Investigational New Drugs 10: 123-128, 1992. 9 1992KluwerAcademic Publishers. Printedin the Netherlands.
Phase II feasibility study of high dose epirubicin plus etoposide and cisplatin (HDEEC) regimen in small cell lung cancer Rafae! Rosell l, Juan Carles 1, Albert Abad 1, Jose M. Jimeno 2, Isabel Moreno 1, Agustin Barnadas 1, Nuria Ribelles 1 and Nassir Haboubi 2 1Medical Oncology Unit. Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 2Research and Development, Oncology Line, Farmitalia Carlo Erba, Milan, Italy Key words: epirubicin, small cell lung cancer
Summary Seventeen patients with small cell lung cancer entered a phase II trial testing the feasibility of adding high dose epirubicin (100-120 mg/m 2, day 1) in combination with etoposide (60-80 mg/m 2, days 1-5) and cisplatin (70 mg/m 2, day 1) courses repeated every three weeks. Complete responders received thoracic (40 Gy) and prophylactic cranial (30 Gy) irradiation. Sixteen patients were evaluable for response and toxicity. Myelosuppression was the dose-limiting side effect. Neutropenic fever was observed in eight patients (53%) and stomatitis in six (40%). No patient had a > 14% decline in the cardiac ejection fraction. Strict adherence to the dose-schedule designed was impossible as doses were trimmed and delayed in 30% of instances. The overall objective response rate was 81% (95% confidence limits, 62% to 100%), in limited disease there were complete remissions in 57%. With a 16 months median follow-up, overall median survival was 13 months. This study was unable to prove the feasibility of epirubicin escalation when added to etoposidecisplatin combination, hampering the dose-intensification Norton-Simon model test.
Introduction The gloomy outcome in chemosensitive neoplasms stems from Norton-Simon's [1] farsightedness about the necessity of increasing rather than decreasing intensity dosage, as the best method of curing a tumor. Dose-escalation studies focus on this logistical approach, primarily in neoplasms where a dose-response is present, lowering drug dosage to limit toxicity will produce a smaller fractional cell kill. Cohen et aI. [21 reported an enhanced response and survival when high-dose chemotherapy was compared with low-dose for the treatment of small cell lung cancer (SCLC). Different studies suggest that a steep dose-response relationship occurs in SCLC for cyclophosphamide and etoposide [3]. Johnson et al. [4] have tested the high-dose combination of cyclophosphamide (100 mg/Kg), etoposide (1200 mg/m 2) and cisplatin (120 mg/m 2)
(HDCEP) without bone marrow support. In extensive staged SCLC patients, a complete remission rate of 65% was observed. Vanderbilt's investigators argued that HDCEP is a relatively safe regimen, nadir leukocyte counts of 100 being witnessed. Furthermore fever was present in 91% of courses with a 10% toxic death toll. These intensive induction chemotherapy studies are jeopardized by substantial toxicities with modest gains on survival. However, Arriagada et al. [5] in a recent study showed a possible dose-effect on survival for initial chemotherapy-dose employed. Fifty-two limited SCLC patients received six courses of doxorubicin (40 mg/m 2 on day 1), etoposide (75 mg/m a on days 1-3), cyclophosphamide (300 mg/m 2 on days 3-6) and cisplatin (100 mg/m; on day 2) which were alternated after the first two courses with thoracic irradiation. 83 % of patients achieved complete remission and the 3-year relapse free survival
124 was 24%. In the multivariate analysis, researchers identified the actual initial doses of cisplatin and cyclophosphamide being independent prognostic factors influencing overall and relapse free survival. Klasa et al. [6] made a perusal of 67 trials in SCLC trying to correlate response and median survival time with relative dose intensity. A trend toward a positive correlation between relative dose intensity and median survival time for cyclophosphamide, adriamycin and vincristine regimen was found in extensive S C L C . When only randomized studies were considered doxorubicin doseintensity equipoised with response rate. Epirubicin is a new anthracycline antibiotic with an antitumoral activity spectrum similar to doxorubicin but which provokes a lower frequency of gastrointestinal toxicity and is less myelosuppressive and cardiotoxic [7,8]. Data pooled from four studies summing up 144 chemotherapy-naive SCLC patients, most of which had extensive disease, yielded 43 % remission frequency (95 070 confidence limits, 3507o to 51070) when epirubicin as a single agent was given at the 100-120 m g / m 2 dose [9,10,11,121. The goal of the present study was to demonstrate the feasibility of adding epirubicin at investigational doses of 100-120 m g / m 2 to the standard twodrug regimen of etoposide and cisplatin. Materials and methods
Eligibility criteria for entry were the following: histological diagnosis of SCLC, no prior chemotherapy, radiation therapy or curative surgical resection, less than 75 years old; white blood cells and platelet counts respectively above 4000 and 150.000; serum creatinine and bilirubin less than 1.5 mg/100 ml; no active cardiac disease (myocardial infarction within 6 months, angor pectoris, congestive heart failure, resting left ventricular ejection fraction less than 0.45); Karnofsky performance status equal to or greater than 60070 [13]. Initial staging consisted of complete physical examination, evaluation of performance status (Karnofsky scale), chest x-ray, computed tomography (CT) of the chest, upper abdomen and brain, bron-
