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© 2001 American Society for Clinical Oncology Use of Hematopoietic Progenitors in Whole Blood to Support Dose-Dense Chemotherapy: A Randomized Phase II Trial in Small-Cell Lung Cancer PatientsFrom the Cancer Research Campaign Department of Clinical Oncology, City Hospital, Nottingham; Cancer Research Campaign Departments of Medical Oncology and Clinical Oncology, Christie Hospital, Manchester; and Amgen Ltd, Cambridge, United Kingdom. Address reprint request to Penella J. Woll, MD, Cancer Research Campaign Department of Clinical Oncology, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom; email: penella.woll@ nott.ac.uk.
PURPOSE: Small-cell lung cancer (SCLC) is exquisitely chemosensitive, but few patients are cured by conventional chemoradiotherapy. Recent studies suggest that increased cytotoxic dose-intensity might improve survival. In this randomized phase II study, we tested the feasibility of dose intensification using sequential reinfusion of hematopoietic progenitors in whole blood. PATIENTS AND METHODS: SCLC patients with a favorable prognosis were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE), at 4-week (standard treatment) or 2-week (intensified treatment) intervals. Intensified treatment was supported by daily subcutaneous filgrastim injections and reinfusion of 750 mL of autologous blood collected immediately before each cycle. RESULTS: Fifty consecutive patients were randomized to standard (n = 25) or intensified (n = 25) ICE. A total of 94% completed at least three treatment cycles, and 70% completed six cycles; 96% of treatments were given at full dose. The planned dose-intensity was 1.0 for standard and 2.0 for intensified ICE. The median received dose-intensity for cycles 1 through 3 was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P < .001). Over all six cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P < .001). Febrile neutropenia was more common on the standard treatment arm (84% v 56%), resulting in more days of intravenous antibiotics (median, 10 v 3 days; P = .035). Transfusion requirements were similar in the two groups. CONCLUSION: Sequential reinfusion of hematopoietic progenitors in whole blood can safely support substantial increases in dose-intensity of ICE chemotherapy for SCLC.
THE HYPOTHESIS that increasing cytotoxic dose-intensity will lead to improved cancer cure rates is compelling. Although supporting evidence for the hypothesis has accrued for several tumor types, including lymphomas and breast and testicular cancers, it remains unproven. Small-cell lung cancer (SCLC) is extremely chemo- and radiosensitive, with response rates of 80% achieved routinely, but few patients are cured by chemoradiotherapy. In this setting, increased cytotoxic dose-intensity might improve cure rates. The finding that response rates in SCLC correlate with received cytotoxic dose-intensity merely confirms that "less is worse" and does not indicate that "more is better."1,2 To test the dose-intensity hypothesis requires a prospective randomized trial of a proven regimen used optimally and a substantially dose-intensified comparator. Many approaches have been used to increase cytotoxic dose-intensity for solid tumors, including the use of increased doses, shorter treatment intervals, hematopoietic growth factor support, and high-dose therapy with bone marrow transplantation. The use of hematopoietic growth factors with standard chemotherapy has been evaluated in patients with SCLC. Granulocyte colony-stimulating factor (G-CSF) reduces the severity and duration of neutropenia, leading to fewer infections and a higher proportion of patients receiving the planned dose on time.3,4 In contrast, granulocyte macrophage colony-stimulating factor (GM-CSF) was associated with more thrombocytopenia, toxic deaths, days in the hospital, and use of blood products and intravenous (IV) antibiotics in a Southwest Oncology Group study.5 The concurrent use of a cisplatin-containing regimen and radiotherapy may have contributed to the excess toxicity noted in that study. Several groups have tested the use of hematopoietic growth factors to increase cytotoxic dose-intensity, but results have been modest, with differences in achieved dose-intensity of 20% to 40%.6-12 Our strategy is to select better-prognosis patients for intensive treatment using ifosfamide, carboplatin, and etoposide (ICE) or ICE with midcycle vincristine (VICE). These regimens are dose