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Oral therapy for small cell lung cancer
LUNG
...-
CANCER ELSEVIER
Lung Cancer 12 Supp!. 3 (1995) S63-S70
Oral therapy for small cell lung cancer Pieter E. Postmus'", Egbert F. Smit'' "Department of Pulmonary Diseases, Free University Hospital, P.O. Box 7057, 1000 MB Amsterdam, The Netherlands "Department of Pulmonary Diseases, University Hospital Groningen, Groningen, The Netherlands
Received 12 December 1994; revision received 21 February 1995; accepted 2 March 1995
Abstract After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to reconsider the role of simple therapy in patients without the prospect of cure. Oral therapy might be worthwhile because it is probably less effecting the quality of life of the patient and makes it unnecessary to visit the hospital frequently. All drugs available for oral use with known activity against small cell lung cancer are reviewed. The best example of the success of oral therapy is etoposide, other candidates that need to be tested in a modern way are oral cyclophosphamide and hexamethylmelamine. New concepts of prolonged chemotherapy and dose-intensity are easier evaluated by using oral drugs. The discovery of the activity of prolonged oral etoposide is an excellent example how to test a new concept in a very simple way. Keywords: Small cell lung cancer, oral therapy; Small cell lung cancer, chemotherapeutic
agents
1. Introduction
Early in the 60s, it became apparent that among all histologically different types of lung cancer, the so-called oat-cell type responded to chemotherapeutic agents in a more favorable way than the other histological types [1,2]. Remarkable responses after minimal amounts of a chemotherapeutic agent were reported [3] and this was
* Corresponding author. 0169-5002/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00454-Z
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considered worthwhile as palliative therapy. However, chemotherapy was not accepted as part of the management of small cell lung cancer (SCLC) until it proved to be superior to placebo in a properly designed clinical trial [4] and resulted in a meaningful improvement of both median survival (5 vs. 2 months) and the l-year survival rate. Since that time, many reports on single agent and combination chemotherapy of SCLC have been published. At the beginning of the 80s, several long-term survivors had been reported and optimistic expectations were published [5]. Unfortunately the rapid progress and dramatic improvement of the prognosis of patients with SCLC observed during the 70s was not followed by the same improvements during the next decade and currently long-term survivors are still a minority of all patients with SCLC. Even patients surviving more than 5 years after the start of therapy without any sign of tumor persistence are at high risk of developing a secondary primary lung tumor. Systematic scoring of prognostic factors in several large chemotherapy trials has demonstrated that of all patients treated with chemotherapy, the ones with so-called limited disease, a good performance status and not older than 65-70 years, have the best chances of becoming long-term survivors and in a minority of them, cure seems to be a realistic goal for the treatment. For all the other patients the main goal of therapy is primarily improvement of symptoms, normally resulting in some improvement of survival as well. The anti-tumor activity of the treatment is not the only important aspect of therapy for these patients. Several aspects of quality of life are considered as very important and the effects of treatment on quality of life have to be considered as well if the therapeutic approaches for these patients are discussed. Some of these aspects are the side-effects of cytostatic treatment such as nausea, vomiting, mucositis, myelosuppression, infections, and anemia. Closely related to this is the burden of visits to the out-patient clinic, time-consuming measures such as hydration to prevent otherwise much more serious side effects, infusion of drugs, frequency of necessary white blood cell and platelet counts, hospitalization for aplasia-related fever and transfusions of red blood cells and platelets. Simplifying therapy is of major importance for these patients if this results in positive effects on quality of live and still produces major responses with improvement of tumor-related symptoms. Several approaches are possible if one wants to develop therapies that fulfil both expectations. The first major improvement during the last decade was the considerable reduction of the length of treatment and nowadays it is more or less accepted to limit the first-line line therapy to 4-6 cycles [6]. Attempts to reduce it to a more or less symptom-related treatment failed. If after the first cycle the next was given if the patient symptomatology made it necessary, this resulted in a negative effect on the quality of life compared to treatment at fixed intervals irrespective of improvement of symptoms of the patient [7]. Another important aspect of therapy for patients with SCLC whom at its best will have temporary benefits from anti-tumor therapy is the cost of the therapy even if this results in important improvements of several aspects of quality of life for
P.E. Postmus, E.F. Sm it I Lung Cancel' /2 Suppl. 3 (/995) S63 -S70
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these patients . A striking example of this is the application of a hematopoitic growth factor (G-CSF). This results in less neutropenic fever, less use of oral and i.v. antibiotics and less hospitalization [8,9]. However, the major costs of this treatment make it a less attractive approach. Experts at the first Euro-American conference on Lung Cancer in Vienna in 1993 concluded unanimously that '... there is no evidence that growth factor support is routinely needed at present ' [29] . A far less appealing approach is the evaluation of simple chemotherapeutic regimens with minor side effects and still adequate anti-tumor activit y. In the literature no prospective studies are available comparing standard combination chemotherapy regimens such as cyclophosphamide, doxorubicin, etoposide (CDE) or cyclophosphamide, doxorubicin, vincristine (CAV) with for instance oral single agent or combination therapy. In this overview, some aspects of oral therapy for SCLC will be discussed. 2. Chemotherapeutic agents for oral use After the first report on the activity of cyclophosphamide against SCLC [4], many agents have been tested and activity against SCLC was found with several agents (Table 1). A number of these drugs are available only for oral use or have been manufactured for both parenteral and oral use. Some are rather old and have been evaluated in a period before the testing of new drugs was done according to guidelines that are considered as standard nowadays. Nevertheless during the initial years of chemotherapy for SCLC, these drugs were frequently used in combination regimens. 2.1. Cyclophosphamide After its introduction in 1958, it has been in use for the treatment of SCLC up to the present and is still considered as one of the most active drugs against SCLC. In combination chemotherapy regimens, it is mostly administered as i.v. bolus . Its use as an oral drug for SCLC is not very frequently reported. In most of the old reports, it is given after the 'intravenous induction' as oral 'maintenance therapy' Table I Active drugs against SCL C Oral formulation
Intr avenous
Cyclophosphamide Ifosfamide Procabazine" Hexamethylmelamine" CCNU" Methotrexate Etop oside
Doxorubicin Epiru bicin Vincristine Vindcsine BCNU Cisplatin Carboplatin Teniposide
"Only for oral usc.