choscopy with biopsy, blood chemistries, hematological counts, ECG and resting left ventricular ejection fraction, and bone marrow biopsy. Limited disease was defined as disease confined to the hemothorax, including bilateral supraclavicular nodes and homolateral pleural effusion. All other cases were considered as extensive disease. Patients were further staged according to the Aisner and Whitley proposed TNM staging system [141. Therapy consisted of a total of six courses of a three-drug combination planned to be tested in two consecutive steps without intraindividual escalation. The first step consisted of intravenous cisplatin (70 m g / m 2 on day 1), epirubicin (100 m g / m 2 divided on days 1-2), and etoposide (60 m g / m 2 on days 1-5). Courses were repeated every three weeks if there was evidence of recovery from previous myelotoxicity (absolute granulocyte count more than 1500 and platelet count more than I00.000). Nadir granulocytes less than 500 or nadir platelets less than 50.000 implied that epirubicin dose was limited to 75% of the initial one. A complete restaging with the same tests as performed initially was carried out during the third course and at the end of treatment. Patients with complete remission received prophylactic cranial irradiation (PCI) and thoracic radiotherapy. PCI consisted of a dose of 30 Gy delivered to the brain in 10 fractions over a period of two weeks. Chest irradiation was given at the primary site, the mediastinum and both supraclavicular fossae. A dose of 45 Gy was given over 4 weeks with five fractions per week by parallel opposed fields from megavoltage equipment. A complete remission was the disappearance of all known disease for at least 4 weeks. Partial remission of measurable disease was a > 50~ decrease in a measurable lesion defined by the multiplication of the longest diameter by the greatest perpendicular one. In addition there could be no appearance of new lesions or progression of any lesion. A four week response period was required. For evaluable disease, partial remission was an estimated decrease in a lesion > 50~ No change was less than a 50~ decrease in a total tumor size or < 25~ increase in the size of one or more measurable or evaluable le-
125 Table 2. Treatment related morbidity (worst toxicity recorded) and severity of toxicity
Table 1. Patient and disease characteristics
Characteristics
Number of patients Toxicity
Entered Evaluable Excluded Male Age < 60 > 60 Initial performance status 80o70-90~ 60~ -70~ Limited/Extensive disease Sites of metastatic involvement Liver Adrenal Bone Brain Lung
17 16 1 17 7 9 10 6 7/9 4 3 2 4 1
sions. Disease was considered progressive where there was 25% or more increase in the size of one or more measurable or evaluable lesions a n d / o r appearance of new lesions. W H O criteria were used to report toxicity [15]. Survival curves were calculated by the KaplanMeier product-limit method [16].
Results A total of seventeen patients were included in the trial, one patient was an early death, and should be assessed in the response rate. The other patient is not accountable as was lost of control in the days following the first cycle. Demographic characteristics of the 15 evaluable patients are depicted in Table 1. All were male, median age 59 (range, 35-74). Nine had a 80070-90070 Karnofsky performance status and 6 0 % - 7 0 % in the remaining six. Nine patients were staged as having extensive disease with liver metastases in four, bone in two, adrenal in three, brain in four and contralateral lung in one. Only the first dose level planned was reached because of severe leukopenia occurring in the vast majority of instances. The median leukocyte, granulocyte, hemoglobin and platelet nadirs were
Anemia Leukopenia Neutropenia Thrombocytopenia Nausea/vomiting Mucositis SGOT/SGPT Creatinine Alopecia Fever Infection (site) Sepsis Pneumonia Skin
No. of patients
(~
WHO grading III
IV 0 36 55 9 9 9 0 0
13 11 11 4 4 6 1 2 15 8
(87) (73) (73) (27) (27) (45) (7) (13) (100) (53)
0 9 9 0 18 9 0 0 100 27
27
5 2 1
(33) (13) (7)
0
0
2350, 600, 9,5 and 200.000 respectively. Episodes of neutropenic fever were observed in eight patients (53~ Stomatitis was experienced in six patients (40~ Alopecia grade 3 was documented in all patients. Nausea and vomiting were recorded in 27% of cases; a plausibly low incidence as a result of the strong antiemetic regimen used [17]. The worst toxicities recorded and their grading are outlined in Table 2. No patient had more than 15~ decline in the left ventricular ejection fraction a n d / o r clinical presentation of cardiac heart failure at any time over the therapy period or in the following assessments. Strict adherence to the dose-schedule designed was kept during the first cycle in all patients, nevertheless, overwhelming hematological toxicity, as displayed in Table 2, led us to trim doses and delay treatment in 30~ of the patients. The number of cycles administered was dependent on response. Three patients received 1 cycle of combined epirubicin, VP16 and cisplatin, 1 patient four cycles and the remaining 13 received six cycles. All patients received the first cycle at the actual dose planned. In the subsequent cycles the epirubicin dose was reduced in four patients at 75, 75, 50 and 50 m g / m 2 respectively in two patients with limited stage disease, one with liver metastases and another with bone lesions. Cisplatin dose was cut down to
126 Table 3. Treatment response according to the extent of disease
Response
Overall n (%)
Complete Partial No change Progression
4 (25) 9 (56) 1 (6) 1 (3)
Limited disease n (%)
Extensive disease n (%)
4 (57) 2 (28)
0 (0) 7 (78) 1 (11) 1 (11)
75 m g / m 2 in only one patient without epirubicin or VP16 reduction. One sole patient with bone metastases had VP16 and epirubicin dose reduced at the same time. The remaining patients received full doses except, in some instances, where a 1 week delay period was needed. Table 3 summarizes the response data. The overall response rate was 87~ (95~ confidence limits, 74~ to 100~ There were 4 complete remissions and nine partial remissions among the fifteen evaluable patients. In those with limited disease, complete remission rate was 67~ Two of the complete remissions were delayed after the fifth cycle, both of which evaluated as partial remissions after the first three chemotherapy courses. Radiotherapy did not upgrade the response achieved after completion of chemotherapy. Overall, median survival was 13 months, with a 16 months median follow-up time.
