Affiliations of authors: Weston Park Hospital, Sheffield, UK (PL, PJW); Nottingham City Hospital, Nottingham, UK (PJW); Royal Marsden Hospital, Surrey, UK (MERO); Amgen, Cambridge, UK (MRS); Christie Hospital, Manchester, UK (PL, LFA, NT)
Correspondence to: Paul Lorigan, MD, Christie Hospital NHS Trust, Wilmslow Rd., Manchester, M20 4BX, United Kingdom (e-mail: paul.lorigan{at}manchester.ac.uk).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The combination of cisplatin and etoposide with thoracic radiation therapy in limited-stage SCLC is associated with a survival advantage over non-platinum-based therapy, albeit not always statistically significantly so (1822). Carboplatin, an analogue of cisplatin, is active in the treatment of SCLC, and its substitution for cisplatin has potential advantages (2326). The Manchester Lung Group has reported 2-year survival rates of 30%33% in patients with zero or one adverse prognostic factor who were treated with vincristine, ifosfamide, carboplatin, and etoposide (VICE) chemotherapy (27). More recently, a large study in the United Kingdom compared VICE chemotherapy with standard treatment (predominantly anthracycline-based chemotherapy) (28) and found a statistically significant survival advantage for limited-stage patients treated with VICE, with a median survival of 15.1 months, compared with 11.6 months for patients treated with standard chemotherapy (P = .026).
If vincristine is omitted from VICE to obtain ICE chemotherapy, the major dose-limiting toxicity is hematologic toxicity. We have recently reported the feasibility of substantial dose intensification of ICE chemotherapy in SCLC supported by sequential reinfusion of growth factor-mobilized hemopoietic progenitor cells from whole blood (29,30). With this approach, it is possible to double the relative dose intensity of ICE chemotherapy. We now report the results from a randomized phase III trial among patients with relatively good prognosis SCLC that compared patients who received ICE chemotherapy with a 4-week interval between cycles without blood progenitor cell or growth factor support (standard therapy) with patients who received ICE chemotherapy with a 2-week interval between cycles and who were supported with filgrastim and autologous blood progenitor cells (dose-dense therapy).
![]() |
PATIENTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Eligible patients had previously untreated, pathologically confirmed SCLC and were between the ages of 18 and 70 years. Staging was carried out by clinical examination, chest radiography, upper abdominal imaging (computed tomography and/or ultrasound), and bone marrow aspirate examination. Patients with a maximum of one of the following adverse prognostic factors were eligible for the study: a Karnofsky performance score of less than 60, extensive-stage disease, a serum sodium level of less than the lower limit of the normal range, a serum lactate dehydrogenase level of more than the upper limit of the normal range, and a serum alkaline phosphate level of more than 1.5 times the upper limit of the normal range (31). Patients were required to have a normal peripheral blood count, a normal bone marrow aspirate examination (i.e., no evidence of malignant infiltration), and a measured creatinine clearance of at least 75 mL/minute. The protocol was approved by the Ethics Committees of the participating institutions, and all patients provided written informed consent. The study was carried out at the Christie Hospital, Manchester; Weston Park Hospital, Sheffield; Nottingham City Hospital, Nottingham; and the Royal Marsden Hospital, Surrey. Patients were enrolled between April 1994 and August 2001.
Treatment Allocation and Regimens
Patient randomization was carried out by the Department of Medical Statistics, Christie Hospital. Patients were stratified by prognostic score (0 or 1). We randomly assigned 318 patients to receive six cycles of standard (n = 159 patients) or dose-dense (n = 159 patients) ICE chemotherapy (ifosfamide at 5 g/m2 intravenously for 24 hours on day 1 with Mesna at 5 g/m2, carboplatin at 300 mg/m2 intravenously on day 1, and etoposide at 180 mg/m2 intravenously on days 1 and 2). Ten patients were ineligible (four patients in the standard arm including two with brain metastasis, one with a creatinine clearance of less than 75 mL/minute, and one with two adverse prognostic factors and six patients in the dose-dense arm including two with positive bone marrow tests and four with brain metastases). Standard ICE chemotherapy was given with a 4-week interval between cycles without growth factor support. Dose-dense ICE chemotherapy was given with a 2-week interval between cycles with subcutaneously administered filgrastim (Amgen Ltd., Cambridge, UK) at 300 µg for patients weighing less than 70 kg and at 5 µg/kg for patients weighing more than 70 kg, daily on days 4 through 14. In addition, patients in the dose-dense arm had 750 mL of blood collected by venesection into standard blood donor bags on day 15, immediately before their next chemotherapy treatment. This autologous blood was stored at 4 °C and reinfused 48 hours later (i.e., 24 hours after the completion of the next cycle of chemotherapy). Before each chemotherapy cycle, the performance status and body weight were determined, and a physical examination, laboratory tests, and chest radiography were performed. A full blood count was carried out weekly.
