Oncology 1992;49(suppl 1):63—70
Department oflnternal Medicine, National Kinki Central Hospital for Chest Diseases, Sakai, Osaka, Japan
Keywords Non-small cell lung cancer Oral etoposide/cisplatin therapy Dose intensity Long-term chemotherapy
Platinum/Oral Etoposide Therapy in IMon-Small Cell Lung Cancer
Abstract Encouraging response rates have been observed with long-term daily adminis tration of oral etoposide to treat lung cancer. Reasons why HP (etoposide cisplatin) has been used to treat non-small cell lung cancer (NSCLC), despite the fact that etoposide has demonstrated only a modest degree of activity against this disease, are preclinical suggestions of cisplatin/etoposide syner gism and successful results for the combination in treating small cell lung can cer (SCLC). We evaluated a long-term daily oral etoposide regimen in com bination with cisplatin for NSCLC. One course consisted of cisplatin on day I and etoposide from day 1 through day 21. The course was repeated, beginning at day 29. We concluded that the maximum tolerated dose in this schedule was 50 mg/nr/day oral etoposide for 21 days plus 80 mg/nr intravenous (i.v.) cis platin on day 1. The major dose-limiting toxic effect was myelosuppression, and mucositis was also significant in some patients. During this phase I study of 22 patients (18 evaluable), we observed partial responses (PRs) in 4 patients. 1 each with uterine cancer and SCLC, and 2 with squamous cell lung cancers. We then designed a phase II pilot study in patients with advanced NSCLC. The recCmmended treatment schedule is 80 mg/nr i.v. cisplatin on day 1 plus 40 mg/nr/day oral etoposide for 21 consecutive days. Of the 13 evaluable pa tients. PRs were observed in 4 (30.8%), in 2 patients with adenocarcinoma and 2 w'ith squamous cell carcinoma. None of the side effects were severe or lifethreatening. Nearly all of the projected doses were given, with delays o f 7 ¡0 days. In this pilot phase II study, the response rate of advanced NSCLC was above 30%. Future studies should combine long-term administration of oral etoposide with radiation therapy or surgery to treat stage 111 NSCLC.
Etoposide, a semisynthetic derivative of podophyllotoxin, when administered in combination with other medications is one of the most effective agents in the treat ment of germ cell tumors, non-Hodgkin’s lymphoma,
Supported by a Grant-in Aid for cancer research from the Ministry of Health and Welfare of Japan.
and advanced neoplasms, including small cell lung can cer (SCLC). Etoposide has demonstrated remarkable schedule dependency in both animal [ I] and clinical [2] stu dies. Thus, the use of continuous intravenous (i.v.) or oral
Kiyoyuki Furuse, MD. Director Department oflnternal Medicine National Kinki Central Hospital for Chest Diseases I ISO. Nakasone-cho Sakai. Osaka (Japan)
< I992S. Karger AG. Basel 0030 2414 92 0497 0063 S 2.75 0
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Kiyoyuki Furuse
Patients and Methods Patient Entry Criteria Patients who met the following criteria were entered into the study: (1) histologically or cytologically confirmed primary or sec ondary lung cancer; (2) no previous treatment or no treatment for at least 4 weeks prior to this therapy; (3) aged 75 years or younger; (4) Eastern Cooperative Oncology G roup (ECOG) performance status of 2 or less; (5) bone marrow, liver, and renal functions within normal limits leukocyte count > 4 .0 x I0'/1, platelet count > 100 x 10’/1. hemoglobin > 1 0 g dl. aspartate aminotransferase (AST) alanine aminotransferase (ALT) < 8 0 IU. total bilirubin < 2 mg dl. blood urea nitrogen (BUN) < 2 5 mg dl. creatinine < 1.2 mg dl and (6) normal cardiac and pulmonary function. Informed consent was ob tained from all patients.