Discussion The present study was stopped because of the inability to keep doses at the first dose level and the evident impossibility of further escalating to the second dose level. In consequence the results obtained are, by and large, in agreement with those of the literature concerning remission frequency and severe hematological toxicity. As we were unable to demonstrate the feasibility of this regimen, the Norton-Simon theory of dose intensification until maximum tumor regression is achieved still remains unproven. Combinations of etoposide, cyclophosphamide, doxorubicin a n d / o r cisplatin has long been tested in our country [18]. Along the same lines Aisner et
[19] referred an outstanding 65~ complete remission frequency in limited disease by means of doxorubicin (45 m g / m 2 on day 1), cyclophosphamide (1 g/m 2 on day 1) and etoposide (50 m g / m 2 on days 1-5) (ACE) repeated every 21 days. Leukopenia was the limiting toxicity with a 100 white count nadir. Adding cisplatin (60 m g / m 2 on day 1) to this regimen (CAVE), Sculier et aL [20] treated 112 patients, courses being repeated every four weeks. Disappointingly, this regimen led to 30O/o complete remission frequency with almost prohibitive hematological toxicity. In our previous experience we employed EVAC regimen, etoposide (300 mg/m2), vincristine (1,5 mg/m2), doxorubicin (50 m g / m 2) and cyclophosphamide (1 g / m 2) every three weeks which brought about an 83~ response rate although the median survival time was anchored at 12 months. Despite the fact that EVAC regimen was well tolerated, its effect on survival was not outstanding [21]. In parallel, trials with cisplatin, doxorubicin and etoposide have yielded a complete remission frequency ranging from 30O7o to 64O7o in limited disease. These response frequencies as well as median survival times have been equal but not better than those claimed with the etoposide-cisplatin combination [22]. To date, high dose epirubicin in combination has not been extensively explored in this disease [23,24]. This prompted us to evaluate the feasibility of incorporating high dose epirubicin to the etoposide-cisplatin regimen to test the dose intensification hypothesis. Bone marrow suppression was severe enough to stop the trial and to proceed to a new trial in which the main target was to determine the optimal dose of epirubicin in combination with cisplatin. In this ongoing trial no dose reduction is being made in febrile neutropenic patients in subsequent cycles as GM-CSF is implemented. This approach has allowed the epirubicin dose to escalate up to 130 m g / m 2 with patients still being included at 140 m g / m 2 epirubicin dose. Two significant provisos should also be made, the first concerns the conundrum of dose-intensity trials as in spite of increasing cisplatin and VP16 doses considerably (actually 44~ increment), no differences were found in comparison with standard doses, al.
127
neither in the response frequency nor in survival [26]. The second caveat concerns the merits of hematopoietic growth factors. Crawford et al. [27] proved their beneficial effect in diminishing the incidence of fever and neutropenia in small cell lung cancer chemotherapy treated patients. However, Bunn et al. [28] when testing GM-CSF in patients receiving VP16 and cisplatin found a significant reduction in granulocytopenia but paradoxically additional infections and more febrile days, as well as thrombocytopenia. In spite of the controversy feasibility phase II studies in small cell lung cancer are still needed. References 1. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986 2. Cohen MH, Creaven P J, Fossieck BE, Broder LE, Selawry OS, Johnston AV, Williams CL, Minna JD: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61:349-354, 1977 3. Harper PG, Souhami RE: Intensive chemotherapy with autologous bone marrow transplantation in small cell carcinoma of the lung. Recent results. Cancer Res 97:146-156, 1985 4. Johnson DH, De Leo M J, Hande KR, Wolff SN, Hainsworth JD, Greco FA: High-dose induction chemotherapy with cyclophosphamide, etoposide and cisplatin for extensive-stage small-cell lung cancer. J Clin Oncol 5:703-709, 1987 5. Arriagada R, De The H, Le Chevalier T, Thomas F, Ruffie P, De Cremoux H, Martin M, Duroux P, Dewar J, SanchoGarnier H: Limited small cell lung cancer: possible prognostic impact of initial chemotherapy doses. Bull Cancer 76:605-615, 1989 6. Klasa R, Murray N, Coldman A: Dose intensity metaanalysis of chemotherapy in small cell carcinoma of the lung. Proc Am Soc Clin Oncol 7:202, 1988 7. Jain KK, Casper ES, Geller NL, Hakes TB, Kaufman RJ, Currie V, Schwartz W, Cassidy C, Petroni GR, Young CW, Wittes RE: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 3:818-826, 1985 8. Torti FM, Bristow MM, Lure BL, Carter SK, Howes AE, Aston DA, Brown BW, Hannigan JF, Meyers F J, Mitchell EP, Billingham ME: Cardiotoxicity of epirubicin and doxorubiein: assessment by endomyocardial biopsy. Cancer Res 46:3722-3727, 1986 9. Eckhardt S, Kolaric K, Vukas D, Kanitz E, Schoket Z, Jassem J, Vuletic L, Jelic S, MechI Z, Koza I, Pawlicki M, Zuchowska B: Phase II study of 4'-epi-doxorubicin in patients with untreated, extensive small cell lung cancer. Med Oncol & Tumor Pharmacother 7:19-23, 1990
