Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin's lymphomas

S. Monfardini1,*, S. M. L. Aversa1, V. Zoli2, L. Salvagno3, A. Bianco3, R. Bordonaro4, G. Benevolo5, M. Crugnola4, G. Crivellari1, P. Vivaldi6, U. Basso1, V. Torri7 On behalf of the Non-Hodgkin's Lymphoma Cooperative Study Group (NHLCSG)

1 Division of Medical Oncology, Azienda Ospedale Università, Padova; 2 Division of Hematology, Hospital ‘S. Camillo’, Roma; 3 Division of Medical Oncology, Hospital of Vittorio Veneto; 4 Cattedra di Ematologia, Parma, Italy; 5 Division of Hematology, Hospital of Novara; 6 Division of Hematology, Hospital of Trento; 7 Mario Negri Istituto, Milano, Italy

* Correspondence to: Prof. S. Monfardini, Division of Medical Oncology, Azienda Ospedale Università Padova, Ospedale Busonera, via Gattamelata 64, 35100 Padova, Italy. Tel: +39-049-8215931; Fax: +39-049-8215932; Email: silvio.monfardini{at}unipd.it


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:: Frail patients with non-Hodgkin's lymphoma (NHL) are generally excluded from clinical trials and not even treated. The aim of this study was to evaluate the efficacy and tolerability of vinorelbine and prednisone in frail elderly patients with NHL.

Patients and methods:: Thirty consecutive frail elderly patients were entered in a phase II study with vinorelbine 25 mg/m2 i.v. on days 1 and 8 and oral prednisone 30 mg total dose on days 1–8 for six cycles. Criteria of frailty were age ≥80 years, or age ≥70 years and three or more comorbidities of grade 3 or at least one comorbidity of grade 4 according to the Cumulative Illness Rating Scale (CIRS), or not self-sufficient or the presence of one or more geriatric syndromes.

Results:: Of 30 evaluable patients, three (10.0%) achieved a complete response (CR), nine (30.0%) showed a partial response (PR), while 10 presented with stable disease and eight with progressive disease. The median duration of CR was 29 months (range 5–36 months), and the median duration of PR was 1 month (range 1–22 months). Three patients had grade 3 neutropenia and one had grade 4. One grade 4 neurotoxicity was observed. Three patients died because of heart failure within 28 days of therapy, and one patient died after 4 days because of rapid progression. The median overall survival was only 10 months.

Conclusion:: Vinorelbine and prednisone is a relatively non-toxic combination with modest activity in frail patients with NHL. If initial aggressive chemotherapy has been excluded, this combination could be tried to obtain a temporary palliation.

Key words: combination chemotherapy, elderly patients, frailty, non-Hodgkin's lymphoma, prednisone, vinorelbine


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
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Advanced age is an adverse prognostic factor in aggressive non-Hodgkin's lymphoma (NHL). The analysis of the cumulative case series of aggressive NHL carried out by The International Non-Hodgkin's Lymphoma Prognostic Factor Project has shown that patients aged >60 years have a worse prognostic outcome than younger patients [1Go], although a direct comparison of response and survival of patients aged >70 years with younger patients is complicated by the fact that the randomized studies were specifically designed for patients aged ≥70 years [2Go, 3Go], and that patients with different age limits were included in earlier retrospective studies [4Go–9Go] and single-arm prospective studies [10Go–18Go]. When the same chemotherapy regimen was used for all patients regardless of age, patients aged >70 years with poor perfomance status and the very old were probably excluded. However, even in the absence of specific data, it is generally accepted that prognosis is worse for patients aged >70 years than for patients aged >60 years.

To reduce the risk of toxicity without decreasing therapeutic activity, novel regimens have been tried in patients aged >70 years. Although various specifically designed regimens have not been shown to be superior to the standard CHOP regimen [2Go, 3Go, 19Go, 20Go], the authors of these various reports deserve merit for having shown that such a chemosensitive disease as NHL can be treated with combination chemotherapy in the framework of a controlled study even in vulnerable elderly patients, i.e. in cases with age-associated comorbidity. However, no information is currently available on the therapeutic strategy to be followed in patients who have severe associated diseases, who are not self-sufficient, who are, for example, incontinent or affected by dementia or delirium, or who are simply older than 80–85 years. These patients are defined by geriatricians as ‘frail’ [21Go–23Go]. To our knowledge, no papers published in the English literature provide any clue as to the best management in these individuals. Should they be left without any treatment? Or should they be treated with the same combination chemotherapy used for other septuagenarians or with a less intense chemotherapy [24Go]? To provide an initial limited answer to these questions, we carried out a prospective trial on a small population of frail patients admitted to the cooperating institutions. Since vinorelbine has been proven as an agent active in NHL [25Go–27Go] and is well tolerated by elderly patients [28Go, 29Go], we decided to use the combination of vinorelbine and prednisone to determine its tolerability and activity in a group of patients in which intensive chemotherapy may not be considered indicated or even feasible. Rituximab could not be considered as a candidate agent to be added to this combination as it only became available 3 years after the start of this trial.