Treatment One course consisted o f cisplatin on day 1 and etoposide from day I through day 21 followed by 1 week of no medication. The same schedule was repeated starting with day 29. The dose escalation plan chosen for this study had five levels (table I ). Starting doses for EP were: on day 1.20 m g;nr oral etopo
64
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side. with this dose to be repeated for the next 20 days, and 80 mg nr i.v. cisplatin. At least 3 patients were enrolled at each level. Patients received cisplatin via i.v. bolus on day I. followed by 2.5 liters of half saline solution containing electrolytes, furosemidc, mannitol, and antiemetics every 4 treatment weeks. The full etoposide dose was given before breakfast in the form o f a soft gelatin capsule. After 21 days, etoposide was discontinued for 1 week. Because etoposide is only available in 25- or 50-mg capsules, some approximations in the calculated daily dose were necessary, as reported previously by 1iainsworth el al. [3]. If. during the 2 1-day etoposide course, the leu kocyte count fell below 2.0 x 1O'*/! or the platelet count below 50 x 10'’ I. etoposide was discontinued until either or both parame ters recovered. Patients who were stable or improved received a
Table 1 . EP dose escalation plan for long-term etoposide dosing
Step
1 *> 3 4 5
Patients, n
Dose, m g/nr cisplatin (i.v.)
etoposide (p.o.)
80 80 80 80 100
20 30 40 50 50
3 5 5 5 5
Table 2. Characteristics of patients with primary or secondary
lung cancer Patients, n Sex. M E Median age. years Range ECOG performance status 0 1 *)
22 20 2 64 44 73 T
14 6
Prior therapy Chemotherapy alone1 Surgery alone Chemotherapy1plus radiotherapy Tumor type Lung Squamous cell Adenocarcinoma Small cell Colon Adenocarcinoma Breast Adenocarcinoma Uterus Squamous cell
9 2 i
7 6 5 2 i i
1 Patients with prior exposure to cisplatin or etoposide: 4 and 3. respectively.
Platinum Oral Etoposide in NSCI.C
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etoposide administered for 3 5 days has evolved clinically. Since the oral form of etoposide recently became available, phase I and II studies of a long-term daily dosing schedule have been conducted. In the phase I study [3], administra tion of 50 mg/nr etoposide for 21 consecutive days proved a safe dose; 5 patients responded to the regimen, 4 of whom had been resistant to etoposide in previous regimens. In the phase II study [4], which was carried out at multiple centers, a 45.5% response rale was reported in patients with relapsed or refractory SCLC. A long-term daily etoposide regimen has been effective in the treatment of non-small cell lung cancer (NSCLC) [5] and cancer of the kidney, neither of which had responded previously to etoposide. Thus, encouraging response rates have been observed with long-term daily administration of oral etoposide for the treatment of lung cancer. These re sults prompted us to evaluate a long-term daily oral etopo side regimen in combination with cisplatin. The F.P (etoposide cisplatin) combination is the most widely used regimen in the first-line treatment of SCLC [6]. For NSCLC, neoadjuvant chemotherapy or radiation therapy combined with the EP regimen for low toxicity is employed widely [7], The objectives of this study were (1) to determine the maximum tolerated dose of the EP combination, using a 2 1-day course of oral etoposide and a single cisplatin dose on day 1; (2) to evaluate and quantify clinical toxicides, and (3) to seek preliminary evidence of therapeutic activity in patients with advanced solid tumors.
second course; those with obvious evidence of disease progression were withdrawn from the study. Before the next course started, the leukocyte count had to be at least 4.0 x 109/1 and the platelet count at least 100 x 109/1. Patients’ doses were escalated on an individual basis. Complete blood cell counts, differential leukocyte counts, and platelet counts were done prior to the first treatment course and twice weekly thereafter. Serum biochemistry studies of renal and hepatic function were done before therapy and once weekly during treat ment, as were electrolyte determinations, urinalyses, clinical record ings, physical examinations, and toxicity evaluations. Tum or re sponse and drug toxicity were classified in accordance with World Health Organization (WHO) criteria. The maximum tolerated dose was defined as the dose that produced WHO grade 3 or 4 toxicity in two thirds of patients duringa course at each dose level. The duration of therapy was calculated as the number of months from the start of treatment with this regimen to the beginning of disease progression.