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[3,10]. In the study by McLean [10] 'induction' consisted of daily injections of 400 mg of cyclophosphamide until the white blood cell counts fell to 2.0 x 109/1 and after recovery to > 2.5 x 109/1 'maintenance' of 100-200 mg oral daily was started and continued on individual tolerance. The response was not scored according to the criteria we use nowadays and a real response rate is not given. If the good ( + + ) and very good ( + + + ) radiological improvements are considered as at least partial responses, 17 out of 21 (81%) patients responded, 10 of these patients had a very good improvement (48%). Data on duration of response were not given. From that same period dates a report in which seven patients with oat-cell tumors were treated and five of them responded to cyclophosphamide daily oral 400 mg till maximally 5 g [3]. Recently investigators from the University of Groningen in the Netherlands reported on daily oral cyclophosphamide at a dose of 150 mg/rrr' for 21 days followed by 2 weeks rest [11]. Maximally five cycles were given. Only patients who were not eligible for other investigational studies with combination chemotherapy or chemo-radiotherapy were entered. Of 20 patients entered, 14 were over 70 years of age and six others had concomitant malignancies. Four patients had been treated with chemotherapy for SCLC more than 6 months before. Thirteen patients had a performance score of 0-1 (ECOG), and seven a PS of 2-3. The most important toxicity was myelosuppression with the white blood cell nadir on day 16, and only one patient experienced neutropenic fever. Nausea and vomiting were controlled with anti-emetic therapy. Four patients reached a CR and five a PR, response rate 45% (95% C.I., 23-68%); median time to progression was 3.5 months and median survival 4 months (range 3-17). 2.2. Procarbazine Early in the 70s, procarbazine was frequently used in combination regimens and its penetration into the central nervous system was considered important because the frequent brain relapse of SCLC was a point of major concern. It was never properly tested in untreated SCLC patients; in four reports, in total 19 patients with SCLC were treated with a dose of 100-200 mg/day, Of these patients, nine responded with a response rate of 47% [13]. After a negative study from Copenhagen [14], its popularity diminished rapidly. In this study, 24 previously treated patients with a relapse after often long-term chemotherapy were treated and it is not surprising that in this situation, no activity was seen at all. Even active drugs such as teniposide and etoposide are almost inactive in heavily pretreated patients with a relapse. 2.3. Methotrexate In a study by Vincent et al. [14], several schedules, including oral therapy, were evaluated. Out of 37 patients, six had a partial response and five a minor response. These 11 patients had a median survival of 5.5 months which was significantly better than the median survival of 2.2 months of the non-responders. Despite its frequent use in the past, it is currently not considered an important drug for the treatment of SCLC.
