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Cancer Investigation, 9(1) 19-25 (1991)

Adjuvant Chemotherapy for Tl-ZNOMO Small Cell Lung Cancer: Single-Agent or Combination Chemotherapy? Paolo Macchiarini, M.D.,*I Michael Hardin, Ph.D.,t Fulvio Basolo, M.D.,* Joseph Bruno, M.D.,$ and Carlo A. Angeletti, M.D.* *Service of Thoracic Surgery Via Roma 67 *Institute of Pathological Anatomy and Histology Via Roma, 55 University of Pisa Pise, Italy +ComprehensiveCancer Center University of Alabama at Birmingham Birmingham, Alabama

ABSTRACT

In an attempt to address the schedule of adfivant chemotherapy in surgically resected TI or l2NOMO small cell lung cancer, 12patients were rMdornized to receive 6 courses of either single-agent (high-dose epirubicin) or combination (cyclophosphamide, epirubicin, and etoposide) chemotherapy, at 3-week intervals. No thoracic radiotherapy was administered while prophylactic cranial irradiation (30 Gy/l Ofiact i o d 2 weeks) was given. Witha 25-month medianfollowup, overall estimated 2-year and median suntival were 83% and 26.5 month (range 1634+),respectively. Ten patients are currently alive and diseasefree. No significant difference in 2-year survival was observed between the two adjuvant treatment modalities and median survival was 28 months (range 13-34+) for combination and 21 months (range 1429+)for single-agent chemotherapy. Although at high doses, epirubicin resulted in

1Dr. Macchiarini is currently affiliated with the Division of Hematology/ Oncology, ComprehensiveCancer Center, University of Alabama at Birmingham, Birmingham, Alabama.

19 Copyright 0 1991 by Marcel Dekker, Inc.

Macchiarini et al.

a moderate clinical and histological cardiotoxicity and a remarkably reduced inci&nce of severe (WHOgrades 3 and 4) treatment-relatedmorbidity compared with the combination regimen. ntese preliminary results suggest that comparable survival and reduced toxicity might be expected with an active single-agent as adjuvant chemotherapy in TI or 12NOMO m a l l cell lung cancer.

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INTRODUCTION Small ceil lung cancer (SCLC) is characteristically a metastatic or locally advanced disease at the time of diagnosis,for which combination chemotherapyis the currently available standard treatment (1). However, for a very small fraction of patients (e.g. < 3%) (2) with T1 or T2NOMO (3,4) or, to a lesser extent, TI-2NlMO disease (5,6), the combination of surgery plus adjuvant chemotherapy has been recently emphasized (7)and found to be superior to surgery alone (for review, see Ref. 8). Unfortunately, there are yet no optimal guidelines for the adjuvant treatment of these patients (8), since most studies have employed different types of chemotherapeutic regimens (2,4,7) and timing of administration (5,6), at the expense of distressing treatment-related toxicity. Moreover, no study has so far demonstrated that drug combination is more effective than single agent. In an attempt to address the schedule of adjuvant chemotherapy in surgically resected patients with T1 or T2NOMO SCLC, a randomized mmparison was made between single-agent (epirubicin) and combination (cyclophosphamide, epirubicin, and etoposide) chemotherapy. The primary purposes were: (i) to test whether a combination regimen is more effective than a single agent in terms of survival; (ii) to explore differences in toxicities between the two treatment modalities, and (iii) to investigate, in the single-agent treatment arm,the general and cardiac toxicity of epirubicin administered at high doses.

MATERIALS AND METHODS Eligibility criteria for entry into the trial included histologically confirmed SCLC staged pathologically as T1 or T2NOMO disease according to the TNM classification(9), age 5 75 years, no prior chemotherapy andlor radiation therapy, no prior history of malignancy, Eastern CooperativeOncology Group @COG) performance status of 0 to 2, adequate bone marrow reserve (WBC, 2 3,500/mm3;platelet count, 2 100,000/mm3),liver (bilirubin s 1.5 mg/dl), and renal (creatinine I 1.5 mg/dl) functions, and written informed consent.