Results Patient Characteristics The study began in August 1989 and ended in March 1990. Of 22 patients enrolled, 17 received two or more
courses. Two patients were treated at more than one dose level, and a total of 40 courses were given. The characteris tics of enrolled patients were: 20 men and 2 women; av erage age, 64 years; ECOG performance status of 0 for 2 patients, 1 for 14, and 2 for 6; 12 patients had received previous treatment - chemotherapy alone in 9, radio therapy plus chemotherapy in 1, and surgery in 2 patients; histologically, 9 tumors were adenocarcinoma, 8 squa mous cell cancer, and 5 small cell carcinoma; the primary cancer sites were lung in 18, colon in 2, and breast and uterus in 1 patient each (table 2). Hematologic Toxicity Table 3 shows the weekly change in leukocyte counts. The frequency of grade 3 or worse leukopenia increased progressively from steps 1 through 5: zero of four courses at step 1, two of 11 (18%) at step 2, four of eight (50%) at step 3, eight of 10(80%) at step 4, and five of seven (71 %) at step 5. The leukocyte nadir usually occurred around day 21, with recovery in most patients by day 35. Changes in platelet counts and hemoglobin concentrations are also
Table 3. Hematologic toxicity of long-term oral etoposide and cisplatin
Etoposide/cisplatin dose levels, m g/nr 20/80
30/80
40/80
50/80
50/100
3 4
7 II
5 8
6 10
4 7
Median nadir Range
3.1 3.0-3.8
2.9 1.3-4.2
2.2 1.1-3.3
1.3 0.7-2.6
0.9 0.4-4.1
Day of nadir Range
18 8-24
21 8-29
23 18-26
21 19-29
19 5-26
Day of recovery Range
30 21-42
31 15 44
38 29-50
41 31-47
29 12-40
2/0
4/0
5/3
1/4
Patients, total n Courses, total n Leukocyte count, x 109/1
Courses with WHO grade 3 or 4 toxicity, n 0/0
Median nadir Range
112 69 224
148 64-231
196 108-265
68 32-215
67 13-148
Day o f nadir Range
26 16-30
24 7-32
22 15-26
10 21 32
21 17-26
Day o f recovery Range
34 18 38
21 10-37
27 23-33
27 17-39
28 24 32
Courses with WHO grade 3 or 4 toxicity, n
0/0
0/0
0/0
4/0
1/1
Hemoglobin, g/dl Median nadir Range
9.5 8.0-11.0
10.1 7.1-12.4
8.7 7.0-11.2
8.7 6.8-10.5
8.2 5.8-10.5
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Platelet count, x 109/1
listed in table 3. Thrombocytopenia occurred less fre quently than leukopenia and was less severe. The nadir in platelet counts also occurred around day 21 and resolved by around day 28 in most patients. For most patients treat ed at the doses of steps 1 through 3. myelosuppression had recovered sufficiently by day 35 to allow a repeat course to begin. The decrease in hemoglobin concentrations seemed to progress as doses escalated to higher steps. Side effects were not severe or life threatening, however. Leukopenia was the principal dose-limiting factor in this study. Based on these results, we concluded that the maximum tolerated dose in this schedule was 50 mg/nr/ day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1. the dose that was used in step 4. The leukocyte nadir usually occurred around day 21, with recovery in most patients by day 35. Table 4 depicts the percentage of the etoposide doseintensity actually administered in each step. Two patients forgot to take etoposide, one at step 4 on day 18 and one at step 2 on day 21. Because the leukocyte count fell to levels
Table 4. Dose escalation scheme and treatment given to patients receiving daily oral EP
Step
1 2 3 4 5
too low to justify continued etoposide administration, the drug was temporarily discontinued between days 15 and 21 in eight of 10 courses at step 4 and in four of seven courses at step 5. In one patient at step 5, chemotherapy was continued on day 16 because of thrombocytopenia. The percentage of the planned etoposide dose actually ad ministered declined with increasing dose levels, although we were able to give all of the planned cisplatin dose. Nonhematologic Toxicities Table 5 details the nonhematologic toxicities. Grade 2 or 3 nausea and vomiting was seen in 16 of 40 courses (40%) but was transient and well controlled by standard antiemetic medication. Grade 2 or 3 alopecia was observed in 13 courses (33%) and seemed to be dose related. Grade 2 mucositis was seen during one course (3%), and grade 4 mucositis was seen duringonecourseat step 5 (3%). Grade 2 liver dysfunction was detected during two courses (5%). No patient developed renal toxicity, and no treatmentrelated deaths occurred.
Dose levels, mg/nr
)
cisplatin (i.v., day 1)
etoposide (p.o.,days 10-21)
80 80 80 80 100
20 30 40 50 50
Table 5. Nonhematologic toxicities of long-term oral EP
Patients n
Courses to taln
Delivered dose/ projected dose of etoposide, %
3 7 5 6 4
4 11 8 10 7
100 99 100 87 60
Etoposide/cisplatin dose levels, m g/nr
Patients, total n Courses, total n Courses with WHO grades 2,3 toxicity, n Nausea/vomiting Alopecia Mucositis Abnormal hepatic function Abnormal renal function
20/80
30/80
40/80
50/80
50/100
3 4
7 11
5 8
6 10
4 7
2 i 0 1 0
5 1 0 0 0
4 2 i i 0
2 4 1 0 0
3 5 2‘ 0 0
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Furuse
Platinum O ral Etoposide in NSCLC
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1 One patient had WHO grade 4 mucositis.
