A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin’s lymphoma

E. M. Bessell1,+, A. Burton2, A. P. Haynes3, J. Glaholm4, J. A. Child5, M. H. Cullen4, J. M. Davies3, G. M. Smith5, I. O. Ellis6, A. Jack7 and E. L. Jones On behalf of the Central Lymphoma Group UK8,§

Departments of 1 Clinical Oncology, 3 Haematology and 6 Histopathology, Nottingham City Hospital, Nottingham; 2 Cancer Research UK Trials Unit, University of Birmingham, Birmingham; 4 Department of Clinical Oncology, Queen Elizabeth Hospital, Birmingham; Departments of 5 Haematology and 7 Histopathology, Leeds General Infirmary, Leeds; 8 Department of Pathology, Birmingham University, Birmingham, UK

Received 5 August 2002; accepted 28 August 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Background:

The aim of this study was to determine in a randomised trial whether there is any significant difference in toxicity between modified CHOP and MCOP chemotherapy in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL) and to determine whether this reduced dose chemotherapy can be administered with full dose intensity, low toxicity and produce acceptable survival.

Patients and methods:

Between 1993 and 2000, 155 eligible patients were randomised into this trial mainly from three centres (Nottingham, Birmingham and Leeds, UK). The patients were newly diagnosed with aggressive NHL and had a median age of 74 years (range 65–91 years). Ninety-six patients (62%) had bulky stage I or II disease; 59 patients (38%) had either stage III or IV disease; 77% had one or more extranodal sites involved at presentation; and 31% showed B symptoms. Seventy-seven patients were randomised to receive six cycles of modified CHOP (cyclophosphamide 600 mg/m2 i.v., doxorubicin 30 mg/m2 i.v., vincristine 1 mg i.v. all on day 1 with prednisolone 20 mg bd for days 1–5) every 21 days and 78 patients to MCOP (mitozantrone 10 mg/m2 i.v. substituted for doxorubicin). Growth factors were not used routinely. After completion of chemotherapy, 39 patients received involved field radiotherapy (35–40 Gy) in 20 fractions.

Results:

One hundred and one patients (65%) completed all six cycles of chemotherapy. The median course dose intensity was 97%. The median follow-up for 53 surviving patients was 51 months. The median survival was 19 months (95% confidence interval 10–36 months) with an actuarial survival of 47% at 2 years and 42% at 3 years (CHOP versus MCOP, P = 0.79). There was no significant difference in any of the toxicities experienced with either CHOP or MCOP, except for white cell count (46 patients on MCOP and 27 patients on CHOP had grade 3 or 4 toxicity, P = 0.002) and red cell transfusion (37 patients, MCOP; 17 patients, CHOP; P = 0.001). Grade 3 or 4 neutropenia was documented in 75 patients (50%). One patient died from toxicity whilst in remission and seven patients died with septicaemia and persistent NHL.

Conclusion:

This multicentre randomised trial provides further information on the dose intensity achievable with CHOP or MCOP regimens in elderly patients (median age 74 years) with aggressive NHL. These dose-reduced regimens can be given with nearly 100% dose intensity with 65% of patients completing all the treatment. Survival is comparable to that observed with the more intensive regimens given in this age group.

Key words: chemotherapy, elderly, dose intensity, non-Hodgkin’s lymphoma, randomised trial


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
The incidence of non-Hodgkin’s lymphoma (NHL) is increasing partly because of the ageing population [1, 2]. In the United Kingdom, 16% of the population are aged >65 years [3] and the median age of patients with aggressive NHL is the early 60s [4]. In addition, associated comorbidity, such as ischaemic heart disease and chronic obstructive pulmonary disease, increases in incidence with increasing age [5, 6]. The standard chemotherapy for large B cell NHL is CHOP [7] [cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v. (2 mg maximum) and prednisolone 100 mg o.d. for 5 days] given every 21 days for 3–8 cycles (depending on stage) followed, in some patients, by radiotherapy [8]. In younger patients this regimen can usually be given with full dose intensity, but with increasing age, particularly >60 years, it becomes increasingly difficult to achieve full dose intensity [912]. This may be due to ageing of the bone marrow and an increased risk of bone marrow suppression, and also to ageing of the immune system such that immunosuppression from chemotherapy will increase with increasing age leading to an increased risk of infection [13]. Clearly there is wide variability in fitness in patients of the same age but over the age of 65 or 70 years more and more patients would have difficulty tolerating CHOP at full dose intensity. Many clinicians managing this disease in the elderly use their clinical judgement to estimate the dose for each drug in the regimen rather than expose the patients to the risks associated with the first cycle of chemotherapy at full dose [even with the use of growth factors such as granulocyte colony-stimulating factor (G-CSF) for chemotherapy] [14].

