Distribution of 2-chloro-2′-deoxyadenosine, 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine, Fludarabine and Cytarabine in mice: a whole-body autoradiography study

The distribution characteristics of tritiated nucleoside analogs, 2-chloro-2'-deoxyadeonosine (CdA), 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), 2-fluoroarabinosyladenine (F-ara-A) and cytosine arabinoside (ara-C) were compared in mice using whole-body autoradiography. CdA, CAFdA and F-ara-A have quite similar molecular structures, but they differ substantially in clinical activity as well as the side effects. Eight mice were injected intravenously in couples. One mouse from each pair was killed 20 min postinjection and the other mouse from each pair 4 h after the injection. The distribution of the label was then analyzed by whole-body autoradiography. The distribution of the nucleoside analogs was rapid and uniform. High concentrations were found in highly perfused organs. After 4 h the overall concentration had decreased but relatively high activities were found in the skin for CdA and CAFdA, in the thymus for ara-C and the bone marrow for CdA. Both CdA and CAFdA were found in the brain, but the concentration was surprisingly lower after 4 h for CAFdA, a lipophilic and more stable analog as compared to CdA. There was an uptake of CdA, F-ara-A and CAFdA in the skin. There were signs of retention of ara-C in parts of the thymus. The present investigations indicate that the nucleoside analog transport to the brain in mice is not primarily dependent upon passive diffusion over a lipophilic barrier, but suggestive of a specific transport mechanism.     

Phase I trial of continuous infusion 5-aza-2′-deoxycytidine

PURPOSE: To identify a dose of the demethylating agent 5-aza-2'-deoxycytidine (DAC) with acceptable side effects, and to study its effect on the methylation patterns of relevant genes in tumor biopsies before and after treatment with a novel methylation assay using real-time PCR. METHODS: A group of 19 patients with metastatic solid tumors were treated with DAC by continuous intravenous infusion over 72 h, days 1-3 of a 28-day cycle. Tumor biopsies were taken before and 7 days after starting DAC. RESULTS: The dose levels studied were 20, 30 and 40 mg/m(2). Grade 4 neutropenia was found in two of five patients at 40 mg/m(2) and one of six patients at 30 mg/m(2). No objective responses were seen in this study. Steady-state DAC levels of 0.1 to 0.2 microM were achieved in the 30 and 40 mg/m(2) cohorts. Changes in methylation were observed, but no single gene consistently demonstrated evidence of demethylation. CONCLUSIONS: DAC was tolerated at a dose of 30 mg/m(2) per day for a 72-h intravenous infusion. Changes in gene methylation were observed.     

Phase I–II trial of doxifluridine (5′DFUR) administered as long-term continuous infusion using a portable infusion pump for advanced colorectal cancer

Doxifluridine, a new fluoropyrimidine analog, was administered to 21 patients with advanced colorectal carcinoma. The starting dose was 1.0 g/m² given over 24 h for 90 consecutive days as a continuous infusion. Due to severe skin reactions (hand-foot syndrome), the dose was reduced stepwise to 0.75 g/m²/day. Twenty patients were evaluable for efficacy, one had an early non-toxic death. Seven out of 20 (35%) showed a partial response; disease stabilization was observed in 10 patients (50%) and three showed progressive disease after 3 months of treatment. All 17 patients who achieved a partial response or a stabilization of disease were treated until progressive disease was documented and some had therapy up to 46 weeks. Toxicity was minimal and mainly defined as hand-foot syndrome which occurred in 50% of the patients of whom three experienced severe reaction. There was no myelosuppression, renal or liver dysfunction, no cardiac alterations and only one patient experienced severe dizziness. Doxifluridine is active in advanced colorectal carcinoma when the drug is given as a continuous infusion for 90 consecutive days at a daily dose of 0.75 g/m².     