Step
Age, years
Sex
Histology (primary site)
Prior therapy
Response
4 4 4 5
55 64 67 73
F M M M
Squamous cell (uterus) Small cell (lung) Squamous cell (lung) Squamous cell (lung)
None Chemotherapy Chemotherapy Surgery
PR PR PR PR
Responses Response to therapy is summarized in table 6. Of 18 pa tients with evaluable disease, partial responses (PRs) were observed in 4 (22%), with response durations of 1.3,5, and over 8 months. Thirteen patients showed no change, and 1 had disease progression. Three patients 1 with a uterine primary cancer, 1 with SCLC, and 1 with squamous cell lung cancer - responded at step 4. The patient with SCLC had been heavily treated previously with a platinum analogue-containing regimen. Another patient with squa mous cell lung cancer achieved a PR at step 5.
Conclusion A single administration ofcisplatin and long-term daily oral etoposide can be given safely in combination at nearly optimal therapeutic single-agent doses of each drug. The major dose-limiting toxic effect was myelosuppression, and mucositis was also significant in some patients. We conclude that the maximum tolerated dose for this re gimen is 50 mg/nr/day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1. During this phase I study of 22 patients, we observed PRs in 4 patients, 1 with uterine cancer, another with SCLC, and 2 patients with squamous cell lung cancers. For future phase II study, the recom mended doses are 40 mg/nr/day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1.
Long-Term Daily Oral Etoposide Combined with Cisplatin in Advanced NSCLC A Pilot Phase II Study Based on results we obtained in the phase I study of cis platin and long-term daily oral etoposide, we designed a phase II study in patients with advanced NSCLC and car ried out a pilot study. The objectives of the phase II study
were to evaluate the activity and toxicity of the regimen in patients with advanced NSCLC and to determine the re sponse rate as the primary end point.
Methods Patient Entry Criteria To be eligible for the pilot study, previously untreated patients had to have measurable stage IIIB or IV histologically or cytologically confirmed NSCLC and no brain metastasis; they had to be aged 75 years or younger and have an ECOG performance status of 0-2: bone marrow, liver, and kidney function had to be within normal limits (leukocyte count > 4 .0 x 109/1, platelet count > 100 x lO’/l. hemoglobin > 9.5g/dl.A S T /A L T < 8 0 IU. total bilirubin < 1.5mg dl, BUN < 1 .5 mg/dl, serum creatinine at or below the normal limit), and cardiac and pulmonary function had to be adequate. Informed consent was obtained from all patients. Patients who had cancers in volving sites in addition to the lung were excluded.
Treatment The treatment schedule is the one recommended in the summary of the phase I study, a combination of 80 m g /n r i.v. cisplatin on day 1 plus 40 mg n r day oral etoposide for 21 consecutive days. Two cour ses were usually administered. Patients who showed objective re sponses continued to receive treatment until the disease progressed. Patients with evidence of disease progression were removed from the study and received other treatment.
Results This pilot study began in August 1990 and ended in Jan uary 1991. Of 14 patients enrolled, 1 was judged ineligible because of stage III A illness. Thus, 13 patients had evalu able disease. Their characteristics were: 12 men and I woman, with an average age of 67 years and a performance status of 0 or 1 for most patients; 4 had stage IIIB and 9 stage IV disease; histologically, 8 had adenocarcinoma, 3 had squamous cell carcinoma, and 2 had large cell car cinoma (table 7).