There has been considerable interest in the use of mitozantrone in aggressive NHL, mainly because it was hoped that a dose per m2 could be established that was as effective as 50 mg/m2 of doxorubicin against aggressive NHL with less cardiac toxicity [12, 1517].

In order to address some of these issues, a phase II study was carried out in Nottingham (UK) in patients with aggressive NHL aged >=70 years using the MCOP regime (mitozantrone 10 mg/m2, cyclophosphamide 600 mg/m2 and vincristine 1 mg i.v. all on day 1 and prednisolone 20 mg bd p.o. days 1–5) given every 21 days [18]. Of all the patients >70 years old diagnosed in a 3.5-year period with aggressive NHL and unsuitable for treatment by radiotherapy alone, 85% were treated with the MCOP regimen. The 3-year overall survival was 21%.

This multicentre randomised trial was then started in 1993 in order to provide further information on the toxicity of the MCOP regimen (mitozantrone, cyclophosphamide, vincristine and prednisolone) in comparison to a modified CHOP regimen, which was identical to MCOP apart from doxorubicin 30 mg/m2 i.v. instead of mitozantrone 10 mg/m2 i.v.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Patient eligibility
Newly diagnosed elderly patients with intermediate- and high-grade NHL (Working Party Formulation) were eligible if they were aged >=65 years and had no other serious medical conditions associated with a poor prognosis, including severe ischaemic heart disease and cardiomyopathy. Patients with previous malignancy (except non-melanomatous skin cancer and treated in situ cervical carcinoma) and patients with non-bulky stage IA disease were also excluded. It was anticipated that the vast majority of patients would be aged >=70 years.

Patient accrual
This was a Central Lymphoma Group trial (NH 3003) involving three major cancer centres (Birmingham, Leeds and Nottingham). The trial office for randomisation was the Cancer Research UK Trials Unit, Institute for Cancer Studies, Birmingham. Patients were randomised to receive six cycles of either modified CHOP or MCOP chemotherapy. Randomisation sheets were prepared without stratification using the random permuted block method. Patients were entered onto the study by telephoning the trial office where the eligibility of the patient was checked and the next available treatment allocated. All participating hospitals obtained local ethical committee approval and all patients gave written informed consent prior to randomisation.

Histopathological review
The histology of the first 125 patients in the trial was reviewed by the Central Lymphoma Group pathology panel (E. L. Jones, Birmingham; A. Jack, Leeds; and I. O. Ellis, Nottingham). These patients were entered between 1993 and 1997. After 1997, patients were only entered from Nottingham and their histology was reviewed (by I.O.E.) between 1998 and 2000 at weekly haematopathology meetings held at Nottingham City Hospital.

Treatment regimens
The modified CHOP and MCOP regimens are shown in Table 1. The anti-emetic regimen was standardised in the protocol. Further dose reduction of chemotherapy was not planned in this trial other than advice to consider reducing the dose of either doxorubicin or mitozantrone if the neutrophil count was <1.5 x 109/l or the platelet count <100 x 109/l when the patient attended for chemotherapy on day 22.


View this table:
[in this window]
[in a new window]
 
Table 1. The modified CHOP and MCOP regimens
 
The doses of the drugs used were based on a phase II study of MCOP chemotherapy in 46 patients aged >=70 years [18]. In particular, the set dose of vincristine of 1 mg i.v. was because the risk of peripheral neuropathy was considered to be greater in the elderly.

Involved field radiotherapy was advised after chemotherapy for patients with stage I or II disease if there was bulky disease at presentation or residual disease after chemotherapy. A dose of 40 Gy in 20 fractions in 4 weeks was suggested for patients with residual disease and 35 Gy in 20 fractions in 4 weeks for patients in complete remission but with bulky disease at presentation.