Chemotherapy was given to patients as long as their white-blood-cell count was more than 3 x 109 cells per liter, their platelet count was more than 30 x 109 platelets per liter without platelet transfusion support for patients in the dose-dense arm or more than 100 x 109 platelets per liter for patients in the standard arm, and their creatinine clearance was more than 50 mL/minute. No dose reductions were permitted in either arm. In the dose-dense arm, venesection, chemotherapy, and subsequent autotransfusion could be delayed and filgrastim could be continued for up to 3 days to permit hematologic recovery. If hematologic recovery did not occur, chemotherapy was deferred for up to 2 weeks and was administered without progenitor cell support, filgrastim was restarted 4 days after chemotherapy, and venesection and autotransfusion were performed with the next cycle of treatment. Patients in the dose-dense arm for whom chemotherapy was delayed for 2 weeks or more because of hematologic or nonhematologic toxicity were transferred to standard ICE chemotherapy. If the delay was 2 weeks or less because of nonhematologic toxicity (excluding renal toxicity), they continued to receive dose-dense chemotherapy on recovery. Patients in the standard arm who experienced a delay in treatment of 2 weeks or more continued treatment at the discretion of the investigator. Patients in either arm with a treatment delay of 2 weeks or more because of renal toxicity were withdrawn from the study. All patients with treatment complications underwent daily biochemistry tests and blood cell counts. Toxicity was graded according to the World Health Organization criteria for evaluation of acute and subacute toxicity (32).
Prophylactic antibiotics were used according to customary practice at each institution. Patients with febrile neutropenia (temperature of 37.5 °C or more on two occasions or 38.0 °C on one occasion and a white-blood-cell count of less than 1.0 x 109 cells per liter) were admitted for parenteral antibiotics. Red-cell and platelet transfusions were used as necessary to maintain a platelet count of more than 20 x 109 platelets per liter and a hemoglobin level of more than 8 g/dL. Patients were assessed for response after the third cycle of treatment and at the end of treatment. Criteria for response have been previously published (33). A complete response was defined as the disappearance of all clinical evidence of tumor that was determined by two observations not less than 4 weeks apart. A partial response was defined as a 50% or greater decrease in the sum of the products of the biperpendicular diameters of measured lesions that was determined by two observations not less than 4 weeks apart, with no simultaneous increase in size of any lesion or appearance of new lesion. Stable disease was defined as a steady-state response that was less than partial response or progression that was less than progressive disease with a duration of at least 4 weeks. Progressive disease was defined as unequivocal increase of at least 25% in the sum of the products of the biperpendicular diameters of measured lesions.
Patients with limited-stage disease who responded to chemotherapy were offered thoracic radiation therapy and were considered for prophylactic cranial radiation therapy. The dose and fractionation of the thoracic radiation therapy were determined by local practice. All patients were reviewed at least once every 6 months from the time of random assignment until death.
Relative Dose Intensity
Relative dose intensity was calculated for each patient and defined as the dose intensity achieved relative to the standard schedule with a 4-week interval between treatments. Relative dose intensity was calculated by assuming that each component of the chemotherapy schedule was equipotent. The relative dose intensity was calculated as
![]() |
where AT is the actual total dose, PT is the planned total dose, carb is carboplatin, ifos is ifosfamide, etop is etoposide, and time is the duration of chemotherapy (from the first day of chemotherapy to the day of the last etoposide dose of the final cycle). Hence, the planned dose intensity was 1 for the standard arm and 2 for the dose-dense arm. Cycles not given were not included in the dose intensity calculation.
Statistical Methods
The primary end point was survival. Secondary end points were response rate, relative dose intensity, time to disease progression, and toxicity. Survival was calculated by the KaplanMeier method. A two-sided log-rank test was used to compare survival in both arms. The sample size of 318 was calculated to have a 90% power at 5% statistical significance level to detect a 15% increase in 2-year survival from 19% to 34%. The first 50 patients were entered into the randomized phase II part of the study to determine the feasibility and safety of dose-dense therapy (30).
