Annals of Oncology Advance Access originally published online on October 27, 2006
Annals of Oncology 2007 18(2):376-380; doi:10.1093/annonc/mdl397
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© 2006 European Society for Medical Oncology
hematologic malignancies |
ABVD for Hodgkin's lymphoma: full-dose chemotherapy without dose reductions or growth factors
Department of Medical Oncology, Southampton General Hospital, CRUK Clinical Centre, Southampton, Hampshire, UK
* Correspondence to: Dr E. Boleti, Department of Medical Oncology, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, Hampshire, UK. Tel: +44-2380-798639; Fax: +44-2380-795176; E-mail: ekaterini.boleti{at}suht.swest.nhs.uk
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Abstract |
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Background: We investigated whether administration of full-dose ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy without growth factors, and irrespective of the granulocyte count, caused treatment delays or increased the number of infective episodes, in patients with Hodgkin's lymphoma (HL).
Patients and methods: Thirty-eight patients with confirmed predominantly early-stage HL were treated with ABVD outside clinical trial protocols over a 5-year period on an outpatient basis.
Results: Ninety-five per cent of patients completed their scheduled ABVD regimen without adverse effects despite the development of neutropenia. Anaemia and thrombocytopenia did not present problems. Febrile neutropenia complicated 0.57% of combination chemotherapy injections. No growth factors were used and no dose modifications were carried out apart from the omission of bleomycin in one patient for the last two cycles of treatment due to the development of lung toxicity. All patients are currently disease-free, although three (7.8%) required salvage high-dose therapy (one relapsed and two with refractory disease).
Conclusions: ABVD administration irrespective of granulocyte counts allowed the treatment to be given at full dose without delays or significant number of infective episodes. There was no need for growth factor support, minimising treatment costs. The use of full-dose ABVD irrespective of granulocyte count should be evaluated in future protocols for HL.
Key words: ABVD, chemotherapy, GCSF, growth factors, Hodgkin lymphoma, neutropenia
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Hodgkin's lymphoma (HL) is a highly curable condition for which almost all patients require chemotherapy as part of their treatment. ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) [1, 2] is the world standard chemotherapy approach with good outcomes and an acceptable toxicity profile, especially with regard to haematopoietic stem cell toxicity and infertility [3]. It was originally tested against established regimens such as MOPP (combination chemotherapy with mechlorethamine, vincristine, procarbazine and prednisone) [4] or alternating protocols such as MOPP/ABVD [5], with superior results to the four-drug alkylator-based regimens and similar ones to the multi-drug combinations.
In the published pilot study comparing ABVD to MOPP, a schedule of dose modifications was applied, on the basis of the peripheral blood counts on the day of treatment, to avoid myelotoxicity [2]. Similarly, reduced-dose schedules or delays have since been widely applied to all patients receiving ABVD chemotherapy, although little information has been provided as to the extent of neutropenic episodes and their implications [5, 6–8]. Delays or dose reduction of ABVD will compromise dose intensity and may jeopardise outcomes as the Reed-Sternberg/Hodgkin cells are chemo-sensitive but also genetically unstable with a tendency to grow fast and develop early secondary resistance. There is evidence for better outcomes in HL with maintenance of dose intensity mainly deriving from studies using MOPP chemotherapy [9–11].
Chemotherapy-related neutropenia is often managed by dose reductions or treatment delays. An alternative and frequently used approach is growth factor support, though this is not evidence based [12] in this setting and is expensive.
In this study, we investigated the effect of administering full doses of ABVD chemotherapy on the designated dates without use of myeloid growth factors irrespective of granulocyte counts and determine whether this increases the risk of neutropenic infective episodes and treatment delays.
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patients and methods |
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This retrospective study looked at patients under the care of one physician (GMM). It was conducted from 2001 to 2005 and included patients aged 16–70 years with a diagnosis of HL. All non-trial patients with early or advanced disease receiving ABVD chemotherapy were included in the study. The University of Southampton Lymphoma database was used to identify patients with HL who received ABVD chemotherapy under the care of GMM. The data were cross-referenced with Southampton University Hospitals Trust Oncology pharmacy records and the Clinical Trials Office to exclude patients receiving ABVD as part of HL trials. All patients received treatment at Southampton General Hospital on an outpatient basis and the histology slides were reviewed by expert lymphoma pathologists.
