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Platinum-Etoposide Chemotherapy in Elderly Patients With Small-Cell Lung Cancer: Results of a Randomized Multicenter Phase II Study Assessing Attenuated-Dose or Full-Dose With Lenograstim Prophylaxis—A Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) Study

From the Oncologia Medica Asl 18, Alba-Bra; Divisione di Pneumologia, Azienda Ospedaliera S. Anna, Como; Divisione di Pneumologia Oncologica, Presidio Ospedaliero Mariano Santo, Cosenza; Oncologia Medica & Centro Trials, Istituto Nazionale per la Ricerca sul Cancro, Genova; Oncologia Medica, Azienda Ospedaliera, Livorno; Oncologia Medica, Azienda Ospedaliera C. Poma, Mantova; Oncologia Medica, Azienda Ospedaliera, Padova; Oncologia Medica, Azienda Ospedaliera Castello, Venice; Divisione di Pneumologia I, Azienda Opsedaliera Cervello, Palermo; Fisiopatologia Respiratoria e Oncologia Medica, Azienda Ospedaliera, Parma; Oncologia Medica, Azienda Ospedaliera S. Chiara, Pisa; Broncopneumologia, Azienda Ospedaliera S. Camillo-Forlanini, Rome, Italy

Address reprint requests to Andrea Ardizzoni, MD, Medical Oncology, Parma University Hospital, Via Gramsci 14, 43100 Parma, Italy; e-mail: aardizzoni{at}ao.pr.it

	ABSTRACT

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PURPOSE: Small-cell lung cancer (SCLC) is increasingly diagnosed in elderly patients, who are at higher risk of treatment-related morbidity and mortality. We conducted a randomized two-stage phase II study to assess the therapeutic index of two different platinum/etoposide regimens, attenuated-dose (AD) and full-dose (FD) plus prophylactic lenograstim.

PATIENTS AND METHODS: SCLC patients older than 70 years were randomized to receive four courses of cisplatin 25 mg/m² on days 1 and 2, and etoposide 60 mg/m² on days 1, 2, and 3 every 3 weeks (AD); or cisplatin 40 mg/m² on days 1 and 2, and etoposide 100 mg/m² on days 1, 2, and 3 every 3 weeks, plus lenograstim 5 mg/kg days 5 through 12, every 3 weeks (FD). A combined primary end point named therapeutic success (TS), which took into account activity, toxicity, and compliance, was used.

RESULTS: Ninety-five patients were enrolled. Seventy-five percent and 72% of the patients in the AD and FD arms, respectively, completed the treatment as per protocol. Response rate was 39% and 69% in the AD and FD arms, respectively, and 1-year survival probability was 18% and 39%, respectively. Treatment was well tolerated in both groups, with no grade 3 to 4 myelotoxicity in the AD arm, and 12% myelotoxicity in the FD arm. Overall, the observed TSs were 10 (36%) of 28 patients and 42 (63%) of 67 patients for AD and FD treatments, respectively.

CONCLUSION: In elderly patients with SCLC a full-dose cisplatin/etoposide regimen combined with prophylactic lenograstim is active and feasible, while attenuated doses of the same regimen are associated with a poor therapeutic outcome.

	INTRODUCTION

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Combination chemotherapy represents the standard of care for the treatment of patients with small-cell lung cancer (SCLC), which accounts for 15% to 20% of all malignant lung neoplasms. Almost all SCLC patients, including those with very advanced stage disease, relapse after first-line treatment, poor performance status, and old age, may benefit from chemotherapy. Thoracic irradiation and prophylactic cranial irradiation are a useful addition to the treatment of selected patients with limited disease, young age, and good performance status. Although several chemotherapy regimens have shown to possess similar efficacy, cisplatin-based regimens, particularly the cisplatin/etoposide doublet (PE), has become the most widely used regimen in clinical practice worldwide, owing to its favorable therapeutic index.¹ In the most commonly studied PE regimen, cisplatin is delivered at the dose of 80 to 100 mg/m² on day 1 and etoposide at a total dose of 240 to 360 mg/m² divided throughout 3 days every 3 to 4 weeks. An alternative PE schedule with the cisplatin dose divided throughout more than one day was developed in the 1980s at the National Cancer Institute of Canada, and has become standard practice in many Canadian and European Institutions owing to its better tolerability, and to the need for reduced outpatient hydration.²

The optimal duration of chemotherapy in SCLC is still uncertain and there is insufficient evidence to recommend a specific number of courses. Three randomized studies have shown that 3 or 4 chemotherapy cycles may provide a similar clinical outcome compared with the more commonly used 6 or 8 cycles.^2,3