All 318 patients were included for survival analysis on an intention-to-treat basis, and those patients who were eligible for the study and received at least one cycle were included in the efficacy and toxicity analysis. All statistical tests were two-sided.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Three hundred eighteen patients were treated in four centers. Ten of the 318 randomly assigned patients turned out to be ineligible (four patients in the standard arm including two with brain metastasis, one with a creatinine clearance of less than 75 mL/minute, and one with two adverse prognostic factors and six patients in the dose-dense arm including two with positive bone marrow tests and four with brain metastases) (Fig. 1). These patients were assessed for toxicity but not efficacy.
|
Patient and tumor characteristics are shown in Table 1. The patient groups were evenly balanced with respect to age, sex, and performance status. Ten percent of patients in the standard arm and 13% in the dose-dense arm had extensive-stage disease. There were more patients with a prognostic score of 0 in the standard arm (92 patients) than in the dose-dense arm (78 patients), but this difference was not statistically significant.
|
One patient in the dose-dense arm died the day after randomization. The remaining 317 patients received 824 cycles of chemotherapy in the standard arm (159 patients) and 852 in the dose-dense arm (158 patients) (Table 2). The numbers of cycles of chemotherapy received between the two arms were not statistically significantly different (P = .888, two-sided Wilcoxon test). Fifty of the 159 patients in the standard arm (31%) and 51 of the 158 patients in the dose-dense arm (32%) discontinued treatment before completing six cycles, and 109 patients (69%) in the standard arm and 108 patients (69%) in the dose-dense arm completed six cycles of treatment. Eighteen patients converted from the dose-dense schedule to the standard schedule (eight because of toxicity, four because they were ineligible for the dose-dense schedule, four because of patient choice, and two because of protocol error). One patient assigned to the dose-dense arm received standard treatment in error.
|
Delivered Dose Intensity
The difference in relative dose intensity between the two arms was statistically significant (Fig. 2). The median dose intensity was 99% (range = 66%158%) for the standard arm (where 100% is defined as a standard cycle of chemotherapy with no dose reductions or delays) and 182% (range = 100%218%) for the dose-dense arm (difference = 83%, Wilcoxon test statistic [z] = 14.92; P<.001). The 18 patients in the dose-dense arm who reverted to the standard arm were analyzed as per intention to treat in the dose-dense arm; for those 18 patients, the delivered dose intensity ranged from 105% to 135%. One patient who had been randomly assigned to the standard arm received the dose-dense schedule in error, accounting for the upper limit of 158% in the dose intensity range for the standard arm. Recorded delivered dose intensity of more than 100% in the standard arm or 200% in the dose-dense arm was attributed to increases in the actual dose-delivered due to increases in the body surface area with subsequent cycles delivered; dose intensity was calculated by use of the body surface area at the start of treatment.
|
Response rates, median time to progression, median survival, and 1- or 2-year survival were not statistically significantly different between the two arms (for overall survival, regression coefficient = 0.011; hazard ratio [HR] = 1.01, 95% CI = 0.80 to 1.29; Tables 3 and 4). Overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm (difference = 8%, 95% CI = 1% to 17%; P = .09). Median overall survival was 13.9 months (95% CI = 12.1 to 15.7) in the standard arm and 14.4 months (95% CI = 13.1 to 15.4) in the dose-dense arm (P = .76); 2-year survivals were 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively (P = .67). Time to disease progression was similar in both arms (336 days in the standard arm and 321 days in the dose-dense arm, difference = 15 days). For patients who received six cycles of treatment, patients in the dose-dense arm were expected to complete their treatment an average of 84 days sooner than those in the standard arm. Patients in the standard arm survived a median of 286 days (95% CI = 229 to 343 days) after the completion of treatment, and patients in the dose-dense arm survived 367 days (95% CI = 321 to 413 days). Consequently, survival after the completion of treatment was on average 81 days longer for patients in the dose-dense arm than for patients in the standard arm (P = .109).
|
|
In most cases, venesection for the collection of blood for reinfusion was performed as planned, but 73 (11%) of 663 blood collections deviated from this schedule, mainly because of a delayed recovery of the platelet count. Consequently, 10 patients (6%) in the dose-dense arm reverted to the standard schedule because of problems with venesection.
The percentages of serious adverse events reported for the two treatment arms were not statistically significantly different; 56% of patients on the standard arm and 63% of patients on the dose-dense arm had at least one serious adverse event (difference = 7%, 95% CI = 4% to 18%; P = .5). A total of 14 patients died, nine deaths in the standard arm (five from neutropenic sepsis and one each from progressive disease, pulmonary embolism, pneumonia and cardiac arrest, and myocardial infarction and cardiac failure) and five in the dose-dense arm (two from neutropenic sepsis, one from progressive disease, and two from myocardial infarction and cardiac failure).