The doses given with each cycle of chemotherapy were recorded on the data collection forms with the date of each cycle. The reason for dose reduction or delay was also recorded.

The intensity of the administered dose for each drug was calculated as the percentage of the administered daily dose (dose given divided by the actual duration of cycle) divided by the planned daily dose. The average of the four drug dose intensities gave a cycle dose intensity. The overall course dose intensity was calculated as the average of all administered cycle dose intensities. The duration of the final cycle received was considered to be 21 days for all cases who survived longer than this.

Staging investigations
The following investigations were recommended in the protocol: haemoglobin; white cell count with differential; platelet count; serum urea and electrolytes; calcium; liver function tests; lactate dehydrogenase (LDH); immunoelectrophoresis of serum and urine; chest radiograph; computed tomography (CT) scan of chest, abdomen and pelvis; cerebrospinal fluid cytology (lymphoblastic histology and/or neurological signs); and bone marrow aspirate and trephine sampling. It was suggested in the protocol that patients aged >=76 years could be offered less intensive investigation with an ultrasound of the abdomen and pelvis instead of a CT scan and no bone marrow examination if they did not wish to proceed to the full recommended investigations. Performance status at diagnosis was recorded.

Toxicity and response
The maximum toxicity was recorded for each cycle of chemotherapy according to the National Cancer Institute (NCI) Common Toxicity Criteria grading system. The following toxicities were recorded: lowest haemoglobin, white cell, neutrophil and platelet count, number of red cell transfusions, nausea and vomiting, stomatitis, diarrhoea, infection, alopecia and neurological signs (loss of motor power or sensory loss or reflexes).

Response was determined, on completion of randomised treatment and after any additional treatment, using the standard UICC criteria. A complete response (CR) represented a resolution of all clinical disease for at least 2 months. Partial remission (PR) corresponded to at least a 50% reduction in the product of the two largest perpendicular diameters of all measurable lesions for a minimum of 1 month. Stable disease was regarded as no change in tumour burden, <50% reduction or no more than a 125% increase of its original size. Finally, progression was classed as unequivocal evidence of an increase in disease despite continuing treatment.

Statistical methods
The primary end point of the trial was toxicity. With an expected amount of severe toxicities (classed as NCI grade 3 or 4) of ~5–10% in this population, 100 patients were required in each arm to allow the detection of differences in excess of 15% at the {alpha} = 0.05 level of significance with an 80% power. However, after discussion with the Independent Data Monitoring Committee the trial closed early when 160 patients had been randomised, because of slower recruitment. Sample size calculations were unaffected when the expected level of severe toxicity was 5%. However, there was a slight loss of power (70%) when detecting the planned 15% differences if the expected level was 10% on the standard treatment, but it does allow differences of 20% to be detected with 85% power.

The proportion of patients that experienced severe toxicities of grade 3 and 4 and the differences in the complete and overall response rates to treatment were compared across treatments using chi-square tests or Fisher’s exact test where appropriate.

Survival was calculated as the time from entry to the trial until the date of death from any cause or until the date last seen alive. Lymphoma-specific survival was defined as the time from randomisation until death from NHL, or censored at the date the patient died of other causes, or the date last seen alive. Failure-free survival was calculated as the time from randomisation until either the date of relapse or progression, the date of death if died without a recorded relapse or progression, or the date last known to be alive. Survival curves were constructed using the method of Kaplan and Meier [19] and compared using the log rank test [20]. The analysis was carried out using the SAS statistical software (SAS Institute, Cary, NC, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Patient characteristics
A total of 160 patients were randomised between 1993 and 2000. Seventy-nine were allocated CHOP chemotherapy and 81 MCOP chemotherapy (Table 2). The accrual by region was Nottingham (75 patients), Birmingham (46 patients), Leeds (35 patients) and North Wales (four patients).


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics
 
Five patients subsequently proved ineligible (two on the CHOP treatment arm and three on MCOP) because the histology on review was not NHL. These five patients have been excluded from all analyses leaving 155 patients eligible for analysis; 77 randomised to CHOP and 78 allocated MCOP.

