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Japanese Journal of Clinical Oncology Pages 33-37

ESHAP as Salvage Therapy for Refractory Non-Hodgkin's Lymphoma: Taiwan Experience
Introduction
Patients and methods
Results
Discussion
Acknowledgment
References
ESHAP as Salvage Therapy for Refractory Non-Hodgkin's Lymphoma: Taiwan Experience

ESHAP as Salvage Therapy for Refractory Non-Hodgkin's Lymphoma: Taiwan Experience

Wei-Shu Wang, Tzeon-Jye Chiou, Jin-Hwang Liu, Frank S Fan, Chueh-Chuan Yen, Shiao-Lin Tung and Po-Min Chen

Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taipei, Taiwan

Background: The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin, has been shown to be active against refractory non-Hodgkin's lymphoma in therapeutic trials. We were interested in determining whether this regimen would be effective and tolerable for Chinese patients.
Methods: Thirty-two patients with refractory/relapsed non-Hodgkin's lymphoma (23 intermediate-grade and nine high-grade) were enrolled in this study. Etoposide was administered at a dose of 40 mg/m2/day as a 1 h intravenous infusion from day 1 to day 4, solumedrol 500 mg/day was given as a 15 min intravenous infusion from day 1 to day 5, ara-C 2 g/m2 was given as a 2 h intravenous infusion on day 5 and cisplatin was given at a dose of 25 mg/m2/day as a continuous infusion from day 1 to day 4. Clinical efficacy and toxicity were assessed on the basis of the WHO criteria.
Results: Ten patients (31.3%, 95% CI 15.2-47.4%) attained complete remission (CR) and seven had partial remission (PR). The overall response rate was 53.1% (95% CI 35.8-70.4%). In eight of the 10 CR patients, the remission lasted for more than 8 months. The remaining two patients had CR of 5 and 6 months. The median duration of CR was 12.2 months (range 5-22 months). Myelosuppression with subsequent infections was the major toxicity. Severe leukopenia (WBC <1000/µl) lasted for an average of 12 days and thrombocytopenia (<25 000/µl) 18 days. One patient (3.1%) died of neutropenia-associated sepsis within 4 weeks after treatment. Non-myeloid toxicities included alopecia in 66% (28% grade 2, 22% grade 3), stomatitis in 72% (25% grade 2, 28% grade 3, 13% grade 4), hepatotoxicity in 9% (3% grade 2), renal toxicity in 13% (6% grade 2, 3% grade 3) and infection in 56% (18% grade 2, 25% grade 3, 13% grade 4). The majority of the responders relapsed within 2 years after ESHAP treatment. Median survival for all patients was 8.6 months.
Conclusions: ESHAP is an active and tolerable regimen in Chinese patients with relapsed/refractory lymphoma, but the duration of remission is brief and without significant impact on survival.

Key words: ESHAP - refractory non-Hodgkin's lymphoma

INTRODUCTION

Although the treatment of advanced diffuse non-Hodgkin's lymphoma (NHL) has improved considerably, long-term patient survival using the current therapies still remains less than 50% (1). Despite a high initial response rate to therapy, relapse of lymphoma is usually associated with a poor prognosis, with a median survival of less than 8 months (2). Salvage chemotherapy for such patients is indicated.

Numerous clinical trials for refractory lymphoma have shown results that are ultimately disappointing: the majority of patients failed to attain remission or only a brief remission was observed (3). The use of high-dose chemotherapy with the support of autologous bone marrow stem cells (autologous bone marrow transplantation) to overcome such resistance has been proposed by some investigators (4). Currently, high-dose chemotherapy with autologous bone marrow transplantation strategy has been applied mostly in a younger population, with good performance status and prior chemotherapy-sensitive disease (5,6). Thus, the majority of lymphoma patients who are old or with prior chemotherapy resistance are not considered as candidates for this approach.

In 1994, the ESHAP regimen, an active combination of etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C) and cisplatin, in the treatment of refractory NHL was reported (7). In that trial, 37% of the patients attained complete remission (CR) and in an additional 27% partial remission (PR) was also observed. In another trial using ESHAP as salvage therapy for 26 patients with relapsed/refractory lymphoma, 27% CR and 42% PR were observed without excessive toxicity (8). Therefore, we were interested in determining whether this regimen would be effective and tolerable for Chinese patients. Here we report preliminary data on the efficacy and toxicity of ESHAP in 32 Chinese patients with refractory or relapsed NHL.

PATIENTS AND METHODS

Between October 1995 and September 1997, 32 patients with advanced NHL, relapsed or refractory to conventional treatment, were considered eligible for this study. All had records of measurable biopsy-confirmed NHL, normal serum creatinine levels, normal or mildly-elevated serum transaminase levels (within 1.5 times the upper limit of normal range) and no active infection. Patients who were carriers of hepatitis virus B or C without active hepatitis were allowed in this study. The classification of disease was based on the Working Formulation. All patients were required to have a performance status (PS) (Zubrod scale) of 2 or less and adequate hematopoietic function as evidenced by leukocyte counts >3000/µl and platelet count >100 000/µl. All patients should have a life expectancy of more than 3 months and no other malignancies except lymphoma. Prior radiotherapy was allowed. All patients gave their written informed consent. Their characteristics are shown in Table 1.

