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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 Medical Research Council Multicenter Randomized Trial

From the Cancer Division, Medical Research Council Clinical Trials Unit, London, and Christie and Wythenshawe Hospital National Health Service Trusts, Manchester, United Kingdom.

Address reprint requests to D.J. Girling, MD, Cancer Division, MRC Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom; email djg{at}ctu.mrc.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: The treatment of small-cell lung cancer patients with good performance status aims to improve survival. Dose-intensification could be a way to achieve improved survival but can be limited by neutropenia and thrombocytopenia. Preliminary, nonrandomized feasibility studies showed that doxorubicin, cyclophosphamide, and etoposide (ACE) could be given every 2 (instead of the usual 3) weeks with granulocyte colony-stimulating factor (G-CSF) (lenograstim; Chugai-Rhône-Poulenc, Tokyo, Japan) support. The present multicenter randomized trial was designed to examine whether such dose-intensification improves survival while maintaining acceptable toxicity levels.

PATIENTS AND METHODS: All patients were randomized to receive six cycles of ACE either every 3 weeks (control [C] group) or every 2 weeks with G-CSF (G group). The standard dose-intensity of ACE was increased by 50% in group G.

RESULTS: Four hundred and three patients (G group: n = 201; C group: n = 202) were randomized. The received dose-intensity was 34% higher in the G group than in the C group. Complete response rates were 40% for the G group and 28% for the C group (P = .02), and overall rates were 78% for the G group and 79% for the C group. Survival was longer in the G group (hazard ratio = 0.80; 95% confidence interval, 0.65 to 0.99; P = .04), survival rates for the G and C groups being 47% and 39% at 12 months and 13% and 8% at 24 months, respectively. Metastasis-free survival, nonhematologic toxicity, and quality of life were similar in the two groups. In the G group, there was less neutropenia but more thrombocytopenia and more frequent blood and platelet transfusions.

CONCLUSION: Increasing the dose-intensity of ACE with G-CSF support improved survival while maintaining acceptable toxicity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
THE ACE CHEMOTHERAPY regimen (doxorubicin, cyclophosphamide, and etoposide)^1,2 is widely used internationally to treat small-cell lung cancer (SCLC). However, the associated neutropenia often prevents the chemotherapy from being given in full doses at standard 3-week intervals.³

When the present trial was planned, two randomized, placebo-controlled trials had shown that prophylactic granulocyte colony-stimulating factor (G-CSF) reduced neutropenic toxicity and enabled a higher proportion of patients with SCLC to receive full protocol doses of ACE.^4,5 However, neither trial was designed to assess a survival benefit or the feasibility of increasing planned dose-intensity.

Dose-intensity is defined for each drug as mg/m²/wk.⁶ The problem with this definition is that dose-intensity can be increased either by increasing dose size or by shortening the interval between doses, and one would not expect the effects of these different approaches to be the same. A randomized trial of high-dose versus standard-dose cisplatin and etoposide restricted to patients with extensive-stage SCLC and good performance status (Eastern Cooperative Oncology Group status score 0 to 3) showed no evidence of therapeutic benefit but worse toxicity from increasing the planned dose-intensity.⁷ However, this was a small trial, with only 90 patients randomized, and could only have detected a large improvement in survival. Moreover, the size of individual doses of cisplatin was in fact lower in the high-dose than in the standard-dose regimen; the dose-intensity was higher because a dose of 27 mg/m² was given daily for 5 days per cycle instead of 80 mg/m² once per cycle. It could be argued that giving small doses of cisplatin daily for 5 days might be a toxic and inefficient way of using the drug, and that other methods of achieving dose-intensification might be successful. Also in the treatment of patients with extensive disease and good performance status, a randomized trial involving 298 patients conducted by the Southeastern Cancer Study Group showed that increasing the dose sizes of cyclophosphamide, doxorubicin, and vincristine without altering the interval between doses resulted in greater toxicity and no improvement in survival.⁸

An analysis of standard chemotherapy regimens in the treatment of SCLC suggested that increasing the planned dose-intensity of ACE but not of other regimens improved survival, but the ranges of dose-intensity in the other regimens were comparatively small.⁹

As a result, the Medical Research Council Lung Cancer Working Party decided to investigate, in a multicenter randomized trial with broad entry criteria, whether reducing the interval between cycles of the ACE regimen in patients able to tolerate potentially curative treatment would improve survival. First, we tested the feasibility of reducing the interval between cycles to 2 weeks by giving G-CSF to shorten the duration of neutropenia after a cycle. We conducted two feasibility studies, one using glycosylated G-CSF (lenograstim; Chugai-Rhône-Poulenc, Tokyo, Japan),¹⁰ and the other methionyl G-CSF (filgrastim).¹¹ The policy was shown to be feasible. In both studies, approximately 60% of the interval periods between cycles were of the prescribed 14 days, and 15% more of the interval periods were of 15 to 20 days. The main reason for delay was hematologic toxicity. The only potentially serious adverse reaction attributed to G-CSF in the 52 total patients studied was one episode of rash with facial edema.

The present trial was then conducted. In this randomized trial, six cycles of ACE chemotherapy were given either with glycosylated G-CSF at 2-week intervals (G group) or without G-CSF at conventional 3-week intervals (control [C] group). Survival, intervals between cycles, toxicity, and quality of life were compared between the G and C groups. An important feature of the trial was that only one cytotoxic drug delivery variable differed between the two regimens, the interval between cycles. Our policy was to conduct a pragmatic trial, with broad entry criteria, that did not require specialized staging procedures or supportive care and provided results widely applicable to patients with SCLC and the clinical community responsible for their care.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Main Eligibility Criteria
Eligible patients had previously untreated, microscopically confirmed SCLC of any extent; good performance status (World Health Organization [WHO] grade 0 to 2);¹² plasma alkaline phosphatase and aminotransferase concentrations 2.5 times the upper limit of normal; normal renal function and blood count; no contraindication to the trial chemotherapy; and no known intolerance to any recombinant drug. Patients were staged clinically and radiographically; marrow examination, computed tomography scans, and upper abdominal ultrasound were not mandatory. This was in keeping with our policy in a pragmatic trial of adopting broad entry criteria and basing eligibility on performance status, not extent of disease. Women patients were not pregnant, were not of child-bearing potential, or were using adequate contraception. Local ethics committee approval of the protocol and individual patient consent were required.

Treatment Allocation
Clinicians telephoned the Medical Research Council Cancer Division who then used a minimization procedure, stratification for clinician, performance status, and extent of disease to randomly allocate the patients to the G-CSF (G) or control (C) regimen.

Patients randomized to the G-CSF regimen were prescribed six cycles of ACE chemotherapy given over 3 days at 2-week intervals (day 1: doxorubicin 40 mg/m² and cyclophosphamide 1 g/m² by intravenous [IV] injection, and etoposide 120 mg/m² by IV infusion over 30 minutes; days 2 and 3: etoposide 240 mg/m² orally; days 4 to 14: glycosylated recombinant human G-CSF one vial (263 µg) per day by subcutaneous injection). Patients randomized to the control regimen were prescribed the same chemotherapy but at the standard 3-week intervals and without G-CSF.

In both groups, it was recommended that a cycle of chemotherapy only be given if the total WBC count was 3,000/µL, the neutrophil count was 1,500/µL, and the platelet count was 100,000/µL, and there was no evidence of septicemic toxicity. If these conditions were not fulfilled, the next cycle was to be delayed until they were and then given in full dosage. Dose reduction was not recommended. Patients with disease limited to the soft tissues of one hemithorax and the ipsilateral and contralateral scalene, lower cervical, and mediastinal lymph nodes at randomization were offered thoracic radiotherapy after chemotherapy; the details were decided by the local radiotherapist. No recommendation was made about prophylactic cranial irradiation.

Reports and Investigations
Patients were assessed pretreatment; at each attendance for treatment; then monthly to 6 months from randomization, then every 2 months to 1 year, and then every 3 months thereafter. Clinicians’ reports included details of treatment and adverse effects; results of blood counts and other relevant tests; clinical and radiographic response of the tumor;¹² performance status; and details of symptoms scored as being present: not at all (0), a little (1), moderately (2), or very much (3). Quality of life was recorded by patients at all assessments up to 6 months using the Rotterdam Symptom Checklist,¹³ to which four symptoms specific to lung cancer (chest pain, cough, hoarseness, and coughing up blood) had been added. Five questions relevant to the impact of daily injections had also been added: (1) Have you felt like going out of the house?; (2) Have you felt like going out socially (eg, to see friends or to the pub)?; (3) Have you felt like having visitors?; (4) Have you needed someone to be at home with you?; and, for G group patients only, (5) Have the daily injections interfered with your day-to-day activities? The best score was always 0; thus, questions 1 to 3 were scored: most days (0), on 2 or 3 days (1), only once (2), or not at all (3), and questions 4 and 5 were scored in the reverse order.

Statistical Design and Methods
The primary outcome measure was overall survival; secondary outcome measures were intervals between cycles of chemotherapy, septicemic myelosuppression, WHO grade 3 or 4 neutropenia (neutrophil granulocyte count < 1000/µL)¹² 2 weeks after each of the first three cycles, and quality of life.

With an estimated 1-year survival rate of 30% in the C group, the trial aimed to detect an improvement of 15% (to 45%) in the G group, with 5% significance and 90% power, which required 400 patients. Response¹² was assessed over the first 3 months, and patients who died during that period were classified as nonresponders. The ² test was used in the response rate comparison. Duration of survival was calculated from the date of randomization to the date of death from any cause; survivors were censored at the date they were last known to be alive. The log-rank test was used to make treatment comparisons. The ² test for interaction or trend was used to assess whether the effect of dose-intensification was different in different subgroups of patients. To calculate absolute improvements in survival, the hazard ratio (HR) was applied to the C group survival rates at 12 and 24 months.¹⁴

Quality-of-life analyses were based on patients who completed a questionnaire pretreatment and at two or more assessments during the first 18 weeks. Palliation was defined as: improvement (change from grade 2 or 3 to 1 or 0 maintained for at least two successive assessments); control (grade 1 not getting worse at any follow-up assessment); or prevention (grade 0 being maintained throughout).¹⁵ Patients dying before 18 weeks without completing two assessments were included but were categorized as unpalliated. The ² test was used for the comparison of each symptom. All P values are two-sided. Psychologic distress was defined as a score 16.¹⁶ The data were managed using the COMPACT program (Cancer Research Campaign and Medical Research Council, London, United Kingdom).¹⁷ Statistical analyses were implemented using SAS software (SAS/STAT User’s Guide, Version 6; SAS Institute, Cary, NC).

	RESULTS

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Patients
Between December 1993 and March 1996, 403 patients (G group: n = 201; C group: n = 202) were randomized from 22 centers in the United Kingdom and Ireland. The two groups were well matched before treatment (Table 1). The distribution of performance status was similar in patients with limited and extensive disease (details not shown).

Thoracic radiotherapy was given as part of primary treatment to 82 of the G group and 78 of the C group patients with limited disease before treatment. The others were not given radiotherapy because of occurrences of metastatic disease, death, and local progression. A total of 32 G patients and 35 C patients received second-line chemotherapy.

Adverse Effects
The proportions of patients with nonhematologic adverse effects reported by clinicians at attendances for treatment were, in general, similar in the two groups (Table 4). Only three patients from G group had adverse effects attributed to G-CSF; one patient had urticaria, one had asymptomatic hypoglycemia, and one had malaise, nausea, lethargy, and headache. As expected, leucopenia and neutropenia were far more common in the C group, but thrombocytopenia was less common. In the G group, the percentages of patients with WHO grade 3 or 4 neutropenia¹² 2 weeks after the first, second, and third cycles of chemotherapy were 1%, 4%, and 1%, respectively; the corresponding figures for the C group were 71%, 81%, and 92%, respectively.

Palliation of Symptoms and Quality of Life
Palliation of the 10 most common pretreatment symptoms was similar in the two groups (Table 5); none of the differences were statistically significant at the 5% level. In both groups, physical thoracic symptoms (eg, cough and shortness of breath) and psychologic symptoms (worrying, anxious feelings, feeling tense, and nervousness) were well-palliated. For example, 70 of 87 group G patients and 54 of 72 group C patients with grade 2 or 3 cough before treatment experienced improvement, 42 of 75 group G and 54 of 80 group C patients with grade 1 had the cough controlled, and five of 26 group G and 12 of 35 group C patients with no cough kept it prevented, giving total palliation rates of 62% for group G and 64% for group C. In contrast, general physical symptoms (tiredness, lack of energy, and lack of appetite), activities of daily living, and the trial-specific questions were, with the exceptions of "care for myself" and "walk about the house," not well-palliated.

Tumor Response and Survival
Of the 197 group G and 197 group C patients assessable, 79 (40%) and 56 (28%) had a complete response (P = .02) and 75 (38%) and 99 (50%) had a partial response, giving total response rates of 78% and 79%, respectively.

The G group had a survival advantage (HR = 0.80; 95% CI, 0.65 to 0.99; P = .04; Fig 1). Survival rates for the G and C groups were 47% and 39% at 12 months and 13% and 8% at 24 months, respectively. The survival curves for limited and extensive disease are shown in Fig 2. In group G and group C, the reported cause of death was treatment in six (4%) and nine (5%) patients (all caused by myelosuppression except one case, in the C group, of suspected radiation pneumonitis), cancer in 144 (87%) and 156 (88%) patients, and other causes in the remaining 15 and 12 patients, respectively.

View larger version (13K): [in this window] [in a new window]   Fig 1. Percentage of patients surviving from date of randomization.

View larger version (19K): [in this window] [in a new window]   Fig 2. Percentage of patients surviving from date of randomization according to extent of disease at randomization.

View larger version (12K): [in this window] [in a new window]   Fig 3. Percentage of patients with limited disease at randomization surviving without metastases.

View larger version (23K): [in this window] [in a new window]   Fig 4. Survival by characteristics at randomization. The center of each square indicates the HR, and the square’s area indicates the amount of information. The lines on either side indicate the CIs for the HRs, and the vertical ticks indicate the 95% and 99% CIs.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

In the present trial, when ACE chemotherapy was used to treat patients with limited or extensive SCLC and WHO performance status 0 to 2, G-CSF support allowed the interval between cycles to be reduced and, hence, the planned dose-intensity to be increased, leading to improved survival. The policy studied was pragmatic, with broad eligibility criteria and no required specialized staging procedures or supportive care. The findings should, therefore, be widely applicable.

An important feature of the trial is that of the three variables of cytotoxic drug delivery (individual dose size, interval between dose cycles, and total dose) only one differed between the regimens, ie, the interval between cycles. Differences in results can, therefore, be attributed to this difference. It is necessary to study the three components of dose-intensification independently because they are not interchangeable.²⁰

The complete response rate and overall survival were higher in the G group, but the overall response rate and metastasis-free survival were not. These findings might suggest that the main effect of dose-intensification was on local tumor control, but comparisons of response rates are unreliable because of the subjective nature of this outcome measure. It is interesting to note that the survival gain (Fig 1) started at approximately 1 year. This suggests that dose-intensification was having a biologic effect against the tumor rather than simply preventing some early deaths from neutropenic infection. The maintained difference in survival rates at 24 months suggests that dose-intensification also increased the curative potential of the ACE regimen.

There was no evidence that the survival advantages varied with pretreatment characteristics. This finding does not support the hypothesis that improvements might be expected in limited but not in extensive disease on the grounds that limited disease is more likely to be potentially curable.²⁰ Indeed, subgroup analyses showed the survival advantage to be as large in extensive as in limited disease, if not larger, although the numbers of patients in these subgroups were inevitably small. Therefore, dose-intensification should continue to be studied in all patients able to tolerate intensive chemotherapy, whatever the extent of their disease.

Dose-intensification was most readily achievable during the first four cycles of chemotherapy. Cycles beyond the fourth probably contribute little to prolonging survival,²¹ and administering high dosages during the early cycles is important.²² Therefore, efforts should be concentrated on achieving high dose-intensity during the early cycles of chemotherapy.

Interestingly, dose-intensification was neither associated with any obvious increase in symptoms of toxicity nor with an excess of toxic deaths. Nevertheless, transfusion requirements, particularly of platelets, were greater in the G-CSF group. Although, with adequate supportive care, symptomatic toxicity was not increased. A study of epirubicin and ifosfamide in the treatment of SCLC suggests that increasing the planned dose-intensity further (for example, by reducing the intervals between cycles to 10 days) could result in greatly increased and unacceptable toxicity.²³ Even so, a randomized phase II study has shown that the dose-intensity of a regimen of ifosfamide, carboplatin, and etoposide can be increased, giving it every 2 weeks instead of the standard 4 weeks, with reduced neutropenic toxicity, if it is supported by G-CSF and by blood progenitor cells collected before and reinfused during each cycle.²⁴ As in the feasibility studies that preceded the present trial,^10,11 G-CSF alone carried minimal risk of toxicity.

One other randomized trial investigated increasing dose-intensity by means of cytokine support in SCLC, although its design differed from that of the present trial.²⁵ Three hundred patients were all prescribed six cycles of ifosfamide, carboplatin, etoposide, and vincristine and were randomized in a 2 x 2 factorial design to receive treatment at either 3-week or 4-week intervals and with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo. Dose-intensity was higher and survival was significantly increased in the 3-week treatment arm, without increased toxicity. These findings are important because they show that the potential survival benefit from dose-intensification by reducing the interval between doses is not confined to the ACE regimen.

In the present trial, the levels of palliation of thoracic symptoms and psychologic distress were high and similar in the two treatment groups. It is notable, however, that general physical symptoms, such as tiredness, lack of energy, and lack of appetite, were far less well-palliated, probably because they are related not only to disease but also to treatment. These symptoms are common and could have a major influence on quality of life. It is important that reports of the palliation of symptoms are not confined to those thought to be cancer site–specific.²⁶

In these relatively fit patients, other aspects of quality of life indicated some deterioration during treatment in both groups, but the great majority of patients in the G-CSF group reported that the daily injections did not interfere at all with their day-to-day activities, an important finding. A potential additional gain from reducing the interval between cycles of chemotherapy is that treatment is planned to be completed more rapidly (in this trial, in 12 as opposed to 18 weeks).

The maximum number of lenograstim 263 µg doses per patient in the G group was 66. Lenograstim costs £77 (United States: $123) per dose, making the additional cost of medicament for this group £5,082 ($8,131) per patient. Research should continue on dose-intensification and on the most cost-effective ways of using G-CSF and other cytokines to this end. It would be particularly valuable to see whether, with cytokine support, the intervals between cycles of other regimens used to treat SCLC can be shortened and, if so, whether this also leads to improvements in survival. This possibility should not be discounted on the evidence of trials that were either confounded with respect to the variables of dose-intensification or used different methods of achieving it.^7,8 Other forms of combined modality treatment, notably concomitant multiple-daily-fraction radiotherapy and chemotherapy, are also worthwhile areas of research.²⁷ Indeed, it would be of great interest to compare the dose-intense regimen of the present trial versus a regimen of concomitant multiple-daily-fraction radiotherapy and chemotherapy in a randomized trial.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Trial Collaborators and Coauthors

The following consultants and their colleagues entered 10 or more patients: M.C. Nicolson (Aberdeen); P.I. Clark, S. O’Reilly, D.B. Smith (Clatterbridge); A. Gregor, J.F. Smyth (Edinburgh); N. Thatcher, H. Anderson (Manchester); J. Carmichael, I.D.A. Johnston, P.J. Woll (Nottingham); I.E. Smith (Royal Marsden); R.J. Coleman, D.J. Radstone (Sheffield, United Kingdom). The remaining patients were entered by: E.D. Gilby (Bath); G. Varghese (Belfast); G. Newman (Brighton); S.J. Falk (Bristol); N.M. Bleehen, R. Hawkins (Cambridge); C.K. Connolly (Darlington); S. Khanna, F.J.F. Madden (Leicester); D.G. Jenkins (Maidstone); J.M. Bozzino (Newcastle); G.C. Ferguson, C.H. Macmillan (Northampton); F.N. Daniel (Plymouth); A.J. Rathmell (South Cleveland, United Kingdom); C.P. Bredin (Cork, Ireland). Local coordinators were: S. Alcock, C. Ball, M. Ball, L. Barnett, A. Bentley, J. Briggs, T. Briggs, J. Brunskill, J. Christmas, E. Decker, E. Durham, J. Elmes, K. Hannigan, L. Heath, J. Hodgetts, J. Hutchinson, L. Lomax, C. Macmillan, D. McGrath, V. Mercer, T. Pomphrey, C. Porter, K. Priest, K. Redman, F. Rose, L. Spencer, K. Stainer, V. Turnbull, and A. Young.

	ACKNOWLEDGMENTS

 
Supported by Chugai-Rhône-Poulenc.

We thank the following Working Party Members: J.J. Bolger (deceased), M.G. Bond, P.I. Clark, C.K. Connolly, D.J. Girling, P.S. Hasleton, P. Hopwood, F.R. Macbeth, R. Milroy, K. Moghissi, M.D. Peake, W. Qian, R.J. Sambrook, M.I. Saunders, I.E. Smith (Chairman), R.J. Stephens, N. Thatcher (Chairman until October 1997), D.C.T. Watson, and R.J. White.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted April 15, 1999; accepted August 12, 1999.

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