A randomized Phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma

An Eastern Cooperative Oncology Group Study (E1587)




Patients with metastatic nonsmall cell lung carcinoma (NSCLC) usually have a poor prognosis. A chemotherapy regimen containing cisplatin is commonly used for symptom palliation. Echinomycin is a potent bifunctional intercalator of double-strand DNA; trimetrexate is a new derivative of methotrexate and is active against methotrexate-resistant tumor cells in vitro.


The Eastern Cooperative Oncology Group conducted a randomized Phase II study. Eligible patients were assigned to receive echinomycin 1200 μg/m2 by intravenous (i.v.) infusion over 30-60 minutes once a week for 4 weeks, repeated every 6 weeks; trimetrexate 12 mg/m2 i.v. bolus on Days 1-5 every 3 weeks, or 8 mg/m2 i.v. bolus on Days 1-5 for patients who had prior radiation to greater than 30% of their bone marrow; or cisplatin 60 mg/m2 i.v. on Day 1 and etoposide 120 mg/m2 i.v. on Days 1-3 every 4 weeks. Patients were evaluated before each cycle for tumor response, toxicity, and quality-of-life measurements.


One hundred thirty-six patients were entered on the study, and 118 were evaluable for toxicity and response. The response rates were 16%, 5%, and 5% in patients treated with cisplatin and etoposide, echinomycin, and trimetrexate, respectively. There were no complete responses. The median survival was 37.9, 24.3, and 28.0 weeks for patients who received cisplatin and etoposide, echinomycin, and trimetrexate, respectively. Although cisplatin and etoposide appeared to give better therapeutic results, the response rate or survival did not reach statistical significance. This may have been due to inadequate sample size. Neither did quality-of-life measurement show any significant differences among treatments.


Echinomycin and trimetrexate had minimal antitumor activity in patients with metastatic NSCLC. Response rate and survival remained poor in all three treatment arms. Patients should be encouraged to participate in clinical trials so that more effective therapy can be identified. Cancer 1998;82:292-300. © 1998 American Cancer Society.

Nearly 180,000 new cases of lung carcinoma will be diagnosed in 1996 in the United States. Eighty percent of these cases will be nonsmall cell lung carcinoma (NSCLC). The majority of the patients will develop recurrent or metastatic disease that will require systemic therapy. The treatment results of chemotherapy administered to patients with Stage IV metastatic NSCLC have been poor at best, with response rates ranging from 20% to 40% and a median survival of 5-10 months. Eighty percent of these patients may not survive longer than 1 year.1-3 It is clear that we need to search for more effective agents. Although meta-analysis has shown a modest prolongation of survival resulting from chemotherapy,4, 5 there is no conclusive evidence of survival benefits resulting from any chemotherapy given to this group of patients. It is also difficult to evaluate the palliative effects of chemotherapy due to its potential side effects. Hence, there has been no standard chemotherapy regimen.

Cisplatin-based chemotherapy has commonly been used to treat patients with metastatic NSCLC. One of the commonly used regimens is a combination of cisplatin and etoposide.6 This combination was evaluated in a previous Eastern Cooperative Oncology Group (ECOG) study. The treatment arm that received it had the best results of the study, with a 20% response rate and a 25% 1-year survival rate.2 Echinomycin is a cyclic peptide that is isolated from Streptomyces echinatus. It belongs to a family of quinoxalic antibiotics and consists of two planar quinoxalines connected by an octapeptide bridge. The antitumor activity of echinomycin is thought to come from its ability to intercalate bifunctionally with double-strand DNA and inhibit RNA synthesis.7 The preclinical studies show good antitumor activity of echinomycin against murine B16 melanomas and P388 leukemia as well as rat hepatoma AH-130 and several hamster tumor models.8

Trimetrexate is a potent inhibitor of dihydrofolate reductase and differs from methotrexate in a number of ways that may prove to be clinically advantageous. Trimetrexate is not a classical antifolate in that it is not polyglutamylated. Unlike methotrexate, trimetrexate does not enter cells by the reduced folate carrier. It has been found to be active against human acute lymphoblastic leukemic cells that were resistant to methotrexate by virtue of reduced transport.9 Preclinical studies demonstrate excellent activity against murine B16 melanoma L1210 and P338 leukemias as well as the subcutaneous implanted CD8F mammary tumor.10 Clinical tumor responses have been observed in initial Phase I studies that have included patients with NSCLC, breast carcinoma, and head and neck cancers.11 More recently, trimetrexate in combination with 5-fluorouracil and leucovorin has been reported to produce a 20% partial response rate in colorectal carcinoma patients.12 Based on the above information, ECOG conducted a randomized Phase II study to evaluate the efficacy of echinomycin, trimetrexate, and cisplatin plus etoposide in the treatment of patients with metastatic NSCLC.