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Table 6. Response to long-term oral EP
Table 7. Patient characteristics hi pilot study of long-term or;,l PP
Patients, total n Sex. M F Median age. years Range ECOG performance status 0
13 12/1 67 46-67 3 9
1
1
Stage II IB IV
9
Adenocarcinoma Squamous cell cancer Large cell cancer Total
Clinical response, n
Total response
CR
PR
NC
PD
n
%
0 0 0 0
2 2 0 4
5 0 2 7
1 1 0 2
8 3 2 13
25.0 66.7 0 30.8
8 3 2
patients
WHO grade
n
%
Leukocyte count, x 109/1 1.0-1.9 < 1.0
7 0
50
Platelet count, x 10’ 1 25 49
Department oflnternal Medicine, National Kinki Central Hospital for Chest Diseases, Sakai, Osaka, Japan
Keywords Non-small cell lung cancer Oral etoposide/cisplatin therapy Dose intensity Long-term chemotherapy
Platinum/Oral Etoposide Therapy in IMon-Small Cell Lung Cancer
Abstract Encouraging response rates have been observed with long-term daily adminis tration of oral etoposide to treat lung cancer. Reasons why HP (etoposide cisplatin) has been used to treat non-small cell lung cancer (NSCLC), despite the fact that etoposide has demonstrated only a modest degree of activity against this disease, are preclinical suggestions of cisplatin/etoposide syner gism and successful results for the combination in treating small cell lung can cer (SCLC). We evaluated a long-term daily oral etoposide regimen in com bination with cisplatin for NSCLC. One course consisted of cisplatin on day I and etoposide from day 1 through day 21. The course was repeated, beginning at day 29. We concluded that the maximum tolerated dose in this schedule was 50 mg/nr/day oral etoposide for 21 days plus 80 mg/nr intravenous (i.v.) cis platin on day 1. The major dose-limiting toxic effect was myelosuppression, and mucositis was also significant in some patients. During this phase I study of 22 patients (18 evaluable), we observed partial responses (PRs) in 4 patients. 1 each with uterine cancer and SCLC, and 2 with squamous cell lung cancers. We then designed a phase II pilot study in patients with advanced NSCLC. The recCmmended treatment schedule is 80 mg/nr i.v. cisplatin on day 1 plus 40 mg/nr/day oral etoposide for 21 consecutive days. Of the 13 evaluable pa tients. PRs were observed in 4 (30.8%), in 2 patients with adenocarcinoma and 2 w'ith squamous cell carcinoma. None of the side effects were severe or lifethreatening. Nearly all of the projected doses were given, with delays o f 7 ¡0 days. In this pilot phase II study, the response rate of advanced NSCLC was above 30%. Future studies should combine long-term administration of oral etoposide with radiation therapy or surgery to treat stage 111 NSCLC.
Etoposide, a semisynthetic derivative of podophyllotoxin, when administered in combination with other medications is one of the most effective agents in the treat ment of germ cell tumors, non-Hodgkin’s lymphoma,
Supported by a Grant-in Aid for cancer research from the Ministry of Health and Welfare of Japan.
and advanced neoplasms, including small cell lung can cer (SCLC). Etoposide has demonstrated remarkable schedule dependency in both animal [ I] and clinical [2] stu dies. Thus, the use of continuous intravenous (i.v.) or oral
Kiyoyuki Furuse, MD. Director Department oflnternal Medicine National Kinki Central Hospital for Chest Diseases I ISO. Nakasone-cho Sakai. Osaka (Japan)
< I992S. Karger AG. Basel 0030 2414 92 0497 0063 S 2.75 0
Downloaded by: Kings's College London 137.73.144.138 - 11/15/2017 10:06:03 AM
Kiyoyuki Furuse
Patients and Methods Patient Entry Criteria Patients who met the following criteria were entered into the study: (1) histologically or cytologically confirmed primary or sec ondary lung cancer; (2) no previous treatment or no treatment for at least 4 weeks prior to this therapy; (3) aged 75 years or younger; (4) Eastern Cooperative Oncology G roup (ECOG) performance status of 2 or less; (5) bone marrow, liver, and renal functions within normal limits leukocyte count > 4 .0 x I0'/1, platelet count > 100 x 10’/1. hemoglobin > 1 0 g dl. aspartate aminotransferase (AST) alanine aminotransferase (ALT) < 8 0 IU. total bilirubin < 2 mg dl. blood urea nitrogen (BUN) < 2 5 mg dl. creatinine < 1.2 mg dl and (6) normal cardiac and pulmonary function. Informed consent was ob tained from all patients.