10. Banham SW, Henderson AF, Milroy R, Monie RD: Phase II study of high dose epirubicin in poor prognosis small cell lung cancer. Proc Am Soc Clin Oncol 7:217, 1988 ll. Blackstein M, Eisenhauer EA, Wierzbicki R, Yoshida S: Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 8:385-389, 1990 12. Macchiarini P, Danesi R, Mariotti R, Marchetti A, Fazzi P, Bevilacqua G, Mariani M, Giuntini C, Del Tacca M, Angeletti CA: Phase II study of high-dose epirubicin in untreated patients with small-cell lung cancer. Am J Clin Oncol (CCT) 13:302-307, 1990 13. Cerny T, Blair V, Anderson H, Bramwell V, Thatcher N: Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 39:146-149, 1987 14. Aisner J, Whitley NO: Staging of small cell lung cancer: do we need a new staging system. Lung Cancer 5:163-172, 1989 15. Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981 16. Kaplan EL, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958 17. Rosell R, Abad Esteve A, Ribas M, Moreno I: Evaluation of a combination antiemetic regimen including iv high-dose metoclopramide, dexamethasone, and diphenhydramine in cisplatin-based chemotherapy regimens. Cancer Treat Rep 69:909-910, 1985 18. Cortes Funes H, Dominguez P, Perez Torrubia A, Lanzos E, Mendez M, Mendiola C: Treatment of small cell lung cancer with a combination of VP 16-213 and cyclophosphamide with cisplatin or radiotherapy. Cancer Chemother Pharmacol 7:181-186, 1982 19. Aisner J, Whitacre M, Van Echo DA, Wesley M, Wiernik PH: Doxorubicin, cyclophosphamide and VP 16-213 (ACE) in the treatment of small cell lung cancer. Cancer Chemother Pharmacol 7:187-193, 1982 20. Sculler JP, Klastersky J, Becquart D, Vandermoten G, Van Houtte P, Rocmans P, Thiriaux J, Longeval E, Ravez P, Libert P, Flemalle A, Michel J, Mairesse M, Mommen P, Dalesio O: Phase II study of an intensive combination chemotherapy with cisplatin, adriamycin, etoposide and cyclophosphamide (CAVE) in small cell lung cancer. Eur J Cancer Clin Oncol 24:519-526, 1988 21. Abad Esteve A, Rosell R, Moreno I, Fernandez Marcial C, Rosello M, Ribas M: VP-16, vincristina, adriamicina y ciclofosfamida (EVAC) en pacientes con cgmcer de pulmdn de cdlulas pequefias. Med Clin (Barc) 90:569-572, 1988 22. Aisner J, Abrams J: Cisplatin for small-cell lung cancer. Sem Oncol 16(Suppl 6):2-9, 1989 23. Bunn PA, Cullen M, Fukuoka M, Green MR, Hansen HH, Harper P, Johnson D, Klastersky J, Le Chevalier T, Sagman U, Splinter T: Chemotherapy in small cell lung cancer: a consensus report. Lung Cancer 5:127-134, 1989 24. Macchiarini P, Chella A, Riva A, Mengozzi G, Silvano G, Solfanelli S, Angeletti CA: Phase II feasibility study of high
128 dose epirubicin-based regimens for untreated patients with small-cell lung cancer. Am J Clin Oncol (CCT) 13:495-500, 1990 25. Gomez Codina A, Anton A, Rosell R, Vadell C, Jimeno J, Ribelles N, Montalar J, Habboubi N, Sanchez JJ, Riggi M: Determining the optimal dose of epirubicin when combined with cisplatin in patients with small cell lung cancer (Abstr). Proc Am Soc Clin Oncol 1992 (submitted) 26. Ihde D, Mulshine J, Kramer B, Steinberg S, Edison M, Phelps R, Lesar M, Phares J, Minna J, Johnson B: Randomized trial of high vs standard dose VP 16/cisplatin in extensive small cell lung cancer. Proc VI World Conf Lung Cancer 1991;6:135 27. Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tab-
bara I, Kris M, Grous J, Picozzi V, Rausch G, Smith R, Gradishar W, Yahanda A, Vincent M, Stewart M, Glaspy J: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164-170, 1991 28. Bunn PA, Crowley J, Hazuka M, Tolley R, Livingston R: A randomized study of VP-16/cisplatin/chest RT and GMCSF in limited stage small cell lung cancer. Preliminary results of a Southwest Oncology Group study (Abstr). Proc VI World Conf Lung Cancer 1991;6:139
Address for offprints: R. RoseU, Medical Oncology Unit. Hospital Universitari Germans Trias i Pujol, Box 72, 08916 Badalona, Barcelona, Spain
Phase II feasibility study of high dose epirubicin plus etoposide and cisplatin (HDEEC) regimen in small cell lung cancer Rafae! Rosell l, Juan Carles 1, Albert Abad 1, Jose M. Jimeno 2, Isabel Moreno 1, Agustin Barnadas 1, Nuria Ribelles 1 and Nassir Haboubi 2 1Medical Oncology Unit. Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; 2Research and Development, Oncology Line, Farmitalia Carlo Erba, Milan, Italy Key words: epirubicin, small cell lung cancer
Summary Seventeen patients with small cell lung cancer entered a phase II trial testing the feasibility of adding high dose epirubicin (100-120 mg/m 2, day 1) in combination with etoposide (60-80 mg/m 2, days 1-5) and cisplatin (70 mg/m 2, day 1) courses repeated every three weeks. Complete responders received thoracic (40 Gy) and prophylactic cranial (30 Gy) irradiation. Sixteen patients were evaluable for response and toxicity. Myelosuppression was the dose-limiting side effect. Neutropenic fever was observed in eight patients (53%) and stomatitis in six (40%). No patient had a > 14% decline in the cardiac ejection fraction. Strict adherence to the dose-schedule designed was impossible as doses were trimmed and delayed in 30% of instances. The overall objective response rate was 81% (95% confidence limits, 62% to 100%), in limited disease there were complete remissions in 57%. With a 16 months median follow-up, overall median survival was 13 months. This study was unable to prove the feasibility of epirubicin escalation when added to etoposidecisplatin combination, hampering the dose-intensification Norton-Simon model test.