Of the 155 patients, 121 (78%) had diffuse large B-cell NHL and only five patients (3%) had peripheral T-cell NHL. Twenty-one patients (14%) had B-cell NHL unspecified (high-grade histology). This pattern is similar to other multicentre trials. For example, in the recent trial of CHOP plus rituximab versus CHOP alone in diffuse large B-cell lymphoma, 12% of patients did not have the typical features of diffuse large B-cell lymphoma on review [21].

The treatment groups seem relatively well balanced in terms of age, stage (I and II versus III and IV), extranodal involvement and symptoms. The patients have a median age of 74 years (range 65–91), 62% stage I and II, 73% had one or more extranodal sites involved at presentation and 69% have B symptoms. However, there appears to be a slight imbalance in the sex distribution across treatment, with 42 males being randomised to receive CHOP chemotherapy and 27 allocated MCOP. The age-adjusted international prognostic index (IPI) score [22] (stage III or IV disease, abnormal LDH value, performance status >=2) was calculated for 118 patients. There were 66 patients with a low or intermediate/low risk (score 0 or 1) and 52 patients with an intermediate/high or high risk (score 2 or 3). The standard score [22] (age >60 years, >1 extranodal site, stage III or IV disease, abnormal LDH value, performance status >=2) was calculated for 83 patients.

Chemotherapy
A total of 396 cycles of CHOP were administered compared to 378 cycles of MCOP chemotherapy (Table 3). The majority of patients on both arms received the full course of randomised chemotherapy consisting of six cycles; 54 (70%) patients allocated CHOP and 47 (60%) patients randomised to MCOP. The main reason in both arms for 54 patients not completing treatment was death during treatment (10 patients allocated CHOP versus 13 on MCOP) or disease progression (four patients on CHOP and six allocated MCOP).


View this table:
[in this window]
[in a new window]
 
Table 3. Chemotherapy details
 
The median course dose intensity in both arms was 97% (inter-quartile range for CHOP was 89–100% compared with 88–100% for those allocated MCOP). The median dose intensities over all cycles for each drug were again extremely high at 99% or 100%. For the majority of patients there were no major delays in treatment or dose reductions. A median delay of a week was experienced for administering 55 (14%) cycles of CHOP (range 3–35 days) and 53 (14%) cycles of MCOP (range 1–42 days). Dose reductions were required in 41 (10%) cycles of CHOP and 42 (11%) cycles of MCOP.

Response to chemotherapy
Response to chemotherapy could not be evaluated in eight patients (three receiving CHOP and five receiving MCOP). Forty-six patients (62%) randomised to CHOP achieved a CR compared to 38 patients (52%) allocated to MCOP ({chi}2 = 1.30, P = 0.26). A partial response was obtained in 12 patients (16%) treated with CHOP and 11 patients (15%) treated with MCOP, static disease in one patient treated with CHOP and four patients treated with MCOP. Progression occurred in 15 patients (20%) treated with CHOP and 20 patients (28%) treated with MCOP.

Toxicity of chemotherapy
The only significant differences in toxicity were in red cell transfusion requirements and white cell count (Table 4). Thirty-seven patients treated with MCOP required a red cell transfusion on one or more cycles compared with 17 patients treated with CHOP (P = 0.001). The only major grade 3 or 4 toxicities were neutropenia (32 patients receiving CHOP, 43 patients receiving MCOP, P = 0.10) and leucopenia (46 patients receiving MCOP and 27 patients receiving CHOP, P = 0.002). Grade 3 or 4 infection was recorded in only seven patients with CHOP and 13 patients with MCOP. Insufficient data on cardiac toxicity were obtained to assess whether mitozantrone was less cardiotoxic than doxorubicin. Information on cause of death and cardiac events, such as myocardial infarction and cardiac failure, was requested, but sequential cardiac scans, such as echocardiography or multiple gated acquisition scans, were not performed. NCI grading of cardiac rhythm was not carried out.


View this table:
[in this window]
[in a new window]
 
Table 4. Toxicity
 
Additional treatment after six or less cycles of chemotherapy
Additional treatment was given to 23 patients randomised to CHOP (18, involved field radiotherapy; two, a further two cycles of chemotherapy; two, other chemotherapy; and one, intrathecal methotrexate) and 34 patients randomised to MCOP (18, involved field radiotherapy; seven, a further one or two cycles of chemotherapy; five, other chemotherapy; three, combined chemotherapy and radiotherapy; and one, intrathecal methotrexate). This improved the CRs from 46 to 47 patients (64%) in the CHOP arm and from 38 to 43 patients (57%) in the MCOP arm.