Ineligibility criteria were active cardiac disease, for example, myocardial infarction occurring within 6 months, congestive heart failure (CHF), severe (WHO3-4) arrhythmias (lo), angina pectoris, baseline resting left ventricular ejection fraction (LVEF) I45 % ; compromised pulmonary function precluding a pulmonary resection and other life-threatening diseases. Patients were not considered for the study if tumor extension, in the opinion of the operating surgeon, would preclude a complete resection of all identifiable pathological tissue (4). Preoperative work-up included a detailed history and physical examination, evaluation of performance status (ECOG scale), chest x-ray, percutaneous needle biopsy, bronchoscopy,computed tomography (CT) of the brain, chest, and the upper abdomen to include adrenal glands, abdominal ultrasonography, bone and 67Galliumscans, and bilateral bone marrow biopsy and aspiration. Baseline investigations also included complete blood count (CBC), biochemical profile, cardiac (12-lead ECG and M-mode echocardiograms), and pulmonary function tests. Preoperative mediastinoscopywas not performed provided that: (i) the primary tumor was gallium-positiveand there was the absence of gallium uptake in the mediastinum and (ii) there was no gross mediastinal involvement by primary tumor extension or mediastinal lymph node involvement greater than 1.5 cm evident on chest CT scan. After completion of staging procedures, patients underwent surgery and,at the time of thoracotomy, the extent of the pulmonary resection was influenced by the location of the tumor: a lobectomy was performed in the presence of lesions limited to a lobe or lobar bronchus; when the tumor was located in a main stem bronchus or at the pulmonary hilum or crossed the lobar fissures, a pneumonemmy was performed. Intraoperatively,the size and the extent of the primary tumor was assessed; all normal or grossly abnormal regional nodes (e.g., intrapulmonary, Mar, and mediastinal lymph nodes, including subcarinal and lymph nodes superior to the carina) were respectively sampled or excised. All the resected or sample specimenswere labeled and examined pathologically. The resection was def'ined as complete, if in the surgeons' judgment all known disease was completely resected, the proximal resection margins were microscopically free of

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Adjuvant Chemotherapy for SCLC

tumor, no known microscopic intrathoracic disease remained, and the highest lymph node excised or sampled was microscopically free of tumor. All pre- and intraoperativespecimenswere fixed in buffered neutral formalin (4% v/v), embedded in paraffin, and 4 pm cuts were stained with hematoxylineosin. Slides were submitted for review by two pathologists specialized in the diagnosis of lung cancer. Each examined the material independently from the other, and for those patients for whom diagnostic agreement could not be reached, a third pathologist reviewed the same material without knowledge of the results of the other two. Histological subclassification was made according to WHO classification of malignant epithelial lung tumors (1l), and the morphologic criteria for each subtype of SCLC were assigned according to the rules of Matthews and Gazdar (12). After the pathologicalexaminations,patients were randomized to receive single-agent or combination adjuvant chemotherapy. Combination chemotherapy consisted of i.v. cyclophosphamide(1 g/m2, Day l), epirubicin (60 mg/m2, Day I), and etoposide (120 mg/m2, Days 1, 3, 5). Single-agentchemotherapy included epirubicin (course 1: 100 mg/m2, Day 1; courses 2 to 6: 140 mg/m2,Day 1). For both treatment modalities, a total number of 6 courses was administered, at 3-week intervals. A 25% reduction of epirubicin and all drugs included in the combination regimen was made if the WBC count fell between 2,000 and 3,500/mm3and the platelet count between 90,OOO and 120,000/mm3by Day 21. If the WBC and the platelet counts were < 2,000/mm3and c 90,OOO/ mm3on Day 21, respectively, treatment was delayed for one week. Epirubicin was reduced by 50% if serum bilirubin level ranged from 1.5 to 3.0 mg/ml and postponed by 1 week at levels 1 3.0 mg/dl. Treatment was interrupted in the presence of clinical signs of CHF or a fall of 20 % or more from the baseline resting LVEF. Physical examination,CBCs, serum chemistry, and cardiac evaluation were performed routinely before each drug course, as well as CBCs at nadir (Days 12-14). To stimulate the recovery from myelosuppression,thymostimulin (Serono S.p.A., Milan, Italy), a calf thymus extract, was administered 1mgkg i.m., Days 7-14 of each course (13). Right heart catheterization and right ventricular endomyocardial biopsy (14) were performed in single-agent-treated patients (with a separateinformed consent) whenever the cumulative dose of epirubicin reached 800 mg/m2.Biopsy specimens were histologically prepared, analyzed, and graded according to Billingham scale (15). The restaging as outlined above was repeated after 4 and 6 courses, and every 6 months for the first 3 years.