Results for the worst hematologic toxicities are shown in Table 5. Grade 3 and 4 toxicity for hemoglobin and platelets was statistically significantly higher in the dose-dense arm than in the standard arm (for hemoglobin, 71% and 46%, respectively, difference = 25%, 95% CI of the difference = 14% to 36%; P = .005; and for platelets, 94% and 83%, respectively, difference = 11%, 95% CI = 4% to 18%; P = .001). In addition, there was an increase in the incidence of grade 3 and 4 thrombocytopenia in both arms with successive cycles of treatment. This increase was more marked in patients receiving dose-dense treatment (grade 3 and 4 thrombocytopenia after cycle 2 = 52% and after cycle 6 = 93%) than in those receiving standard treatment (46% for cycle 2 and 71% for cycle 6). However, when we considered clinically relevant toxicity, fewer patients in the dose-dense arm had at least one episode of neutropenic sepsis (18.2% versus 24.4%, respectively), although the difference was not statistically significant. In addition, fewer cycles of dose-dense chemotherapy than of standard chemotherapy were complicated by neutropenic sepsis (11.6% versus 15.3%, respectively; difference = 3.7%, 95% CI = 2.0% to 9.6%; P = .031). There were more serious adverse events related to thrombocytopenia in the dose-dense arm than in the standard arm (24 versus 10 events, respectively).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cytotoxic dose intensity is defined as chemotherapy dose per unit time and is usually expressed as a relative dose intensityi.e., the ratio of the received dose intensity in the study arm to that planned in the standard arm. Variations in dose intensity and total dose can be achieved by differences in the dose per cycle, number of cycles, interval between cycles (dose density), or a combination of these factors.
Three randomized studies that used growth factor support to reduce the interval between treatment cycles have reported a modest improvement in survival for patients receiving dose-dense treatment compared with patients receiving standard treatment. We have previously shown that it is possible to intensify the dose of VICE simply by treating patients as soon as they have recovered from a toxicity rather than waiting for a fixed cycle interval (12). The delivered dose intensity could be further increased from 118% to 125% with lenograstim. Although there was no difference in median survival, this modest increase in dose intensity was associated with an improvement in the 2-year survival from 15% (95% CI = 2% to 27%) to 32% (95% CI = 16% to 48%) (P not given). A larger European study randomly assigned 299 patients to six cycles of VICE with intervals of 3 or 4 weeks between cycles and to granulocytemacrophage colony-stimulating factor or placebo (13). The delivered dose intensity was 26% higher in the dose-dense arm, and this translated into a statistically significantly better survival for patients in the dose-dense arm (2-year survival, 33% versus 18%; P = .001).
The UK Medical Research Council studied 403 patients randomly assigned to receive doxorubicin, cyclophosphamide, and etoposide (ACE) with a 3-week interval between cycles or to receive the same treatment with a 2-week interval between cycles plus lenograstim support (14). The increased dose intensity of 34% was associated with a statistically significantly improved 2-year survival (13% versus 8%, respectively; P = .04) without a deterioration in the quality-of-life assessment.
Three studies have been reported that examined a combination of the variables of interval, dose per cycle, and number of cycles. James et al. (15) randomly assigned 167 patients with poor prognosis SCLC to receive alternating cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin and etoposide (CAV/PE) with a 3-week interval between cycles for six cycles or to receive 12 cycles at a 50% dose reduction per cycle, with an 11- or 12-day interval between cycles. They found no difference in received dose intensity or survival between the two arms. Pujol et al. (16) examined the effect of an increased dose per cycle for a reduced number of cycles by randomly assigning 125 patients with extensive-stage SCLC to cyclophosphamide, cisplatin, epirubicin, and etoposide with a 3-week interval between cycles for six cycles or for four cycles of treatment given at 150% dose per cycle (except for cisplatin, which was given at 120%) with granulocytemacrophage colony-stimulating factor support. Planned cumulative doses of the drugs were the same in both treatment arms except for cisplatin (which was 80% in the higher-dose arm). The trial was closed after an interim analysis showed that the cumulative dose of chemotherapy delivered was statistically significantly lower in the dose-intensified arm because of the higher toxicity encountered. The relative dose intensity achieved is not recorded. Although the overall response rates were similar, the median survival was inferior for patients in the dose-dense arm compared with patients in the standard arm (8.9 months versus 10.8 months, respectively).
The European Organisation for Research and Treatment of Cancer (EORTC) recently reported a randomized comparison of standard-dose doxorubicin, cyclophosphamide, and etoposide given for five cycles with a 3-week interval between cycles versus intensified treatment given at 125% of the dose plus filgrastim support for four cycles with a 2-week interval between cycles (17). The median dose intensity delivered was 70% higher in the dose-dense arm than in the standard arm, and the median relative cumulative dose was similar in both arms (99% for standard arm and 90% for dose-intensified arm). There were no differences in median or 2-year survival between the two arms. There was some evidence of improved outcome among patients with limited-stage disease treated with the dose-dense regimen compared with the standard regimen (median survival = 77 weeks versus 62 weeks, respectively), however, and the reverse was observed in patients with extensive-stage disease (median survival = 40 weeks versus 51 weeks, respectively); neither difference reached statistical significance.