limited by myelosuppression, with 81% of cycles resulting in World Health Organization grade 3 or 4 leukopenia as judged by weekly blood counts.13 To maintain cytotoxic dose-intensity, dose reductions are avoided. However, patients treated with VICE or ICE have 2-year survival rates of more than 30% (minimum follow-up time, 24 months), with 5-year survival rates of 19% (minimum follow-up time, 4.5 years).14 In a randomized study, VICE was given at intervals determined by hematologic recovery in 65 patients allocated to G-CSF (lenograstim) support or no additional treatment. The median cytotoxic dose-intensity (relative to a standard 4-week cycle) was increased to 1.17 over the first three cycles without growth factor support and to 1.34 in patients receiving G-CSF (P = .001). Over six cycles of chemotherapy, the median cytotoxic dose-intensity was 1.18 without growth factor support and 1.25 in patients receiving G-CSF (P = .03).8 This modest but statistically significant result led us to explore the use of hematopoietic progenitors to support further increases in cytotoxic dose-intensity in multicyclic chemotherapy.15 We established that ICE + G-CSF was effective in mobilizing hematopoietic progenitors, leading to 120-fold (median) increases in circulating GM-CFC numbers, maximal 12 to 14 days after starting chemotherapy. Furthermore, we showed that repeated cycles of ICE chemotherapy do not lead to stem-cell depletion, assessed by long-term culture-initiating cell numbers. In addition, we demonstrated that hematopoietic progenitors remain viable for up to 48 hours in whole blood at 4°C.16 We therefore developed a novel means of supporting dose-intensified ICE chemotherapy, in which hematopoietic progenitors were collected in whole blood at each treatment cycle, stored for 48 hours at 4°C, and reinfused 15 hours after completion of chemotherapy.15 In the current study, we tested the practicability and safety of using this approach to increase cytotoxic dose-intensity in a routine clinical setting.
The disease of previously untreated patients 18 to 70 years of age with pathologically confirmed SCLC was staged by clinical examination, chest radiography, biochemical screening, and upper abdominal scanning (computed tomography or ultrasound). Patients with not more than one of the following five adverse prognostic features17,18 were eligible for the study: extensive disease, Karnofsky performance status score less than 60, serum sodium level below the lower limit of normal, serum lactate dehydrogenase level above the upper limit of normal, and serum alkaline phosphatase level more than 1.5 times the upper limit of normal. Patients were required to have a normal peripheral blood count and creatinine clearance  75 mL/min at the time of study entry. A bone marrow aspirate was obtained at study entry. Patients found to have tumor-contaminated bone marrow were withdrawn from the study and treated either with standard ICE or with cyclophosphamide, doxorubicin, and etoposide. All patients gave written informed consent to participate in the study.
Treatment Regimens
Chemotherapy was given if the WBC count was 3.0 x 109/L, the platelet count was 30 x 109/L without platelet transfusion support, and creatinine clearance was 60 mL/min. No dose reductions were permitted on either arm. In the intensified treatment group, chemotherapy could be delayed, and G-CSF continued, for up to 3 days to permit hematologic recovery. Failing this, chemotherapy was deferred 1 week and given without progenitor cell support. Patients whose chemotherapy was deferred for a total of 2 weeks were taken off the intensified schedule and given standard ICE at 4-week intervals. All patients underwent weekly assessments (including body temperature measurement and full blood counts). Patients admitted with treatment complications underwent daily blood counts. Before each chemotherapy cycle, the Rotterdam quality-of-life questionnaire was administered, Eastern Cooperative Oncology Group (ECOG) performance status and body weight were determined, and a physical examination, serum biochemistry , and chest radiography were performed.
In accordance with unit policy, patients with febrile neutropenia (temperature Immediately after completing chemotherapy, responding patients with limited disease were treated with thoracic radiotherapy.19 They were also considered for the United Kingdom Coordinating Committee on Cancer Research randomized trial of prophylactic cranial irradiation.