21

No thoracic radiation therapy was given, while prophylactic cranial irradiation (PCI) was delivered at the end of the 6 courses of adjuvant chemotherapy in all patients at the dose of 30 Gy in 10 fractions over a period of 2 weeks. Patients were considered evaluable for survival and toxicity if they completed one course of therapy. Treatmentrelated toxicity was graded according to WHO criteria (10). Survival was measured from the date of randomization until death or until last date of followup (May 1, 1989). Statistical Analysis Survival curves were calculated according to the Kaplan and Meier method (16) and compared via the log rank test (17). Differences between treatment groups in the patient characteristics and median survival were made by the chi-square test or Fisher’s exact test as appropriate. The treatment-relatedtoxicities were reported by courses and compared with the chi-square test. The randomization process was conducted using standard statistical software. The acronym NS denotes a significantlevel > 0.05, and two-sided tests were used.

RESULTS Between January 1986and December 1987, 15 patients were enrolled on the study. Of these, 3 were unevaluable (29%) because of change of diagnosis to non-SCLC on pathological review (one) and War lymph nodes involvement at pathological examination (two). There was no disagreement between the two pathologists and in no instance was it necessary to involve a third pathologist. The characteristicsof all evaluablepatients are shown in Table 1; they were well balanced between the two treatment modalities. All patients underwent a complete surgical resection. No serious postoperative complication was observed, and all patients started administration of adjuvant chemotherapy within 4 weeks after operation. The total number of courses delivered was 72 (36 per treatment group). The median interval between courses was overall 23 days (range 21-28), and did not differ between the two treatment modalities. No dose reduction was made for single-agent epirubicin. In the combination regimen, the median drug dose protocol delivered was 95% (range 75-loo%), and etoposidewas the major doselimiting drug. Table 2 illustrates the incidence and severity of toxicity by number of coursesand treatment groups. The overall toxicity was mild to moderate, with myelosuppression

Macchiarini et al.

22

Table 1 Patient Characteristics According to Treatment Modality

Characteristics

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Maleslfemales Age, median (yrs) (range) Performance status: 0-1 2 Extent of disease: TlNOMO T2NOMO Tumor greatest diameter: c 2 cm 2.0-2.9 cm 3.0-3.9 cm 2 4 cm Type of resection hbectomy :

Combination regimen

Single agent

Total

610 59 (47-73)

511 61 (53-64)

1111 61 (47-73)