Patient Selection

The eligibility criteria for patients to enter the study included histologically confirmed NSCLC with measurable and metastatic disease (Stage IV disease by AJCC TNM staging); ECOG performance status of 0 or 1; adequate bone marrow, liver, and renal function; no prior chemotherapy or concurrent radiation; and no brain metastases. Patients with uncontrolled diabetes mellitus, hypertension, unstable angina, congestive heart failure, myocardial infarction within the last 12 months, or cardiac arrhythmia were ineligible for this study. Every patient had to sign an informed consent document to enter the study.

Treatment Plan

Patients were randomized equally to receive one of three treatments: 1) echinomycin 1200 μg/m2 in 250 cc of normal saline over 30-60 minutes weekly ×4 every 6 weeks; 2) trimetrexate 12 mg/m2 i.v. bolus on Days 1-5 every 3 weeks or 8 mg/m2 i.v. bolus on Days 1-5 every 3 weeks for patients who had prior radiation to greater than 30% of their bone marrow (trimetrexate was administered in 100 mL of D5W over 10 minutes); 3) cisplatin 60 mg/m2 in 250 cc of normal saline over 30 minutes with prehydration of 2 liters of 5% glucose in 1/2 normal saline plus 10 milliequivalent potassium chloride per liter to run over 2 hours. Furosemide 40 mg i.v. by bolus push was given after hydration and before cisplatin. Patients also received 12.5 g mannitol i.v. over 15 minutes after cisplatin and etoposide 120 mg/m2/day on Days 1-3 in 250 cc of normal saline i.v. over 45 minutes. Cisplatin and etoposide were repeated every 4 weeks.

Dose modifications were based on hematologic, hepatic, and renal toxicity. For white blood count (WBC) nadirs between 1000/mL and 1500/mL or below 1000/mL, a 25% or 50% dose reduction was made on each treatment medication, respectively. The same dose modifications were also made for platelet nadir counts between 25,000/mL and 50,000/mL or less than 25,000/mL. The treatment was delayed until WBC was >4000/mL and platelet count was ≥100,000/mL. The dose of trimetrexate, etoposide, and echinomycin was not given if the patient developed bilirubin >1.6 mg/dL or serum glutamic-oxaloacetic transaminase 5 times greater than normal. There was a 50% reduction of echinomycin, trimetrexate, and cisplatin, if the patient developed a creatinine between 1.5 and 2.5 mg/dL.

Treatment was withheld for creatinine ≥2.5 mg/dL. If any other Grade 3 or 4 toxicities occurred, the treatment was also withheld and restarted with 50% of the original dose when toxicity was resolved. The dose would then increase in subsequent cycles by 25% if there was no recurrence of toxicity.

Patients were evaluated prior to entry with history and physical examination, measurement of the indicator lesions, performance status, complete blood count (CBC), serum chemistry profile, electrolytes, chest X-ray, radionuclide bone scan, abdominal computed tomography (CT) scan, brain scan, and quality-of-life evaluation (a study of the degree of nausea and vomiting, analgesic requirement with pain assessment, and performance status). These instruments had not been previously validated in Stage IV NSCLC and only partially evaluated the quality of life; our study was the first by the ECOG to evaluate any quality of life for patients with this disease. History and physical examination, tumor response evaluation, CBC, and serum chemistry profile were done before each cycle. In addition, CBC, serum creatinine, and SGOT were repeated weekly for patients receiving echinomycin to monitor its potential hepatic toxicity. Patients had to be on study for at least one cycle to be classified as evaluable for toxicity and two cycles for response. They could be removed from the study for progressive disease (PD) at any time. Patients with partial response (PR) or complete response (CR) continued on study until disease progression. The primary end point of our study was to evaluate the response rate and toxicity of each treatment. The secondary end point was the evaluation of quality of life under each treatment. The evaluation of response and toxicity were based on standard ECOG solid tumor criteria.13 In brief, CR indicated complete disappearance of all clinical detectable disease for at least 4 weeks without a new lesion. PR indicated a ≥50% decrease in tumor size of indicative lesions lasting for at least 4 weeks, without increase in size of any area of known malignant disease or appearance of new disease. Progression (PD) indicated an increase of >25% in the size of lesions, appearance of new metastatic disease, deterioration of performance status by more than one ECOG level, or weight loss >10% of the pretreatment level. In addition, the need for palliative radiotherapy was taken as evidence of PD. Patients were assigned a stable disease status when they did not qualify for either response or progression. The quality of life was evaluated by documenting changes in weight, performance status, narcotic requirement, and nausea/vomiting.