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2.4. CCNU
The high lipid solubility of the nitrosureas explains the incorporation of the drug in combination regimens against SCLC with its high CNS relapse rate. In the early 70s, the results of therapy in usually small groups of patients with SCLC were described in several reports concerning chemotherapy of lung cancer. Out of 76 evaluable patients, only 11 had a response, including three complete responses [12]. Since it was found that the relapse rate in the CNS was not lower in patients treated with chemotherapy regimens including CCNU, the most important reason to use it had disappeared. Furthermore, the long interval between the subsequent administrations made it difficult to incorporate it in combination regimens. 2.5. Hexamethylmelamine This drug has been available for around 30 years. Already in the report describing the Phase I data, activity against lung cancer was mentioned. In four single agent studies, 131 patients have been treated at doses ranging from 4 to 15 mgjkg over 21-90 days . Overall, a 36% response rate was found and median response duration was 3.5 months. No myelotoxicity was seen. The major toxicity was nausea and vomiting and it seems to be dose-related [IS). Despite its demonstrated activity, it has never become an important drug against SCLC. 2.6. Ifosfamide Ifosfamide is one of the drugs with high activity against SCLC if given intravenously [16]. The bioavailability after oral use is close to 100% [17]. It has not been tested as a single oral agent for SCLC. Cerny et al. [18] evaluated oral ifosfamide with oral etoposide in a group of 65 elderly or unfit patients. This combination resulted in a response rate of 90% in this poor prognosis group including 32% complete responses. Median survival of both limited and extensive disease patients was impressive: 13 months and 9.5 months, respectively. Hematologic toxicity was low; during only 4% of the courses intravenous antibiotics were required. However, the 30% rate of CNS toxicity was higher than expected. In an as yet unpublished study in NSCLC of the EORTC, this CNS toxicity led to premature closure of patient entry. Based on these data, new studies with oral use of ifosfamide will not be started, although one might question whether this has to be reconsidered after the report on the protective effects of methylene-blue [19]. 2. 7. Etoposide
Since its introduction in the clinic in the early 70s, etoposide has become a more and more important drug for many cancers including SCLC. From the beginning, it has been used as an oral drug . Initially administered by drinking the solution for intravenous use, this was associated with considerable gastro-intestinal toxicity [20). Later on, the use of capsules reduced this considerably and the popularity of the use of oral etoposide became much greater. Currently many, more or less standard, regimens for several tumors include etoposide either i.v., i.v. and oral, or only oral. In 1978, Cavalli et al. [21] showed the clear schedule dependency of etoposide in SCLC. This was confirmed in a very elegant study by Slevin et al. [22] and
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pharmacokinetic data pointed out that low serum levels of etoposide during several days after bolus infusions on 5 consecutive days are much more important than the higher levels obtained with a 24-h infusion of the same total dose. This much higher activity is explained by the recently elucidated anti-tumor mechanism of etoposide. Its major intracellular target is an essential nuclear enzyme, topoisomerase II. With this schedule dependency it is essential to administer etoposide during longer periods, 3-5 days, which makes its oral use even more attractive. In a large Phase II trial in elderly patients, its safety and efficacy have been demonstrated. Etoposide capsules were administered during 5 days, the total dose equaling 800 mg/m" A response rate of over 70% and a median survival of 9.5 months are comparable with the efficacy of more toxic and complicated combination chemotherapy schedules. Hematologic and gastro-intestinal toxicity were minimal, and hospitalization for treatment-related toxicity was seldom necessary [23,24]. Despite this safe profile, the same regimen resulted in very severe toxicity in patients with a very poor performance status (ECOG 4) and if one wants to treat these patients, a low dose of oral etoposide is preferable [25]. An explanation for this severe toxicity is the unpredictable bioavailability after these doses of oral etoposide, which is also influenced by liver and renal function. There is an almost linear relationship up to doses of 200 mg/day with plasma concentrations. Above this dose bioavailability tapers off. The bioavailability is at low doses (100 mg oral) 76 ± 22% and is much higher than at a dose of 400 mg (48 ± 18%) [26]. During the last few years, prolonged administration of low doses of oral etoposide has gained in popularity and responses in tumors considered resistant to normal schedules of etoposide have even been reported. Whether prolonged inhibition of topoisomerase II could be responsible for this is so far unclear. Johnson et al. [27] reported a high response rate of 47% in patients with relapsing or resistant SCLC after 21 days of oral etoposide 50 mg/nr' every 5 weeks. The majority of the responses was in patients with a treatment-free interval of over 90 days and recurrence after a response on first line chemotherapy. Currently these patient are considered as chemotherapy-sensitive patients and standard dose etoposide would have produced probably the same response rate in these patients. In a Phase II study of 100 mg oral etoposide daily for 21 days in elderly patients, we found a very high response rate especially in patients with a rather good performance status (ECOG 0-2). Thirteen out of 15 evaluable patients responded and survival was comparable to other frequently used regimens [28].
3. Conclusions Of the drugs with sufficient activity against SCLC which are available for oral use, very limited information is available with regard to first-line therapy. Except for oral etoposide, most data come from rather old studies which were performed in a period without strict standardization of evaluation of drugs in Phase II studies and less clearly defined response criteria. From the drugs listed in Table 1, etoposide is by far the most frequently used oral drug for SCLC. Of the others, only cyclophosphamide and hexamethylmelamine seem of any value for SCLC. The
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CNS-toxicity of oral ifosfamide makes its use problematic, despite its important activity against SCLC. Since treatment results from extensive disease SCLC patients have reached a plateau during the last 10-15 years, it seems necessary to reconsider how to treat these patients. More emphasis should be given to quality of life, costs and simplicity of palliative therapy for these patients. Incorporation of oral drugs into treatment protocols for these SCLC patients should be considered. Studies comparing combinations of oral drugs with standard i.v. regimens are necessary. A major advantage is the possibility of using oral drugs for longer periods and by this approach, a higher dose-intensity of therapy might become possible.