Survival and causes of death
All patients have been followed up for a minimum of 1 year and a maximum of 8 years. The median length of follow-up for the 53 patients who were alive at the end of the study was 51 months (interquartile range 28–73 months) and is reasonably balanced across the treatment arms. A total of 102 (66%) patients are known to have died; 51 on each treatment arm (Table 5). Seventy-two (71%) patients died of NHL disease, five (5%) died from septicaemia and NHL disease, and one (1%) died as a result of their randomised treatment from doxorubicin-induced cardiomyopathy. One patient died from cholangiocarcinoma, 20 patients died from other causes (predominantly cardiovascular and respiratory), and three from unknown causes.


View this table:
[in this window]
[in a new window]
 
Table 5. Causes of death
 
The median survival for the 155 eligible patients was 19 months [95% confidence interval (CI) 10–36 months] with an actuarial survival rate at 2 years of 47%, and 42% at 3 years. There was no evidence of a significant difference in survival between the treatment groups ({chi}2 = 0.07, P = 0.79): median 20 months (95% CI 10–42 months) for patients on the CHOP arm and 16 months (95% CI 8–47 months) for those randomised to MCOP (Figure 1).



View larger version (9K):
[in this window]
[in a new window]
 
Figure 1. Actuarial overall survival by treatment. MCOP (78 patients) and modified CHOP (77 patients). No significant difference in survival ({chi}2 = 0.07, P = 0.79).

 
The median lymphoma-specific survival was 41 months with an actuarial rate at 2 years of 55%, and 50% at 3 years; again, there was no difference between treatment groups ({chi}2 = 0.01, P = 0.93) (Figure 2).



View larger version (9K):
[in this window]
[in a new window]
 
Figure 2. Lymphoma-specific survival by treatment. MCOP (78 patients) and modified CHOP (77 patients). No significant difference in survival ({chi}2 = 0.01, P = 0.93).

 
Although the median failure-free survival was 7 months longer for those randomised to CHOP (17 months, 95% CI 9–32 months) than for those allocated MCOP (10 months, 95% CI 6–20 months), this did not translate into a significant difference between the two arms ({chi}2 = 0.15, P = 0.70) (Figure 3). Patients with a low or intermediate/low risk, using the age-adjusted IPI, had a significantly longer survival than those with a intermediate/high or high risk (P <0.0001). The 3-year actuarial survival rate was 57% for those with a low or intermediate/low risk compared with 26% for those with an intermediate/high or high risk (Figure 4).



View larger version (10K):
[in this window]
[in a new window]
 
Figure 3. Failure-free survival by treatment. MCOP (78 patients) and modified CHOP (77 patients). No significant difference in survival ({chi}2 = 0.15, P = 0.70).

 


View larger version (11K):
[in this window]
[in a new window]
 
Figure 4. Survival by age-adjusted International Prognostic Index. Low or intermediate/low risk, score 0 or 1 (66 patients) and intermediate/high or high risk, score 2 or 3 (52 patients). There was better survival for those with low or intermediate/low risk ({chi}2 = 16.21, P <0.0001).

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
The 2-year survival of 47% in patients with a median age of 74 years treated with either modified CHOP or MCOP for aggressive B-cell NHL is similar to the survival obtained in the other randomised trials of patients of a similar age (EORTC: CHOP versus VMP [11]; GELA: CVP versus CTVP [10]; BNLI: PAdriaCEBO versus PmitCEBO [15]; Dutch Study Group: CNOP versus CHOP [12]), but less than CHOP plus rituximab [22] or two weekly CHOP with G-CSF [23]. CHOP plus rituximab given on day 1 of each 21-day cycle for eight cycles gives a 2-year survival of 70% in patients of median age 69 years. If CHOP plus rituximab proves to be the new gold standard for elderly patients with diffuse large B-cell NHL there is still a need for information on the optimum dose intensity of CHOP in patients in their 70s and 80s in different parts of the world.

