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The Oncologist, Vol. 6, No. 5, 428-434, October 2001
© 2001 AlphaMed Press

Activity of Infusional Etoposide, Vincristine, and Doxorubicin with Bolus Cyclophosphamide (EPOCH) in Relapsed Hodgkin's Disease

Christopher T. Stokoe, Julie Ogden, Vinay K. Jain

Baylor-Sammons Cancer Center, Dallas, Texas, USA; Texas Oncology, P.A., Dallas, Texas, USA

Correspondence: Vinay K. Jain, M.D., Baylor-Sammons Cancer Center, Directory, Lymphoma Biology Section, 3500 Gaston Avenue, Dallas, Texas 75246, USA. Telephone 214-820-8439; Fax: 214-820-8844; e-mail: vinayj{at}baylordallas.edu


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Introduction. A phase II study of EPOCH chemotherapy in relapsed Hodgkin's disease was performed in 14 patients in a multicenter community setting.

Patients and Methods. A total of 14 patients (9 males and 5 females) were included in the study. Ages ranged from 21-72 with a median age of 33. Eleven out of 14 patients had advanced (stage III or IV) disease, but all patients had good performance status. All 14 patients had received prior chemotherapy with ABVD, MOPP, or MOPP/ABVD hybrid.

Results. A total of 57 cycles of EPOCH were administered during this trial. Patients received a median of four cycles of chemotherapy. An overall response rate of 86% was seen among the 14 patients with one patient achieving a complete response. Following EPOCH chemotherapy, 7 of 12 patients who responded underwent high-dose chemotherapy with stem cell support. Six out of 14 patients are currently alive, and three had no evidence of disease at the time of last follow-up. Toxicity with EPOCH chemotherapy consisted mainly of myelosuppression, and most patients were managed on an outpatient basis.

Conclusion. This multicenter community study confirms the activity of EPOCH chemotherapy in the treatment of patients with relapsed Hodgkin's disease.

Key Words. EPOCH • Hodgkin's • Relapse • Chemotherapy


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Hodgkin's disease is a lymphoid neoplasm with an annual incidence of 0.003%. Affected patients are generally young adults, although the disease is also seen in older populations. Despite excellent responses to therapy, a small minority of patients with early-stage Hodgkin's disease and approximately 30% with advanced disease will relapse. In an effort to identify pretreatment prognostic factors that can predict a patient's risk of relapse, the International Prognostic Factors Project on Advanced Hodgkin's Disease reviewed data from 1,618 patients with advanced Hodgkin's disease who completed standard therapy [1]. They compiled progression-free and overall survival data based on a number of predetermined prognostic factors within this cohort. The progression-free survival ranged from 80% in patients with good prognostic factors to 45% in those with poor prognostic factors.

The choice for salvage treatment in Hodgkin's disease is based on several factors including duration of first remission, number of relapse sites, previous treatment, performance status, and health of the patient [2, 3]. Current recommendations for patients in chemosensitive relapse include consolidation with high-dose chemotherapy and stem cell support. Salvage chemotherapy regimens are used to decrease tumor burden in preparation for high-dose chemotherapy or to treat patients who are not candidates for high-dose therapy.

There are some salvage regimens such as etoposide, vincristine, and doxorubicin with EPOCH and ABDIC that deliver chemotherapy drugs by continuous infusion instead of by intravenous bolus. By continually exposing lymphoma cells to chemotherapy, it is felt that cellular resistance induced by the multidrug resistance (MDR) gene can be overcome. This strategy has been demonstrated in vitro by Lai et al. [4].