References [I] Levine B, Weisberger AS. The response of various types of bronchogenic carcinoma to nitrogen mustard. Ann Intern Med 1955; 42: 1089. [2] Watson WL, Berg JW. Oat cell lung cancer. Cancer 1962; 15: 759. [3] Barran KM, Helm WH, King DA. Bronchial carcinoma treated with nitrogen mustard and cyclophosphamide. Br Med J 1965; 2: 685. [4] Green RA, Humphrey E, Close H et al. Alkylating agents in bronchogenic carcinoma. Am J Med 1969; 46: 516. [5] Oldham RK, Greco FA. Small cell lung cancer: a curable disease. Cancer Chemother Pharmacol 1980; 4: 173. [6] Giaccone G, Dalesio 0, McVie JG et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. J Clin Oncol 1993; 11: 1230. [7] Earl HM, Rudd RM, Spiro SG et al. A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a cancer research campaign trial. Br J Cancer 1991; 64: 566. [8] Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small cell lung cancer. New Eng! J Med 1991; 325: 164. [9] Trillet-Lenoir V, Green J, Manegold C et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993; 29A: 319. [10] McLean RDW. Cyclophosphamide in the management of advanced bronchial carcinoma. Thorax 1965; 20: 555. [II] Groen HJM, Bakker M, Smit EF, Postmus PE. Daily oral cyclophosphamide for patients with small cell lung cancer unsuitable for standard treatment. A phase 1/11 study. Lung Cancer 1994; II Suppl I: 108 (Abstr 4 I3). [12] Broder LE, Cohen MH, Selawry as. Treatment of bronchogenic carcinoma II. Small cell. Cancer Treat Rev 1977; 4: 219. [13] Pedersen AG, Sorensen S, Aabo K et al. Phase II study of procarbazine in small cell carcinoma of the lung. Cancer Treat Rep 1982; 66: 273. [14] Vincent RG, Pickren JW, Fergen TB et al. Evaluation of methotrexate in the treatment of bronchogenic carcinoma. Cancer 1975; 36: 873. [15] Comis RL. Hexamethylmelamine (alretamine) in small cell lung cancer (SCLC). Cancer Treat Rev 1991; 18 Suppl A: 85. [16] Brade WP, Herdrich K, Varini M. Ifosfamide: pharmacology, safety and therapeutic potential. Cancer Treat Rev 1985; 12: 1. [17] Cerny T, Margison JM, Thatcher N et al. Bioavailability in patients with bronchial carcinoma. Cancer Chemother Pharmacol 1986; 18: 261. [18] Cerny T, Lind M, Thatcher N et al. A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). Br J Cancer 1989; 60: 258.
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[19] Kupfer A, Aeschliman C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene blue. Lancet 1994; 343: 763. [20] Brunner KW, Sonntag RW, Ryssel HJ et al. Comparison of the biological activity of Vp-16-213 given IV and orally in capsules or drink ampules. Cancer Treat Rep 1976; 60: 1377. [21] Cavalli F, Sonntag RW, Jungi Pet al. Vp-16-213 monotherapy for remission induction of small cell lung cancer: a randomized trial using three dosage schedules. Cancer Treat Rep 1978; 62: 473. [22] Slevin M, Clark PI, Joel SP et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 1989; 7: 1333. [23] Smit EF, Carney DN, Harford Pet al. A phase II study of oral etoposide in elderly patients with small cell lung cancer. Thorax 1989; 44: 631. [24] Carney DN, Grogan L, Smit EF et al. Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 1990; 17 Suppl 2: 49. [25] Postmus PE, Smit EF, Berendsen HH et al. A feasibility study of testing new drugs for small cell lung cancer in patients with a poor performance status. Cancer Chemother Pharmacol 1991; 27: 490-491. [26] Hande KR, Krozely MG, Greco FA et al. Bioavailability of low-dose oral etoposide. J Clin Oncol 1993; II: 374. [27] Johnson DH, Greco FA, Strupp J et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small cell lung cancer: a phase II trial. J Clin Oncol 1990; 8: 1613. [28] Smit EF, Postmus PE. Three week daily oral etoposide for elderly and/or unfit patients with newly diagnosed small cell lung cancer - a phase II study. Lung Cancer 1995; in press. [29] Bunn PA, van Zandwijk N, Pastorino U, Aisner J, Alberto P, Arriagada R, Carney D, Comis R, Dittrich C, Gatzememeier U, Ginsburg R, Greco FA, Hansen HH, Harper P, Henriksson R, Huber H, Kiener P, LeChevalier T, Lewensohn R, Murray N, Niederle N, Postmus P, Rosell R, Scagliotti G, Sculier JP, Splinter T, Stahel R, Symann M, Thatcher N, Tonato M, Turrisi A. European School of Oncology. First Euro-American Forum on Lung Cancer Treatment. Eur J Cancer 1994, 30A, 710-713.