Introduction The gloomy outcome in chemosensitive neoplasms stems from Norton-Simon's [1] farsightedness about the necessity of increasing rather than decreasing intensity dosage, as the best method of curing a tumor. Dose-escalation studies focus on this logistical approach, primarily in neoplasms where a dose-response is present, lowering drug dosage to limit toxicity will produce a smaller fractional cell kill. Cohen et aI. [21 reported an enhanced response and survival when high-dose chemotherapy was compared with low-dose for the treatment of small cell lung cancer (SCLC). Different studies suggest that a steep dose-response relationship occurs in SCLC for cyclophosphamide and etoposide [3]. Johnson et al. [4] have tested the high-dose combination of cyclophosphamide (100 mg/Kg), etoposide (1200 mg/m 2) and cisplatin (120 mg/m 2)
(HDCEP) without bone marrow support. In extensive staged SCLC patients, a complete remission rate of 65% was observed. Vanderbilt's investigators argued that HDCEP is a relatively safe regimen, nadir leukocyte counts of 100 being witnessed. Furthermore fever was present in 91% of courses with a 10% toxic death toll. These intensive induction chemotherapy studies are jeopardized by substantial toxicities with modest gains on survival. However, Arriagada et al. [5] in a recent study showed a possible dose-effect on survival for initial chemotherapy-dose employed. Fifty-two limited SCLC patients received six courses of doxorubicin (40 mg/m 2 on day 1), etoposide (75 mg/m a on days 1-3), cyclophosphamide (300 mg/m 2 on days 3-6) and cisplatin (100 mg/m; on day 2) which were alternated after the first two courses with thoracic irradiation. 83 % of patients achieved complete remission and the 3-year relapse free survival
124 was 24%. In the multivariate analysis, researchers identified the actual initial doses of cisplatin and cyclophosphamide being independent prognostic factors influencing overall and relapse free survival. Klasa et al. [6] made a perusal of 67 trials in SCLC trying to correlate response and median survival time with relative dose intensity. A trend toward a positive correlation between relative dose intensity and median survival time for cyclophosphamide, adriamycin and vincristine regimen was found in extensive S C L C . When only randomized studies were considered doxorubicin doseintensity equipoised with response rate. Epirubicin is a new anthracycline antibiotic with an antitumoral activity spectrum similar to doxorubicin but which provokes a lower frequency of gastrointestinal toxicity and is less myelosuppressive and cardiotoxic [7,8]. Data pooled from four studies summing up 144 chemotherapy-naive SCLC patients, most of which had extensive disease, yielded 43 % remission frequency (95 070 confidence limits, 3507o to 51070) when epirubicin as a single agent was given at the 100-120 m g / m 2 dose [9,10,11,121. The goal of the present study was to demonstrate the feasibility of adding epirubicin at investigational doses of 100-120 m g / m 2 to the standard twodrug regimen of etoposide and cisplatin. Materials and methods
Eligibility criteria for entry were the following: histological diagnosis of SCLC, no prior chemotherapy, radiation therapy or curative surgical resection, less than 75 years old; white blood cells and platelet counts respectively above 4000 and 150.000; serum creatinine and bilirubin less than 1.5 mg/100 ml; no active cardiac disease (myocardial infarction within 6 months, angor pectoris, congestive heart failure, resting left ventricular ejection fraction less than 0.45); Karnofsky performance status equal to or greater than 60070 [13]. Initial staging consisted of complete physical examination, evaluation of performance status (Karnofsky scale), chest x-ray, computed tomography (CT) of the chest, upper abdomen and brain, bron-
choscopy with biopsy, blood chemistries, hematological counts, ECG and resting left ventricular ejection fraction, and bone marrow biopsy. Limited disease was defined as disease confined to the hemothorax, including bilateral supraclavicular nodes and homolateral pleural effusion. All other cases were considered as extensive disease. Patients were further staged according to the Aisner and Whitley proposed TNM staging system [141. Therapy consisted of a total of six courses of a three-drug combination planned to be tested in two consecutive steps without intraindividual escalation. The first step consisted of intravenous cisplatin (70 m g / m 2 on day 1), epirubicin (100 m g / m 2 divided on days 1-2), and etoposide (60 m g / m 2 on days 1-5). Courses were repeated every three weeks if there was evidence of recovery from previous myelotoxicity (absolute granulocyte count more than 1500 and platelet count more than I00.000). Nadir granulocytes less than 500 or nadir platelets less than 50.000 implied that epirubicin dose was limited to 75% of the initial one. A complete restaging with the same tests as performed initially was carried out during the third course and at the end of treatment. Patients with complete remission received