The median age of patients with a diagnosis of SCLC is typically 60 years. More than one third of patients with SCLC are older than 70 years and the rate of elderly SCLC patients is continuously increasing. Elderly SCLC patients may benefit from chemotherapy as much as younger patients.⁴ However, there is sufficient evidence to suggest that older age is associated with an increased risk of chemotherapy-related morbidity (especially myelosupression and sepsis), and mortality, probably as a result of associated comorbid diseases.^5-9 In addition, maintaining optimal chemotherapy dose-intensity in elderly SCLC patients is difficult because of frequent dose reductions and delays.¹⁰ For this reason, the optimal treatment of elderly patients with SCLC is still controversial. Some physicians favor the use of the same form of treatment adopted for younger patients, provided that more attention is paid to possible side effects, and increased supportive care during chemotherapy is given. Conversely, others prefer to use attenuated doses of standard chemotherapy regimens; however, this strategy may compromise the efficacy of chemotherapy treatment. Finally, other investigators have attempted to identify new regimens specifically designed for the elderly, but equivalence of these alternative strategies has not been conclusively proven.¹¹ In particular, a previously widely adopted strategy of treating elderly and other poor-risk SCLC patients with single-agent oral etoposide has been proven inferior to standard combination chemotherapy in two prospective randomized trials.^12-13

Our randomized cooperative phase II trial was designed to prospectively assess the activity and the feasibility of two different therapeutic strategies for the treatment of SCLC in elderly patients. The results of this study provide evidence that a full-dose PE regimen combined with prophylactic lenograstim is feasible and active, while attenuated doses of the same regimen, although also feasible, are associated with a poor therapeutic outcome.

	PATIENTS AND METHODS

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Patient Selection
Patients older than 70 years with histologically or cytologically confirmed SCLC were considered candidates for this study. Eligibility criteria also included the presence of at least one measurable lesion that was not previously irradiated; an Eastern Cooperative Oncology Group performance status of less than 3; and adequate hematologic, hepatic, cardiac, and renal functions. Exclusion criteria were previous or concurrent malignancies (except for nonmelanoma skin cancer or cervical in situ carcinoma), clinically evident infections, or systemic diseases. Written informed consent was required for all patients.

Study Design
The aim of the study was to evaluate the therapeutic index of two platinum/etoposide chemotherapy regimens: an attenuated-dose (AD) arm and a full-dose (FD) arm that was combined with prophylactic lenograstim. A randomized phase II design was used. A combined primary end point, named "therapeutic success" (TS), was used; it took into account activity, toxicity, and compliance. A TS was defined as a patient receiving at least three cycles of chemotherapy at the planned dose (without dose reductions) and schedule (no re-treatment delays beyond 2 weeks), and having an objective response (either complete or partial based on WHO criteria) without (1) grade 3–4 nonhematological toxicity, (2) complications associated with hematologic toxicity such as febrile neutropenia, infection, bleeding, or transfusion, or (3) any toxicity leading to hospitalization or death.

Treatments
AD chemotherapy consisted of cisplatin 25 mg/m² intravenously (IV) on days 1 and 2, and etoposide 60 mg/m² IV days 1 to 3, whereas FD chemotherapy included cisplatin 40 mg/m² IV on days 1 and 2, and etoposide 100 mg/m² IV days 1 to 3, plus lenograstim 5 µg/kg from days 5 to 12. At least four cycles were planned. Treatment was given on an outpatient basis and was repeated at 21-day intervals. Antibiotic prophylaxis with amoxicillin plus clavulanic acid was to be given when leukopenia grade 4 occurred. Antiemetic prophylaxis with 5-HT₃ antagonists plus dexamethasone was used at the treating physician's discretion. Blood counts were performed on a weekly basis. Response evaluation was performed by chest and upper abdomen computed tomography scan after three cycles. Treatment was delayed for a maximum of 2 weeks if the WBC count was less than 4,000/µL, or platelets less than 100,000/µL, at the time of recycle. On day 36, the following dose reductions were applied: 50% of the cisplatin and etoposide doses for a WBC count 2,000/µL and less than 4,000/µL, or platelets 75,000 and less than 100,000/µL; treatment was suspended for grade 3 to 4 leukopenia and/or grade 2 to 4 thrombocytopenia after 2 weeks of delay. A 50% dose reduction of lenograstim was applied if the WBC count was more than 30,000/µL.

Patients with limited disease were evaluated at the end of the chemotherapy program for possible consolidation thoracic radiotherapy at the discretion of the treating physician. Prophylactic cranial irradiation was not planned.