...-
CANCER ELSEVIER
Lung Cancer 12 Supp!. 3 (1995) S63-S70
Oral therapy for small cell lung cancer Pieter E. Postmus'", Egbert F. Smit'' "Department of Pulmonary Diseases, Free University Hospital, P.O. Box 7057, 1000 MB Amsterdam, The Netherlands "Department of Pulmonary Diseases, University Hospital Groningen, Groningen, The Netherlands
Received 12 December 1994; revision received 21 February 1995; accepted 2 March 1995
Abstract After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to reconsider the role of simple therapy in patients without the prospect of cure. Oral therapy might be worthwhile because it is probably less effecting the quality of life of the patient and makes it unnecessary to visit the hospital frequently. All drugs available for oral use with known activity against small cell lung cancer are reviewed. The best example of the success of oral therapy is etoposide, other candidates that need to be tested in a modern way are oral cyclophosphamide and hexamethylmelamine. New concepts of prolonged chemotherapy and dose-intensity are easier evaluated by using oral drugs. The discovery of the activity of prolonged oral etoposide is an excellent example how to test a new concept in a very simple way. Keywords: Small cell lung cancer, oral therapy; Small cell lung cancer, chemotherapeutic
agents
1. Introduction
Early in the 60s, it became apparent that among all histologically different types of lung cancer, the so-called oat-cell type responded to chemotherapeutic agents in a more favorable way than the other histological types [1,2]. Remarkable responses after minimal amounts of a chemotherapeutic agent were reported [3] and this was
* Corresponding author. 0169-5002/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00454-Z
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P.E. Postmus, E.F. Smit / Lung Cancer 12 Suppl. 3 (1995) S63 -S70
considered worthwhile as palliative therapy. However, chemotherapy was not accepted as part of the management of small cell lung cancer (SCLC) until it proved to be superior to placebo in a properly designed clinical trial [4] and resulted in a meaningful improvement of both median survival (5 vs. 2 months) and the l-year survival rate. Since that time, many reports on single agent and combination chemotherapy of SCLC have been published. At the beginning of the 80s, several long-term survivors had been reported and optimistic expectations were published [5]. Unfortunately the rapid progress and dramatic improvement of the prognosis of patients with SCLC observed during the 70s was not followed by the same improvements during the next decade and currently long-term survivors are still a minority of all patients with SCLC. Even patients surviving more than 5 years after the start of therapy without any sign of tumor persistence are at high risk of developing a secondary primary lung tumor. Systematic scoring of prognostic factors in several large chemotherapy trials has demonstrated that of all patients treated with chemotherapy, the ones with so-called limited disease, a good performance status and not older than 65-70 years, have the best chances of becoming long-term survivors and in a minority of them, cure seems to be a realistic goal for the treatment. For all the other patients the main goal of therapy is primarily improvement of symptoms, normally resulting in some improvement of survival as well. The anti-tumor activity of the treatment is not the only important aspect of therapy for these patients. Several aspects of quality of life are considered as very important and the effects of treatment on quality of life have to be considered as well if the therapeutic approaches for these patients are discussed. Some of these aspects are the side-effects of cytostatic treatment such as nausea, vomiting, mucositis, myelosuppression, infections, and anemia. Closely related to this is the burden of visits to the out-patient clinic, time-consuming measures such as hydration to prevent otherwise much more serious side effects, infusion of drugs, frequency of necessary white blood cell and platelet counts, hospitalization for aplasia-related fever and transfusions of red blood cells and platelets. Simplifying therapy is of major importance for these patients if this results in positive effects on quality of live and still produces major responses with improvement of tumor-related symptoms. Several approaches are possible if one wants to develop therapies that fulfil both expectations. The first major improvement during the last decade was the considerable reduction of the length of treatment and nowadays it is more or less accepted to limit the first-line line therapy to 4-6 cycles [6]. Attempts to reduce it to a more or less symptom-related treatment failed. If after the first cycle the next was given if the patient symptomatology made it necessary, this resulted in a negative effect on the quality of life compared to treatment at fixed intervals irrespective of improvement of symptoms of the patient [7]. Another important aspect of therapy for patients with SCLC whom at its best will have temporary benefits from anti-tumor therapy is the cost of the therapy even if this results in important improvements of several aspects of quality of life for
P.E. Postmus, E.F. Sm it I Lung Cancel' /2 Suppl. 3 (/995) S63 -S70
S65
these patients . A striking example of this is the application of a hematopoitic growth factor (G-CSF). This results in less neutropenic fever, less use of oral and i.v. antibiotics and less hospitalization [8,9]. However, the major costs of this treatment make it a less attractive approach. Experts at the first Euro-American conference on Lung Cancer in Vienna in 1993 concluded unanimously that '... there is no evidence that growth factor support is routinely needed at present ' [29] . A far less appealing approach is the evaluation of simple chemotherapeutic regimens with minor side effects and still adequate anti-tumor activit y. In the literature no prospective studies are available comparing standard combination chemotherapy regimens such as cyclophosphamide, doxorubicin, etoposide (CDE) or cyclophosphamide, doxorubicin, vincristine (CAV) with for instance oral single agent or combination therapy. In this overview, some aspects of oral therapy for SCLC will be discussed. 2. Chemotherapeutic agents for oral use After the first report on the activity of cyclophosphamide against SCLC [4], many agents have been tested and activity against SCLC was found with several agents (Table 1). A number of these drugs are available only for oral use or have been manufactured for both parenteral and oral use. Some are rather old and have been evaluated in a period before the testing of new drugs was done according to guidelines that are considered as standard nowadays. Nevertheless during the initial years of chemotherapy for SCLC, these drugs were frequently used in combination regimens. 2.1. Cyclophosphamide After its introduction in 1958, it has been in use for the treatment of SCLC up to the present and is still considered as one of the most active drugs against SCLC. In combination chemotherapy regimens, it is mostly administered as i.v. bolus . Its use as an oral drug for SCLC is not very frequently reported. In most of the old reports, it is given after the 'intravenous induction' as oral 'maintenance therapy' Table I Active drugs against SCL C Oral formulation
Intr avenous
Cyclophosphamide Ifosfamide Procabazine" Hexamethylmelamine" CCNU" Methotrexate Etop oside
Doxorubicin Epiru bicin Vincristine Vindcsine BCNU Cisplatin Carboplatin Teniposide
"Only for oral usc.