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results |
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patient characteristics
A total of 38 patients were treated with ABVD (Adriamycin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2 on days 1 and 15 of a 28-day cycle). There were 19 female and 19 male patients with a median age at diagnosis of 34 (range 17–68) years. Thirty-two patients (84.2%) had an (ECOG) performance status (PS) of zero, while 7.8% had PS one and two, respectively. The review of the pathology slides revealed that 30 patients (78.9%) had nodular sclerosis, seven had mixed cellularity (18.4%) and one patient (2.6%) had nodular lymphocyte-predominant disease. Staging investigations before receiving treatment revealed that 14 patients (36.8%) had Ann Arbor stage I disease, 19 (50%) had stage II, two (5.2%) had stage III and three patients (7.8%) had stage IV disease. Following the prognostic score developed by Hasenclever and Diehl [13], 35 patients (92%) had a score of 0–2 while three patients (8%) had a score of 3–7. ‘B’ symptoms were noted in seven cases (18.4%) at diagnosis (Table 1).
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treatment administration
ABVD chemotherapy was given on days 1 and 15 (injection days) of a 28-day cycle. Patients with early-stage disease were given three or four cycles of chemotherapy followed by involved field radiotherapy, while those with advanced disease were treated with six cycles. Ninety-five per cent of patients completed their planned cycles of chemotherapy treatment with two patients receiving one injection day less in our centre for reasons unrelated to myelosuppression. More specifically, four patients (10.5%) received six chemotherapy injection days (three cycles) of ABVD, 21 (55.2%) received eight injection days (four cycles), 11 patients (28.9%) received 12 injection days (six cycles), while two patients (5.2%) received 11 ABVD injection days. The total number of chemotherapy injection days was 346 (173 cycles). The median number of chemotherapy injection days was eight (Table 2). Twenty-five patients (65.7%) received post-chemotherapy radiotherapy as part of their scheduled therapeutic regimen.
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haematological toxicity
Toxicity was assessed according to the USA National Cancer Institute Common Toxicity Criteria (version 2.0, 1999). Of a total of 346 injection days, 117 (33.8%) were given when the absolute neutrophil count (ANC) was <1.0 x 109/l. Thirty patients (78.9%) experienced at least one episode of grade III (ANC
0.5 x 109 to <1.0 x 109/l) or grade IV (<0.5 x 109/l) neutropenia on injections days. Among them, 15 patients (50%) had between one and three episodes, 11 (36.6%) had four and six episodes while four (13.3%) patients had seven episodes of neutropenia. Eleven patients (36.6%) had at least one episode of grade IV neutropenia. The median neutropenic count was 0.6. Grade I (<lower limit of normal – 100 g/l) haemoglobin toxicity was detected on seven of the treatment days (2.0%), not requiring treatment; no grade II–IV toxicity was noted. No platelet count toxicity was seen (Table 3).
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febrile neutropenia
Two patients (5.2%) developed a single episode of uncomplicated febrile neutropenia (FN) during the chemotherapy treatment. The first of those patients received her last injection a day before her infective episode with an ANC of 1.0 x 109/l. She developed a lower respiratory tract infection on day 9 of cycle 4A with a neutrophil count at the time of 0.2 x 109/l. She was hospitalised for 3 days and received intravenous antibiotics as per the current neutropenic protocol with rapid clinical and neutrophil count improvement. This patient later developed bleomycin-related lung toxicity. The second patient suffered a urinary tract infection due to a renal calculus. She received her last injection day before her infective episode with an ANC of 1.9 x 109/l, and on admission to hospital on day 19 of cycle 2B, her neutrophil count was 0.9 x 109/l. She was hospitalised for 2 days with again rapid resolution of her symptoms on 48 hours of intravenous antibiotics. A week's delay of treatment was given to each patient to allow recovery. No dose modifications were carried out as a result of the neutrophil counts and granulocyte colony-stimulating factor (G-CSF) was not used in any case.
other chemotherapy-related toxicity
One patient (2.6%) had bleomycin omitted for the last two cycles of treatment due to lung toxicity—the same patient who experienced the neutropenic lower respiratory tract infection—and three patients (8%) described intermittent grade I nausea/vomiting successfully treated with modification of their anti-emetic regimen.
treatment outcome
The median follow-up is 23.4 months (range 5.0–66.7 months). Thirty-five patients (92%) remain in complete remission following ABVD. Three patients (8%), one with relapsed and two with refractory disease, received high-dose therapy followed by peripheral blood stem cell transplant and were disease-free at their latest follow-up appointment (Table 4).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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In this retrospective study, we investigated whether administration of full-dose ABVD chemotherapy without the use of G-CSF, dose modifications or delays, increased the patients' risk of infective neutropenic episodes or caused unacceptable treatment delays. We found no increased risk of infective episodes despite the vast majority of patients experiencing at least one episode of grade III or IV neutropenia of which one third had at least one episode of grade IV toxicity. There were no treatment-compromising delays and the toxicity profile was remarkably good.