    Patients and methods
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 Introduction
 Patients and methods
 Results
 Discussion
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All frail patients with a newly diagnosed biopsy-proven NHL referred to the Italian participating institutions were entered in this present phase II study.

Patients were required to have stage II, stage III, stage IV or stage I bulky disease and were not eligible if they had lymphoblastic NHL, HIV positivity or other malignancy, with the exception of basal skin carcinoma. To provide evidence of frailty, all patients with NHL were tested in each centre with a shortened version of the Comprehensive Geriatric Assessment (CGA) [30Go, 31Go] including a functional evaluation in terms of activities of daily living (ADL) [32Go] and number and rate of comorbidities according to their severity assessed using the Cumulative Illness Rating Scale (CIRS) in similar manner to the Common Toxicity Criteria grading [33Go]. This scale classifies the associated disease by organ system, and grades each condition from 0 (no problems) to 4 (extremely severe condition). Both potentially lethal and non-lethal comorbid conditions are included in the scale. Patients were also examined with the Mini-Mental Status Examination (MMSE) [34Go] to allow diagnosis and grading of dementia and the Geriatric Depression Scale (GDS) [35Go] as a screening tool for depression. In addition to dementia and depression, patients were screened for other geriatric syndromes such as delirium, incontinence, osteoporosis, neglect and abuse, failure to thrive, and more than three falls in a month. The criteria used to define a patient as frail were age ≥80 years or age ≥70 years and three or more comorbidities of grade 3 or at least one comorbidity of grade 4 according to the CIRS, or dependence in one or more activities of daily living (bathing, dressing, toilet use, transferring, urine and bowel continence, eating) or the presence of one or more of the geriatric syndromes. CIRS items, dementia and delirium were assessed by the haematologist or medical oncologist taking care of the patient, and ADL, MMS and GDS were assessed by the same physician or a psychologist.

The required staging procedures included physical examination, ear, nose and throat examination, blood analysis, CT of chest and abdomen, and bone marrow biopsy. The clinical evaluation of response was carried out after three cycles, or earlier in the case of clinical progressive disease. The protocol was revised and approved by the Scientific Committee of the Non-Hodgkin's Lymphoma Cooperative Study Group. Informed consent was obtained from each patient, in accordance with the rules and regulations of the ethics committee in each of the participating institutes.

Treatment protocol
The treatment consisted of vinorelbine 25 mg/m2 i.v. on days 1 and 8 and oral prednisone 30 mg total dose (two prednisone tablets of 25 mg and 5 mg) on days 1–8, which was repeated after a 3-week interval. If neutrophils were <1500 x 109/litre and platelets were ≤100 x 109/litre the treatment was postponed for up to 2 weeks. If after 2 weeks there was no improvement in neutrophil and platelet counts, treatment was interrupted except for patients with bone marrow invasion. G-CSF prophylaxis with filgrastim 300 mg s.c. on days 5–15 was recommended, but not mandatory.

Patients with CR, PR and stable disease after three cycles received three additional cycles. In cases of progression or stable disease further treatment was at the discretion of the participating investigators. Most patients were treated with the regimen MVP-BV (mitoxantrone, etoposide, prednisone, bleomycin and vincristine) specifically designed for elderly patients [36Go], with other combinations or with radiotherapy on involved sites.

Response criteria
The guidelines recommended by the 1999 report of the International Workshop to Standardize Response Criteria for NHL [37Go] were followed.

Complete response (CR) required complete disappearance of all detectable clinical and radiographic evidence of disease, normalization of biochemical abnormalities, clearance of bone marrow infiltrates, if there was initial bone marrow involvement, and disappearance of all disease-related symptoms that were present before therapy.

Partial response (PR) required a decrease of ≥50% in the sum of the greatest parameters (SPD) of the six largest dominant nodes or masses, without any increase in size of the other lesions or appearance of new sites of disease.

Stable disease (SD) was defined as less than a PR, but not progressive disease.

Relapsed disease (after CR) required appearance of any new lesion or and increase of ≥50% in the size of previously involved sites.