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[3,10]. In the study by McLean [10] 'induction' consisted of daily injections of 400 mg of cyclophosphamide until the white blood cell counts fell to 2.0 x 109/1 and after recovery to > 2.5 x 109/1 'maintenance' of 100-200 mg oral daily was started and continued on individual tolerance. The response was not scored according to the criteria we use nowadays and a real response rate is not given. If the good ( + + ) and very good ( + + + ) radiological improvements are considered as at least partial responses, 17 out of 21 (81%) patients responded, 10 of these patients had a very good improvement (48%). Data on duration of response were not given. From that same period dates a report in which seven patients with oat-cell tumors were treated and five of them responded to cyclophosphamide daily oral 400 mg till maximally 5 g [3]. Recently investigators from the University of Groningen in the Netherlands reported on daily oral cyclophosphamide at a dose of 150 mg/rrr' for 21 days followed by 2 weeks rest [11]. Maximally five cycles were given. Only patients who were not eligible for other investigational studies with combination chemotherapy or chemo-radiotherapy were entered. Of 20 patients entered, 14 were over 70 years of age and six others had concomitant malignancies. Four patients had been treated with chemotherapy for SCLC more than 6 months before. Thirteen patients had a performance score of 0-1 (ECOG), and seven a PS of 2-3. The most important toxicity was myelosuppression with the white blood cell nadir on day 16, and only one patient experienced neutropenic fever. Nausea and vomiting were controlled with anti-emetic therapy. Four patients reached a CR and five a PR, response rate 45% (95% C.I., 23-68%); median time to progression was 3.5 months and median survival 4 months (range 3-17). 2.2. Procarbazine Early in the 70s, procarbazine was frequently used in combination regimens and its penetration into the central nervous system was considered important because the frequent brain relapse of SCLC was a point of major concern. It was never properly tested in untreated SCLC patients; in four reports, in total 19 patients with SCLC were treated with a dose of 100-200 mg/day, Of these patients, nine responded with a response rate of 47% [13]. After a negative study from Copenhagen [14], its popularity diminished rapidly. In this study, 24 previously treated patients with a relapse after often long-term chemotherapy were treated and it is not surprising that in this situation, no activity was seen at all. Even active drugs such as teniposide and etoposide are almost inactive in heavily pretreated patients with a relapse. 2.3. Methotrexate In a study by Vincent et al. [14], several schedules, including oral therapy, were evaluated. Out of 37 patients, six had a partial response and five a minor response. These 11 patients had a median survival of 5.5 months which was significantly better than the median survival of 2.2 months of the non-responders. Despite its frequent use in the past, it is currently not considered an important drug for the treatment of SCLC.