Treatment One course consisted o f cisplatin on day 1 and etoposide from day I through day 21 followed by 1 week of no medication. The same schedule was repeated starting with day 29. The dose escalation plan chosen for this study had five levels (table I ). Starting doses for EP were: on day 1.20 m g;nr oral etopo
64
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side. with this dose to be repeated for the next 20 days, and 80 mg nr i.v. cisplatin. At least 3 patients were enrolled at each level. Patients received cisplatin via i.v. bolus on day I. followed by 2.5 liters of half saline solution containing electrolytes, furosemidc, mannitol, and antiemetics every 4 treatment weeks. The full etoposide dose was given before breakfast in the form o f a soft gelatin capsule. After 21 days, etoposide was discontinued for 1 week. Because etoposide is only available in 25- or 50-mg capsules, some approximations in the calculated daily dose were necessary, as reported previously by 1iainsworth el al. [3]. If. during the 2 1-day etoposide course, the leu kocyte count fell below 2.0 x 1O'*/! or the platelet count below 50 x 10'’ I. etoposide was discontinued until either or both parame ters recovered. Patients who were stable or improved received a
Table 1 . EP dose escalation plan for long-term etoposide dosing
Step
1 *> 3 4 5
Patients, n
Dose, m g/nr cisplatin (i.v.)
etoposide (p.o.)
80 80 80 80 100
20 30 40 50 50
3 5 5 5 5
Table 2. Characteristics of patients with primary or secondary
lung cancer Patients, n Sex. M E Median age. years Range ECOG performance status 0 1 *)
22 20 2 64 44 73 T
14 6
Prior therapy Chemotherapy alone1 Surgery alone Chemotherapy1plus radiotherapy Tumor type Lung Squamous cell Adenocarcinoma Small cell Colon Adenocarcinoma Breast Adenocarcinoma Uterus Squamous cell
9 2 i
7 6 5 2 i i
1 Patients with prior exposure to cisplatin or etoposide: 4 and 3. respectively.
Platinum Oral Etoposide in NSCI.C
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etoposide administered for 3 5 days has evolved clinically. Since the oral form of etoposide recently became available, phase I and II studies of a long-term daily dosing schedule have been conducted. In the phase I study [3], administra tion of 50 mg/nr etoposide for 21 consecutive days proved a safe dose; 5 patients responded to the regimen, 4 of whom had been resistant to etoposide in previous regimens. In the phase II study [4], which was carried out at multiple centers, a 45.5% response rale was reported in patients with relapsed or refractory SCLC. A long-term daily etoposide regimen has been effective in the treatment of non-small cell lung cancer (NSCLC) [5] and cancer of the kidney, neither of which had responded previously to etoposide. Thus, encouraging response rates have been observed with long-term daily administration of oral etoposide for the treatment of lung cancer. These re sults prompted us to evaluate a long-term daily oral etopo side regimen in combination with cisplatin. The F.P (etoposide cisplatin) combination is the most widely used regimen in the first-line treatment of SCLC [6]. For NSCLC, neoadjuvant chemotherapy or radiation therapy combined with the EP regimen for low toxicity is employed widely [7], The objectives of this study were (1) to determine the maximum tolerated dose of the EP combination, using a 2 1-day course of oral etoposide and a single cisplatin dose on day 1; (2) to evaluate and quantify clinical toxicides, and (3) to seek preliminary evidence of therapeutic activity in patients with advanced solid tumors.
second course; those with obvious evidence of disease progression were withdrawn from the study. Before the next course started, the leukocyte count had to be at least 4.0 x 109/1 and the platelet count at least 100 x 109/1. Patients’ doses were escalated on an individual basis. Complete blood cell counts, differential leukocyte counts, and platelet counts were done prior to the first treatment course and twice weekly thereafter. Serum biochemistry studies of renal and hepatic function were done before therapy and once weekly during treat ment, as were electrolyte determinations, urinalyses, clinical record ings, physical examinations, and toxicity evaluations. Tum or re sponse and drug toxicity were classified in accordance with World Health Organization (WHO) criteria. The maximum tolerated dose was defined as the dose that produced WHO grade 3 or 4 toxicity in two thirds of patients duringa course at each dose level. The duration of therapy was calculated as the number of months from the start of treatment with this regimen to the beginning of disease progression.
