Primary systemic treatment of advanced Hodgkin’s disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up

G. P. Canellos1,+, J. Gollub2, D. Neuberg1, P. Mauch3 and L. N. Shulman1

1 Dana-Farber Cancer Institute, Boston, MA; 2 Duke University Medical Center, Durham, NC; 3 Brigham and Women’s Hospital, Boston, MA, USA

Received 25 June 2002; revised 14 October 2002; accepted 25 October 2002


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

The most commonly used regimen for the treatment of advanced Hodgkin’s disease (HD) is ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Two of these components, bleomycin and dacarbazine, have defined toxicities such as pulmonary fibrosis and nausea/vomiting, and also uncertain single-drug activity.

  The EVA regimen (etoposide, vinblastine, doxorubicin) is an attempt to substitute a known active agent, etoposide, for bleomycin and dacarbazine.

Patients and methods:

A series of 51 patients with advanced HD without prior systemic therapy were treated. The series included 12 stage II patients with bulky (>10 cm) mediastinal tumors, 10 of whom received complementary radiation therapy. The remaining patients received EVA only. Response, duration of response, survival, toxicity and the efficacy of salvage therapy were evaluated in all patients. The median follow-up time was 111 months and permitted an assessment of the long-term effects of treatment and natural history of a cohort of treated patients.

Results:

EVA achieved a complete response (or clinical complete response) in 48/51 patients (94%). Of these 48 responders, 16 relapsed in a median of 11 months (range 3–48 months). In follow-up, 32/51 patients had no evidence of relapsed HD, although three died from other causes (two from vascular events and one from large cell lymphoma), resulting in progression-free survival for the entire group of 57% at 111 months. Eight of the 16 were alive and free from disease at follow-up at 111 months. In the entire series, only seven patients (14%) died of HD. 37 patients (73%) continued free from disease. There was no pulmonary toxicity.

Conclusions:

The EVA regimen appears to have an overall survival (OS) outcome comparable to ABVD, but without the lung toxicity. The high salvage rate of second-line therapy, in most instances at conventional dosage, suggests an absence of cross-resistance to alkylating agents in patients treated with EVA.

Key words: EVA, Hodgkin’s disease chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The chemotherapy of advanced Hodgkin’s disease (HD) has evolved from the initial success of the MOPP program (mechlorethamine, vincristine, procarbazine, prednisone) through the use of alternating combinations of MOPP and ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and hybrid regimens composed of seven to eight drugs derived from MOPP or ABVD [16]. The direct comparison of MOPP to ABVD by the Cancer and Leukemia Group B (CALGB) indicated a consistent superiority of ABVD in response rate and progression-free survival (PFS) but a comparable overall survival (OS) [7]. The results of that trial suggested that there may be a modicum of absent cross-resistance when using ABVD, since, on cross-over to MOPP the response in ABVD failures was superior to ABVD in MOPP failures. Because most of these chemotherapeutic regimens have a broad similarity in efficacy, the major differences appear to be in toxicity. The MOPP regimen, despite its demonstrated efficacy, is clearly more toxic to bone marrow cells and germ cells than ABVD [810]. Serious septic complications are also higher in MOPP-containing regimens or hybrids than ABVD alone. Furthermore, an Intergroup trial with 860 patients failed to show a superiority of hybrid chemotherapy (MOPP–ABV hybrid) over ABVD alone [11]. The limitations of the ABVD regimen are: (i) the inability to safely escalate the component drugs; (ii) the uncertain and possibly limited benefits of bleomycin and dacarbazine; and (iii) the pulmonary toxicity of bleomycin, especially when combined with radiation therapy in some patients [12, 13].