prophylactic cranial irradiation (PCI) and thoracic radiotherapy. PCI consisted of a dose of 30 Gy delivered to the brain in 10 fractions over a period of two weeks. Chest irradiation was given at the primary site, the mediastinum and both supraclavicular fossae. A dose of 45 Gy was given over 4 weeks with five fractions per week by parallel opposed fields from megavoltage equipment. A complete remission was the disappearance of all known disease for at least 4 weeks. Partial remission of measurable disease was a > 50~ decrease in a measurable lesion defined by the multiplication of the longest diameter by the greatest perpendicular one. In addition there could be no appearance of new lesions or progression of any lesion. A four week response period was required. For evaluable disease, partial remission was an estimated decrease in a lesion > 50~ No change was less than a 50~ decrease in a total tumor size or < 25~ increase in the size of one or more measurable or evaluable le-
125 Table 2. Treatment related morbidity (worst toxicity recorded) and severity of toxicity
Table 1. Patient and disease characteristics
Characteristics
Number of patients Toxicity
Entered Evaluable Excluded Male Age < 60 > 60 Initial performance status 80o70-90~ 60~ -70~ Limited/Extensive disease Sites of metastatic involvement Liver Adrenal Bone Brain Lung
17 16 1 17 7 9 10 6 7/9 4 3 2 4 1
sions. Disease was considered progressive where there was 25% or more increase in the size of one or more measurable or evaluable lesions a n d / o r appearance of new lesions. W H O criteria were used to report toxicity [15]. Survival curves were calculated by the KaplanMeier product-limit method [16].
Results A total of seventeen patients were included in the trial, one patient was an early death, and should be assessed in the response rate. The other patient is not accountable as was lost of control in the days following the first cycle. Demographic characteristics of the 15 evaluable patients are depicted in Table 1. All were male, median age 59 (range, 35-74). Nine had a 80070-90070 Karnofsky performance status and 6 0 % - 7 0 % in the remaining six. Nine patients were staged as having extensive disease with liver metastases in four, bone in two, adrenal in three, brain in four and contralateral lung in one. Only the first dose level planned was reached because of severe leukopenia occurring in the vast majority of instances. The median leukocyte, granulocyte, hemoglobin and platelet nadirs were
Anemia Leukopenia Neutropenia Thrombocytopenia Nausea/vomiting Mucositis SGOT/SGPT Creatinine Alopecia Fever Infection (site) Sepsis Pneumonia Skin
No. of patients
(~
WHO grading III
IV 0 36 55 9 9 9 0 0
13 11 11 4 4 6 1 2 15 8
(87) (73) (73) (27) (27) (45) (7) (13) (100) (53)
0 9 9 0 18 9 0 0 100 27
27
5 2 1
(33) (13) (7)
0
0
2350, 600, 9,5 and 200.000 respectively. Episodes of neutropenic fever were observed in eight patients (53~ Stomatitis was experienced in six patients (40~ Alopecia grade 3 was documented in all patients. Nausea and vomiting were recorded in 27% of cases; a plausibly low incidence as a result of the strong antiemetic regimen used [17]. The worst toxicities recorded and their grading are outlined in Table 2. No patient had more than 15~ decline in the left ventricular ejection fraction a n d / o r clinical presentation of cardiac heart failure at any time over the therapy period or in the following assessments. Strict adherence to the dose-schedule designed was kept during the first cycle in all patients, nevertheless, overwhelming hematological toxicity, as displayed in Table 2, led us to trim doses and delay treatment in 30~ of the patients. The number of cycles administered was dependent on response. Three patients received 1 cycle of combined epirubicin, VP16 and cisplatin, 1 patient four cycles and the remaining 13 received six cycles. All patients received the first cycle at the actual dose planned. In the subsequent cycles the epirubicin dose was reduced in four patients at 75, 75, 50 and 50 m g / m 2 respectively in two patients with limited stage disease, one with liver metastases and another with bone lesions. Cisplatin dose was cut down to
126 Table 3. Treatment response according to the extent of disease
Response
Overall n (%)
Complete Partial No change Progression
4 (25) 9 (56) 1 (6) 1 (3)
Limited disease n (%)
Extensive disease n (%)
4 (57) 2 (28)
0 (0) 7 (78) 1 (11) 1 (11)
75 m g / m 2 in only one patient without epirubicin or VP16 reduction. One sole patient with bone metastases had VP16 and epirubicin dose reduced at the same time. The remaining patients received full doses except, in some instances, where a 1 week delay period was needed. Table 3 summarizes the response data. The overall response rate was 87~ (95~ confidence limits, 74~ to 100~ There were 4 complete remissions and nine partial remissions among the fifteen evaluable patients. In those with limited disease, complete remission rate was 67~ Two of the complete remissions were delayed after the fifth cycle, both of which evaluated as partial remissions after the first three chemotherapy courses. Radiotherapy did not upgrade the response achieved after completion of chemotherapy. Overall, median survival was 13 months, with a 16 months median follow-up time.