These measurements were taken at the beginning of each cycle and were assessed by the patient with questionnaires.

Statistical Analysis

Patients entering the study were randomized according to the permuted block randomization,14 stratified by histologic cell type, and weight loss in previous 6 months (>5% vs. <5%). The initial design was to accrue 132 patients, allowing for 10% exclusion rate due to cancellations and ineligibility, so that there would be 40 analyzable patients on each treatment.

The rate of toxicity was compared among treatments using Kruskal-Wallis test.15 The objective response rate was analyzed by Fisher exact test and the survival time by the log rank test. The survival curve was estimated by the Kaplan-Meier method.16 The logistic regression model and the proportional hazards regression model17, 18 were used to estimate the joint prognostic factors on the objective responses and survival, respectively. A step-down procedure, consisting of dropping the least significant covariates one at a time, was used to obtain a more parsimonious model. The time to treatment failure was measured from the date of randomization to the date of relapse, disease progression, or death, whichever occurred first.

The survival time was measured from the date of randomization to the date of death or the date the patient was last known to be alive.


From October 1987 to September 1988, 136 patients were registered and entered on the protocol. Three patients canceled before the treatment started, one due to receiving other treatments; one developed pneumonia and died before treatment started; and one developed brain metastases. Fifteen patients were deemed ineligible after a review of the records, for the following reasons: four patients were found to have no metastases, two patients had brain metastases, two patients were without pretreatment CT scan, one patient had a performance status of 2, one patient was without measurable disease, one patient's diagnosis was not confirmed, one patient had had prior chemotherapy, two patients had a prior history of cardiac arrhythmia, and one patient was lost to follow-up. The remaining 118 patients were evaluable for toxicity and response, and they were the basis of the following reports.

Patient Characteristics

Table 1 summarizes the distribution, by treatment, of baseline patient characteristics on the study. All the characteristics were evenly distributed among the three treatment arms. The majority of patients were male and ambulatory and had had previous surgery but no prior radiotherapy. The median age was 59 years, with a range of 33-82 years. Fifty-three percent of the patients had adenocarcinoma, and 71% had <5% weight loss during the 6 months prior to study response.

Table 1. Distribution of Patient Characteristics (%) by Treatment
Patient characteristicECM (n = 41)TMQ (n = 40)VPP (n = 37)Overall (n = 118)
  1. ECM: echinomycin; TMQ: trimetrexate; VPP: VP-16 (etoposide) + cisplatin; adeno: adenocarcinoma.

  Squamous cell27303230
  Large cell15201617
Weight loss previous 6 mos
Age (yrs)
Initial performance status
  Fully active44382436
Previous treatment
Associated chronic diseases
Chronic medications
Albumin (g/dL)
Metastatic lesion
  Ipsilateral lung76636869
  Contralateral lung39402736
  Scalene/supraclavicular lymph nodes27331926
  Bone marrow0101


Objective response was documented in 10 patients, all of whom had PR. Six patients had no change, and 95 patients had PD. Seven patients were unevaluable for response for various reasons. Sixteen percent (6 of 37) of patients responded to cisplatin and etoposide (95% confidence interval, 6.2-32%). Echinomycin had a 5% response rate (95% confidence interval, 0.6-16.6%). Trimetrexate also had a 5% response rate (95% confidence interval, 0.6-16.9%). A low initial level of alkaline phosphatase seemed to be an indicator of a positive response (P = 0.006), as did a high initial level of albumin (P = 0.050). A logistic regression model that included these two factors was constructed. We found that albumin was no longer significant in the presence of alkaline phosphatase. The response rate was not significantly different among the three treatment arms after adjustment for the initial level of alkaline phosphatase. However, there was a difference of marginal statistical significance in the response rate between the "standard" treatment, cisplatin plus etoposide, and the "new" treatment, echinomycin and methotrexate combined (P = 0.069). The median time to treatment failure was 8 weeks for echinomycin, 8.4 weeks for trimetrexate, and 11.6 weeks for cisplatin and etoposide. These were not statistically significant. However, there was a marginally statistically significant difference in the time to treatment failure between the "standard" treatment with cisplatin plus etoposide and the "new" treatment with either echinomycin or methotrexate (median time to failure was 11.6 weeks vs. 6 weeks; P = 0.080, log rank test).