In order to explore the value of an alternative non-alkylating-agent-containing regimen without bleomycin, the EVA regimen (etoposide, vinblastine, doxorubicin) was developed and first utilized as a second-line salvage regimen in patients following relapse from MOPP. The regimen incorporated i.v. etoposide, which had been previously demonstrated to have anti-Hodgkin’s activity [14, 15]. It was hoped that the EVA regimen, if effective, could be substituted for ABVD, especially in circumstances where pulmonary function has been compromised by prior lung disease or radiation therapy. Furthermore, it might be substituted in clinical settings where a decline in pulmonary function occurred during therapy with ABVD. The CALGB salvage trial with EVA demonstrated a 73% second-line response rate with 40% complete responses (CRs). The durability of these second-line responses was especially good in those first (MOPP) remissions which lasted >12 months [16]. In order to explore the value of EVA as a primary treatment, the regimen was investigated in a phase II study in a series of 52 patients presenting to the Dana-Farber Cancer Institute (Boston, MA, USA) or the Brigham and Women’s Hospital (Boston, MA, USA) with advanced HD previously untreated with chemotherapy. Complete long-term follow-up has been carried out in these patients for 90–126 months and is the subject of this report.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Patients eligible for the protocol included presenting stages previously untreated with chemotherapy who required systemic therapy alone or with radiation therapy (see below). These stages could include clinical stage IIA and IIB with bulky mediastinum (mass size >10 cm or mediastinal mass/thoracic diameter >0.33) or stage II presenting with extension into contiguous tissue (E disease). Newly diagnosed patients in IIIA/B or IVA/B were eligible, as were patients in relapse from primary radiation therapy. The protocol was approved by the review boards of the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital. All patients signed an informed consent.

Review of relevant pathological material was performed by the Hematopathology Section of the Brigham and Women’s Hospital. Patients >18 years of age were eligible after initial staging evaluation by history, physical examination, bone marrow biopsy, baseline measurements of hepatic and renal function, chest radiographs, computed tomography (CT) scans (chest, abdomen, pelvis) and, in most but not all instances, 67gallium/SPECT scans. Five patients had a staging laparotomy. Baseline pulmonary and cardiac functional studies were undertaken in most patients. Patients were treated with a protocol of doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 on days 1, 2 and 3, and vinblastine 6 mg/m2 on day 1. All drugs were given intravenously. The cycle was repeated every 28 days for six cycles. Patients were evaluated after three cycles to assess initial response. A dose reduction scheme was employed based on the blood counts at each successive cycle. Dose modification to 75% was activated for absolute granulocyte count between 1000 and 1500 x 103/µl and platelet counts in the range 50–75 x 103/µl. Below these hematologic parameters, treatment was delayed 1 week for recovery. Bilirubin 1.5–3.0 mg/dl required reduction to 50% of the doses; >3.0 mg/dl therapy was withheld. Upon completion of the six cycles, patients were re-evaluated in all the previously abnormal sites. Patients were followed-up every 3 months for the first 2 years and at intervals of 4–6 months thereafter for the first 5 years.

Radiation therapy to bulky sites was permitted for patients in clinical stage II presenting with masses >10 cm at the longest dimension or >33% of the thoracic diameter. The protocol was conducted between February 1991 and March 1994 and follow-up data are as of 1 July 2001.

Patients who relapsed from initial remission received alkylating-agent-containing regimens. In all but two patients, it was the ChlVPP regimen, a modification of MOPP consisting of chlorambucil 6 mg/m2 p.o. (maximum 10 mg), vinblastine 6 mg/m2 i.v. (or vincristine 2 mg given on days 1 and 8), procarbazine 100 mg/m2 p.o. and prednisone 60 mg/m2 p.o. all given on days 1–14 every 28 days [17, 18]. Consolidation salvage radiation therapy was also permitted following ChlVPP if the relapse site was clinically localized and appropriate for irradiation (see below).