Results Patient Characteristics The study began in August 1989 and ended in March 1990. Of 22 patients enrolled, 17 received two or more
courses. Two patients were treated at more than one dose level, and a total of 40 courses were given. The characteris tics of enrolled patients were: 20 men and 2 women; av erage age, 64 years; ECOG performance status of 0 for 2 patients, 1 for 14, and 2 for 6; 12 patients had received previous treatment - chemotherapy alone in 9, radio therapy plus chemotherapy in 1, and surgery in 2 patients; histologically, 9 tumors were adenocarcinoma, 8 squa mous cell cancer, and 5 small cell carcinoma; the primary cancer sites were lung in 18, colon in 2, and breast and uterus in 1 patient each (table 2). Hematologic Toxicity Table 3 shows the weekly change in leukocyte counts. The frequency of grade 3 or worse leukopenia increased progressively from steps 1 through 5: zero of four courses at step 1, two of 11 (18%) at step 2, four of eight (50%) at step 3, eight of 10(80%) at step 4, and five of seven (71 %) at step 5. The leukocyte nadir usually occurred around day 21, with recovery in most patients by day 35. Changes in platelet counts and hemoglobin concentrations are also
Table 3. Hematologic toxicity of long-term oral etoposide and cisplatin
Etoposide/cisplatin dose levels, m g/nr 20/80
30/80
40/80
50/80
50/100
3 4
7 II
5 8
6 10
4 7
Median nadir Range
3.1 3.0-3.8
2.9 1.3-4.2
2.2 1.1-3.3
1.3 0.7-2.6
0.9 0.4-4.1
Day of nadir Range
18 8-24
21 8-29
23 18-26
21 19-29
19 5-26
Day of recovery Range
30 21-42
31 15 44
38 29-50
41 31-47
29 12-40
2/0
4/0
5/3
1/4
Patients, total n Courses, total n Leukocyte count, x 109/1
Courses with WHO grade 3 or 4 toxicity, n 0/0
Median nadir Range
112 69 224
148 64-231
196 108-265
68 32-215
67 13-148
Day o f nadir Range
26 16-30
24 7-32
22 15-26
10 21 32
21 17-26
Day o f recovery Range
34 18 38
21 10-37
27 23-33
27 17-39
28 24 32
Courses with WHO grade 3 or 4 toxicity, n
0/0
0/0
0/0
4/0
1/1
Hemoglobin, g/dl Median nadir Range
9.5 8.0-11.0
10.1 7.1-12.4
8.7 7.0-11.2
8.7 6.8-10.5
8.2 5.8-10.5
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Platelet count, x 109/1
listed in table 3. Thrombocytopenia occurred less fre quently than leukopenia and was less severe. The nadir in platelet counts also occurred around day 21 and resolved by around day 28 in most patients. For most patients treat ed at the doses of steps 1 through 3. myelosuppression had recovered sufficiently by day 35 to allow a repeat course to begin. The decrease in hemoglobin concentrations seemed to progress as doses escalated to higher steps. Side effects were not severe or life threatening, however. Leukopenia was the principal dose-limiting factor in this study. Based on these results, we concluded that the maximum tolerated dose in this schedule was 50 mg/nr/ day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1. the dose that was used in step 4. The leukocyte nadir usually occurred around day 21, with recovery in most patients by day 35. Table 4 depicts the percentage of the etoposide doseintensity actually administered in each step. Two patients forgot to take etoposide, one at step 4 on day 18 and one at step 2 on day 21. Because the leukocyte count fell to levels
Table 4. Dose escalation scheme and treatment given to patients receiving daily oral EP
Step
1 2 3 4 5
too low to justify continued etoposide administration, the drug was temporarily discontinued between days 15 and 21 in eight of 10 courses at step 4 and in four of seven courses at step 5. In one patient at step 5, chemotherapy was continued on day 16 because of thrombocytopenia. The percentage of the planned etoposide dose actually ad ministered declined with increasing dose levels, although we were able to give all of the planned cisplatin dose. Nonhematologic Toxicities Table 5 details the nonhematologic toxicities. Grade 2 or 3 nausea and vomiting was seen in 16 of 40 courses (40%) but was transient and well controlled by standard antiemetic medication. Grade 2 or 3 alopecia was observed in 13 courses (33%) and seemed to be dose related. Grade 2 mucositis was seen during one course (3%), and grade 4 mucositis was seen duringonecourseat step 5 (3%). Grade 2 liver dysfunction was detected during two courses (5%). No patient developed renal toxicity, and no treatmentrelated deaths occurred.
Dose levels, mg/nr
)
cisplatin (i.v., day 1)
etoposide (p.o.,days 10-21)
80 80 80 80 100
20 30 40 50 50
Table 5. Nonhematologic toxicities of long-term oral EP
Patients n
Courses to taln
Delivered dose/ projected dose of etoposide, %
3 7 5 6 4
4 11 8 10 7
100 99 100 87 60
Etoposide/cisplatin dose levels, m g/nr
Patients, total n Courses, total n Courses with WHO grades 2,3 toxicity, n Nausea/vomiting Alopecia Mucositis Abnormal hepatic function Abnormal renal function
20/80
30/80
40/80
50/80
50/100
3 4
7 11
5 8
6 10
4 7
2 i 0 1 0
5 1 0 0 0
4 2 i i 0
2 4 1 0 0
3 5 2‘ 0 0
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Furuse
Platinum O ral Etoposide in NSCLC
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1 One patient had WHO grade 4 mucositis.