A preliminary report of a randomized phase II study with the same study design that we used in this study has been presented (35). That study reported statistically significantly better median survival (29.8 months versus 17.4 months, respectively; P = .02) and 2-year survival (62% versus 36%, respectively; P = .05) for the dose-dense arm than for the standard arm. However, given the small study size (only 70 patients), these results should be viewed with caution.
We have previously reported (27) 2-year survival rates with standard VICE chemotherapy with a 4-week interval between treatments of 30%33% for successive phase II trials in SCLC patients, higher than the 22% 2-year survival with standard ICE chemotherapy with a 4-week interval between treatments in this study. However, the median survival and 2-year survival for patients receiving standard ICE chemotherapy in this study were similar to these outcomes for patients receiving VICE with a 4-week interval between treatments reported in phase III studies by Steward (13) (median survival = 11.5 months and 2-year survival = 18%), Woll et al. (12) (median survival = 15 months and 2-year survival = 15%), and a Medical Research Council trial (28) comparing VICE with standard, predominantly doxorubicin, cyclophosphamide, and etoposide (ACE) chemotherapy (median survival = 15 months and 2-year survival = 19%), indicating that the ICE regimen used was not inferior to the standard VICE regimen. Furthermore, the 2-year survival reported in our study is higher than that reported in the EORTC study, but this difference may be, in part, the result of the lower number of extensive-stage patients (10% in this study versus 40% in EORTC study) (17) and the use of a nonplatinum-based regimen. It is tempting to suggest that substantial dose intensification has little impact on survival in patients with extensive-stage disease; however, the two largest studies (13,14) reporting a survival advantage for dose-dense chemotherapy included 41% and 23% patients with extensive-stage disease, respectively. There is also evidence that early dose intensification is associated with an improved outcome, although only 105 patients were studied (2); early dose intensity was maintained in this study, with only 18 patients crossing over from the dose-dense to the standard regimen.
Radiation therapy has an established role in consolidating the response of the primary tumor to chemotherapy and in reducing the risk of brain metastases as a site of recurrence. Prophylactic cranial irradiation is associated with a 5% increase in survival at 5 years of follow-up in patients achieving a complete response to chemotherapy (36). Given the complete response rate of 35% in the standard arm, the prophylactic cranial irradiation rate in this study was appropriate. Although it is unclear why the number of patients in the dose-dense arm receiving prophylactic cranial irradiation was higher in this study, patients may have been more willing to accept consolidation radiotherapy when they had completed chemotherapy sooner on the dose-dense arm. These imbalances in rates of prophylactic irradiation would have been expected to favor the dose-dense arm over the standard arm.
In this study, thoracic radiotherapy was given after completion of chemotherapy. In younger patients with limited-stage disease responding to chemotherapy, thoracic radiotherapy is associated with a 5% increase in survival at 5 years of follow-up (37). Since this study was initiated, the importance of the dose, timing, and fractionation schedule for radiation therapy to outcome has become somewhat clearer (3846). A recent meta-analysis (47) suggested a survival advantage for early concurrent radiation therapy that was started before 9 weeks after the start of platinum-based chemotherapy, compared with delayed radiotherapy, and for hyperfractionated radiation therapy. However, results of the London Lung Cancer Group study (43), which showed no difference in outcome between concurrent and sequential radiation therapy, were not included in the meta-analysis. A subsequent Cochrane Review (48) that includes the London Lung Cancer Group study found an advantage for early compared with late radiation therapy at the 5-year follow-up but not at the 2-year follow-up. Importantly, there were only 3 years of follow-up available for the London Lung Cancer Group study, so the positive results at 5 years should be interpreted with caution. There are no published data from clinical trials combining ifosfamide-based chemotherapy for lung cancer and early, concurrent radiation therapy, but anecdotal evidence suggests that substantial toxicity is associated with this regimen (47).