Statistical Methods
Received cytotoxic dose-intensity, number of days of IV antibiotics, and blood and platelet transfusion requirements were compared between the treatment groups using the Wilcoxon rank sum test and the Hodges-Lehmann estimate of treatment difference and its 95% confidence interval (CI). The proportions of patients experiencing events (such as febrile neutropenic episodes) were compared using the continuity-adjusted
Fifty-seven consecutive patients were considered for the study. Five were ineligible and two refused consent. Fifty consenting patients were therefore enrolled onto the study, 25 on each treatment arm ( Fig 2). The treatment groups were well balanced in terms of pretreatment prognostic variables, except that the intensified treatment group had more women and performance status scores were higher on that arm ( Table 1). The proportion of patients completing each cycle of chemotherapy on the intensified and standard schedules is listed in Table 2. Forty-seven patients (94%) received at least three treatment cycles, and 35 (70%) completed six treatment cycles. There was no statistically significant difference in the number of treatment cycles received by each group. On the standard treatment arm, 10 patients withdrew from the study early (one was ineligible because of low creatinine clearance at study entry, five had treatment toxicity, one had disease progression, and three died on study). On the intensified treatment arm, seven patients withdrew from the study early (five had treatment toxicity, one chose to withdraw, and one died on study) and seven switched to standard treatment (three through an investigator decision because bone marrow involvement was discovered after randomization, two with treatment delays for hematologic recovery, one with treatment toxicity, and one by patient choice). Of the patients who died on study, one died after cycle 1 (cause of death, sepsis and pulmonary embolism), one died after cycle 4 (cause of death, septic shock), and two died after cycle 6 (causes of death, acute coronary events in both and complicating sepsis in one). Thoracic irradiation was performed in 17 patients (74%) on the standard treatment arm and 22 (92%) on the intensified treatment arm. Prophylactic cranial irradiation was performed in three patients (13%) on the standard treatment arm and nine (39%) on the intensified treatment arm.
Cytotoxic Dose-Intensity In accordance with unit policy, no dose reductions were made. A total of 96% of treatments were given at the planned dose, and the total delivered dose was identical on the two treatment arms. The planned cytotoxic dose-intensity was 1.0 for standard ICE and 2.0 for intensified ICE. The received dose-intensity is shown in Fig 3. For cycles 1 through 3, the median received dose-intensity was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P < .001, Wilcoxon rank sum test; Hodges-Lehmann estimate of difference between treatment arms, 0.82; 95% CI, 0.66 to 0.93]). Over all six treatment cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P < .001, Wilcoxon rank sum test; difference between treatment arms, 0.67; 95% CI, 0.30 to 0.93).
Toxicity and Supportive Care ICE is a myelosuppressive treatment. Full blood counts were performed weekly and showed WBC count nadirs to be frequently less than 109/L and slightly lower in the standard than in the intensified treatment group. Twenty-one patients (84%) on the standard treatment arm and 14 (56%) on the intensified treatment arm developed febrile neutropenia, as indicated by IV antibiotic use (P = .064,  2 test; difference between treatment arms, 28%; 95% confidence limits, -0.2, 56.2]). Significantly fewer days of IV antibiotics ( Fig 4) were required on the intensifed treatment arm (median, 3; range, 0 to 27 days) compared with the standard treatment arm (median, 10 days; range, 0 to 29 days; P = .035, Wilcoxon rank sum test; difference between treatment arms, 5 days; 95% CI, 0 to 5). On both treatment arms, the incidence of febrile neutropenia was highest in the first treatment cycle (56% on the standard treatment arm and 28% on the intensified treatment arm) than in subsequent treatment cycles (eg, 27% on the standard treatment arm and 16% on the intensified treatment arm for cycle 2).
Platelet nadirs in both groups were lower in cycles 4 through 6 (grade 4 thrombocytopenia was seen in 65% of patients on the standard treatment arm and 60% of patients on the intensified treatment arm) than in cycles 1 through 3 (35% and 20%, respectively). During the study, 76% of patients on the standard treatment arm and 84% of patients on the intensified treatment arm required platelet transfusions. Despite chemotherapy being given to patients with relatively low platelet counts ( 30 x 109/L), the platelet transfusion requirements were similar on the two treatment arms (Fig 4). Blood transfusions were required by 88% of patients on the standard treatment arm and 100% of patients on the intensified treatment arm to maintain hemoglobin levels at more than 8 g/dL, but similar numbers of units were given on each treatment arm (Fig 4). Other toxicities were those previously reported for this chemotherapy regimen. Alopecia was universal. Seven patients experienced grade 3 or 4 nausea or vomiting. Mucositis was common among patients admitted with febrile neutropenia but was not dose limiting. Hypokalemia was noted in 18 patients; both carboplatin and ifosfamide can cause electrolyte disturbances. Musculoskeletal symptoms were reported by five patients on the standard treatment arm and 11 patients on the intensified treatment arm. Five patients on each treatment arm withdrew because of treatment toxicity, and one patient elected to switch from the intensified to the standard treatment arm.