5

5

1

1

10 2

1

2 4

3

5

Upperlhwer Pneumooectomy Side RightILeft Histology Oat Intermediate Mixeda

9

1 1 3 1

2 1 3

-

3 2 6 1

312

213

10

1

1

2

412

313

12

2 2 2

1 2 3

3 4 5

~~~

~

aMixed (specimens with a mixture of cells displaying largecell type features and intermediate cell-type features) (12).

and stomatitis being dose-limiting side effects. Median WBC and neutrophilic nadirs were 2,200/mm3 and 1082/mm3 for combination and 3,500/mm3 and 1,800/mm3for single-agentadjuvant chemotherapy (p = NS). Episodes of neutropenic fever were experienced in 36% (drug combination)and 25 % (single-agent)of treatment courses (p = NS). As shown, patients receiving the combination regimen experienceda remarkably higher incidence of severe (WHOgrade 3 and 4) side effects. No patient developed a fall from the baseline LVEF of 20% or clinical evidence of CHF during any stage of adjuvant chemotherapy and after 24 months. Three patients underwent endomyocardialbiopsies at cumulative doses of 800 mg/mz; histological examination showed a moderate (grade 2) degree of anthracycline-induced myocardial damage. The overall survival is shown in Figure 1. With 25 months median followup (range 16-34), estimated 2-year survival was 83 % and median survival was 26.5 months (range 13-34+) for all patients; ten patients are current-

ly alive and disease free. Two patients, developing multiple extrathoracic metastatic disease, died at 13 and 14 months, respectively; both had a mixed SCLC cell type. Table 3 points out the survival rate and median survival by treatment group; no significant differenceswere noted.

DISCUSSION Epirubicin is a new doxorubicin analog developed for its preclinical and clinical similar antitumor activity and lower toxicity when compared with its parent drug (18). At the time this trial was initiated, several authors demonstrated both its activity as single agent in SCLC and its significantly reduced chronic cardiotoxicity when used as adjuvant treatment at equiactive doxorubin dose. Due to its more favorable therapeutic index, the maximum tolerated dose of epirubicin was felt to be approximately twice as much as doxorubicin (18-20). Based on these findings, we elected to use and compare epirubicin,

Adjuvant Chemotherapy for SCLC

23

Table 2 Toxicity of Chemotherapy (Worst Toxicity Recorded) According to Nwnber of Courses, Adjuvant Treatment Modality (Single-Agent: A Versus Combination Regimen: B), and WHO Grading

Number courses

(%I

1

2

3

AIB

AIB

AIB

Am

AIB

9 (25)l 9 (25) 28 (78)/32 (89) 5 (14)l 6 (17)

210 1611 310

413 1113

010

010

316 1/18 213

11 (31)lll (31) 14 (39)/29 (81) 26 (72)/29 (81) 0 (0)l 5 (14)

81 1 315 1I0 012

012 315 112 013

315 8/19 24/24 010

010

9 (25)/ 9 (25)

913

015

011

010

3 (8)l 7 (19)

213

114

010

010

Toxicity

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Hematological Anemia Leukopenia Thrombocytopenia Gastrointestinal Oral NausedVomiting Alopecia

Infection

WHO grade

Fever (drug-related) Cardiac r y h

4

0110 013

013 010

013

Total number of courses delivered per treatment modality was 36.

RISK AT NUMBER

.1

0

1 0

1;

6

1;

1;

1;

1;

1;

12

18

24

30

36

TIME (months)

Figure 1. Survival of all evaluable patients. Arrows indicate patients currently alive and disease-kee.

administered at high doses (e.g., > 90 mg/m2) with the present combination chemotherapy, previously investigated and found to be an active adjuvant regimen for T13NOMO SCLC (21). The major finding of this ongoing study is that adjuvant chemotherapy with an active single agent is feasible in patients with Tlor "2NOMO SCLC and yields comparable 2-year and median survival than a standard combination regimen (2,4,8,21,22). However, this does not imply that epirubicin, at the present dose and schedule, should be employed routinely as adjuvant chemotherapy in this subset of SCLC patients, since definitive conclusions regarding its therapeutic efficacy are too p r e h m r y . This because the total number of patients entered in the study is still small and the followup is rather short, precluding any meaningful statistical comparison. Whether the results of single-agent adjuvant chemotherapy depend on the dose-related sensitivity of SCLC (23) and/or the effectiveness of high-dose adjuvant treatment, administered in the early postoperative period and in early staged patients, in decreasing the prevalence of resistance phenotypes (24) remains an open question.