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors

Purpose: BMS-214662 is a novel farnesyltransferase (FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration. Patients and methods: Infusion of BMS-214662 was prolonged from 2, 4, 8, 16, 24 h in single patient cohorts and repeated weekly for 3 out of 4 weeks. The initial dose was 56 mg/m². When the infusion duration reached 24 h, the dose was escalated at a constant multiples of 1.4 in single patient cohorts until the occurrence of toxicity greater than grade 1, upon which groups of at least three patients were evaluated at each dose level. The plasma pharmacokinetics and FT inhibition in PBMCs were measured in all patients at the prospective maximum tolerated dose. Results: Nineteen patients participated in the study (11 males/8 females) and the weekly dose was increased to a maximum of 300 mg/m² given as a 24 h i.v. infusion. Drug-related toxicity greater than grade 1 first occurred at 300 mg/m², with two patients experiencing dose-limiting toxicity. One patient developed a grade 3 hyponatremia and another developed reversible grade 3 diarrhea, grade 2 renal toxicity, and grade 3 transaminitis. A 275 mg/m² dose was then evaluated, where one of the three patients treated experienced reversible grade 4 renal toxicity and grade 3 diarrhea. In view of the identical renal toxicity at 275 mg/m² in another study and limited drug availability, there was no further accrual to this dose level and the study was closed. No evidence of antitumor activity was observed. The plasma pharmacokinetics of BMS-214662 was linear with high interpatient variability. In the three patients evaluated at the 275 mg/m² dose level, the maximum inhibition of FT activity in PBMCs was 47±23% of the baseline. Conclusion: Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs. Preliminary results were presented at the 38th annual meeting of the American Society for Clinical Oncology, May, 2002, Orlando, FL, USA.     

Pharmacokinetics and disposition of 4′-O-tetrahydropyranyladriamycin in mice by HPLC analysis

Summary The plasma level of 4-O-tetrahydropyranyladriamycin (THP) declined rapidly after IV injection to mice, with a t_1/2() of 0.453 min. Only 1.2 g/ml THP was detected 2 min after injection of 5 mg/kg. The drug was immediately transferred to various tissues, where the drug levels were much higher than the plasma concentration. In the lung and spleen, 8.26 and 13.6 g/g THP was present, respectively, 2 h after administration. Major metabolites of THP were 13-dihydro-THP, ADM, 7-deoxyadriamycinone, and 7-deoxy-13-dihydro-adriamycinone. Only 1.12% of the dose had been recovered in the urine by 48 h after injection as THP and its metabolites, according to analysis by HPLC fluorospectroscopy. The observed disposition of THP was compared with that of adriamycin (ADM). The plasma disappearance and tissue transfer of THP were faster than those of ADM. THP levels in the spleen and lung were higher and those in the heart and liver were lower than the corresponding ADM levels. Drug levels declined more quickly in most tissues in the case of THP than of ADM. Tissue distributions after single bolus and multiple injections were also compared and discussed.     

Renal handling of 2′-deoxyadenosine and adenosine in humans and mice

Summary In a child lacking adenosine deaminase and in patients treated with deoxycoformycin (a potent inhibitor of the enzyme), apparent renal secretion of 2-deoxyadenosine (dAdo) and reabsorption of adenosine (Ado) were observed. The renal clearance of dAdo in humans was approximately five-fold that of creatinine, whereas the renal clearance of Ado was only one-fifth that of creatinine. In mice treated with deoxycoformycin, a similar paradigm was observed. Specifically, plasma levels of Ado and dAdo were elevated to detectable levels and apparent renal secretion and reabsorption of these purine nucleosides became manifest. Thus, the mouse may serve as a suitable model to study the renal handling of these two compounds. The active renal secretion of dAdo may occur because the compound has not been appreciably synthesized by mouse kidney in situ, and ion-trapping of dAdo in acid urine could not explain the net secretion. The differential transport of these similar purine nucleosides suggests a very selective transport system in mammalian kidney. Although carrier-mediated, facilitated diffusion of purine nucleosides across cell membranes is a well-known phenomenon, the present data indicate the existence of (an) active transport sysem(s) for the transepithelial secretion of dAdo, and possibly for the reabsorption of Ado.The abbreviations used in this paper are ADA adenosine aminohydrolase EC 3.5.4.4 - Ado adenosine - dAdo 2-deoxyadenosine - DCF 2-deoxycoformycin - HPLC high-performance liquid chromatography - PBS 0.14 M NaCl plus 0.01 M phosphate buffer, pH 7.4 - PNPase purine nucleoside: orthophosphate ribosyltransferase EC 2.4.2.1 - SCID: ADA^- severe combined immunodeficiency disease associated with ADA deficiency     

Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2′-deoxyadenosine

2-Chloro-2-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD₁₀) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD₁₀ (AUC_{approx. one-half the LD 10})/AUC_MTD was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (K _m) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (V_max)/K _m indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded theK _m in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.     