Criteria for response, progression and relapse

Complete response (CR) was the disappearance of evaluable disease, signs, symptoms and biochemical changes related to the tumor for >4 weeks, during which no new lesions appeared.
Clinical complete response (CCR) was defined as absence of physical findings and symptoms (if previously present) with an incomplete but >50% reduction of the original tumor mass, measured as the sum of the products of perpendicular dimensions of lesions in the chest. Gallium scans of residual masses must be negative (if initially positive) to qualify for CCR status.
Partial response was a reduction of >=50% in the sum of the products of two perpendicular dimensions of all measurable lesions, when compared with pretreatment measures, lasting >4 weeks during which no new lesions appeared and no existing lesion enlarged. Other criteria were: constitutional symptoms disappeared, if initially present; clinical regression of the liver; and change in spleen size clinically undetectable, but considered enlarged by CT scan.
Stable disease was a <50% reduction and <25% increase in the sum of the products of two perpendicular dimensions of all measured lesions, and the appearance of no new lesions for >8 weeks.
Progressive disease (PD) or relapse was an increase in the product of two perpendicular dimensions of any measured lesion by >25% above the size present at entry into the study, or for patients who respond, the size at the time of maximum regression. The appearance of new areas of malignant disease also qualifies as progressive disease.

Statistical considerations
Progression-free survival (PFS) was measured from study entry until relapse from response, onset of PD, or death in remission; patients remaining alive and well were censored. Overall survival (OS) was measured from study entry to date of death or date last known to be alive. The method of Kaplan and Meier was used to estimate PFS and OS. Time to death from HD was estimated using the method of competing risks, with all other deaths combined as the alternative. Exact binomial confidence intervals (CIs) were calculated for the proportion of responding patients.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Fifty-two patients were eligible for the EVA protocol as primary systemic therapy; one patient developed an allergic reaction to the first injection of etoposide and was removed from the trial. Patient characteristics and clinical stages at presentation are shown in Table 1.


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Table 1. Characteristics of the 51 patients who received EVA treatment
 
Of the 51 evaluable patients who were treated with EVA, 48 (94%; 90% CI 85% to 95%) achieved a CR or CCR (the majority in the latter category). One patient received only three cycles and died a sudden and undefined cardiovascular death. There were two induction failures with PD (both stage IVB). Median follow-up was 111 months at the time of writing. Of the 48 responders, 16 patients (33%) relapsed, with a median time of 11 months (range 3–48) (Figure 1). Only four patients relapsed after >14 months (21, 20, 33 and 48 months). Treatment of these 16 relapsers with second-line salvage therapy resulted in a second-line CR/CCR response in 11/16 (69%; 90% CI 45% to 87%) patients (Table 2). Second-line chemotherapy was ChlVPP in 14 patients (seven of whom also received localized radiation). Ifosfamide-containing regimens were used in the other two patients. Three patients had a follow-up autologous stem-cell transplant following chemotherapy. One died of acute transplant-related toxicity, one relapsed and died of HD, and one remained alive and well. Four other relapsed patients died of progressive HD. Two ChlVPP patients died free of HD with myelodysplasia (MDS)/acute leukemia, 60 and 96 months after diagnosis. Including two induction failures, a total of seven patients (14%) have died of HD. Eight of the 16 patients treated with second-line therapy were alive and well, free from HD after >100 months. The remaining 32 patients (67%) did not relapse. Two older patients have died of unrelated cardiovascular disease (72 and 90 months) with no evidence of relapse. One patient died of a late second tumor (large cell lymphoma) at 90 months after diagnosis. The remaining 29 patients continued free from disease as of 1 July 2001 in follow-up of 90–126 months (median 111 months).



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Figure 1. Progression-free survival of the 51 patients who received EVA.

 

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Table 2. Analysis of 16 patients who received salvage therapy following first relapse after EVA
 
The toxicity of the regimen was primarily hematological. Colony-stimulating factors were used at the discretion of the treating physician. The average nadir leukocyte count was 1800–2000/mm3 and only 10 patients had a nadir platelet count <100 000/mm3. One patient had congestive cardiac failure beginning 2 years after EVA plus mantle irradiation but is now stable. Another combined modality patient is being evaluated for arrhythmia and low cardiac ejection fractions 90 months after treatment. Complementary mantle or involved radiation was given to 10/12 bulky stage II patients with two relapses (both stage IIB).

Of the entire group, only seven deaths (out of 51 patients total) were attributed to HD. Of the original responders, 37/48 (77%) were alive and free from disease at 90–126 months follow-up, including those successfully salvaged. Overall, 37/51 (73%) were alive and free of disease at the time of writing (Figure 2). Of the patients with stage III/IV disease at presentation and extranodal relapse from radiation therapy, 24/36 (67%) remain in their first remission.