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2.4. CCNU
The high lipid solubility of the nitrosureas explains the incorporation of the drug in combination regimens against SCLC with its high CNS relapse rate. In the early 70s, the results of therapy in usually small groups of patients with SCLC were described in several reports concerning chemotherapy of lung cancer. Out of 76 evaluable patients, only 11 had a response, including three complete responses [12]. Since it was found that the relapse rate in the CNS was not lower in patients treated with chemotherapy regimens including CCNU, the most important reason to use it had disappeared. Furthermore, the long interval between the subsequent administrations made it difficult to incorporate it in combination regimens. 2.5. Hexamethylmelamine This drug has been available for around 30 years. Already in the report describing the Phase I data, activity against lung cancer was mentioned. In four single agent studies, 131 patients have been treated at doses ranging from 4 to 15 mgjkg over 21-90 days . Overall, a 36% response rate was found and median response duration was 3.5 months. No myelotoxicity was seen. The major toxicity was nausea and vomiting and it seems to be dose-related [IS). Despite its demonstrated activity, it has never become an important drug against SCLC. 2.6. Ifosfamide Ifosfamide is one of the drugs with high activity against SCLC if given intravenously [16]. The bioavailability after oral use is close to 100% [17]. It has not been tested as a single oral agent for SCLC. Cerny et al. [18] evaluated oral ifosfamide with oral etoposide in a group of 65 elderly or unfit patients. This combination resulted in a response rate of 90% in this poor prognosis group including 32% complete responses. Median survival of both limited and extensive disease patients was impressive: 13 months and 9.5 months, respectively. Hematologic toxicity was low; during only 4% of the courses intravenous antibiotics were required. However, the 30% rate of CNS toxicity was higher than expected. In an as yet unpublished study in NSCLC of the EORTC, this CNS toxicity led to premature closure of patient entry. Based on these data, new studies with oral use of ifosfamide will not be started, although one might question whether this has to be reconsidered after the report on the protective effects of methylene-blue [19]. 2. 7. Etoposide
Since its introduction in the clinic in the early 70s, etoposide has become a more and more important drug for many cancers including SCLC. From the beginning, it has been used as an oral drug . Initially administered by drinking the solution for intravenous use, this was associated with considerable gastro-intestinal toxicity [20). Later on, the use of capsules reduced this considerably and the popularity of the use of oral etoposide became much greater. Currently many, more or less standard, regimens for several tumors include etoposide either i.v., i.v. and oral, or only oral. In 1978, Cavalli et al. [21] showed the clear schedule dependency of etoposide in SCLC. This was confirmed in a very elegant study by Slevin et al. [22] and
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pharmacokinetic data pointed out that low serum levels of etoposide during several days after bolus infusions on 5 consecutive days are much more important than the higher levels obtained with a 24-h infusion of the same total dose. This much higher activity is explained by the recently elucidated anti-tumor mechanism of etoposide. Its major intracellular target is an essential nuclear enzyme, topoisomerase II. With this schedule dependency it is essential to administer etoposide during longer periods, 3-5 days, which makes its oral use even more attractive. In a large Phase II trial in elderly patients, its safety and efficacy have been demonstrated. Etoposide capsules were administered during 5 days, the total dose equaling 800 mg/m" A response rate of over 70% and a median survival of 9.5 months are comparable with the efficacy of more toxic and complicated combination chemotherapy schedules. Hematologic and gastro-intestinal toxicity were minimal, and hospitalization for treatment-related toxicity was seldom necessary [23,24]. Despite this safe profile, the same regimen resulted in very severe toxicity in patients with a very poor performance status (ECOG 4) and if one wants to treat these patients, a low dose of oral etoposide is preferable [25]. An explanation for this severe toxicity is the unpredictable bioavailability after these doses of oral etoposide, which is also influenced by liver and renal function. There is an almost linear relationship up to doses of 200 mg/day with plasma concentrations. Above this dose bioavailability tapers off. The bioavailability is at low doses (100 mg oral) 76 ± 22% and is much higher than at a dose of 400 mg (48 ± 18%) [26]. During the last few years, prolonged administration of low doses of oral etoposide has gained in popularity and responses in tumors considered resistant to normal schedules of etoposide have even been reported. Whether prolonged inhibition of topoisomerase II could be responsible for this is so far unclear. Johnson et al. [27] reported a high response rate of 47% in patients with relapsing or resistant SCLC after 21 days of oral etoposide 50 mg/nr' every 5 weeks. The majority of the responses was in patients with a treatment-free interval of over 90 days and recurrence after a response on first line chemotherapy. Currently these patient are considered as chemotherapy-sensitive patients and standard dose etoposide would have produced probably the same response rate in these patients. In a Phase II study of 100 mg oral etoposide daily for 21 days in elderly patients, we found a very high response rate especially in patients with a rather good performance status (ECOG 0-2). Thirteen out of 15 evaluable patients responded and survival was comparable to other frequently used regimens [28].
3. Conclusions Of the drugs with sufficient activity against SCLC which are available for oral use, very limited information is available with regard to first-line therapy. Except for oral etoposide, most data come from rather old studies which were performed in a period without strict standardization of evaluation of drugs in Phase II studies and less clearly defined response criteria. From the drugs listed in Table 1, etoposide is by far the most frequently used oral drug for SCLC. Of the others, only cyclophosphamide and hexamethylmelamine seem of any value for SCLC. The
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CNS-toxicity of oral ifosfamide makes its use problematic, despite its important activity against SCLC. Since treatment results from extensive disease SCLC patients have reached a plateau during the last 10-15 years, it seems necessary to reconsider how to treat these patients. More emphasis should be given to quality of life, costs and simplicity of palliative therapy for these patients. Incorporation of oral drugs into treatment protocols for these SCLC patients should be considered. Studies comparing combinations of oral drugs with standard i.v. regimens are necessary. A major advantage is the possibility of using oral drugs for longer periods and by this approach, a higher dose-intensity of therapy might become possible.