Although, in our trial, hematologic toxicity was statistically significantly worse in the dose-dense arm than in the standard arm, this finding was not of major clinical relevance for the majority of patients. Fewer patients in the dose-dense arm had an episode of febrile neutropenia, probably reflecting the shorter duration of neutropenia resulting from the use of filgrastim and autologous blood. The levels of natural killer cell precursors may be maintained in autologous salvaged blood but not in allogeneic blood or autologous blood that was collected before therapy, and these cells may have protected patients in the dose-dense arm from infection (50). A recent study in patients undergoing joint replacement surgery examined natural killer cell precursors before and 5 days after surgery in five groups of patients according to the type of transfusion received, including the following types: not transfused, allogeneic non-leuko-depleted, allogeneic leuko-depleted, autologous predeposited a minimum of 3 days before surgery, and autologous salvaged blood collected within 24 hours of surgery. The mean levels of natural killer cell precursors were lower after surgery in all groups after surgery than were preoperative levels, except for the autologous salvaged blood group, which had higher results than did all the other groups (P<.001). The incidence of neutropenic sepsis reported in this study was comparable to that reported elsewhere (9,44) for the VICE regimen. Blood product use was higher for patients in the dose-dense arm than in the standard arm. In this study, we also found that, when autologous blood stem cells supported with filgrastim are used, it is possible to safely treat patients with low but increasing platelet counts at threshold levels that are lower than those conventionally used.
The major limitations of this study were centered around thoracic radiotherapy, which was delivered sequentially rather than concurrently. It remains unclear whether early concurrent radiotherapy is superior to sequential radiotherapy, but the best survival rates in this group of patients have been reported for early hyperfractionated radiotherapy given concurrently with cisplatin and etoposide (44). The other area of weakness is the lack of formal quality-of-life analysis; we depended instead on physician-assessed toxicity. Patient-reported quality of life is now considered a gold standard in assessing the impact of palliative treatments. However, both of these considerations would be more important if we had observed a survival advantage associated with the dose-dense approach compared with the standard approach and were recommending the dose-dense regimen as a standard treatment.
We did not set out to assess quality of life in this trial. However, given the similarity of nonhematologic toxicity for patients in both arms and the fewer episodes of febrile neutropenia and the shorter treatment course for patients in the dose-dense arm, the dose-dense regimen was acceptable to patients, with only four patients choosing to convert to standard therapy. The move from leukapheresis and cryopreservation to collection and refrigeration of autologous whole blood also renders the dose-dense regimen relatively easy and safe to undertake.
In this investigation, therefore, we have validated the use of the dose-dense regimen in terms of safety, deliverability, and acceptability in a large, multicenter trial, and so this regimen can be applied to other tumor types in which dose intensity may have a greater impact on survival. We suggest that the current literature on dose intensification in SCLC indicates that survival rates have reached a plateau and that further attempts at dose intensification are not justified. However, reduced dose-intensity and single-agent studies (5153) emphasize the importance of maintaining cytotoxic dose intensity to obtain the benefits of chemotherapy treatment in SCLC.
![]() |
NOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Dr. Thatcher has received research support and honoraria for lecturing and advising Amgen and other companies producing hematopoietic growth factors. Dr. Sampson is an employee of Amgen and holds stock options in the company. Dr. Lorigan has received a travel grant from Amgen.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
(1) Cohen M, Creaven P, Fossieck B, Broder L, Selawry O, Johnson A, et al. Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treatment Rep 1977;61:34954.[ISI][Medline]
(2) Arriagada R, Le Chevalier T, Pignon JP, Riviere A, Monnet I, Chomy P, et al. Initial chemotherapeutic doses and survival of patients with limited SCLC. N Engl J Med 1993;329:184852.
(3) Ettinger D, Finkelstein D, Abeloff M, Ruckdeschel J, Aissuers S, Eggleston J. A randomised comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive stage small-cell lung cancer. J Clin Oncol 1990;8:23040.[Abstract]
(4) Cullen M, Morgan D, Gregory W, Robinson M, Cox D, McGivern D, et al. Maintenance chemotherapy for anaplastic small cell carcinoma of the bronchus: a randomised, controlled trial. Cancer Chemother Pharmacol 1986;17:15760.[CrossRef][ISI][Medline]
(5) Medical Research Council Lung Cancer Working Party. Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Br J Cancer 1989;59:58490.[ISI][Medline]
(6) Giaccone G, Dalesio O, McVie G, Kirkpatrick A, Postmus P, Burghouts J, et al. Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1993;11:123040.[Abstract]
(7) Spiro S, Souhami R, Geddes D, Ash C, Quinn H, Harper P, et al. Duration of chemotherapy in small cell lung cancer: a Cancer Research campaign trial. Br J Cancer 1989;59:57883.[ISI][Medline]
(8) Lebeau M, Chastang C, Allard P, Migueres J, Boita H, Fichet D. Six versus 12 cycles for complete responders to chemotherapy in small cell lung cancer: definitive results of a randomised clinical trial. Eur Respir J 1992;5:28690.[Abstract]
(9) Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by granulocyte colony stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. New Engl J Med 1991;325:16470.[Abstract]
(10) Trillet-Lenoir V, Green J, Manegold C, Von Pawel J, Gatzemeier U, Lebeau B, et al. Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 1993;29A:31924.[CrossRef][ISI][Medline]
(11) Fukuoka M, Masuda M, Negoro S, Matsui K, Yana T, Kudoh S, et al. CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 1997;75:3069.[ISI][Medline]
(12) Woll PJ, Hodgetts J, Lomax L, Bildet F, Cour-Chabernaud V, Thatcher N. Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomised controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 1995;13:6529.[Abstract]
(13) Steward W, von Pawel J, Gatzemeier U, Woll P, Thatcher N, Koschel G, et al. Effects of granulocytemacrophage colony-stimulating factor and dose intensification of VICE chemotherapy in small-cell lung cancer (SCLC): a prospective randomised study of 300 patients. J Clin Oncol 1998;16:64250.[Abstract]
(14) Thatcher N, Girling D, Hopwood P, Sambrook R, Qian W, Stephens R. Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony stimulating factor support: results of a British MRC multi-centre randomised trial. J Clin Oncol 2000;18:395404.