Echinomycin and trimetrexate in general were well tolerated. One patient on echinomycin developed respiratory failure, and this was thought to be secondary to progressive lung carcinoma and not related to the treatment. Two patients had anaphylactic reactions to echinomycin. One patient had deep vein thrombophlebitis and pulmonary emboli from echinomycin. The most severe side effect of trimetrexate was hematologic, with four patients developing Grade 4 myelosuppression, mainly leukopenia. Cisplatin and etoposide resulted in more frequent Grade 3 nausea and vomiting and myelosuppression than the other two treatments. Table 2 shows the worst complications by treatment by the ECOG grade. There was a marginally significant difference among the treatments (Kruskal-Wallis test, P = 0.09). Cisplatin and etoposide seemed to cause fewer Grade 4 complications but caused more Grade 3 complications.

Table 2. Worst Complication (%) by Treatment
 ECOG grade
  1. ECOG: Eastern Cooperative Oncology Group; ECM: echinomycin; TMQ: trimetrexate; VPP: VP-16 (etoposde) + cisplatin.

ECM410 (0)5 (12)22 (54)10 (24)3 (7)1 (2)
TMQ401 (3)5 (13)13 (33)17 (43)4 (10)0 (0)
VPP370 (0)2 (5)10 (27)24 (65)1 (3)0 (0)
Overall1181 (1)12 (10)45 (38)51 (43)8 (7)1 (1)


Only four patients were alive at the time of analysis. Figure 1 (3K) shows the estimated Kaplan-Meier survival distribution by treatment. Table 3 shows the median survival by selected patient characteristics and the P value for the log rank test. The log rank test was stratified according to previous weight loss. Weight loss was strongly associated with survival, whereas histology was not. There was no significant difference in survival among the three treatments. High initial albumin levels, no loss of appetite, and no bone pain seemed to favor survival. However, treatment was not a significant prognostic factor. The median survival was 24.3, 28.0, 37.9 weeks for echinomycin, trimetrexate, and cisplatin plus etoposide, respectively. The estimated overall 1-year survival rate was 25%; it was 32% for cisplatin and etoposide, 20% for echinomycin, and 25% for trimetrexate.

Figure 1.

Treatment with echinomycin, with 39 deaths, is represented by the solid line; treatment with trimetrexate, with 40 deaths, is represented by long dashes; and treatment with etoposide plus cisplatin, with 35 deaths, is represented by short dashes.

Table 3. Median Survival by Selected Patient Characteristics
    P value
FactorLevelNo. of patientsMedian survival (weeks)Log rank testStratified log rank test
  1. ECM: echinomycin; TMQ: trimetrexate; VPP: VP-16 (etoposide) + cisplatin; adeno: adenocarcinoma.

HistologySquamous cell3526.1
 Large cell2024.00.16930.2844
Prior weight loss<58437.0
Prior surgeryNo3626.9
Prior radiotherapyNo8537.1
Initial performance status04239.4
Albumin<3.9 g/dL6022.1
 ≥3.9 g/dL5838.6<0.00010.0009
Bone painNo9937.1
Age (yrs)<596026.9
Liver metastasesNo9932.9
Subcutaneous metastasesNo10336.6

Quality-of-Life Measurements

We measured changes of weight, performance status, narcotic requirement for pain control, and symptoms of nausea and vomiting as part of the evaluation of quality of life for every patient. Because of the rapid progression of disease and patients' dropping out of the study due to death or PD, only a few data points were available in the latter cycles of treatment.

There were no discernible differences among patients regarding the percentage of change in body weight. In the evaluation of performance status (Table 4), patients treated with etoposide and cisplatin showed higher percentages of improving performance status in cycles 2-4 than patients treated with echinomycin or trimetrexate. This was not statistically significant. The degree of nausea and vomiting did not change over time and did not vary among treatments in spite of the fact that cisplatin and etoposide caused more Grade 3 nausea or vomiting. Again, there were no differences in the requirements for pain medication among the three treatment arms. However, over the course of treatment, there were more patients with less pain (Table 5) and more who complied with the follow-up among those who received cisplatin and etoposide than among those who received the other two treatments.

Table 4. Changea in Performance Status from On-Study
ToChange in P.S.ECMTMQVPPOverall
  • ECM: echinomycin; TMQ: trimetrexate; VPP: VP-16 (etoposide) + cisplatin.

  • a

    A negative value indicates improvement in performance status, "0" indicates no change, and a positive value indicates deterioration.