Macchiarini et al.

24

Table 3 Median Survival (MS)and 2-Year Survival According to Treatment Modality

MS (months)

(range)

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2-year survival (%)

Combination

Single

regimen

agent

p Value

28 (13-34') 83

21 (14-29') 83

NS

potentially able to determine a survival comparable with that expected from a combination regimen. Thereby, the incidence of severe treatment-related toxicities can be reduced, minimizing the adverse impact of treatment on quality of life. However, a larger number of patients and further followup is required before definitive conclusions can be drawn.

NS

The present data are attractive with respect to two considerations: (i) the major cause of deaths in resected SCLC patients is metastatic disease, for which the currently available therapeutic resources are limited (25); (ii) the combination of cisplatin and etoposide is a noncrossresistent and active second-line regimen in relapsing patients previously treated with epirubicin (26). Therefore, a potential helpful therapeutic benefit for T1 or nNOMO SCLC patients receiving epirubicin as adjuvant chemotherapy could be expected. An important concern is that our results have been obtained with a reduced treatment-related morbidity, raising the question whether intensive adjuvant drug combinations (22) are necessary. In effect, although delivered at high doses, epirubicin resulted in a lower incidence of severe side effects than combination chemotherapy, and therefore in better patient compliance. Additionally, its administrationdid not result in significant acute or chronic dose-limitingclinical and histological cardiotoxicity, confirming previous reports demonstrating epirubicin's reduced cardiotoxicity (26,27). There is yet no optimal agreement concerning the duration of adjuvant chemotherapy in this uncommon stage disease. The number of courses administered has been reported to vary from more than 2 to 12 (4-6,22). Our results were obtained by the administration of 6 courses, suggesting that this number may be sufficient. However, one must be cautious in interpreting these suggestions because they are not protected by a randomized comparison. Nonetheless, neither retrospective nor prospective studies have demonstrated any advantage for more than 6 courses of chemotherapy for the treatment of SCLC (28). In summary, the results of this ongoing study add weight to our earlier conclusion (4) that the combination of surgery plus adjuvant chemotherapy represents the treatment of choice for early stage SCLC patients. In particular, adjuvant chemotherapy including an active drug is feasible in patients with T1 or T2NOMO SCLC and

ACKNOWLEDGMENTS This work was supported by grants of the Italian Ministry of Education (60%funds). The authors are indebted to Dr. AF Lo Buglio and Dr. RH Wheeler for their review of the manuscript and very helpful discussions, and would like to thank Michele Granucci, RN, for his assistance.

Address reprint reqi jsts to Dr. Paolo Macchiarini, M.D., Service of Thoracic Surgery, University of F'isa, Via Roma 67,l-56100 Pisa, Italy.

REFERENCES 1. Aisner J: Chemotherapy for small cell lung cancer. In Lung Cancer. A Comprehensive Trear'se. Edited by JD Bitran, HM Colomb, AG

2.

3. 4.

5.

6. 7.

8.

9.

10. 11.

12.