Statistical Methods
An optimal two-stage phase II Simon design was used within each of the two treatment arms.¹⁴ It was assumed that a regimen, in order to warrant additional studies, should be associated with a TS rate of at least 70%, whereas a regimen associated with a proportion of TS 50% was of no interest. According to Simon, for a power of 90% against the hypothesis of a 70% rate of TSs and a 5% false-positive error rate against the hypothesis of a TS rate of 50%, 24 patients have to be enrolled onto the first stage, in each arm. If 13 or fewer TSs were observed in one arm, then the enrollment onto that arm had to be terminated. If 14 TSs were observed, then an additional 37 patients had to be accrued. The regimen was then considered sufficiently promising to deserve additional studies if 37 TSs were seen among the total of 61 patients. The calculation of relative dose intensity was limited to the number of cycles actually delivered. Probabilities of survival were estimated using the method of Kaplan and Meier. No formal statistical comparison between the regimens was planned. The study protocol was approved by the institutional review board ethical committee of the Istituto Nazionale per la Ricerca sul Cancro di Genova.

	RESULTS

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Patients
Between April 1997 and May 2001, 95 patients were enrolled onto the trial from 22 participating institutions. Of these, 54 patients were enrolled by March 1999 during the first stage of the trial and randomly assigned to the AD (28 patients) or FD (26 patients) arms, respectively. Due to inadequate number of TSs in the AD arm, accrual was continued in the second stage of the trial only in the FD arm to a total of 67 patients.

The main characteristics of the 95 enrolled patients are listed in Table 1. In summary, the majority of the patients were men (84%), had a good performance status (Eastern Cooperative Oncology Group performance status 0–1, 88%) and nearly half of the patients (46%) had extensive stage disease, including 10% with brain metastases. The median age was 73 years (range, 70 to 80 years). Main prognostic factors were evenly distributed between treatment arms.

Reasons for not qualifying for a TS are reported in Table 2. Whereas a lack of objective response was the main reason for not achieving a TS in the AD arm (13 of 28; 46%), toxicity and/or patient refusal was the most frequent cause of therapeutic failure in FD arm (12 of 67; 18%). The primary outcome could not be assessed in three patients enrolled onto the FD arm, because of a lack of adequate information; according to the intent-to-treat principle, these patients were considered as therapeutic failure.

Treatment Compliance and Toxicity
The median number of administered cycles was four in both arms (AD arm range, 1 to 8; FD arm range, 1 to 6). Approximately the same percentage of patients completed the treatment as per protocol in both arms (21 [75%] of 28 patients in the AD arm, and 48 [72%] of 67 patients in the FD arm). Treatment delays and/or dose reductions were required in 18% and 16% of the patients in the AD and FD arms (14% and 10% because of chemotherapy-related toxicity), respectively. Seven patients (25%) in the AD arm and 16 (24%) patients in the FD arm did not complete the four courses of chemotherapy as planned by treatment protocol. The causes for interruption in AD arm were toxicity in three patients (11%; cardiac G3, fatigue G3, and infection), disease progression in two patients (7%), and disease-related early death in two patients (7%). In the FD arm, eight patients (12%) interrupted treatment because of toxicity (three patients for G3-4 hematologic toxicity, one patient for cardiac G2, one patient for gastrointestinal bleeding in absence of severe thrombocytopenia, one patient for G3 vomiting, one patient for G3 fatigue, and one patient for syncope), one patient (1%) because of progression, two patients (3%) for refusal of treatment, and one patient (1%) for myocardial infarction. Four patients (6%) died early before treatment completion: one patient's death was as a result of congestive heart failure, and three patients' deaths were disease related. Lenograstim was well tolerated in all patients, with no dose reduction or withdrawal.

The planned dose intensity for cisplatin was 16.7 mg/m²/wk and 26.7 mg/m²/wk in the AD and FD arms, respectively; the planned dose intensity for etoposide was 60 mg/m²/wk and 100 mg/m²/wk in the AD and FD arms, respectively. The median actually delivered relative dose intensity for both drugs was 96% (range, 65% to 125%) in the AD arm, and 98% (range, 13% to 125%) in the FD arm.

