a new drug. Moreover, patients usually could not be included after failure of current target therapy or immunotherapy due to insufficient hepatic and/or renal reserved function.
In conclusion, our novel colchicine dosage schedule is clinically feasible and has the potential to be applied in the palliative treatment of advanced HCC especially based on the cost‐effectiveness consideration. Further phase IIb study with large number of patients is mandatory to confirm the anti‐cancer effect of colchicine on advanced HCC.
CONFLICT OF INTEREST
All authors declare no conflict of interest.
Lin Z‐Y, Yeh M‐L, Huang C‐I, et al. Potential of novel colchicine dosage schedule for the palliative treatment of advanced hepatocellular carcinoma. Kaohsiung J Med Sci. 2021;37:616–623. 10.1002/kjm2.12374
Funding information Taiwan Liver Research Foundation
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