In this trial, doxorubicin given at a dose intensity of 10 mg/m2/week was almost equivalent to mitozantrone given at a dose intensity of 3.3 mg/m2/week. There was no difference in survival between modified CHOP and MCOP but there was more bone marrow suppression with mitozantrone. Without G-CSFs the achievable dose intensity of doxorubicin in CHOP is up to 13 mg/m2/week and the achievable dose intensity of mitozantrone is up to 3.5 mg/m2/week in this age group of patients (median age 74 years) [11, 12, 24, 25]. A dose intensity of mitozantrone of only 2.5 mg/m2/week in the Sonneveld et al. study of CHOP versus CNOP was associated with a significantly worse survival for patients receiving CNOP [12].

In this trial, only 76% of the deaths were due to lymphoma and the lymphoma-specific survival was 55% at 2 years and 50% at 3 years. The 19% improvement in survival (42% overall, to 50% lymphoma-specific at 3 years) was also seen in the original phase II study of 46 patients treated with MCOP (21% overall, to 26% lymphoma-specific at 3 years) with a similar population of patients (age 70–93 years; median 75 years) [18]. Some of the patients who were treated in the phase II study would have been excluded from the phase III study because of severe ischaemic heart disease.

Comorbidity varies [5] and trials conducted in patients with relatively low incidences of chronic obstructive pulmonary disease and ischaemic heart disease may not be applicable to patients with high incidences of these diseases.

Patient selection because of comorbidity will frequently occur in multicentre phase III trials. The number of eligible patients seen at each centre who have aggressive NHL and are in the correct age range is usually not known. The normal IPI and the age-adjusted IPI have helped in comparisons between different trials [22]. Using the age-adjusted IPI, the 3-year actuarial survival rate for those patients with a low or intermediate/low index was 57% compared with only 26% for those with an intermediate/high or high index (P <0.0001). This is a similar result to the GELA study [10] and the NHL Classification Project for patients aged 60 years or older with an intermediate/high or high index [4].


    Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
This multicentre randomised trial has shown that there is little difference in clinically significant toxicity between the MCOP and modified CHOP regimens at the doses given, with no difference in survival. These two regimens were given at almost 100% dose intensity and indicate that a median dose intensity of doxorubicin of 10 mg/m2/week and of mitozantrone of 3.3 mg/m2/week are both achievable in this type of regimen. There is, however, very little scope for further dose intensification in this age group without using growth support such as G-CSF. In the future, the use of monoclonal antibodies in combination with chemotherapy might mean that the type of dose reduction, used in modified CHOP or MCOP in this trial, could be employed to reduce toxicity and the need for growth-factor support in elderly patients with aggressive NHL.


    Acknowledgements
 
This work was supported by a grant from Wyeth Laboratories.

Authorship, by agreement at the start of the trial, depended on entering at least 5% of the patients and involvement in the writing of the paper or on being a member of the histopathology review panel. The following persons who were not included as authors and their institutions participated in this trial: D. Parry and N. Stuart (Ysbyty Gwynedd Hospital); A. Hunter and J. Fletcher (Nottingham City Hospital); H. Earl, D. Rea and D. Spooner (Birmingham City Hospital); I. Fernando, A. Goodman and N. James (Queen Elizabeth Hospital, Birmingham); D. Gilson and G. Morgan (Cookridge Hospital, Leeds); M. Lewis (Kidderminster Hospital); M. Galvin (Pinderfields General Hospital); A. Chetiyawardana (Manor Hospital, Walsall); C. Irwin (Walsgrove Hospital, Coventry).


    Footnotes
 
+ Correspondence to: Dr E. M. Bessell, Department of Clinical Oncology, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail: ebessell{at}ncht.trent.nhs.uk Back

§ Additional members of the Central Lymphoma Group UK are listed in the Acknowledgements. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
1. D’Amore F, Brincker H, Christensen BE et al. Non-Hodgkin’s lymphoma in the elderly: a study of 602 patients aged 70 or older from a Danish population-based registry. The Danish LYEO-Study Group. Ann Oncol 1992; 3: 379–386.[Abstract]

2. Glass AG, Karnell LH, Menck HR. The National Cancer Data Base report on non-Hodgkin’s lymphoma. Cancer 1997; 80: 2311–2320.[CrossRef][ISI][Medline]

3. 2001 Census. Office of Population Censuses and Surveys. London, UK: Her Majesty’s Stationery Office 2002.