Pharmacokinetics of the anticancer agent 2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine in rats

The pharmacokinetics of a new 2-halo-2-deoxyadenosine analogue, 2-chloro-9-(2-deoxy-2-fluoro--d-arabinofuranosyl) adenine [CL-F-ara-A], was characterized in rats following the development of a new high-performance liquid chromatography (HPLC) technique. This halogenated derivative was thought to have improved gastrointestinal stability that would facilitate oral administration. The HPLC method consisted of a single ethyl acetate extraction and reverse-phase chromatographic conditions. The method resulted in approximately 83% recovery of CL-F-ara-A from plasma and a sensitivity of 20 ng/ml. At i. v. doses of 10 and 25 mg/kg, the total clearance of CL-F-ara-A decreased from 2.1 to 1.5 l h^–1 kg^–1, with the reduction being attributed to saturation of metabolism. The elimination half-lives following i. v. bolus administrations were estimated to be a mean of 1.35 and 1.84 h at the two respective doses. The volume of distribution at steady state was not significantly different at the two doses, being 3.6 and 3.2 l/kg. The percentage of protein binding of CL-F-ara-A in rat plasma was only 13.3%. Administration of equivalent oral doses resulted in biovailability estimates of approximately 50%, indicating that oral treatment regimens of CL-F-ara-A are feasible.     

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

Summary Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, -2-deoxythioguanosine (-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of -TGdR in patients with cancer after intravenous administration. [³⁵S]--TGdR (5.4 mg/kg, 200 mg/m², 200 Ci total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t_1/2) of 14 min and a terminal t_1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [³⁵S]-6-TG (3.4 mg/kg, 125 mg/m², 200 Ci total) the average initial t_1/2 was 40 min while the terminal phase t_1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that -TGdR is merely a latent form of TG.Deceased, to whose memory this paper is dedicated     

A phase I trial of 5-day continuous infusion cisplatin and interferon α

Combination therapy of cisplatin with interferon (IFN) has been shown in several in vitro as well as in vivo models to be synergistic. In order to decrease toxicity seen with cisplatin, 5-day continuous infusions, in place of bolus administration, have been introduced. This led us to investigate the combination of 5-day continuous infusion cisplatin with repeated IFN dosing in a phase I cisplatin dose escalation study. A group of 17 patients were enrolled in this trial. The maximum tolerated dose (MTD) of cisplatin was 20 mg/m² per day when combined with 3×10⁶ units IFN given three times a week. The dose-limiting toxicities seen included thrombocytopenia, leukopenia, and nausea and vomiting. Pharmacokinetic analyses of free (unbound or ultrafilterable) platinum revealed that the decay curve fitted a monoexponential model. Pharmacokinetic parameters of cisplatin were found to correlate with toxicity. Both increases in the maximum concentration of cisplatin achieved (Cpmax) as well as the area-under-the-curve (AUC) for free platinum, correlated with the incidence of nausea and vomiting (both acute and delayed) and hematological toxicities (leukopenia and thrombocytopenia). None of the patients exhibited significant changes in renal function while on this study. The free platinum levels were higher than found in similar studies evaluating comparable cisplatin infusions alone. The enhanced toxicities seen in this trial may be explained by the results of an in vitro study using human plasma spiked with cisplatin and IFN that revealed decreased protein binding of cisplatin by 2.5–3.0-fold. Of the 17 patients treated, two non-small cell lung cancer patients obtained a partial response and one malignant melanoma patient obtained complete resolution of a malignant pleural effusion. Considering the acceptable toxicity seen in this trial, we recommend phase II trials be conducted with continuous infusion cisplatin with IFN in the treatment of non-small cell lung cancer.Supported in part by ACS grant IN-163 and by a grant from Schering Corporation, Kenilworth, N.J.MPG is a recipient of an Astra Clinical Pharmacology Young Investigator Award     

A phase I pharmacokinetic study of PM00104 (Zalypsis®) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors

Purpose

PM00104 (Zalypsis^®) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).