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Figure 2. Overall survival of the entire series of 51 patients. Survivors are free of disease at 90–132 months follow-up.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In clinical research, HD chemotherapy has been the search for a balance between efficacy to achieve a long-term cure rate and minimizing the risk of toxicity that can result in fatal complications from both chemotherapy and radiation. The EVA regimen was developed over a decade ago to seek an alternative to ABVD, both to eliminate bleomycin and dacarbazine and to substitute a relatively new (at the time) active agent, etoposide. In the absence of a prospective stratified randomized trial a true comparison with ABVD is impossible. However, it can be said that published series of ABVD ± radiation in patients with advanced disease and with shorter follow-up than this study have shown generally comparable results [7, 1921].

The relatively high second-line remission rate in patients who achieved an initial CR/CCR but subsequently relapsed is noteworthy. It supports the observation from the CALGB trial mentioned above wherein MOPP was more effective in relapse from ABVD than ABVD in relapse after MOPP [7]. It is possible that resistance to the drugs contained in EVA is mediated by the multi-drug resistance gene. Cellular resistance to alkylating agents is likely to be via a different mechanism. Ultimately, only five out of 16 patients who relapsed died of HD. The sequential addition of ChlVPP did result in MDS/leukemia in 2/16 relapsed patients who survived 60 and 96 months free from HD. In both instances, cytogenetics showed abnormalities of chromosome 5, suggesting an alkylating agent effect. Regimens devoid of alkylating agents, such as ABVD, are very rarely associated with MDS/leukemia [11]. As mentioned above, the use of MOPP alternating with ABVD or hybrid MOPP–ABV have not shown a superiority over ABVD alone, but do have the increased risk of MDS/leukemia. The risk of secondary leukemia following etoposide has been noted in solid tumors, but most patients also received other drugs, including alkylating agents. The latency period is short and usually has a characteristic cytogenetic abnormality (11q23) [22]. There was no pulmonary toxicity resembling that seen following bleomycin with or without radiation therapy. Several other pilot trials have examined similar regimens. In a trial from Britain, a 58% response rate was noted in 19 heavily pretreated patients treated with etoposide 200 mg/m2 p.o., vincristine and doxorubicin 50 mg/m2 as a salvage [23]. An EVA regimen plus irradiation to nodal sites in 26 patients had a relatively high rate (46%) of induction failure at 2 years, but an OS of 86% suggesting a discrepancy in the assessment of CR compared with CCR; radionuclide scans were not used [24]. A British cooperative trial showed a superiority of a hybrid of ChlVPP/EVA over MVPP alone in response and relapse-free survival [25].

In summary, a few statements can be made regarding the use of EVA as primary chemotherapy. The EVA regimen was designed initially as a possible replacement for ABVD. The regimen is active and appears to be comparable to ABVD in similar populations, but a definitive statement cannot be made in the absence of a randomized trial. Sixty-three percent of all patients continue disease-free in their first remission. When those patients successfully treated with second-line therapy are included, 77% continue disease-free at the time of writing. These data suggest that relapse from regimens such as ABVD or EVA can be salvaged with alkylating agent-containing regimens. Only three patients went on to high-dose therapy with autologous cell support and, of those, only one went on to long-term survival. The remaining 13 patients were treated with conventional dose second-line therapy with only 4/13 deaths from HD. Most high-dose series would not be expected to have better results since most large transplant series rarely show a long-term salvage rate better than 50% [2628]. EVA could be an option in circumstances where pulmonary compromise exists before treatment or develops during therapy with ABVD. Long-term follow-up of a series of treated Hodgkin’s patients demonstrates that the mortality from other causes, possibly related to treatment, is equivalent to the mortality from HD.


    Footnotes
 
+ Correspondence to: Dr G. P. Canellos, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +1-617-632-3470; Fax: +1-617-632-3477; E-mail: george_canellos{at}dfci.harvard.edu Back


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 Patients and methods
 Results
 Discussion
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