Quality of Life
Tumor Response and Survival
This randomized study shows that ICE chemotherapy can be given at substantially increased dose-intensity when supported by G-CSF injections and hematopoietic progenitor cells in whole blood. A phase III study is now addressing the question of whether this increase in cytotoxic dose-intensity has a survival advantage. We previously found that the dose-intensity of VICE chemotherapy can be increased to 1.17 (over three treatment cycles) without hematopoietic growth factor support and to 1.34 with G-CSF.8 Consistent with this, Steward et al11 found that the dose-intensity of VICE could only be increased to 1.26 using GM-CSF. In the present study, a dose-intensity of 1.80 was obtained with ICE, representing a dose-intensity that could not be achieved without hematopoietic progenitor cell support. Protocol policies were closely adhered to, with 96% of treatments given at the planned dose and 94% of patients receiving at least three treatment cycles. The total dose administered was therefore the same on the two treatment arms, and dose intensification was achieved by reducing the treatment interval. In accordance with unit policy, dose reductions were not permitted and patients unable to tolerate full-dose treatment discontinued therapy. The standard treatment was given without hematopoietic growth factor support. In North America, patients receiving such myelosuppressive therapy might be offered G-CSF as primary prophylaxis, or secondary prophylaxis after an episode of febrile neutropenia, but in Europe, this is not standard practice for lung cancer patients with normal bone marrow reserve.20 Although G-CSF can reduce the incidence of febrile neutropenia, it has not been definitively shown to reduce the number of septic deaths. Furthermore, its routine use in the treatment of SCLC was not justified by clinical benefits, improved patient comfort, or economic considerations in a French study.21 Nor is there evidence that dose reduction after an episode of febrile neutropenia improves patient safety.22 Consistent with this, we found that the incidence of febrile neutropenia was highest in cycle 1 and reduced in subsequent treatment cycles.
ICE is a severely myelosuppressive treatment regimen with appreciable morbidity in patients with SCLC. It was therefore particularly important to find that the safety of patients receiving the dose-intensive schedule was not compromised. One death occurred on the intensified treatment arm and three on the standard treatment arm. This is consistent with the mortality rate of approximately 10% reported in previous studies of chemotherapy for SCLC.3,8,19 Blood and platelet transfusions were required at similar rates on the two treatment arms. The unexpected finding that patients on the intensified treatment arm experienced significantly fewer days of neutropenic sepsis (3 v 10 days, P = .034) indicates that the use of hematopoietic progenitor cells led to substantially reduced risk of infection. In this study, ICE chemotherapy was associated with a high febrile neutropenia rate. However, the definition of febrile neutropenia used (temperature Studies that have used G-CSF with standard chemotherapy have found a reduction in septic complications,3,4 although in one study, GM-CSF use was associated with more infective complications.5 Studies testing the use of hematopoietic growth factors to support increased cytotoxic dose-intensity have shown no reduction in the incidence of sepsis.8,11,23 Indeed, sepsis and thrombocytopenia are currently regarded as the dose-limiting toxicities in the treatment of SCLC.7,24 We have shown that the use of hematopoietic progenitors in whole blood can reduce these toxicities. The finding that modest increases in cytotoxic dose-intensity (26%, 34%) can result in longer survival for patients with SCLC11,12 has encouraged us to test the effects of a more substantial increase in the dose-intensity of ICE in this patient group. Three prospective studies of increased cytotoxic dose-intensity in SCLC have shown a survival benefit. In the first, 105 patients with limited-stage SCLC were randomized to standard- or higher-dose chemotherapy in the first treatment cycle only. A significant survival benefit (2-year survival rates of 43% v 26%, P = .02) was found on the higher-dose arm,10 confirming the findings of an earlier study by the same group.25 Results of a larger international study were recently reported.11 In that study, 300 patients with good- or intermediate-prognosis SCLC were treated with VICE chemotherapy and randomized in a 2 x 2 design to treatment at 4-week (standard) or 3-week (intensified) intervals, with GM-CSF or placebo. Received cytotoxic dose-intensity was 26% greater among patients allocated to intensified VICE than among those allocated to standard treatment. This increase was associated with prolonged survival (median, 443 v 351 days; P = .0014) and higher 2-year survival rates (33% v 18%). In a third study, performed by the British Medical Research Council, 403 patients received doxorubicin, cyclophosphamide, and etoposide at 3-week (control) or 2-week (using subcutaneous G-CSF) intervals .12 The higher dose-intensity was associated with higher survival rates (47% v 39% at 1 year and 25% v 18% at 2 years; P = .04). The trials of accelerated chemotherapy that have shown statistically significant survival benefits have several common features: the selection of a better-prognosis patient group defined not by stage alone, a policy of no dose reductions, and avoidance of cisplatin in the regimens. These studies suggest that further benefits may accrue from the use of more dose-intensive regimens for favorable-prognosis groups of SCLC patients. Conversely, dose intensification has not proved effective in improving survival in patients with extensive-stage SCLC.26 Consideration should be given not only to optimizing the dose-intensity of existing regimens but also to incorporating new drugs with high antitumor activity and nonadditive toxicity, to maximize summation dose-intensity.27 Consolidation or maintenance therapy has not proved useful for patients with SCLC, but it is hoped that biologically targeted agents, such as cancer vaccines, metalloproteinase inhibitors, and growth factor antagonists, may play a role in future treatments of minimal residual disease. An alternative approach to increasing dose-intensity of multicyclic chemotherapy for SCLC is to use high-dose therapy with hematopoietic progenitor cell transplantation. Initial studies used autologous bone marrow rescue after high-dose chemotherapy. The complete remission rate was high, but an advantage in terms of relapse-free survival (but not overall survival) with high-dose treatment was noted by only one group.28,29 The use of chemoradiotherapy and the introduction of blood progenitor cells for transplantation have led to renewed interest in high-dose therapy by SCLC.30-33 Among selected patients with a favorable prognosis, high complete response rates and encouraging survival rates have been obtained. However, this approach is expensive (requiring leukapheresis and storage) and has not yet been tested against best conventional treatment in a randomized trial. Other groups are also studying the use of multicyclic dose-intensive therapy and/or unprocessed hematopoietic progenitor cells in whole blood.34-37 The novelty of our approach is the use of a "low-technology," multicyclic treatment schedule that can be safely used in a general patient population.
We thank James Chang and Godfrey Morgenstern (Department of Haematology, Christie Hospital), Penelope Hopwood (Cancer Research Campaign Psychological Medicine Group, Christie Hospital), and Peter Clarke and Liz McCann (Amgen Ltd) for their assistance with this study.
1. Sheehan RG, Balaban EP, Frenkel EP: The impact of dose intensity of standard chemotherapy regimens in extensive stage small cell lung cancer. Am J Clin Oncol 16: 250-255, 1993[Medline] 2. Sirzea F, Westberg R, Lewensohn R, et al: Dose intensity of the CAVE regimen in small cell lung cancer correlates to response rate. Lung Cancer 11: 393-400, 1994[Medline] 3. 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: 164-170, 1991[Abstract] 4. 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: 319-324, 1993
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Arriagada R, Le Chevalier T, Pignon J-P, et al: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329: 1848-1852, 1993 11. Steward WP, von Pawel J, Gatzemeier U, et al: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small cell lung cancer (SCLC): A prospective randomized study of 300 patients. J Clin Oncol 16: 642-650, 1998[Abstract]
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Thatcher N, Girling DJ, Hopwood P, et al: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with G-CSF: Results of a British Medical Research Council multicenter randomized trial. J Clin Oncol 18: 395-404, 2000 13. Thatcher N, Lind M, Stout R, et al: Carboplatin, ifosfamide and etoposide with mid-course vincristine and thoracic radiotherapy for ‘limited’ stage small cell carcinoma of the bronchus. Br J Cancer 60: 98-101, 1989[Medline] 14. Lorigan PC, Lee SM, Betticher D, et al: Chemotherapy with vincristine/ifosfamide/carboplatin/etoposide in small cell lung cancer. Semin Oncol 22: 32-41, 1995 (suppl 7)
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Pettengell R, Woll PJ, Thatcher N, et al: Multicyclic, dose-intensive chemotherapy supported by sequential reinfusion of hematopoietic progenitors in whole blood. J Clin Oncol 13: 148-156, 1995 16. Pettengell R, Woll PJ, O’Connor DA, et al: Viability of haemopoietic progenitors from whole blood, bone marrow and leukapheresis product: Effects of storage media, temperature and time. Bone Marrow Transplant 14: 703-709, 1994[Medline] 17. Cerny T, Blair V, Anderson H, et al: Pretreatment prognostic factors and scoring system in 407 small-cell lung-cancer patients. Int J Cancer 39: 146-149, 1987[Medline] 18. Rawson NS, Peto J: An overview of prognostic factors in small cell lung cancer: A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research. Br J Cancer 61: 597-604, 1990[Medline] 19. Prendiville J, Radford J, Thatcher N, et al: Intensive therapy for small-cell lung cancer using carboplatin alternating with cisplatin, ifosfamide, etoposide, mid-cycle vincristine, and radiotherapy. J Clin Oncol 9: 1446-1452, 1991[Abstract] 20. Croockewit AJ, Bronchud MH, Aapro MS, et al: A European perspective on haematopoietic growth factors in haemato-oncology: Report of an expert meeting of the EORTC. Eur J Cancer 33: 1732-1746, 1997 21. Chouaid C, Bassinet L, Fuhrman C, et al: Routine use of granulocyte colony-stimulating factor is not cost-effective and does not increase patient comfort in the treatment of small-cell lung cancer: An analysis using a Markov model. J Clin Oncol 16: 2700-2707, 1998[Abstract] 22. Radford JA, Ryder WDJ, 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: 81-86, 1993
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Pujol J-L, Douillard J-Y, Rivière A, et al: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: A multicenter randomized phase III study. J Clin Oncol 15: 2082-2089, 1997 24. Gridelli C, Perrone F, D’Aprile M, et al: Phase II study of intensive CEV (carboplatin, epirubicin and VP-16) plus G-CSF in extensive stage small cell lung cancer. Eur J Cancer 31A: 2424-2426, 1995 25. de Vathaire F, Arriagada R, de Thé H, et al: Dose intensity of initial chemotherapy may have an impact on survival in limited small cell lung carcinoma. Lung Cancer 8: 301-308, 1993
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Fetscher S, Brugger W, Engelhardt R, et al: Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 100 consecutive patients with limited- and extensive-disease small-cell lung cancer. Ann Oncol 8: 49-56, 1997 33. Humblet Y, Bosquée L, Weynants P, et al: High-dose chemo-radiotherapy cycles for LD small cell lung cancer patients using G-CSF and blood stem cells. Bone Marrow Transplant 18: S36-S39, 1996 (suppl 1) 34. Perey L, Rosti G, Lange A, et al: Sequential high-dose ICE chemotherapy with circulating progenitor cells (CPC) in small cell lung cancer. Bone Marrow Transplant 18: S40-S43, 1996 (suppl 1) 35. Ossenkoppele GJ, Jonkhoff AR, Huijgens PC, et al: Peripheral blood progenitors mobilised by G-CSF (filgrastim) and reinfused as unprocessed autologous whole blood shorten the pancytopenic period following high-dose melphalan in multiple myeloma. Bone Marrow Transplant 13: 37-41, 1994[Medline] 36. Ossenkoppele GJ, Schuurhuis GJ, Jonkhoff AR, et al: G-CSF (filgrastim)-stimulated whole blood kept unprocessed at 4°C does support a BEAM-like regimen in bad-risk lymphoma. Bone Marrow Transplant 18: 427-431, 1996[Medline] 37. Leyvraz S, Ketterer N, Perey L, et al: Intensification of chemotherapy for the treatment of solid tumours: Feasibility of a 3-fold increase in dose intensity with peripheral blood progenitor cells and granulocyte colony-stimulating factor. Br J Cancer 72: 178-182, 1995[Medline] Submitted November 16, 1999; accepted September 13, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2. The nadir for performance status occurred approximately 8 weeks before study completion on each treatment arm, at cycle 5 on the standard treatment arm and cycle 3 on the intensified treatment arm. Cancer symptoms (chest pain, dyspnea, cough, hemoptysis, and lack of energy) improved significantly during chemotherapy. Psychologic symptoms (irritability, worrying, depressed mood, nervousness, despondency, restlessness, tenseness, anxiety, difficulty concentrating, and loneliness) also improved during chemotherapy. Comparison of estimates and 95% CIs showed no significant difference between the two treatment groups with regard to any aspect of quality of life (cancer symptoms, psychologic symptoms, physical symptoms, and activities of daily living). 