Discussion The present study was stopped because of the inability to keep doses at the first dose level and the evident impossibility of further escalating to the second dose level. In consequence the results obtained are, by and large, in agreement with those of the literature concerning remission frequency and severe hematological toxicity. As we were unable to demonstrate the feasibility of this regimen, the Norton-Simon theory of dose intensification until maximum tumor regression is achieved still remains unproven. Combinations of etoposide, cyclophosphamide, doxorubicin a n d / o r cisplatin has long been tested in our country [18]. Along the same lines Aisner et
[19] referred an outstanding 65~ complete remission frequency in limited disease by means of doxorubicin (45 m g / m 2 on day 1), cyclophosphamide (1 g/m 2 on day 1) and etoposide (50 m g / m 2 on days 1-5) (ACE) repeated every 21 days. Leukopenia was the limiting toxicity with a 100 white count nadir. Adding cisplatin (60 m g / m 2 on day 1) to this regimen (CAVE), Sculier et aL [20] treated 112 patients, courses being repeated every four weeks. Disappointingly, this regimen led to 30O/o complete remission frequency with almost prohibitive hematological toxicity. In our previous experience we employed EVAC regimen, etoposide (300 mg/m2), vincristine (1,5 mg/m2), doxorubicin (50 m g / m 2) and cyclophosphamide (1 g / m 2) every three weeks which brought about an 83~ response rate although the median survival time was anchored at 12 months. Despite the fact that EVAC regimen was well tolerated, its effect on survival was not outstanding [21]. In parallel, trials with cisplatin, doxorubicin and etoposide have yielded a complete remission frequency ranging from 30O7o to 64O7o in limited disease. These response frequencies as well as median survival times have been equal but not better than those claimed with the etoposide-cisplatin combination [22]. To date, high dose epirubicin in combination has not been extensively explored in this disease [23,24]. This prompted us to evaluate the feasibility of incorporating high dose epirubicin to the etoposide-cisplatin regimen to test the dose intensification hypothesis. Bone marrow suppression was severe enough to stop the trial and to proceed to a new trial in which the main target was to determine the optimal dose of epirubicin in combination with cisplatin. In this ongoing trial no dose reduction is being made in febrile neutropenic patients in subsequent cycles as GM-CSF is implemented. This approach has allowed the epirubicin dose to escalate up to 130 m g / m 2 with patients still being included at 140 m g / m 2 epirubicin dose. Two significant provisos should also be made, the first concerns the conundrum of dose-intensity trials as in spite of increasing cisplatin and VP16 doses considerably (actually 44~ increment), no differences were found in comparison with standard doses, al.
127
neither in the response frequency nor in survival [26]. The second caveat concerns the merits of hematopoietic growth factors. Crawford et al. [27] proved their beneficial effect in diminishing the incidence of fever and neutropenia in small cell lung cancer chemotherapy treated patients. However, Bunn et al. [28] when testing GM-CSF in patients receiving VP16 and cisplatin found a significant reduction in granulocytopenia but paradoxically additional infections and more febrile days, as well as thrombocytopenia. In spite of the controversy feasibility phase II studies in small cell lung cancer are still needed. References 1. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986 2. Cohen MH, Creaven P J, Fossieck BE, Broder LE, Selawry OS, Johnston AV, Williams CL, Minna JD: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61:349-354, 1977 3. Harper PG, Souhami RE: Intensive chemotherapy with autologous bone marrow transplantation in small cell carcinoma of the lung. Recent results. Cancer Res 97:146-156, 1985 4. Johnson DH, De Leo M J, Hande KR, Wolff SN, Hainsworth JD, Greco FA: High-dose induction chemotherapy with cyclophosphamide, etoposide and cisplatin for extensive-stage small-cell lung cancer. J Clin Oncol 5:703-709, 1987 5. Arriagada R, De The H, Le Chevalier T, Thomas F, Ruffie P, De Cremoux H, Martin M, Duroux P, Dewar J, SanchoGarnier H: Limited small cell lung cancer: possible prognostic impact of initial chemotherapy doses. Bull Cancer 76:605-615, 