Although investigators at the National Cancer Institute (NCI) first developed the EPOCH regimen for relapsed non-Hodgkin's lymphoma patients [5], Wilson et al. in their 1995 abstract, showed a high response rate for 44 relapsed or refractory Hodgkin's disease patients from the NCI treated with EPOCH [6]. Since results from a single institution are not always reproducible in multiple practice sites, we wanted to investigate the use of EPOCH in relapsed Hodgkin's patients drawn from a multicenter community setting. Those findings are reported here.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Eligibility Criteria
Between August 1993 and July 1997, 14 patients with relapsed Hodgkin's disease were treated with EPOCH chemotherapy in a multicenter community setting at the offices of Texas Oncology P.A. Eligibility for this protocol included patients with Hodgkin's disease who had relapsed following at least one prior chemotherapy regimen and/or radiation. All patients had a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale, were at least 18 years of age and gave informed consent. Patients who had received >450 mg/m2 of doxorubicin prior to trial entry were eligible if their ejection fraction by multiple gated acquisition (MUGA) scan was within normal institutional limits at the start of therapy. Patients with a history of active coronary artery disease and angina or congestive heart failure were excluded from the trial. Patients with renal (serum creatinine >=1.8 mg/dl) or hepatic (serum bilirubin >=2.5mg/dl) dysfunction were also ineligible for treatment.

Prechemotherapy Assessment
Pretreatment history and physical examination were performed and included measurement of all palpable peripheral lymph nodes, liver, spleen, and other measurable lesions. A CBC with differential and chemistry studies (electrolytes, liver function, serum lactic dehydrogenase [LDH]) was also performed. Each patient had a pretreatment iliac crest bone marrow biopsy, and all patients had chest and abdominal computerized tomography (CT) scans. Other radiological studies such as head and neck CTs, and bone, and gallium scans were performed if indicated. All patients who had previously received >450 mg/m2 of doxorubicin had a MUGA scan before starting chemotherapy and at completion of the study if clinically indicated.

Treatment
EPOCH chemotherapy consisted of etoposide 50 mg/m2/day, vincristine 0.4 mg/m2/day and doxorubicin 10 mg/m2/day each given as a continuous intravenous infusion over 24 hours for a total of four doses (total infusion time was 96 hours). Cyclophosphamide 750 mg/m2 was given by a bolus infusion on day 6. Prednisone 60 mg/m2/day was given orally on days 1-6. All patients were required to have a central venous catheter prior to therapy for continuous intravenous infusion. EPOCH was normally administered on an outpatient basis unless hospitalization was required for other reasons.

The daily dose of etoposide was diluted in 250 ml normal saline each day as it was thought to be unstable for greater than 24 hours in a diluted form and administered over 24 hours using an infusion pump. The total 96-hour dose of vincristine and doxorubicin was prepared as an admixture in 100 ml of normal saline and administered continuously via a portable infusion pump. Cyclophosphamide was diluted in 100 ml of D5W or NS and infused over 15 minutes on day 6. Prophylactic antiemetics were not given during the continuous 96-hour infusion but were administered prior to the cyclophosphamide bolus. Adequate amounts of fluid intake and frequent emptying of the bladder were encouraged throughout the duration of treatment.

Filgrastim was given to all patients starting on day 6 of the treatment cycle and continued daily until the ANC was >10,000/µl. The dose of filgrastim was 300 µg s.c. each day for patients under 60 kg and 480 µg s.c. daily for patients greater than 60 kg. To avoid missed doses, arrangements were made for self-administration over the weekend. Patients were started on the next cycle of EPOCH if their ANC was greater than 1,500/µl on day 22, which corresponded to day 1 of the next EPOCH cycle. No filgrastim was given on the day chemotherapy was started. Throughout treatment, a weekly CBC and SMA-20 were performed.

Dose Adjustments
A 50% reduction was made in the initial dose of cyclophosphamide for patients older than 60 and for those who had received two or more previous chemotherapy cycles. Additional dose modification was based on the ANC and platelet count on day 1 of therapy. If the ANC was >1,500/µl on day 1 of treatment, the full doses of all drugs were administered. For an ANC of 1,000-1,500/µl, only cyclophosphamide was reduced by 25%. Therapy was held until the ANC had recovered to >1,000/µl.

Full doses of all drugs were given if the platelet count on day 1 was greater than 100,000/µl. A 50% reduction in cyclophosphamide was made for a platelet count of 50,000-99,999/µl. A 75% reduction of cyclophosphamide was made for platelet counts <50,000/µl.