Methods

Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 + 3 patients per cohort). Plasma samples were collected for PK analysis.

Results

DLTs comprised severe neutropenia lasting >5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay >2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m². Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosuppression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adenocarcinoma and prostate adenocarcinoma had response evaluation criteria in solid tumors stable disease ≥3 months.

Conclusions

PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitumor activity was observed.     

Saturation of 2′, 2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine

Summary The plasma and cellular pharmacology of 2, 2-difluorodeoxycytidine (dFdC, Gemcitabine) was studied during a phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m² per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5-triphosphate (dFdCTP), were determined in mononuclear cells of 22 patients by anion-exchange highpressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m² per 30 min, during which steady-state dFdC levels of 15–20 M were achieved in plasma. A comparison of patients infused with 800 mg/m² over 60 min with those receiving the same dose over 30 min demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10–15 M dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable. In the design of future protocols, a dose rate should be considered that produces maximal nucleotide analogue formation, with increased intensity being achieved by prolonging the duration of infusion.Abbreviations ara-C I--d-arabinosylcytosine - ara-C _ss steady-state concentration of ara-C - ara-CTP 5-triphosphate of ara-C - dFdC 2, 2-difluorodeoxycytidine, Gemcitabine - dFdC _ss steady-state concentration of dFdC - dFdCTP 5-triphosphate of dFdC Supported in part by grants CA28596 and CA32839 from the National Cancer Institute, Department of Health and Human Services, and by grant CH-130 from the American Cancer Society     

Lack of cross-resistance between cytosine arabinoside and a new halogenated nucleoside analogue, 2-bromo-2′-deoxyadenosine in human acute myeloid leukaemia cells

Summary 2-Bromo-2-deoxyadenosine (BdA) is one of a group of recently synthesised halogenated deoxyadenosine analogues that are relatively resistant to inactivation by adenosine deaminase (ADA). Its activity has been studied in human acute myeloid leukemia (AML) in vitro. In these studies BdA behaved as a cycle-active, phase-active agent that blocked cells at the G₁-S transition. It did not exhibit significant cross-resistance with cytosine arabinoside (Ara-C) in either clinical AML samples (from patients who exhibited Ara-C resistance in vivo) or in HL60 in which Ara-C resistance had been induced in vitro. Deoxycytidine kinase levels were not reduced in resistant lines. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase (ADA) inhibitor, with BdA produced a simple additive respose without the dramatic synergism reported when it is used with deoxyadenosine. This is consistent with the idea that BdA is a poor substrate for ADA. This group of compounds warrants further investigation to determine their suitability for clinical use, especially in situations where Ara-C resistance is likely to be a problem.Supported by grants from The Queensland Cancer Fund and Mount Isa Mines Ltd.     

A randomized trial of intrahepatic arterial infusion of 4′-epidoxorubicin with Lipiodol versus 4′-epidoxorubicin alone in the treatment of hepatocellular carcinoma

We conducted a prospective randomized trial to evaluate the efficacy of Lipiodol in intrahepatic arterial infusion chemotherapy for patients with hepatocellular carcinoma (HCC). A total of 38 patients with unresectable HCCs and underlying cirrhosis were entered in this trial, and 36 of them were evaluable. Every 4 weeks, 17 patients received 70 mg of 4-epidoxorubicin (epirubicin) alone (group A), whereas 19 patients received a Lipiodol emulsion containing the same dose of epirubicin (group B) through the hepatic artery. A tumor response (CR+PR) was observed in 12% of group A patients and in 42% of group B patients. The group B patients showed a significantly higher response rate than the group A patients. There was a tendency for an increased duration of survival (P=0.09) in the group B patients. These results suggested that the infusion of the Lipiodol emulsion with epirubicin was more effective than epirubicin alone for the treatment of these patients with HCC.Work presented at the Third International Symposium on Treatment of Liver Cancer, Scoul, Korea, 12–13 February 1993     