Neutropenia following ABVD chemotherapy is regularly documented, although its impact has not been sufficiently investigated. In the pre-G-CSF era, dose modifications and treatment delays were standard practice [2, 14–15]. Currently, many clinicians favour the use of G-CSF to avoid myelotoxicity and most study groups, when developing protocols, make provisions for G-CSF support to minimise delays or dose modifications [16–19]. This can significantly affect treatment costs with at times questionable benefits.
Guidelines on the use of G-CSF recommended by major oncology organisations, such as the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), European Organisation for Research and Treatment of Cancer (EORTC) and ESMO, place ABVD in a low-risk category with <10% risk of FN. These groups recommend the use of G-CSF in patients receiving systemic chemotherapy with a much higher risk of developing FN (20% for ASCO and NCCN, 40% according to ESMO) as well as in cases where treatment delays may compromise outcome or where patient-related adverse risk factors are present [12, 17, 20–22].
In our study, 95% of the chemotherapy injection days were given as planned with only two patients stopping treatment early for reasons unrelated to the treatment. Twenty-five of the 38 patients received radiotherapy following completion of their chemotherapy course.
Seventy-nine per cent of patients experienced at least one episode of neutropenia <1.0 x 109/l with one in three patients reaching at least once counts <0.5 x 109/l. These results are in keeping with two studies describing neutropenia rates of 79% and 63%, respectively [6, 23] but are higher than other reports describing rates between 21% and 57% [5, 16, 24]. Furthermore, four of our patients received seven out of eight chemotherapy injection days (from day 15 of cycle 1 onwards) with grade III or IV toxicity without experiencing FN. These patients tolerated the treatment surprisingly well without compromising their quality of life. Additionally, no haemoglobin or platelet toxicity was noted even among patients with advanced-stage disease. Low rates of FN, in patients who did not receive G-CSF, were also noted by Chand et al. [23] who also suggested that FN episodes could be unrelated to the neutrophil count at the time of chemotherapy.
Bleomycin-induced pneumonitis during ABVD chemotherapy has been documented in a number of studies. Hirsch et al. [25] needed to discontinue bleomycin in 23% of patients who received ABVD with or without radiotherapy. This was not noted in the current study. The low incidence of bleomycin-induced pulmonary toxicity could also be explained by the omission of G-CSF as growth factors have been implicated in increased rates of pneumonitis when given in patients receiving bleomycin [19, 26]. A possible synergy between G-CSF and bleomycin has been implicated, although this is contradicted in another study involving patients with germ-cell tumours [27].
Anthracyclines have been associated with increased risk of neutropenic complications. In the present study though, we were able to maintain dose intensity without compromising the patients' overall clinical state despite administering full chemotherapy doses. HL is a disease with a median age of 30 years reflected in our study where the median age was 34 years. Most of our patients had limited-stage disease which may have influenced increased tolerability. The influence of these factors and their association with prognosis is well documented [13]. Furthermore, most patients had good PS and lacked significant co-morbidities. The few patients, however, who had more advanced disease or were older did not experience any episodes of neutropenic sepsis. Survival data so far have also been excellent and compare favourably with published reports.
Avoiding the use of myeloid growth factors enabled us to minimise the cost of the chemotherapy course at a time when treatment costs are escalating. The need to commence treatment with growth factors with a lower risk of FN and its financial implications remain a subject for discussion and debate [28]. Although 25%–75% of patients receiving standard chemotherapy for malignancies such as lung and breast cancer or lymphoma will probably develop grade IV neutropenia at some stage during their treatment, only 10%–15% of these patients will require hospitalisation for FN [29, 30]. Administration of a 7-day course of G-CSF for afebrile neutropenia in the context of standard chemotherapy for these malignancies increases costs two- to three-fold without practical clinical benefit [29].
We conclude that ABVD chemotherapy can be given safely irrespective of granulocyte counts while dose intensity is successfully maintained. These conclusions apply at least in the limited-disease setting as the majority of patients in the present study had early-stage disease. It is a cost-effective approach with a favourable toxicity profile. Despite frequent episodes of neutropenia, there is no increased incidence of neutropenic infective episodes or higher rate of hospitalisation. These positive findings merit further investigation in prospective trials as they may be applicable to patients with more advanced HL or other types of tumours.
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The authors would like to thank Ms Gill Jackson, University of Southampton Data Officer for her valuable help with the collection of data.
Received for publication August 16, 2006. Revision received September 8, 2006. Accepted for publication September 14, 2006.
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