Step
Age, years
Sex
Histology (primary site)
Prior therapy
Response
4 4 4 5
55 64 67 73
F M M M
Squamous cell (uterus) Small cell (lung) Squamous cell (lung) Squamous cell (lung)
None Chemotherapy Chemotherapy Surgery
PR PR PR PR
Responses Response to therapy is summarized in table 6. Of 18 pa tients with evaluable disease, partial responses (PRs) were observed in 4 (22%), with response durations of 1.3,5, and over 8 months. Thirteen patients showed no change, and 1 had disease progression. Three patients 1 with a uterine primary cancer, 1 with SCLC, and 1 with squamous cell lung cancer - responded at step 4. The patient with SCLC had been heavily treated previously with a platinum analogue-containing regimen. Another patient with squa mous cell lung cancer achieved a PR at step 5.
Conclusion A single administration ofcisplatin and long-term daily oral etoposide can be given safely in combination at nearly optimal therapeutic single-agent doses of each drug. The major dose-limiting toxic effect was myelosuppression, and mucositis was also significant in some patients. We conclude that the maximum tolerated dose for this re gimen is 50 mg/nr/day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1. During this phase I study of 22 patients, we observed PRs in 4 patients, 1 with uterine cancer, another with SCLC, and 2 patients with squamous cell lung cancers. For future phase II study, the recom mended doses are 40 mg/nr/day oral etoposide for 21 days plus 80 mg/nr i.v. cisplatin on day 1.
Long-Term Daily Oral Etoposide Combined with Cisplatin in Advanced NSCLC A Pilot Phase II Study Based on results we obtained in the phase I study of cis platin and long-term daily oral etoposide, we designed a phase II study in patients with advanced NSCLC and car ried out a pilot study. The objectives of the phase II study
were to evaluate the activity and toxicity of the regimen in patients with advanced NSCLC and to determine the re sponse rate as the primary end point.
Methods Patient Entry Criteria To be eligible for the pilot study, previously untreated patients had to have measurable stage IIIB or IV histologically or cytologically confirmed NSCLC and no brain metastasis; they had to be aged 75 years or younger and have an ECOG performance status of 0-2: bone marrow, liver, and kidney function had to be within normal limits (leukocyte count > 4 .0 x 109/1, platelet count > 100 x lO’/l. hemoglobin > 9.5g/dl.A S T /A L T < 8 0 IU. total bilirubin < 1.5mg dl, BUN < 1 .5 mg/dl, serum creatinine at or below the normal limit), and cardiac and pulmonary function had to be adequate. Informed consent was obtained from all patients. Patients who had cancers in volving sites in addition to the lung were excluded.
Treatment The treatment schedule is the one recommended in the summary of the phase I study, a combination of 80 m g /n r i.v. cisplatin on day 1 plus 40 mg n r day oral etoposide for 21 consecutive days. Two cour ses were usually administered. Patients who showed objective re sponses continued to receive treatment until the disease progressed. Patients with evidence of disease progression were removed from the study and received other treatment.
Results This pilot study began in August 1990 and ended in Jan uary 1991. Of 14 patients enrolled, 1 was judged ineligible because of stage III A illness. Thus, 13 patients had evalu able disease. Their characteristics were: 12 men and I woman, with an average age of 67 years and a performance status of 0 or 1 for most patients; 4 had stage IIIB and 9 stage IV disease; histologically, 8 had adenocarcinoma, 3 had squamous cell carcinoma, and 2 had large cell car cinoma (table 7).
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Table 6. Response to long-term oral EP
Table 7. Patient characteristics hi pilot study of long-term or;,l PP
Patients, total n Sex. M F Median age. years Range ECOG performance status 0
13 12/1 67 46-67 3 9
1
1
Stage II IB IV
9
Adenocarcinoma Squamous cell cancer Large cell cancer Total
Clinical response, n
Total response
CR
PR
NC
PD
n
%
0 0 0 0
2 2 0 4
5 0 2 7
1 1 0 2
8 3 2 13
25.0 66.7 0 30.8
8 3 2
patients
WHO grade
n
%
Leukocyte count, x 109/1 1.0-1.9 < 1.0
7 0
50
Platelet count, x 10’ 1 25 49