Dose modifications for vincristine were based on neurotoxicity. For moderate paresthesia (e.g., inability to button clothing) a maximum dose of 2 mg was given during each cycle. A 50% dose reduction of vincristine was made for patients unable to walk on heels or obstipation. The vincristine was held in patients with ambulation difficulties.

Response Criteria
All patients had staging evaluation prior to therapy. Following two cycles of EPOCH chemotherapy, imaging studies of involved sites were performed and repeated every 6-8 weeks thereafter. A complete remission was defined as having no evidence of disease on restaging studies performed 1 month after the last cycle of chemotherapy. Partial remission was defined as a 50% or greater decrease in the sum of the products of the diameters of all measurable lesions for at least 1 month without increased size in other nodes, liver, or spleen. Stable disease was defined as having less than a partial response. Relapsed disease occurred with appearance of any new lesion or an increase in size by 50% of previously involved areas.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient Characteristics
A total of 14 patients were accrued for this trial between August 1993 and July 1997 (Table 1Go). Most of the patients were young, had a good performance status and no underlying comorbid conditions. There were nine males and five females with a median age of 38 (range 21-72). However, only two patients were older than 60 years. Nine patients had an ECOG performance status of 1, and the remaining five patients were ECOG status 0 reflecting the general good health of our patient population. At the time of study entry, most patients had advanced disease. Eleven of 14 patients had stage III or IV disease. Bone marrow involvement was documented in only one of the patients who entered the trial.


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  		Table 1. Patient characteristics
 
Patients either had nodular sclerosing or mixed cellular Hodgkin's disease and 12/14 (86%) patients had normal baseline serum LDH levels. Prior to the initiation of the study, the Hasenclever prognostic index was calculated for each patient based on albumin, hemoglobin, sex, stage, age, WBC, and lymphocyte count. Seven patients (50%) had a Hasenclever score between 0 and 2 and seven patients had a score greater than or equal to 3. Only one patient had a score of 5.

The disease-free interval from time of last remission to enrollment in the EPOCH trial was also examined. Remission duration less than 1 year has generally been considered to be an adverse prognostic factor. In this study, 11/14 patients either relapsed within 1 year of receiving prior chemotherapy or progressed while on therapy. Two patients had previous remissions lasting 5 years prior to enrollment in the EPOCH trial. Details of each patient's clinical history are shown in Table 2Go.


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  		Table 2. Clinical history
 
All patients on this study had received prior chemotherapy for their Hodgkin's disease. Two patients were initially treated with XRT at the time of diagnosis and received chemotherapy at first relapse. Most people were not heavily pretreated prior to enrolling in the trial. Eleven patients entered the trial at first relapse and one patient entered at second relapse. The two heavily pretreated patients enrolled in the study at the fourth and fifth relapse respectively.

Treatment and Toxicity
A total of 57 cycles of EPOCH were administered to 14 patients. Patients received a median of four cycles with a range of one to six cycles (Table 3Go). Most of the cycles were administered on an outpatient basis. The six cycles administered in the hospital were due to anxiety in one patient and geographical factors in another. Treatment was, overall, well tolerated by most patients enrolled in the study and there were no treatment-related deaths. No chemotherapy dose reductions were required during therapy due to hematological toxicity. However, cyclophosphamide was reduced by 50% per protocol in one patient older than 60 years at the time of study entry. A similar dose reduction was made in another patient who had received more than three previous treatments. Treatment delays were uncommon and, when they did occur, were due to neutropenia. Fifty of 57 cycles were given on time and 1-week treatment delays occurred in only seven cycles.


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  		Table 3. Treatment details
 
Hematological side effects, although frequent, were not severe. Neutropenia was uncommon possibly due to the prophylactic administration of filgrastim in all patients. Only 8/57 cycles (14%) resulted in grade 4 neutropenia (ANC < 500/µl). Grade 3 neutropenia (ANC 500-1,000/µl) occurred in only three cycles (5%) (Table 4Go). Six cycles resulted in hospitalization for neutropenic fever but only three patients had documented culture-positive bacterial infections. These patients made an uneventful recovery with appropriate antibiotic therapy. There were no fungal or opportunistic infections in any of our patients; however, two patients had documented Herpes simplex viral infection.


