Platinum-Etoposide Chemotherapy in Elderly Patients With Small-Cell Lung Cancer: Results of a Randomized Multicenter Phase II Study Assessin
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▲還散笫雖悝◎
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
ABSTRACT
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
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
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每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 米g/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/米L, or platelets less than 100,000/米L, 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/米L and less than 4,000/米L, or platelets ≡ 75,000 and less than 100,000/米L; 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/米L.
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
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每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.
Primary Outcome
At the first stage of the study the observed TSs were 10 (36%; 95% CI, 19% to 56%) in AD arm, and 16 (62%; 95% CI, 41% to 79%) in FD arm. The number of TSs in AD arm was less than that required by the study design (ie, 13) to proceed with accrual onto the second stage of the trial. Conversely, accrual was resumed at the second stage in FD arm, and a total of 42 (63%; 95% CI, 50% to 74%) TSs were recorded among the 67 registered patients overall.
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.
Secondary Outcomes
In the AD arm, a partial response was observed in 11 (39%) of 28 patients (95% CI, 22% to 59%); no complete responses were observed. Eleven patients (39%) had stable disease and only four patients (14%) had disease progression; two patients were not assessable. In the FD arm, a partial response was observed in 37 (55%) of 67 patients; 9 complete responses (13%) were observed for an overall response rate of 69% (95% CI, 56% to 79%). Six patients (9%) had stable disease, and only four patients (6%) had disease progression; 11 patients were not assessed for response (Table 3).
At the time of final analysis, 27 of 28 patients in the AD arm had died: 25 patients as a result of disease progression or related complications, one patient as a result of congestive heart failure, and one patient from unknown causes. In the FD arm, 58 of 67 patients had died: 41 patients as a result of disease progression or related complications, one patient as a result of toxicity (febrile neutropenia and renal failure), one patient as a result of myocardial infarction, one patient as a result of congestive heart failure, one patient as a result of pulmonary embolism, one patient from a worsening of general conditions, and in 12 patients the cause of death could not be precisely determined. Median overall survival in the AD arm was 31 weeks with a probability of survival of 18% and 0% at 1 and 2 years, respectively, whereas, in the FD arm, median survival was 41 weeks with a probability of survival at 1 and 2 years of 39% and 12%, respectively (Table 3).
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每4 myelotoxicity, and only four cases of grade 3每4 nonhematologic toxicity. In the FD arm, toxicity was also mild, with grade 3每4 leukopenia and/or thrombocytopenia occurring in approximately 10% of patients. Grade 3每4 nonhematologic toxicity rate was also low, always less than 10% in all patients (Table 4).
Overall, only one patient in the FD arm died of toxicity during the fourth course of therapy, as a result of grade 4 renal toxicity and febrile neutropenia.
DISCUSSION
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每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每4 leukopenia and/or thrombocytopenia occurring in approximately 10% of the patients, and grade 3每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每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
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
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2. Laurie SA, Logan D, Markman BR, et al: Practice guideline for the role of combination chemotherapy in the initial management of limited-stage small-cell lung cancer. Lung Cancer 43:223每240, 2004
3. Bleehen NM, Girling DJ, Machin D, et al: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC), I: Survival and prognostic factors〞Medical Research Council Lung Cancer Working Party. Br J Cancer 68:1150每1156, 1993
4. Siu LL, Shepherd FA, Murray N, et al: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14:821每828, 1996
5. Poplin E, Thompson B, Whitacre M, et al: Small cell carcinoma of the lung: Influence of age on treatment outcome. Cancer Treat Rep 71:291每296, 1987
6. Rinaldi M, De Marinis F, Ardizzoni A: Correlation between age and prognosis in patients with advanced non small cancer (NSCLC) treated with cisplatin (DDP) containing chemotherapy: A retrospective multicenter study. Ann Oncol 5:58, 1994 (suppl 8, abstr 0289)
7. Findlay MP, Griffin AM, Raghavan D, et al: Retrospective review of chemotherapy for small cell lung cancer in the elderly: Does the end justify the means Eur J Cancer 27:1597每1601, 1991
8. Clamon GH, Audeh MW, Pinnick S: Small cell lung carcinoma in the elderly. J Am Geriatr Soc 30:299每302, 1982
9. Radford JA, Ryder WD, Dodwell D, et al: Predicting septic complications of chemotherapy: An analysis of 382 patients treated for small cell lung cancer without dose reduction after major sepsis. Eur J Cancer 29A:81每86, 1992