Phase I/II tolerability/pharmacokinetic study with one-hour intravenous infusion of doxifluiridine (5′-dFUrd) 3 g/m2 VS 5 g/m2 QD x 5 per month

Summary Eighteen patients with advanced solid cancer were treated with daily 5-dFUrd infusions given over 1 h on days 1–5 of a 4-week cycle. Nine patients received 3 g/m² 5-dFUrd daily and another nine patients 5 g/m². One patient on 5 g/m² 5-dFUrd was not fully evaluable for tolerability due to early death (progressive disease) 4 weeks after the first cycle. A total of 48 cycles was given. The gastrointestinal and hematological toxicity was generally mild (grade 1–2). Central neurotoxicity (ataxia, unsteadiness, diplopia, dysarthria, sometimes confusion) was observed in 7 of 8 patients on 5 g/m² 5-dFUrd leading to premature discontinuation of treatment in 3 patients (after 2 cycles). Only 3 of the 9 patients in the 3 g/m² group had slight signs of cerebellopathy. Typically, the reversible neurological side effects started at the end of the 2nd week of a cycle. The serum elimination kinetics of 5-dEUrd and its metabolites 5-FU and 5-dFUH₂ have been investigated in the serum and showed very low intra- and interindividual variations. Peak concentrations of the 5-dFUrd at the end of the infusion approximated 500 mol/l and 1000 mol/l for the 3 g/m² and 5 g/m² group, respectively. The peak of the serum 5-FU was reached at the same time, the ratio 5-FU/5-dFUrd being around 10%. The elimination half-life time for 5-FU was protracted by a factor of 2–3 compared with the direct injection of 5-FU.Monthly infusion of 5-dFUrd 5 mg/m² per day on days 1–5 lead to an unacceptable frequency and degree of neurological toxicity. Similar infusions of 5-dFUrd 3 g/m² per day on days 1–5 were well tolerated.     

rhGM-CSF subcutaneously combined with rhIL-2 intravenous drip for relieving radiation esophagitis in patients with esophageal cancer undergoing radiotherapy北大核心CSCD

Objective: To investigate the effect of subcutaneous injection of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) combined with intravenous drip of recombinant human interleukin-2 (rhIL-2) on radiation esophagitis in the patients with esophageal cancer undergoing radiotherapy. Methods: Seventy patients with esophageal cancer were randomly divided into the experimental group and the control group. Thirty-five patients in the experimental group were treated with subcutaneous injection of rhGM-CSF combined with intravenous drip of rhIL-2 and radiotherapy, while 35 patients in the control group were just treated with radiotherapy alone. The occurrence of radiation esophagitis, the degree of pain, intervention measures and treatment compliance were compared between the two groups. Results: There were 3 cases with grade 3 or 4 radiation esophagitis in the experimental group, and 12 cases in the control group (P < 0.05). The number of patients with swallowing pain (more than 7 points) caused by radiation esophagitis in the experimental group was significantly less than that in the control group (P < 0.05). The number of patients used the intervention drugs of radiation esophagitis in the experimental group was significantly less than that in the control group (P < 0.05). After the treatment, the nausea and vomiting, loss of appetite, pain, and insomnia in the experimental group were significantly better than those in the control group (all P < 0.05). There was no interruption of radiotherapy in the experimental group, while the radiotherapy of 3 cases in the control group was interrupted (P < 0.05). Conclusion: Subcutaneous injection of rhGM-CSF combined with intravenous drip of rhIL-2 significantly reduce the proportion of radiation esophagitis-related symptoms in the patients with esophageal cancer, improve the quality of life by reliving the swallowing pain, as well as improve the treatment compliance of patients. © 2019 by TUMOR All rights reserved.