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  		Table 4. Toxicity
 
Because of the modest hematologic toxicity of EPOCH, only four patients required red cell transfusions during the study. One patient was anemic prior to entering the study and received red cells prior to and during EPOCH chemotherapy. Two other patients required red cell transfusions with EPOCH chemotherapy, and one heavily pretreated patient required red cells and platelets with only one course of EPOCH. There were no significant bleeding complications during the study. It should be noted that erythropoietin was not administered to any patient during the study.

All other side effects associated with EPOCH therapy were mild and managed on an outpatient basis (Table 4Go). Nausea, vomiting, and diarrhea (any grade) occurred in 12/57 cycles (21%). Mucositis occurred in seven cycles (12%) and resolved with outpatient antibiotics and appropriate oral care. Peripheral neuropathy occurred in four cycles (7%) and vincristine was discontinued in two patients due to neurologic symptoms.

There were no symptoms of cardiac toxicity in any of the 14 patients treated with doxorubicin. As a result, no formal cardiac assessments were required at the conclusion of therapy. However, all patients who received high-dose chemotherapy did undergo pretransplant MUGA scan and were found to have normal cardiac function.

Treatment Response and Patient Follow-Up
All 14 patients with advanced Hodgkin's disease were evaluable for a response. Twelve out of 14 patients responded giving an overall response rate of 86% (Table 5Go). Of the responders, one patient had a complete response while 11 patients (79%) had a partial response. One patient had a minor response and another who progressed while on EPOCH was taken off study after two cycles. The complete responder sustained a disease-free interval of 5 years after completing initial chemotherapy and remained free of disease 3 years after completing EPOCH.


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  		Table 5. Response to EPOCH
 
Following a response to EPOCH, seven patients underwent consolidation with high-dose chemotherapy and stem cell support. Two patients received radiation therapy after completion of the study and both remained in remission at the time of last follow-up. All three patients who received no further therapy following EPOCH have died (one due to complications of AIDS and the others from progressive Hodgkin's disease).

Table 6Go lists the follow-up and post-EPOCH therapy received by each patient after study completion. Six patients (43%) remain alive (although one has been lost to follow-up since 1996) and four are still receiving some form of treatment for their disease. Median overall survival for relapsed Hodgkin's disease patients receiving EPOCH was 1,501 days (Fig. 1Go).


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  		Table 6. EPOCH follow-up
 


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  		Figure 1. Overall survival for patients with relapsed Hodgkin's lymphoma receiving EPOCH.

 
We analyzed the patients in the study by their Hasenclever prognostic index. Two patients with Hasenclever scores of 4 died of progressive disease, but one patient with a Hasenclever score of 5 is alive and without disease 3 years after completion of EPOCH. Five out of 11 patients with Hasenclever scores of 3 or lower are alive, although three patients have relapsed Hodgkin's.


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Salvage chemotherapy regimens for relapsed Hodgkin's disease usually have been designed to incorporate chemotherapy agents different from drugs previously received. Salvage regimens that have been used include ABDIC [7], CAV [8] (CCNU, melphalan, etoposide), EVA [9], and MINE [3]. In ABDIC, the doxorubicin and dacarbazine are given as a continuous infusion.

In a 1995 abstract, Wilson et al. demonstrated an 81% response rate in patients with relapsed or refractory Hodgkin's disease who were treated with EPOCH [6]. In this regimen, vincristine, doxorubicin, and etoposide are given as a continuous infusion. This is based on the principle that resistance to these drugs is due to the MDR gene, which produces a protein (p170 glycoprotein) that causes drug efflux from the cell [10, 11].