(15) James L, Gower N, Rudd R, Spiro S, Harper P, Trask C, et al. A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1996;73:15638.[ISI][Medline]
(16) Pujol JL, Douillard JY, Riviere A, Quoix E, Lagrange JL, Berthaud P, et al. Dose intensity with four drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony stimulating factor in extensive stage small-cell lung cancer: a multi-centre randomised phase III trial. J Clin Oncol 1997;15:20829.[Abstract]
(17) Ardizzoni A, Tjan-Heijnen V, Postmus P, Buchholz E, Biesma B, Karnicka-Mlodkowska H, et al. Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organisation for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 2002;20:394755.
(18) Bonomi P. Review of selected randomized trials in small-cell lung cancer. Semin Oncol 1998;25(4 Suppl 9):708.
(19) Janne P, Freidlin B, Saxman S, Johnson D, Livingston R, Shepherd F, et al. Twenty five years of clinical research for patients with limited stage small-cell lung cancer in North America. Cancer 2002;95:152832.[CrossRef][ISI][Medline]
(20) Sundstrøm S, Bremnes R, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 2002;20:466572.
(21) Chute J, Chen T, Feigal E, Simon R, Johnson B. Twenty years of Phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794801.
(22) Pujol J, Corestia L, Daures J. Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomised trials of cisplatin containing regimen versus a regimen without this alkylating agent. Br J Cancer 2000;83:815.[CrossRef][Medline]
(23) Bunn P. Review of therapeutic trials of carboplatin in lung cancer. Semin Oncol 1989;16(2 Suppl 5):2733.
(24) Gatzemeier U, Hossfeld D, Neuhauss R, Reck M, Achterrath W, Lennaz L, et al. Phase II and III studies with carboplatin in small-cell lung cancer. Semin Oncol 1992;19(1 Suppl 2):2836.[Medline]
(25) Thatcher N, Lind M. Carboplatin in small-cell lung cancer. Semin Oncol 1990;17(1 Suppl 2):408.
(26) Kosmidis P, Samantas E, Fountzilas G, Pavlidis N. Cisplatin etoposide versus carboplatin etoposide chemotherapy and irradiation in small-cell lung cancer: a randomised phase 3 trial. Semin Oncol 1994;21:2330.[ISI][Medline]
(27) Lorigan P, Lee SM, Betticher D, Woodhead M, Weir D, Hanley S, et al. Chemotherapy with vincristine/ifosfamide/carboplatin/etoposide in small cell lung cancer. Semin Oncol 1995;22(3 Suppl 7):3241.
(28) Thatcher N, Qian W, Girling D. Ifosfamide, carboplatin and etoposide with mid-cycle vincristine versus standard chemotherapy in patients with small-cell lung cancer and good performance status: results of a MRC randomised trial (LU21). Proc Am Soc Clin Oncol 2003;22:2489.
(29) Pettengell R, Woll PJ, Thatcher N, Dexter M, Testa N. Multicyclic, dose-intensive chemotherapy supported by sequential reinfusion of haemopoietic progenitors in whole blood. J Clin Oncol 1995;13:14856.[Abstract]
(30) Woll PJ, Thatcher N, Lomax L, Hodgetts J, Lee SM, Burt P, et al. Use of haemopoietic progenitors in whole blood to support dose dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients. J Clin Oncol 2001;19:7129.
(31) Cerny T, Blair V, Anderson H, Bramwell V, Thatcher N. Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 1987;39:1469.[ISI][Medline]
(32) WHO handbook for reporting results of cancer treatment. Geneva (Switzerland): WHO; 1979.