Progressive disease (PD) (after PR or no response) required an increase from the nadir in the SPD of any previously identified abnormal node for PRs or non-responders, or the appearance of new lesions during or at the end of therapy.

Statistical analysis
In the calculation of the expected number of patients to be entered in the study, the CR rate was the primary endpoint. It was expected that the treatment with vinorelbine and prednisone could be considered of significant activity if the CR rate was 30%. A Simon minimax design was used, setting {alpha}=0.10 at CR ≤15% and ß=0.15 at CR ≥30%. At least four CRs had to be observed after 27 patients; otherwise the trial would have stopped accrual. If the first step was obtained, the minimum number of CRs required had to be 10 out of 42 patients. The expected accrual rate was 10–15 patients per year.


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 Patients and methods
 Results
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Thirty patients from seven Italian hospitals were enrolled between October 1999 and October 2003. When data for the first 27 patients were available, the study was stopped since only three CRs were observed.

Patient characteristics are listed in Table 1. Ten were male and 20 were female. The median age was 83 years (range 70–96 years). Twenty-two patients were considered frail because they were aged ≥80 years, 11 because of severe comorbidities according to the CIRS and 13 because of their level of dependence in ADL. Two patients had follicular histology (6.7%) and 23 (76.7%) had diffuse large cell lymphoma. Peripheral T-cell lymphoma was diagnosed in four cases (13.3%) and mantle cell in one (3.3%). Only three patients had stage I bulky disease; the others were stage II, III or IV. The median time from diagnosis to treatment was 20 days (range 1–60 days). Less than half had an elevated lactate dehydrogenase and >50% an intermediate-high or high age-adjusted International Prognostic Index (IPI). None had been pretreated.


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Table 1. Patient characteristics

 
Response to treatment
The median number of courses administered was 4 (range 1–8). No dose reduction for vinorelbine was necessary, and only four patients were recycled with a delay of 1 week.

One patient died after 4 days because of progressive disease and was included in the evaluation. Only three patients achieved CR [10%; confidence interval (CI) 2.1% to 26.5%] and nine achieved PR (30%; CI 14.7% to 59.4%) (Table 2). A higher response rate was observed in stage III and IV than in stage I and II (P=0.016). No correlation of response was found between IPI 0 and 1 compared with IPI 2 and 3 (P=0.098).


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Table 2. Stage, IPI, causes of frailty and response to vinorelbine and prednisone in 30 patients

 
The three patients who achieved CR were frail because of advanced age only. Three of the nine patients who achieved PR were judged to be frail because of age only, five because of age and other age-associated conditions, and one because of severe comorbidities only. Only one long-lasting CR (36 months) was achieved. Only two of the 18 patients with stable disease or progression were judged to be frail because of advanced age only.

The median duration of the CRs was 29 months (range 5–36+ months) and that of the PRs was 1 month (range 1–22 months). Stable disease occurred in eight patients.

Toxicity (Table 3)
Three patients had grade 1–2 neutropenia, three had grade 3 and one had grade 4. Granulocyte colony-stimulating factor (G-CSF) was used prophylactically in three patients and on occurrence of granulocytopenia in seven patients, one of whom had granulocytopenic fever. One patient presented with grade 4 anaemia. Only one patient presented with grade 4 motor neurotoxicity. Two patients with previous severe cardiac failure after recent myocardial infarction, who were classified as frail because of the cardiac comorbidity (CIRS grade IV), died of heart failure 12 days and 28 days after the beginning of the third and fourth cycles, respectively. Another patient died of interstitial pneumonia followed by heart failure 4 days after chemotherapy.


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Table 3. Toxicity in 30 evaluable patients

 
Second-line therapy
The results of second-line therapy are reported in Table 4. After MVP-BV, three relatively long lasting CRs and three PRs were achieved out of a total of eight patients (overall response rate 75%). One of two patients treated with cyclophosphamide, vincristine and chlorambucil achieved PR. CHOP at reduced doses produced one CR, which was still continuing after 10 months.


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Table 4. Causes of frailty and response to second-line therapy

 
Three CRs were achieved in patients who were frail because of advanced age, one in a patient who was frail because of advanced age and depression, and one in a patient who was frail because of functional deficit, comorbidity and old age. Of five patients with PR, one was judged frail because of advanced age only, while the other four were frail according to at least two parameters. Only one of the five patients with stable or progressive disease was judged to be frail because of age.

Survival
The median follow-up was 10.5 months (range 4–1344 days). Figure 1 shows the overall survival curve from diagnosis of all patients. The median survival was only 10 months.