In the trial by Wilson et al., 34 of 42 patients responded. Of the 34 responses, there were 13 (31%) complete responses (CR), 7 (17%) complete remissions unconfirmed, and 14 (33%) partial responses (PR). An ANC below 500/µl occurred in 27% of cycles, and platelet counts less than 50,000/µl occurred in 24% of cycles. Only 5% of patients required hospitalization for neutropenic fever. Other continuous infusion regimens have been used in relapsed or refractory Hodgkin's disease. Smith et al. demonstrated a 64% response rate (53% PR and 11% CR) in 19 patients treated with ABDIC continuous infusion [7].

In our study, most patients (11/14, 79%) had relapsed within 12 months of their prior chemotherapy implying more aggressive or potentially chemorefractory disease. Our response rate of 86% with EPOCH is encouraging and similar to results obtained by Wilson et al. Fifty percent (7/14) of our patients underwent successful high-dose chemotherapy after EPOCH and in this group, EPOCH lowered the tumor burden prior to transplant. For patients who were not candidates for high-dose therapy, EPOCH served as second-line salvage chemotherapy. Two patients who were not candidates for transplant because of age were treated with EPOCH followed by local radiation and remain free of disease.

Most of the EPOCH chemotherapy cycles were administered in the outpatient setting using a portable infusion pump, which is more convenient for the patient. Toxicity was mild and the regimen was well tolerated. There was no end organ damage with EPOCH as may occur with other regimens containing platinum, bleomycin, and doxorubicin. This is important as the seven patients who proceeded to high-dose chemotherapy with stem cell support all had good performance status as well as preserved renal, pulmonary, and cardiac function.

The EPOCH regimen has an excellent response rate and is easy to administer in an outpatient setting. In addition, it has a favorable toxicity profile and is at least as efficacious as other salvage regimens. We believe that EPOCH is a reasonable choice for patients with relapsed or refractory Hodgkin's disease either for tumor debulking prior to high-dose chemotherapy with stem cell support, or as a palliative regimen in patients who might not be candidates for high-dose chemotherapy.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Hasenclever D, Diehl V, Armitage J et al. A prognostic score for advanced Hodgkin's disease. N Engl J Med 1998;339:1506–1514.[Abstract/Free Full Text]
  2. Bonfante V, Santoro A, Viviani S et al. Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. J Clin Oncol 1997;15:528–534.[Abstract/Free Full Text]
  3. Ferme C, Bastion Y, Lepage E et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin's disease. Ann Oncol 1995;6:543–549.[Abstract/Free Full Text]
  4. Lai GM, Chen YN, Mickley LA et al. P-glycoprotein expression and schedule dependence of adriamycin cytotoxicity in human colon carcinoma cell lines. Int J Cancer 1991;49:696–703.[Medline]
  5. Wilson WH, Bryant G, Bates S et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol 1993;11:1573–1582.[Abstract/Free Full Text]
  6. Wilson WH, Bryant G, Wittes R et al. EPOCH chemotherapy is effective in relapsed and refractory Hodgkin's disease. Proc Annu Meet Am Soc Clin Oncol 1995;14:1224a.
  7. Smith MR, Khanuja PS, Al-Katib A et al. Continuous infusion ABDIC therapy for relapsed or refractory Hodgkin's disease. Cancer 1994;73:1264–1269.[CrossRef][Medline]
  8. Brusamolino E, Orlandi E, Canevari A et al. Results of CAV regimen (CCNU, melphalan, and VP-16) as third line salvage therapy for Hodgkin's disease. Ann Oncol 1994;5:427–432.[Abstract/Free Full Text]
  9. Canellos GP, Petroni GR, Barcos M et al. Etoposide, vinblastine, and doxorubicin: an active regimen for the treatment of Hodgkin's disease in relapse following MOPP. J Clin Oncol 1995;13:2005–2011.[Abstract/Free Full Text]
  10. Sandor V, Wilson W, Fojo T et al. The role of MDR-1 in refractory lymphoma. Leuk Lymphoma 1997;28:23–31.[Medline]
  11. Yuen AR, Sikic BI. Multidrug resistance in lymphomas. J Clin Oncol 1994;12:2453–2459.[Abstract/Free Full Text]
Received May 29, 2001; accepted for publication August 20, 2001.





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