Little, RR Weichselbaum. Grune and Stratton, Orlando, 1988, pp 307-327. Hoffman PC:The role of surgical resection in management of small cell carcinoma of the lung. In Lung Cancer. A Comprehensive Treatise. Edited by JD Bitran, HM Colomb, AG Little, RR Weichselbaum. Gmne and Stratton, Orlando, 1988, pp 359-367. Klastersky J: Therapy of small cell lung cancer: Anything new? Eur J Cancer Clin Oncol 24:107-112, 1988. Angeletti, CA, Macchiarini P, Mussi A et al: Influence of T and N stages on long-term survival in resectable small cell lung cancer. Eur J Surg Oncol 15:337-340, 1989. Baker RR, Ettinger DS, RuckdeschelJD et al: The role of surgery in the management of selected patients with small-cell carcinoma of the lung. J Clin Oncol 5697-702, 1987. Mountain CF: Operation for small-cell carcinoma revised. J Clin Oncol 5:687-688, 1987. Friess GG,Mc Cracken JD, Troxell ML et al: Effect of initial resection of smallall carcinoma of the lung: a review of Southwest Oncology Group study 7628. J Clin Oncol 3:964-968, 1985. Graham BL, Balducci L, Khansur T et al: Surgery in small cell lung cancer. AM Thorac Surg 45:687-692, 1988. Mountain CF: A new international staging system for lung cancer. Chest 89:225S-233S, 1986. Miller AB, Hoogstraten B, Staquet M et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981. World Health Organization: The World Health Organization histological typing of lung tumors. Am J Clin Pathol77: 123-136, 1982. Matthews MJ, Gazdar AF: Pathology of small cell carcinoma of the lung and its subtypes. A clinico-pathologic correlation.In: Lung Cancer I ; Cancer Treatment and Research. Editied by RB Livingston. Martinus Nijhoff, The Hague 1980, pp 283-306.

Cancer Invest Downloaded from informahealthcare.com by Mcgill University on 10/27/14 For personal use only.

Adjuvant Chemotherapy for SCLC 13. Macchiarini P, Danesi R, Del Tacca M et al: Effects of thymostimulin of chem&erapy-induced toxicity and long-term survival in small cell lung cancer patients. Anticancer Res 9:193-196, 1989. 14. Richardson PJ: King's endomyocardial bioptome. Lancet 1:660-661, 1972. 15. Billingham ME, Bristow MR: Evaluation of anthracycline cardiotoxicity: predictive ability and functional correlation of endomyocardial biopsy. Cancer Treat Symp 3:71-76,1984. 16. Kaplan EL, Meier P:Nonparametricestimation from incomplete observations. J Am Stat AS= 53:457-481, 1958. 17. Pet0 R, Pike MC, Armitage P et al: Design and analysis of randomized clinical trials requiring prolonged observations of each patient. II. Analysis and Examples. Br J Cancer 35:l-39, 1977 18. Weiss RB, Sarosy G, Clagget-Cm K et al: Anthracycline analogs: the past, present, and future. Cancer Chemother Phannacol 18~185-197, 1986. 19. Ganzina F: 4'-Epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rep 1O:l-22, 1983. 20. Cersosimo RJ, Hong WK: Epirubicin, a review of the pharmacology, clinical activity, and adverse effect of an adriamycin analogue. J Clin Oncol 4:425-439, 1986.

25 21. Macchiarini P, Mussi A, Basolo F et al: Optimal treatment of T1-3NOMO small cell lung cancer: surgery plus adjuvant chemotherarpy. Anticancer Res 9: 1623-1626, 1989. 22. Karrer K, Shields TW,Denck H et al: The importance of surgical and multimodality treatment for small cell bronchial carcinoma. J Thorac Cardiovasc Surg 97: 168-176, 1989. 23. Frei E, IU, Caneilos GP: Dose: a critical factor in cancer chemotherapy. Am J Med 69585-594, 1980. 24. Wittes RE: Adjuvant chemotherapy-clinical Vials and laboratory models. Cancer Treat Rep 70:87-103, 1986. 25. Macchiarini P,Hardin M, Chella A et al: Surgery plus adjuvant chemotherapy for TI-3NOMO small cell lung cancer. Am J CIin Oncol (in press). 26. Macchiarini P, Danesi R, Mariotli R et al: Phase II study of highdose epirubicin in untreated small cell lung cancer. Am J Clin Onml 13:302-307, 1990. 27. Torti FM, Bristow MM, Lum BI: Cardiotoxicityof epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 46:3722-3727, 1986. 28. Einhorn LH,Crawford J, Birch R et al: Cisplatin plus etoposide consolidationfollowing cyclophosphamide,doxorubicin, and vincristinein liited small-cell lung cancer. J Clin Oncol6451-456, 1988.