4. The Non-Hodgkin’s Lymphoma Classification Project. Effect of age on the characteristics and clinical behaviour of non-Hodgkin’s lymphoma patients. Ann Oncol 1997; 8: 973–978.[Abstract]

5. Havlik RJ, Yancik R, Long S et al. The National Institute on Ageing and the National Cancer Institute SEER collaborative study on co-morbidity and early diagnosis of cancer in the elderly. Cancer 1994; 74: 2101–2106.[ISI][Medline]

6. Department of Health. Our healthier nation. London, UK: Her Majesty’s Stationery Office 1998.

7. Fisher RI, Gaynor FR, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1993; 328: 1002–1006.[Abstract/Free Full Text]

8. Miller TP, Dahlberg S, Cassady JR et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localised intermediate and high-grade non-Hodgkin’s lymphoma. N Engl J Med 1998; 339: 21–26.[Abstract/Free Full Text]

9. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am Geriatr Soc 1984; 32: 269–273.[ISI][Medline]

10. Bastion Y, Blay JY, Divine M et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment and survival—a Groupe d’Etude des Lymphomes de l’Adulte study on 453 patients older than 69 years. J Clin Oncol 1997; 15: 2945–2953.[Abstract]

11. Tirelli U, Errante D, van Glabbeke M et al. CHOP is the standard regimen in patients <=70 years of age with intermediate-grade and high-grade non-Hodgkin’s lymphoma: Results of a randomised study of the European Organization for Research and Treatment of Cancer Lymphoma. Cooperative Study Group. J Clin Oncol 1998; 16: 27–34.[Abstract]

12. Sonneveld P, de Ridder M, van der Lelie H et al. Comparison of doxorubicin and mitozantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin’s lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995; 13: 2530–2539.[Abstract]

13. Horan MA, Ashcroft GS. Ageing, defence mechanisms and the immune system. Age Ageing 1997; 26 (Suppl 4): 15–19.[Abstract]

14. Meyer RM, Gyger M, Langley R et al. A phase I trial of standard and cyclophosphamide dose-escalated CHOP with granulocyte colony stimulating factor in elderly patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 1998; 30: 591–600.[ISI][Medline]

15. Mainwaring PN, Cunningham D, Gregory W et al. Mitozantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high grade lymphoma: results of a BNLI randomised trial of PAdriaCEBO versus PMitCEBO. Blood 2001; 97: 2991–2997.[Abstract/Free Full Text]

16. Guglielmi C, Gherlinzoni F, Amardori S et al. A phase III comparative trial of m-BACOD vs m-BNCOD in the treatment of stage II–IV diffuse non-Hodgkin’s lymphomas. Haematologica 1989; 74: 563–569.[ISI][Medline]

17. Pavlovsky S, Santarelli MT, Erazo A et al. Results of a randomised study of previously untreated intermediate and high grade lymphoma using CHOP vs CNOP. Ann Oncol 1992; 3: 205–209.[Abstract]

18. Bessell EM, Coutts A, Fletcher J et al. Non-Hodgkin’s lymphoma in elderly patients: a phase II study of MCOP chemotherapy in patients aged 70 years or over with intermediate or high grade histology. Eur J Cancer 1994; 30A: 1337–1341.[CrossRef]

19. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[ISI]

20. Peto R, Pike MC, Armitage P et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35: 1–39.[ISI][Medline]

21. Coiffier B, Lepage E, Brière J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 2002; 346: 235–242.[Abstract/Free Full Text]

22. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 987–994.[Abstract/Free Full Text]

23. Pfreundschuh M, Trümper L, Kloess M et al. Two-weekly CHOP (CHOP-14): the new standard regimen for patients with aggressive non-Hodgkin’s lymphoma >60 years of age. Ann Oncol 2002; 13 (Suppl 2): 27 (Abstr 081).

24. Meyer RM, Browman GP, Sumosh ML et al. Randomised phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995; 13: 2386–2393.[Abstract]

25. Zinzani PL, Storti S, Zaccaria A et al. Elderly aggressive-histology non-Hodgkin’s lymphoma: first line VNCOP-B regimen experience on 350 patients. Blood 1999; 94: 33–38.[Abstract/Free Full Text]