1989 6. Klasa R, Murray N, Coldman A: Dose intensity metaanalysis of chemotherapy in small cell carcinoma of the lung. Proc Am Soc Clin Oncol 7:202, 1988 7. Jain KK, Casper ES, Geller NL, Hakes TB, Kaufman RJ, Currie V, Schwartz W, Cassidy C, Petroni GR, Young CW, Wittes RE: A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 3:818-826, 1985 8. Torti FM, Bristow MM, Lure BL, Carter SK, Howes AE, Aston DA, Brown BW, Hannigan JF, Meyers F J, Mitchell EP, Billingham ME: Cardiotoxicity of epirubicin and doxorubiein: assessment by endomyocardial biopsy. Cancer Res 46:3722-3727, 1986 9. Eckhardt S, Kolaric K, Vukas D, Kanitz E, Schoket Z, Jassem J, Vuletic L, Jelic S, MechI Z, Koza I, Pawlicki M, Zuchowska B: Phase II study of 4'-epi-doxorubicin in patients with untreated, extensive small cell lung cancer. Med Oncol & Tumor Pharmacother 7:19-23, 1990
10. Banham SW, Henderson AF, Milroy R, Monie RD: Phase II study of high dose epirubicin in poor prognosis small cell lung cancer. Proc Am Soc Clin Oncol 7:217, 1988 ll. Blackstein M, Eisenhauer EA, Wierzbicki R, Yoshida S: Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study. J Clin Oncol 8:385-389, 1990 12. Macchiarini P, Danesi R, Mariotti R, Marchetti A, Fazzi P, Bevilacqua G, Mariani M, Giuntini C, Del Tacca M, Angeletti CA: Phase II study of high-dose epirubicin in untreated patients with small-cell lung cancer. Am J Clin Oncol (CCT) 13:302-307, 1990 13. Cerny T, Blair V, Anderson H, Bramwell V, Thatcher N: Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 39:146-149, 1987 14. Aisner J, Whitley NO: Staging of small cell lung cancer: do we need a new staging system. Lung Cancer 5:163-172, 1989 15. Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207-214, 1981 16. Kaplan EL, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958 17. Rosell R, Abad Esteve A, Ribas M, Moreno I: Evaluation of a combination antiemetic regimen including iv high-dose metoclopramide, dexamethasone, and diphenhydramine in cisplatin-based chemotherapy regimens. Cancer Treat Rep 69:909-910, 1985 18. Cortes Funes H, Dominguez P, Perez Torrubia A, Lanzos E, Mendez M, Mendiola C: Treatment of small cell lung cancer with a combination of VP 16-213 and cyclophosphamide with cisplatin or radiotherapy. Cancer Chemother Pharmacol 7:181-186, 1982 19. Aisner J, Whitacre M, Van Echo DA, Wesley M, Wiernik PH: Doxorubicin, cyclophosphamide and VP 16-213 (ACE) in the treatment of small cell lung cancer. Cancer Chemother Pharmacol 7:187-193, 1982 20. Sculler JP, Klastersky J, Becquart D, Vandermoten G, Van Houtte P, Rocmans P, Thiriaux J, Longeval E, Ravez P, Libert P, Flemalle A, Michel J, Mairesse M, Mommen P, Dalesio O: Phase II study of an intensive combination chemotherapy with cisplatin, adriamycin, etoposide and cyclophosphamide (CAVE) in small cell lung cancer. Eur J Cancer Clin Oncol 24:519-526, 1988 21. Abad Esteve A, Rosell R, Moreno I, Fernandez Marcial C, Rosello M, Ribas M: VP-16, vincristina, adriamicina y ciclofosfamida (EVAC) en pacientes con cgmcer de pulmdn de cdlulas pequefias. Med Clin (Barc) 90:569-572, 1988 22. Aisner J, Abrams J: Cisplatin for small-cell lung cancer. Sem Oncol 16(Suppl 6):2-9, 1989 23. Bunn PA, Cullen M, Fukuoka M, Green MR, Hansen HH, Harper P, Johnson D, Klastersky J, Le Chevalier T, Sagman U, Splinter T: Chemotherapy in small cell lung cancer: a consensus report. Lung Cancer 5:127-134, 1989 24. Macchiarini P, Chella A, Riva A, Mengozzi G, Silvano G, Solfanelli S, Angeletti CA: Phase II feasibility study of high
128 dose epirubicin-based regimens for untreated patients with small-cell lung cancer. Am J Clin Oncol (CCT) 13:495-500, 1990 25. Gomez Codina A, Anton A, Rosell R, Vadell C, Jimeno J, Ribelles N, Montalar J, Habboubi N, Sanchez JJ, Riggi M: Determining the optimal dose of epirubicin when combined with cisplatin in patients with small cell lung cancer (Abstr). Proc Am Soc Clin Oncol 1992 (submitted) 26. Ihde D, Mulshine J, Kramer B, Steinberg S, Edison M, Phelps R, Lesar M, Phares J, Minna J, Johnson B: Randomized trial of high vs standard dose VP 16/cisplatin in extensive small cell lung cancer. Proc VI World Conf Lung Cancer 1991;6:135 27. Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tab-
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Address for offprints: R. RoseU, Medical Oncology Unit. Hospital Universitari Germans Trias i Pujol, Box 72, 08916 Badalona, Barcelona, Spain