10. Shepherd FA, Amdemichael E, Evans WK, et al: Treatment of small cell lung cancer in the elderly. J Am Geriatr Soc 42:64每70, 1994
11. Gridelli C, De Vivo R, Monfardini S: Management of small-cell lung cancer in the elderly. Crit Rev Oncol Hematol 41:79每88, 2002
12. Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small cell lung cancer: A stopped multicentre randomized trial〞Medical Research Council Lung Cancer Working Party. Lancet 348:563每566, 1996
13. Souhami RL, Spiro SG, Rudd RM, et al: Five-day oral etoposide treatment for advanced small-cell lung cancer: Randomised comparison with intravenous chemotherapy. J Natl Cancer Inst 89:577每580, 1997
14. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1每10, 1989
15. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319每324, 1993
16. 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. N Engl J Med 325:164每170, 1991
17. Ihde DC, Mulshine JL, Kramer BS, et al: Prospective randomized comparison of high-dose and standard-dose etoposide-cisplatin chemotherapy in patients with extensive-stage small cell lung cancer. J Clin Oncol 12:2022每2034, 1994
18. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10:282每291, 1992
19. Ozer H, Armitage JO, Bennet CL, et al: Update of recommendations for the use of hematopietic colony-stimulating factor: Evidence-based, clinical practice guidelines. J Clin Oncol 18:3558每3585, 2000
20. Klastersky J, Paesmans M, Rubenstein EB, et al: The multinational association for supportive care in cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038每3051, 2000(Andrea Ardizzoni, Adolfo )
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
ABSTRACT
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
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
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每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 米g/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/米L, or platelets less than 100,000/米L, 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/米L and less than 4,000/米L, or platelets ≡ 75,000 and less than 100,000/米L; 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/米L.
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
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每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.
Primary Outcome
At the first stage of the study the observed TSs were 10 (36%; 95% CI, 19% to 56%) in AD arm, and 16 (62%; 95% CI, 41% to 79%) in FD arm. The number of TSs in AD arm was less than that required by the study design (ie, 13) to proceed with accrual onto the second stage of the trial. Conversely, accrual was resumed at the second stage in FD arm, and a total of 42 (63%; 95% CI, 50% to 74%) TSs were recorded among the 67 registered patients overall.
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.
Secondary Outcomes
In the AD arm, a partial response was observed in 11 (39%) of 28 patients (95% CI, 22% to 59%); no complete responses were observed. Eleven patients (39%) had stable disease and only four patients (14%) had disease progression; two patients were not assessable. In the FD arm, a partial response was observed in 37 (55%) of 67 patients; 9 complete responses (13%) were observed for an overall response rate of 69% (95% CI, 56% to 79%). Six patients (9%) had stable disease, and only four patients (6%) had disease progression; 11 patients were not assessed for response (Table 3).
At the time of final analysis, 27 of 28 patients in the AD arm had died: 25 patients as a result of disease progression or related complications, one patient as a result of congestive heart failure, and one patient from unknown causes. In the FD arm, 58 of 67 patients had died: 41 patients as a result of disease progression or related complications, one patient as a result of toxicity (febrile neutropenia and renal failure), one patient as a result of myocardial infarction, one patient as a result of congestive heart failure, one patient as a result of pulmonary embolism, one patient from a worsening of general conditions, and in 12 patients the cause of death could not be precisely determined. Median overall survival in the AD arm was 31 weeks with a probability of survival of 18% and 0% at 1 and 2 years, respectively, whereas, in the FD arm, median survival was 41 weeks with a probability of survival at 1 and 2 years of 39% and 12%, respectively (Table 3).
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每4 myelotoxicity, and only four cases of grade 3每4 nonhematologic toxicity. In the FD arm, toxicity was also mild, with grade 3每4 leukopenia and/or thrombocytopenia occurring in approximately 10% of patients. Grade 3每4 nonhematologic toxicity rate was also low, always less than 10% in all patients (Table 4).
Overall, only one patient in the FD arm died of toxicity during the fourth course of therapy, as a result of grade 4 renal toxicity and febrile neutropenia.
DISCUSSION
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每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每4 leukopenia and/or thrombocytopenia occurring in approximately 10% of the patients, and grade 3每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每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
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.
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