References [I] Levine B, Weisberger AS. The response of various types of bronchogenic carcinoma to nitrogen mustard. Ann Intern Med 1955; 42: 1089. [2] Watson WL, Berg JW. Oat cell lung cancer. Cancer 1962; 15: 759. [3] Barran KM, Helm WH, King DA. Bronchial carcinoma treated with nitrogen mustard and cyclophosphamide. Br Med J 1965; 2: 685. [4] Green RA, Humphrey E, Close H et al. Alkylating agents in bronchogenic carcinoma. Am J Med 1969; 46: 516. [5] Oldham RK, Greco FA. Small cell lung cancer: a curable disease. Cancer Chemother Pharmacol 1980; 4: 173. [6] Giaccone G, Dalesio 0, McVie JG et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. J Clin Oncol 1993; 11: 1230. [7] Earl HM, Rudd RM, Spiro SG et al. A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a cancer research campaign trial. Br J Cancer 1991; 64: 566. [8] Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small cell lung cancer. New Eng! J Med 1991; 325: 164. [9] Trillet-Lenoir V, Green J, Manegold C et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993; 29A: 319. [10] McLean RDW. Cyclophosphamide in the management of advanced bronchial carcinoma. Thorax 1965; 20: 555. [II] Groen HJM, Bakker M, Smit EF, Postmus PE. Daily oral cyclophosphamide for patients with small cell lung cancer unsuitable for standard treatment. A phase 1/11 study. Lung Cancer 1994; II Suppl I: 108 (Abstr 4 I3). [12] Broder LE, Cohen MH, Selawry as. Treatment of bronchogenic carcinoma II. Small cell. Cancer Treat Rev 1977; 4: 219. [13] Pedersen AG, Sorensen S, Aabo K et al. Phase II study of procarbazine in small cell carcinoma of the lung. Cancer Treat Rep 1982; 66: 273. [14] Vincent RG, Pickren JW, Fergen TB et al. Evaluation of methotrexate in the treatment of bronchogenic carcinoma. Cancer 1975; 36: 873. [15] Comis RL. Hexamethylmelamine (alretamine) in small cell lung cancer (SCLC). Cancer Treat Rev 1991; 18 Suppl A: 85. [16] Brade WP, Herdrich K, Varini M. Ifosfamide: pharmacology, safety and therapeutic potential. Cancer Treat Rev 1985; 12: 1. [17] Cerny T, Margison JM, Thatcher N et al. Bioavailability in patients with bronchial carcinoma. Cancer Chemother Pharmacol 1986; 18: 261. [18] Cerny T, Lind M, Thatcher N et al. A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC). Br J Cancer 1989; 60: 258.
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P.E. Postmus, E.F. Smit / Lung Cancer 12 Suppl. 3 (1995) S63-S70
[19] Kupfer A, Aeschliman C, Wermuth B, Cerny T. Prophylaxis and reversal of ifosfamide encephalopathy with methylene blue. Lancet 1994; 343: 763. [20] Brunner KW, Sonntag RW, Ryssel HJ et al. Comparison of the biological activity of Vp-16-213 given IV and orally in capsules or drink ampules. Cancer Treat Rep 1976; 60: 1377. [21] Cavalli F, Sonntag RW, Jungi Pet al. Vp-16-213 monotherapy for remission induction of small cell lung cancer: a randomized trial using three dosage schedules. Cancer Treat Rep 1978; 62: 473. [22] Slevin M, Clark PI, Joel SP et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 1989; 7: 1333. [23] Smit EF, Carney DN, Harford Pet al. A phase II study of oral etoposide in elderly patients with small cell lung cancer. Thorax 1989; 44: 631. [24] Carney DN, Grogan L, Smit EF et al. Single-agent oral etoposide for elderly small cell lung cancer patients. Semin Oncol 1990; 17 Suppl 2: 49. [25] Postmus PE, Smit EF, Berendsen HH et al. A feasibility study of testing new drugs for small cell lung cancer in patients with a poor performance status. Cancer Chemother Pharmacol 1991; 27: 490-491. [26] Hande KR, Krozely MG, Greco FA et al. Bioavailability of low-dose oral etoposide. J Clin Oncol 1993; II: 374. [27] Johnson DH, Greco FA, Strupp J et al. Prolonged administration of oral etoposide in patients with relapsed or refractory small cell lung cancer: a phase II trial. J Clin Oncol 1990; 8: 1613. [28] Smit EF, Postmus PE. Three week daily oral etoposide for elderly and/or unfit patients with newly diagnosed small cell lung cancer - a phase II study. Lung Cancer 1995; in press. [29] Bunn PA, van Zandwijk N, Pastorino U, Aisner J, Alberto P, Arriagada R, Carney D, Comis R, Dittrich C, Gatzememeier U, Ginsburg R, Greco FA, Hansen HH, Harper P, Henriksson R, Huber H, Kiener P, LeChevalier T, Lewensohn R, Murray N, Niederle N, Postmus P, Rosell R, Scagliotti G, Sculier JP, Splinter T, Stahel R, Symann M, Thatcher N, Tonato M, Turrisi A. European School of Oncology. First Euro-American Forum on Lung Cancer Treatment. Eur J Cancer 1994, 30A, 710-713.