(33) Stahel RA, Ginsberg R, Havemann K, Hirsch F, Ihde D, Jassem J, et al. Staging and prognostic factors in small-cell lung cancer. Lung Cancer 1989;5:11926.[CrossRef]
(34) Pettengell R, Woll P, O'Connor D, Dexter T, Testa N. Viability of haemopoietic progenitors from whole blood, bone marrow and leukapheresis product: effects of storage media, temperature and time. Bone Marrow Transplant 1994;14:7039.[ISI][Medline]
(35) Bucholz E, Drings P, Pilz L, Manegold C. Final results from a single centre, controlled study of standard versus dose intensified chemotherapy with sequential reinfusion of haemopoietic progenitor cells in SCLC. Proc Am Soc Clin Oncol 2003;22:2572.
(36) Auperin A, Arrigada R, Pignon J, le Pechoux C, Gregor A, Stephens R, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. New Engl J Med 1999;341:47684.
(37) Pignon J, Arrigada R, Ihde D, Johnson D, Perry M, Souhami R, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. New Engl J Med 1992;327:161824.[Abstract]
(38) Murray N, Coy P, Pater J, Hodson I, Arnold A, Zee B, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited stage SCLC. The NCIC Clinical Trials Group. J Clin Oncol 1993;1:33644.
(39) Work E, Nielsen O, Bentzen S Fode K, Palshof T. Randomised study of initial versus late chest irradiation in limited stage SCLC. Aarhus Lung Cancer Group. J Clin Oncol 1997;1:30307.
(40) Perry MC, Herndon JE III, Eaton WL, Green MR. Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083. J Clin Oncol 1998;16:24667.[Abstract]
(41) Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Initial versus delayed hyperfractionated therapy and concurrent chemotherapy in limited stage SCLC. J Clin Oncol 1997;15:893900.[Abstract]
(42) Takada M, Fukuoka M, Kawahara M, Sugiura T, Yokoyama A, Yokota S, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 2002;20:305460.
(43) James L, Spiro S, O'Donnell K, Rudd R, Clarke P, Trask C, et al. A randomised study of timing of thoracic irradiation in small-cell lung cancer Study 8. Lung Cancer 2003;41 (Suppl 2):69.[CrossRef]
(44) Turissi A, Kim K, Blum R, Sauve W, Livingston R, Komaki R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. New Engl J Med 1999;340:26571.
(45) Schild S, Brindle J, Geyer S, Krook J, Kugler J, Mailliard J, et al. Long term results of a phase III trial comparing once a day radiotherapy or twice a day radiotherapy in limited stage small-cell lung cancer. Lung Cancer 2003;41 (Suppl 2):68.
(46) Bonner J, Hillman S, Vigliottii A, Kozelsky T, Marks R, Frank A, et al. High dose, twice daily thoracic radiotherapy with daily chemotherapy in limited stage small-cell lung cancer. Lung Cancer 2003;41 (Suppl 2):73.[CrossRef]
(47) Fried D, Morris D, Poole C, Rosenman J, Halle J, Detterbeck F, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited stage small-cell lung cancer. J Clin Oncol 2004;22:478592.[CrossRef][Medline]
(48) Pijls-Johannesma MCG, De Ruysscher DKM, Lambin P, Rutten I, Vansteenkiste JF. Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev 2005:25;CD004700.
(49) Hand S, Baker J, Smith P, Macbeth F. Outpatient intensive chemotherapy for small-cell lung cancer: five years experience with modified ICE ifosfamide, carboplatin and etoposide. Clin Oncol 2002;14;36771.[CrossRef][ISI]
(50) Gharenhbaghian A, Haque K, Truman C, Evans R, Morse R, Newman J, et al. Effects of autologous salvaged blood on postoperative natural killer cell precursor frequency. Lancet 2004;363:120530.
(51) Medical Research Council Lung Cancer Working Party. Comparison of oral etoposide and standard intravenous multi-drug chemotherapy for small-cell lung cancer: multicentre randomised trial. Lancet 1996;348:5636.[CrossRef][ISI][Medline]
(52) Souhami R, Spiro S, Rudd RM, Ruiz de Elviva M, James L, Gower N, et al. Five day oral etoposide for advanced small-cell lung cancer: randomised comparison with intravenous chemotherapy. J Natl Cancer Inst 1997;89:57780.
(53) Earl H, Rudd R, Spiro S, Ash C, James L, Law C, et al. Randomised trial of planned versus as required chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1991;64:56672.[ISI][Medline]
Manuscript received July 13, 2004; revised March 3, 2005; accepted March 22, 2005.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |