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© 2003 American Society for Clinical Oncology CHOP Compared With CHOP Plus Granulocyte Colony-Stimulating Factor in Elderly Patients With Aggressive Non-Hodgkin’s Lymphoma
From the For the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), Erasmus, Rotterdam, the Netherlands. Address reprint requests to J.K. Doorduijn, MD, Department of Hematology, Erasmus Medisch Centrum Rotterdam, PO Box 2040, 3000 CA, Rotterdam, the Netherlands; email: j.doorduijn{at}erasmusmc.nl.
Purpose: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. Results: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P = .01) and doxorubicin (median, 95.4% v 93.3%; P = .04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P = .63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P = .76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P = .006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. Conclusion: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.
THE SURVIVAL of elderly patients with aggressive non-Hodgkin’s lymphoma (NHL) is relatively poor.1–5 Age older than 60 years is an adverse prognostic variable of the International Prognostic Index.6 Several age-dependent factors are comorbidity, altered drug pharmacokinetics, reduced tissue tolerance, attenuated dose-intensity of chemotherapy, and different intrinsic susceptibility of NHL to chemotherapy. Attempts have been made to design less toxic, still effective treatment for elderly patients. In general, these regimens have resulted in a lower efficacy compared with standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment.7–17 However, even with CHOP, the results in elderly patients are inferior to those in younger patients. This may be explained by the clinical practice to reduce the dose-intensity of CHOP in order to prevent leucopenia and infections in this fragile population. An alternative approach to avoid chemotherapy-induced leucopenia and infections is prophylactic treatment with granulocyte colony-stimulating factor (G-CSF).18–21 Many clinicians nowadays routinely use prophylactic G-CSF to prevent infections and treatment delays in elderly patients who undergo chemotherapy.22 However, the literature does not provide evidence for this practice.23 In a multicenter phase III study in elderly patients with aggressive NHL, the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) has investigated whether prophylactic G-CSF plus standard CHOP chemotherapy reduces the incidence and severity of neutropenia and infections. The main purpose was to maintain the relative dose-intensity (RDI) of CHOP at standard dose, and by doing so, to improve the response rate and the survival of these patients.
Patients 65 years of age and older, with a biopsy-proven, newly diagnosed aggressive NHL according to the Working Formulation, as defined at the start of the study in 1994, were eligible.24 They were required to have stage II, III, or IV disease and a cardiac left ventricular ejection fraction  45%. Patients were not eligible if they had lymphoblastic NHL, positive HIV serology, other malignancy except localized squamous skin carcinoma, abnormal liver or kidney function unless caused by NHL, previous indolent lymphoma, or CNS involvement. The required staging procedure included physical examination, blood analysis, computed tomography (CT) of the chest and abdomen, and bone marrow aspiration plus biopsy. The staging procedure was repeated after 3 cycles of chemotherapy and at the end of treatment. All patients gave informed consent for study participation according to the regulations of the Dutch health authorities. The study was performed and evaluated by the independent Dutch-Belgian HOVON group according to the Helsinki agreement. The study investigators are listed in the Appendix.
Treatment Protocol
Patients with a complete response (CR) after three cycles of CHOP received 3 additional cycles. Patients with a partial remission (PR) after three cycles received an additional five CHOP cycles, while patients with progression discontinued protocol treatment. Patients with stable disease were allowed to discontinue protocol treatment or to continue with three more cycles of CHOP, to the discretion of the physician. Patients with residual lesions from bulky mass (
Response Criteria
Quality-of-Life Study
Cost Analysis
Statistical Analysis The expected accrual rate was 75 to 100 patients per year, which would result in 375 to 500 patients after 5 years’ accrual. With these numbers of patients, the power for the detection of an improvement of 15% would be 83% to 92%. The eligible patients were analyzed according to the intention-to-treat principle (ie, analyzed according to the treatment arm they were assigned to). The data were analyzed as of October 22, 2001.
Patient characteristics were compared between the two treatment arms using Pearson’s The RDI of each drug in the CHOP regimen was calculated by dividing the received cumulative dose by the full dose the patient should have received during the treatment period. OS was calculated from the date of random assignment until death. Patients still alive at the date of last contact were censored. EFS was measured from random assignment until there was no CR on protocol, relapse, or death from any cause, depending on which came first. Patients who did not achieve a CR on protocol treatment were considered to have experienced treatment failure at one day after random assignment. PFS was determined from the date of randomization until disease progression or death from NHL (including death due to treatment of NHL). Patients who were still alive or died from a non–NHL-related cause were censored at the date of last contact or date of death, respectively. DFS was calculated from date of CR until relapse. Patients who died in CR, irrespective the cause of death, were censored at the date of death. OS, EFS, PFS, and DFS were estimated by the Kaplan-Meier method.30 Kaplan-Meier curves were generated to illustrate differences between the two treatment arms, and the log-rank test was used to compare the survival curves.31 The RDI of cyclophosphamide and doxorubicin were compared between the two treatment arms using the Wilcoxon rank sum test. The proportion of patients who achieved a CR on protocol in the two treatment arms were compared using logistic regression, and a 95% confidence interval (CI) for the difference was calculated. Univariate logistic regression was used to see whether there was a difference in CR rate between subgroups according to patient characteristics at diagnosis. Univariate survival analysis was performed with Cox regression to determine differences in survival between subgroups.32 The univariate analyses were performed unadjusted as well as adjusted, for the Age-adjusted Prognostic Index (AAPI) score, to see which variables contained additional information besides the AAPI.6
At registration, the following variables were included in the analysis of prognostic factors: treatment arm, sex, age (continuous as well as in 4 subgroups), World Health Organization (WHO) performance status (0 to 1 v 2 to 4), histology, B cell versus T cell, "B" symptoms, Ann Arbor stage (2 v 3 to 4), bulky disease, LDH (normal v elevated), erythrocyte sedimentation rate (normal v elevated), bilirubin (
All reported P values are two-sided, and a significance level of
Patient Characteristics Four hundred eleven patients from 57 hospitals in the Netherlands and Belgium were enrolled between August 1994 and September 2000. Central pathology review was completed in 80% (313 of 389) of the patients. The diagnosis of intermediate- or high-grade was made according to the Working Formulation. In 10% of the cases, a definitive subclassification between the Working Formulation groups D through H or J was not possible, due to small biopsies or disagreement between pathologists. At central review by the study coordinators, 22 patients were evaluated as ineligible because of stage I disease (n = 7), low-grade NHL (n = 5), poor cardiac status (n = 4), no NHL (n = 1 each: acute myeloid leukemia, myelodysplastic syndrome, Hodgkin’s disease, no malignancy), renal insufficiency (n = 1), or administrative reasons (n = 1), and were excluded from further analysis. The remaining 389 patients were randomized to CHOP (n = 192) or CHOP plus G-CSF (n = 197). All risk factors were balanced between the two treatment groups except for bulky disease, which was more prevalent in the CHOP plus G-CSF arm (P = .04; Table 1  ). The median age at random assignment was 72 years. According to the AAPI, 54% of patients had high-intermediate or high-risk NHL.
Treatment and Dose-Intensity Seventy-five percent of the patients completed six or eight cycles of CHOP. In 32% of the patients, the scheduled treatment was prematurely stopped because of toxicity (13%), disease progression (9%), or other reason (Table 2 ). In eight patients randomly assigned to CHOP plus G-CSF, G-CSF was not given during 26 cycles because of bone pain, fatigue, patient refusal, or other reason.
The difference in the median RDI of cyclophosphamide was 2.4% (ie, 96.3% in patients treated with CHOP plus G-CSF, compared with 93.9% with CHOP alone; P = .01). For doxorubicin the difference in RDI was 2.1% (95.4 v 93.3%, respectively; P = .04; Table 3 ).
Toxicity Three-times-weekly CHOP therapy was generally well tolerated. Neutropenic fever (>38.5°C) was observed in 86 patients treated with CHOP and in 72 patients treated with CHOP plus G-CSF. The median duration of fever in these patients in all cycles together was 3 days (range, 1 to 32) and 2 days (range 1 to 14), respectively (P = .04). One hundred eighty (15%) of 1,195 CHOP cycles were complicated by an infection with WHO grade 2 to 4, compared with 135 (11%) of 1,191 CHOP plus G-CSF cycles (P = .007). The number of severe infections (WHO grade, 3 to 4) was equal in both treatments (Table 4 ). The number of infectious complications decreased sharply beyond the first cycle (CHOP, 32% v CHOP plus G-CSF, 20%; P = .01) and second cycle (CHOP, 14% v CHOP plus G-CSF, 13%; P = .92). The lower incidence of grade 2 infections with CHOP plus G-CSF was associated with a significant reduction in antibiotic prescriptions. The median duration of antibacterial treatment was 6 days (range, 0 to 180) in patients treated with CHOP and 0 days (range, 0 to 126) in patients treated with CHOP plus G-CSF (P = .006). However, the number of days of hospital stay was equal with both treatments (ie, 6 days with CHOP [range, 0 to 111] and 5 days with CHOP plus G-CSF [range 0 to 157]; P = .40). The nonhematologic toxicity is shown in Table 5.
The observed toxicity was not influenced by age (Table 6 ). However, patients older than 80 years completed significantly fewer treatments compared with younger patients due to toxicity, refusal, or death (43% v 80%; P < .001). The treatment-related mortality was 7.5% (29 patients), of which 17 were cardiac deaths (Table 7).
Response to Therapy The overall response rate in patients treated with CHOP was 83%, compared with 85% in patients treated with CHOP plus G-CSF (P = .70). The CR rates were 55% and 52%, respectively (P = .63). The 95% CI for the difference of the CR rates is -12% to 8%. In 96% of the patients who attained at least a PR, this response was already achieved with 3 cycles. The number of CRs increased from 43% after 3 cycles to 53% after 8 cycles of CHOP or CHOP plus G-CSF, with no difference between the treatment arms.
Survival
Prognostic Factors Univariate logistic regression showed that B symptoms, elevated bilirubin (both P < .05), tumor stage III to IV, anemia, bone marrow involvement, more than one extranodal site, and a higher AAPI score (all P < .01) were associated with a lower CR rate. Univariate Cox regression showed that elevated erythrocyte sedimentation rate, abnormal WBC count (both P < .05), higher age, WHO grade 2 to 4, B symptoms, stage III to IV, elevated LDH, elevated bilirubin, anemia, and a higher AAPI score (all P < .01) predicted an inferior OS. Prophylactic G-CSF was not associated with an improvement of any of the end points, while a higher AAPI score predicted for worse outcome for both CR rate and OS. Therefore the univariate analyses were also performed with adjustment for the three factors of the AAPI (WHO grade 2 to 4, stage III to IV, and elevated LDH) to find variables that were significant on top of the AAPI. Only variables that were significant in the unadjusted univariate analyses were included.
Older age (P < .05), bone marrow involvement, and more than one extranodal site (both P < .01) were associated with a lower CR rate. Adverse prognostic factors for OS were elevated bilirubin, anemia and abnormal WBC count (all P < .05), and higher age (P < .01; Tables 8
QoL Assessment One hundred sixty-two patients were asked to participate in the QoL study. Thirty patients refused (19%). They differed from the total study population only by the higher frequency of B symptoms (36% v 26%). During the study period, 96% of the questionnaires were returned, and in the follow-up period, 88% were returned. In patients with progressive disease or relapse, the questionnaire return rate decreased to 77%. Since there was no difference in QoL between both treatments, the results are combined. During treatment, the EuroQol did not change (Fig 3 ). The mean QLQ-C30 scores for the different domains did not change in time. Patients with B symptoms scored significantly lower before treatment on almost all scales. This difference was no longer present after four chemotherapy cycles. There was an inverse association between fatigue and hemoglobin level at all time points.
During follow-up, the QoL scores were attributed to the different clinical outcomes: CR, PR, or progression or relapse. Three months after completion of therapy, patients with PR or CR reported significantly higher levels of QoL compared with pretreatment and during-treatment values. Only the patients with progression or relapse reported a significantly lower QoL. With longer follow-up, no major changes occurred in QoL.
Cost Analysis
CHOP chemotherapy in elderly patients is frequently complicated by neutropenic fever. Because of the risk of severe morbidity and mortality in this population clinical practice is to postpone CHOP cycles or to reduce the dose in order to prevent (cumulative) toxicity. However, this may result in a lower dose-intensity of the required treatment. It has been shown that dose reduction of CHOP is associated with a lower response rate and a relatively poor OS.3 Several studies have suggested that G-CSF improves the adherence to the chemotherapy schedule and minimizes dose modifications in elderly patients with NHL.33,34 Therefore, prophylactic treatment with G-CSF has become routine clinical practice in these patients. This study was designed to evaluate whether prophylactic administration of G-CSF may indeed improve the probability that a potentially curative treatment such as CHOP is administered at the RDI, and whether this improves long-term OS and DFS. Unexpectedly, with standard CHOP, the median RDI was greater than 90%, indicating that the need for dose reduction is relatively rare. With prophylactic G-CSF, the median dose of doxorubicin and cyclophosphamide increased by only 2.1% and 2.4%, respectively. This small increase of dose did not lead to a better response rate or OS. In a recently published study from the Nordic Lymphoma Group, prophylactic G-CSF with CHOP or cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP) in elderly patients improved the RDI, but this did not result in a higher CR rate, longer time to treatment failure or better OS.35 An additional potential advantage of prophylactic G-CSF (ie, to reduce serious complications from neutropenia) was also not demonstrated. While G-CSF reduced the number of mild infections (WHO grade 2) and the use of antibiotics, the frequency of serious infections was identical. Moreover, the number of hospital admissions during chemotherapy was similar in both groups. Also, the toxic death rate (6%) with or without G-CSF was in accordance with other controlled studies.13,16,22,36 In this study, there was no upper age limit. As expected, patients of higher age more often retracted from treatment before the completion of the planned treatment cycles. Prophylactic G-CSF did not influence this pattern, nor did G-CSF reduce the incidence of severe neutropenic fever in patients older than 70 years. Higher age proved to be a negative prognostic factor for OS, but not for PFS and DFS. Therefore, this observation seems to be the result of death causes not related to NHL. In this fragile patient group, QoL is an important issue when deciding to administer chemotherapy. The QoL significantly improved during CHOP in patients with B symptoms, and remained equal in all other patients. This implies that a poor QoL before start of CHOP is no reason to adjust treatment. G-CSF had no effect on the QoL. After completion of treatment, most chemotherapy-related symptoms disappeared, and the patients’ QoL improved rapidly. Prophylactic G-CSF was not cost-effective. The number of hospital admissions was not reduced, while the use of antibiotics was marginally less. In economic studies, prophylactic G-CSF is cost-neutral at an infection incidence of 40%.37,38 In conclusion, we could not demonstrate an improvement of OS with prophylactic G-CSF administration. It is, however, possible that a small difference between the arms may have been missed due to the sample size. The OS at 5 years was only 22% to 24%. The majority of the patients (67%) died from NHL. Prophylactic G-CSF did not prevent severe infections or lower the number of hospital admissions. Evidently, the high relapse rate indicates that the treatment of elderly patients with aggressive NHL should be reconsidered. Other modalities such as antibody therapy or intensification of CHOP are needed to improve the clinical outcome of NHL in these patients.36,39
The following persons and institutions participated in this Dutch-Belgian Hemato-OncologyCooperative Group (HOVON) study: J.K. Doorduijn, M.B. van’t Veer, and P. Sonneveld, Erasmus Medisch Centrum; B. van der Holt, M.M.C. Steijaert, HOVON Data Center, Erasmus Medisch Centrum; I. Buijt, C.A. Uyl-de Groot, M. van Agthoven, Institute of Medical Technology Assessment; A.G.C. Bauer, Havenziekenhuis; and A.A. van Houten, M.B.L. Leys, Medical Center Rijnmond-Zuid, Rotterdam; G.J. Ossenkoppele, Academisch Ziekenhuis Vrije Universiteit; M.H.J. van Oers, Academisch Medisch Centrum; K.J. Roozendaal, Onze Lieve Vrouwe Gasthuis; J.W. Baars, Antoni van Leeuwenhoek Hospital; and M. Soesan, Slotervaart, Amsterdam; M.H.H. Kramer, Eemland, Amersfoort; K.G. van der Hem, De Heel, Zaandam; M.R. Schaafsma, MS Twente, Enschede; P.W. Wijermans, Leyenburg; and W.A. van Deijk, Juliana Kinderziekenhuis/Rode Kruis Ziekenhuis, Den Haag; G.W. van Imhoff, Academisch Ziekenhuis Groningen; and H. Piersma, Martini, Groningen; P. Joosten, Medisch Centrum Leeuwarden, Leeuwarden; H.C. Kluin-Nelemans, Leids Universitair Medisch Centrum, Leiden; L.F. Verdonck, Universitair Medisch Centrum; S.G.L. van der Vegt, Oudenrijn; R. van der Griend, Diakonessenhuis; R. Oltmans, Overvecht Utrecht; M. van Marwijk Kooy, Isala Klinieken, Zwolle; W.G. Peters, Catharina, Eindhoven; D.H. Biesma, Antonius, Nieuwegein; P.W.G. van der Linden, Kennemer; and C.A.M. de Swart, Spaarne, Haarlem; J.J. Braun, Vlietland, Schiedam; W.J. Molendijk, Rijnland, Leiderdorp; H.P. Muller, Gooi-Noord, Blaricum; G.J. Goverde, O.J.L. Loosveld, Amphia Ziekenhuis, Breda; C. van der Heul, Elisabeth Ziekenhuis, and H.T.J. Roerdink, Tweesteden Ziekenhuis, Tilburg; J.B. Ruit, Vlietland, Vlaardingen; H.W.A. Berenschot, F.H.W Kauw, J.P.H.B. Sybesma, Albert Schweitzer, Dordrecht; J.J. Keuning, L.-T. Vlasveld, Maxima Medical Center, Veldhoven; M.G. Herben, Antoniushove, Leidschendam; D.J. de Gooyer, Franciscus, Roosendaal; P.P. Schiphorst, Beatrix, Winterswijk; P.C. van der Velden, van Weel, Dirksland; J.A.C. Brakenhoff, Waterland, Purmerend; L.H. van Hulsteijn, Joseph, Veghel; D.W. van Toorn, Lukas, Apeldoorn; F.A.A. Valster – Lievensberg, Bergen op Zoom; E. Maartense, Reinier de Graaf, Delft; H.A.M. Sinnige, Bosch Medisch Centrum, Den Bosch; L.D. de Haan, Scheper Emmen; R.E.H. Smeets, St Anna, Geldrop; T.M. van Maanen-Lamme, West Fries Gasthuis, Hoorn; P.R. van der Werf, Refaja, Stadskanaal; H.I.J. de Jong, Gemini, Den Helder; M.B. van Hennik, Beatrix, Gorinchem; K.J. Heering, Groene Hart, Gouda; K.D. van der Stadt, Spaarne, Heemstede; W. Tel, Tjongerschans, Heerenveen; H. de Korte, Diaconessenhuis, Meppel; P.L.M. Thunnissen, Lorentz, Zeist, the Netherlands; G.E.G. Verhoef, Gasthuisberg, Leuven, Belgium.
Supported by the Dutch National Health Council, the Hague, the Netherlands.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= 0.05 and a power of 1 - ß = 0.80, the number of patients needed to detect a 15% (10%) increase in CR rate was 352 (792) and 344 (762) for OS4.
2 test in case of discrete variables, or the Wilcoxon rank sum test in case of continuous variables. End points in the study included RDI, CR rate, OS, event-free survival (EFS), progression-free survival (PFS), and disease-free survival (DFS). 
18 v > 18 µmol/L), creatinine (normal v elevated), hemoglobin (Hb; anemia v normal; ie, Hb > 8.6 mmol/L for men and Hb > 7.5 mmol/L for women), platelets (