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Figure 1. Overall survival of 30 frail patients with NHL treated with vinorelbine and prednisone.

 

    Discussion
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 Patients and methods
 Results
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Patients aged >80–85 years or >70 years, but with severe comorbidity or with geriatric syndromes and advanced solid tumous, can be treated with simple palliation of symptoms. However, such patients with chemosensitive neoplasia such as acute myeloblastic leukaemia and NHL could probably benefit from chemotherapy. Until recently, at least in Italy, frail patients with NHL have probably not even been referred for consultation to haematologists and medical oncologists. At present they see only a few frail patients in their everyday practice. For this reason (the relatively low referral) and because of the difficulty of carrying out a clinical trial in such patients, no guidelines or suggestions, or even simple case reports, are available. However, in the future, with the progressive increase in life expectancy, there will be a greater incidence of cancer with more likelihood of a severe comorbidity burden, and it will be considered as one of various diseases requiring possible treatment by non-oncologists as well as oncologists.

Elderly patients with NHL are usually subject to an empirical clinical judgement which assesses them as patients who can be treated in the same way as younger adults, patients who are to be treated with an adapted approach, and patients who are too old, or with too many age-associated conditions, to be offered any treatment other than palliation or an attenuated chemotherapy. In a small group of elderly patients with NHL the CGA has been already used in an attempt to tailor the treatment plan to the patient [38Go]. The CGA allows a more precise division into prognostic categories (fit, vulnerable and frail patients) through the measurement of several parameters in a more subtle and accurate way than the simple Performance Status (PS) score. It has recently been demonstrated that the CGA adds to the PS [31Go]. Of course, the CGA requires more time to administer, but it also helps to show how patients can be supported to overcome their deficits and be treated with chemotherapy. Thus the definition of frailty is fundamental since it allows us to categorise these patients and to have a rough estimate of their life expectancy, independently of tumour evolution.

In the present study the accrual was lower than expected. Better results were observed in patients without severe comorbidity and/or a low ADL score, although the small number of patients does not allow us to draw any firm conclusions. Enrolment of frail patients in a clinical study is difficult, but not impossible. Without family consensus and support and without adequate home nursing and medical care after chemotherapy administered in hospital, these patients cannot be safely entered in a clinical trial. Since no results of trials of frail elderly patients with any type of cancer have been reported in the English literature, the first positive conclusion is that this can be accomplished, although at a slower speed. The slow accrual and the low percentage of CRs (10.0%) were the reasons for the early closure of this trial. However, since patients achieving PR had the chance of transient palliation, this study should not be considered as entirely negative. Second-line combination chemotherapy was administered and produced some useful responses, although the number of patients is too small to draw conclusions. The low CR rate and frailty resulted in a low survival.

The use of rituximab in combination chemotherapy has been shown to increase CR and overall survival in elderly patients [39Go]. Since the use of this monoclonal antibody is associated with only mild to moderate side effects, it would appear to be ideal for elderly frail patients. However, at the time of this study, it was not available in Italy. The use of antibodies conjugated with a radioisotope (Zevalin, Bexxar) is of less interest because their administration is followed by myelosuppression [40Go].

The toxicity of vinorelbine and prednisone was mild. Only one patient presented with granulocytopenic fever. Neurotoxicity was rarely observed. Heart failure in three patients could not be clearly attributed to the chemotherapy.

Vinorelbine and prednisone can be considered as a relatively well tolerated combination but, as anticipated, it has a low therapeutic activity. Therefore it cannot be recommended as the initial therapeutic approach in all frail patients. However, this combination could be clinically useful for temporary palliation in a substantial number of patients for whom aggressive combination chemotherapy has been excluded, mainly because of severe comorbidity and lack of social and family support. In cases of no response or progression, combination chemotherapy at reduced doses could be used, with the risk of an excessive toxicity.

It is understood that this approach conflicts with the conventional approach requiring the achievement of a CR with intensive combination chemotherapy as the necessary premise for increased survival and possibly cure. However, these patients are often not even referred to the medical oncologist or haematologist for any antineoplastic therapy.

In the future, an initial treatment with a less aggressive chemotherapy may be proved to be inappropriate for frail patients with NHL. However, whatever alternatives are adopted (no treatment, intensive combination chemotherapy, less intensive chemotherapy, different chemotherapeutic approaches for different aspects of frailty), these should no longer be based on enlightened empiricism, but on the results of prospective studies, even if these are small and imperfect.

Received for publication February 7, 2005. Revision received March 8, 2005. Accepted for publication March 14, 2005.


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 Results
 Discussion
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