Treatment in the AD arm was well tolerated, showing no grade 3–4 myelotoxicity, and only four cases of grade 3–4 nonhematologic toxicity. In the FD arm, toxicity was also mild, with grade 3–4 leukopenia and/or thrombocytopenia occurring in approximately 10% of patients. Grade 3–4 nonhematologic toxicity rate was also low, always less than 10% in all patients (Table 4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The optimal therapeutic strategy in the treatment of elderly patients with newly diagnosed SCLC is still a matter of debate. Only a few nonrandomized studies have addressed this increasingly important issue. Standard practice varies widely worldwide, ranging from the use of full-dose standard platinum-based chemotherapy to single-agent chemotherapy or investigational new drugs.¹¹ Our study, which is the first prospective randomized study conducted in elderly patients with SCLC, has assessed two of the most commonly used chemotherapeutic strategies: the use of full-dose standard PE chemotherapy with prophylactic lenograstim support versus the use of attenuated doses of the same chemotherapy regimen. In the FD arm, prophylactic lenograstim was given to reduce the occurrence of febrile neutropenia/infection that is known to be the most frequent and serious chemotherapy-induced complication in poor-risk/elderly SCLC patients.⁹ The prophylactic use of granulocyte colony-stimulating factor has been proven to reduce the incidence of febrile neutropenia associated with cyclophosphamide/doxorubicin/etoposide chemotherapy in patients with SCLC.^15-16 Although in the normal population, platinum/etoposide chemotherapy is associated with a lower risk of febrile neutropenia/infections,^17-18 which does not justify the routine use of myelopoietic growth factors, patients with older age, poor performance status, or compromised organ function may carry an increased risk of such a worrisome chemotherapy side effect. According to the American Society of Clinical Oncology guidelines for the use of myelopoietic growth factors,¹⁹ the use of prophylactic granulocyte colony-stimulating factor might be justified in this group of patients. Considering the increased risk of mortality associated with febrile neutropenia/infection in elderly patients,²⁰ prophylactic oral antibiotic treatment was also given to patients developing grade 4 neutropenia despite lenograstim use. Therefore, the strategy in the FD arm of this trial was to give standard full-dose chemotherapy with maximal supportive treatment to minimize side effects, particularly febrile neutropenia/infection, associated with chemotherapy. In contrast, in the other arm of the trial, a more conservative approach was used based on the concept that given the palliative purpose of treatment in this category of patients, a reduced chemotherapy dose may be equally effective in producing palliation, with less trade-off in terms of chemotherapy-associated complications and lower costs.

Although the ultimate goal of SCLC treatment, even in elderly patients, is to extend patient survival, an earlier objective was to produce an objective response, which is known to be associated with subjective improvement and with survival prolongation, possibly in the absence of severe toxicity. For this reason, we selected the rate of therapeutic successes as the primary end point of this trial, which was arbitrarily defined as patients receiving at least three cycles of chemotherapy at the planned dose and schedule, and having an objective response without grade 3–4 toxicity or complications such as febrile neutropenia, infection, bleeding, transfusion, or death.

Using this definition of therapeutic success, the AD arm was abandoned at the first stage of the trial because of an insufficient rate of success among the first 28 patients enrolled. The main reason patients in the AD arm did not qualify for therapeutic success was their failure to achieve an objective response, obtained in only 39% of this group of patients. Meanwhile, toxicity and ability to complete the planned three courses at full chemotherapy dose were both excellent with the attenuated-dose chemotherapy program. Survival was disappointing in this arm of the study, being only 18% at 1 year. This poor outcome from the use of a suboptimal level of chemotherapy intensity is not surprising, and has already been reported in other studies.^12-13

In contrast, full-dose platinum/etoposide supported by prophylactic lenograstim was proven active and feasible. In fact, a therapeutic success was obtained in 63% of patients, with an overall response rate of 69% and a 1-year survival rate of 39%, which are remarkably similar to what can be achieved in younger patients. In this arm, toxicity was mild, with grade 3–4 leukopenia and/or thrombocytopenia occurring in approximately 10% of the patients, and grade 3–4 nonhematologic toxicity rate always observed as less than 10%. Only one patient treated with FD died as a result of treatment-related toxicity (renal toxicity and febrile neutropenia). Ten percent of patients had dose reductions or delays because of toxicity, and 12% of patients had to withdraw because of treatment side effects. Four patients (6%) died early while being treated for causes apparently unrelated to the FD regimen (disease progression in three patients and cardiac failure in one patient). This rate of early deaths is similar to the early death rates reported in younger patients treated with standard chemotherapy regimens.

It could be argued that the good outcome achieved with the full-dose chemotherapy regimen could also be achieved without the use of lenograstim prophylaxis. However, it has to be noted that despite the use of lenograstim in our study, grade 3–4 leukopenia occurred in 10% of patients, and one patient died as a result of this complication. In addition, retrospective subgroup analyses assessing the effect of age in patients treated with standard-dose chemotherapy but without growth factors support suggest an increased rate of early deaths and sepsis with older age.^6-9

In conclusion, a policy of delivering standard full-dose platinum/etoposide chemotherapy with lenograstim support is feasible and active in elderly patients with SCLC. In contrast, a policy of delivering attenuated doses of the same chemotherapy regimen without growth factor support, although feasible and well tolerated, appears to provide insufficient therapeutic results. Whether a strategy of full-dose standard platinum/etoposide is superior in terms of survival than that of using attenuated chemotherapy doses of the same chemotherapy regimen remains to be proven in a randomized prospective trial, which is currently being planned.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Caterina Donato for careful data management and scientific record keeping of the study.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted November 24, 2003; accepted October 13, 2004.

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