Cycle 1032 (89)31 (89)34 (100)97 (92)
 14 (11)4 (11)0 (0)8 (8)
Cycle 2-10 (0)0 (0)1 (3)1 (1)
 017 (68)16 (64)23 (79)56 (71)
 16 (24)7 (28)4 (14)17 (22)
 22 (8)2 (8)1 (3)5 (6)
Cycle 3-10 (0)0 (0)2 (10)2 (4)
 010 (67)9 (60)16 (76)35 (69)
 14 (27)5 (33)3 (14)12 (24)
 20 (0)1 (7)0 (0)1 (2)
 31 (7)0 (0)0 (0)1 (2)
Cycle 4-10 (0)0 (0)2 (14)2 (6)
 04 (50)5 (45)10 (71)19 (58)
 13 (38)5 (45)2 (14)10 (30)
 20 (0)1 (9)0 (0)1 (3)
 31 (13)0 (0)0 (0)1 (3)
Table 5. Change in Pain Medications
ToChangea in pain medicationECMTMQVPPOverall
  • ECM: echinomycin; TMQ: trimetrexate; VPP: VP-16 (etoposide) + cisplatin.

  • a

    A negative value indicates improvement in performance status, "0" indicates no change, and a positive value indicates deterioration.

Cycle 2-30 (0)0 (0)1 (5)1 (2)
 -11 (6)1 (8)2 (11)4 (8)
 016 (94)8 (62)16 (84)40 (82)
 10 (0)3 (23)0 (0)3 (6)
 20 (0)1 (8)0 (0)1 (2)
Cycle 3-30 (0)0 (0)1 (8)1 (3)
 -10 (0)0 (0)1 (8)1 (3)
 09 (100)4 (50)8 (62)21 (70)
 10 (0)3 (38)3 (23)6 (20)
 20 (0)1 (13)0 (0)1 (3)
Cycle 4-10 (0)0 (0)1 (13)1 (6)
 04 (100)3 (60)5 (63)12 (71)
 10 (0)2 (40)2 (25)4 (24)


The principal objective of our study was to screen the activity of echinomycin and trimetrexate in Stage IV NSCLC. We used cisplatin and etoposide as the reference arm in case response rates changed as a result of differing patient characteristics. We wanted to avoid the chance that various mixtures of prognostic factors would lead us to discard promising new agents.19

Our study shows that echinomycin and trimetrexate have minimal activity against metastatic NSCLC. Each had only a 5% PR rate, although the toxicities were well tolerated. Unlike previous studies of trimetrexate, which showed 15-19% PR rates in Stage IIIB and IV NSCLC patients,20-22 our study does not suggest further investigation of these two new agents in this disease at the dose and schedule tested.

Although patients who received cisplatin and etoposide had a 16% response rate and a 1-year survival rate of 32% (which appeared better than the results observed with the other two treatments), there were no statistical differences in the response rate, time to treatment failure, or survival among the three treatment arms. This may have been due to the small sample size in each treatment arm and the fact that our study was not designed to compare response rates or survival among treatments. The ECOG Lung Steering Committee has conducted three separate trials of cisplatin and etoposide in the treatment of Stage IV NSCLC patients with similar entry criteria. Table 6 shows that the results were also similar.2, 23 Therefore, we did not include a reference arm in subsequent studies evaluating new agents. We need to evaluate new agents and innovative therapies in this disease as rapidly as possible. In the last few years, active novel agents have been identified, such as paclitaxel, docetaxel, vinorelbine, irinotecan, and gemcitabine.24 We continue to advocate putting patients on peer-reviewed protocols with these promising agents as the choice of first-line therapy for this group of patients.

Table 6. Therapeutic Results of Cisplatin and Etoposide in Stage IV NSCLC from ECOG Studies
ECOG studiesNo. of patients% CR + PR (95% confidence intervals)Median survival (weeks)
  1. NSCLC: nonsmall cell lung carcinoma; ECOG: Eastern Cooperative Oncology Group; CR: complete response; PR: partial response.

EST 158112420 (13.5-27)26.6
EST 15854211 (4-25)29.7
EST 15873716 (6.2-32)37.6

More patients treated with cisplatin and etoposide had improved performance status and decrease in pain from treatment than those treated with trimetrexate or echinomycin. This was not statistically significant. Cisplatin and etoposide caused more severe nausea and vomiting, which were most likely due to the chemotherapy rather than disease progression, especially in view of the fact that this study was conducted before the modern era of 5-HT3 antagonists.25 Nausea and vomiting may have obscured the other benefit of cisplatin and etoposide. In this regard, our study demonstrated the complexity of performing an evaluation of quality of life in patients with metastatic NSCLC due to rapid progression of disease, short survival, and toxicity from therapy. We suggest continuing efforts in evaluating patients' quality of life in clinical trials, which will be of vital importance in identifying better therapy.


This study was conducted by the Eastern Cooperative Oncology Group (Robert L.Comis, M.D., Chair)

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.