Etoposide was administered at a dose of 40 mg/m2/day as a 1 h intravenous infusion from day 1 to day 4, solumedrol 500 mg/day was given as a 15 min intravenous infusion from day 1 to day 5, ara-C 2 g/m2 was given as a 2 h intravenous infusion on day 5 and cisplatin was given at a dose of 25 mg/m2/day as a continuous infusion from day 1 to day 4. Granulocyte colony-stimulating factor (G-CSF) was administered at a dose of 300 µg/day by subcutaneous injection when patients' WBC was less than 1000/µl for three consecutive days. Response was evaluated after the first course of treatment and toxicities were evaluated after each course. CR was defined as complete disappearance of all measurable disease for at least 4 weeks. PR was defined as >50% reduction in the sum of the product of the cross-sectional diameters of all measurable lesions for at least 4 weeks. Non-responders (NR) were patients with grossly residual or progressive disease. Treatment-related death was considered to have occurred when patients died within 4 weeks after the start of therapy.

Toxicities were assessed on the basis of the WHO criteria and graded from 0 to 4. Time of recovery from myelosuppression was defined as the duration from the first day of treatment to the day when the white blood cell count exceeded 1000/µl and the platelet count exceeded 25 000/µl without platelet transfusion. Curves relating patients' overall survival constructed using the method of Kaplan and Meier (9).

Table 1. Patients' characteristics
Characteristic Patients (n = 32)
Age (median/range) (years) 52/20-68
Gender (male/female) 18/14
Histology
   Intermediate grade 23
   High grade 9
Stage (at the time of receiving ESHAP)
   III 19
   IV 13
Performance status
   0 7
   1 11
   2 14
Hepatitis carrier status
   Hepatitis B virus carrier 5
   Hepatitis C virus carrier 2
Prior chemotherapy regimens
   CHOP alone 23
   CHOP and m-BACOD 5
   CHOP and COPBLAM 2
   CHOP, m-BACOD and OPDL 2
Prior complete remission
   Yes: >12 months' duration 15
   Yes: <12 months' duration 8
   No (refractory) 9
CHOP, cyclophosphamide, adriamycin, oncovin, prednisolone; m-BACOD, methotrexate, bleomycin, adriamycin, cyclophosphamide, oncovin, dexamethasone; COPBLAM, cyclophosphamide, oncovin, prednisolone, bleomycin, adriamycin, procarbazine; OPDL, oncovin, prednisolone, daunorubicin, leunase.

RESULTS

Among the 32 eligible patients, one died of treatment-related toxicity (neutropenia-associated sepsis) and was categorized as a non-responder. Ten patients (31.3%, 95% CI 15.2-47.4%) attained CR and seven had PR. The overall response rate was 53.1% (95% CI 35.8-70.4%). In eight of the 10 CR patients, the remission lasted for more than 8 months. The other two patients had CR for 5 and 6 months, respectively. The median duration of CR was 12.2 months (range 5-22 months). The remaining 14 were non-responders. Median survival for all patients was 8.6 months. The overall survival of all patients is shown in Fig. 1. The majority of the responders relapsed within 2 years after ESHAP treatment. In this study, subsequent high-dose chemotherapy with autologous blood stem cell transplantation was not performed in the responding patients because of poor performance status, old age or poor cardiac performance or pulmonary functions.


Figure 1. Kaplan-Meier plots of overall survival in 32 patients who received ESHAP.

Treatment-related myelosuppression was found in all patients. Grade 4 neutropenia (neutrophils <500/µl), grade 4 leukopenia (WBC <1000/µl) and thrombocytopenia (platelets <25 000/µl) were found in all patients. Myelosuppression with subsequent infection was the major toxicity of this regimen. Severe leukopenia (WBC <1000/µl) lasted for an average of 12 days and thrombocytopenia (<25 000/µl) 18 days. One patient (3.1%) died of neutropenia-associated sepsis within 4 weeks after treatment.

Non-hematological toxicities including nausea, vomiting, stomatitis, alopecia, skin rashes, chemical conjunctivitis, central nervous system toxicity and elevation of serum transaminase and creatinine levels are shown in Table 2. Severe stomatitis (grade 3 or 4) was found in 13 patients. Mild to moderate skin rash was found in three patients. Mild elevation of the serum transaminase level was noted in three patients, one grade 2. Elevation of the serum creatinine level was noted in four patients, including two grade 2 and one grade 3. Alopecia was found in 21 patients, grade 2 and 3 being seen in the majority. Infection was found in 18 patients, eight with grade 3 and four with grade 4. Only one patient had transient chemical conjunctivitis, grade 2. No significant cardiac toxicity was found.

DISCUSSION

Conventional chemotherapy can cure 35-50% of all newly diagnosed intermediate- and high-grade NHLs. For those whose disease relapsed or was refractory to conventional treatment, salvage therapy is indicated. Although high-dose chemotherapy and bone marrow/stem cell transplantation have replaced standard-dose salvage regimens in patients younger than 60-65 years, there remain patients who, because of old age or other reasons, are not eligible for this approach. In addition, there is also a need for an effective standard-dose salvage regimen capable of inducing good-quality remissions before proceeding to high-dose chemotherapy with stem cell transplantation.

In 1988, Velasquez et al. (10) reported the preliminary results of a combination regimen DHAP (dexamethasone, high-dose ara-C and cisplatin) as salvage therapy for refractory/relapsed NHL. In their study, a total of 90 patents achieved an overall response rate of 55%, including 31% CR. In a second study reported in 1994 (7), the authors added etoposide to DHAP to form a new regimen ESHAP. The dose of cytarabine in the ESHAP regimen was reduced to only one dose to accommodate etoposide. With long-term follow-up, by historical comparison, several differences were observed between ESHAP and DHAP. First, ESHAP regimen is associated with a longer survival and time-to-treatment failure (TTF) compared with DHAP. Second, although the ESHAP combination seemed superior to DHAP, neither of them is associated with a cured fraction of >10%. The majority of these patients had recurrence, except those who had bone marrow transplantation for consolidation. The authors also found that only very few patients, irrespective of histological diagnosis, survived for more than 3 years (11). However, because of superior activity, milder myelosuppressive effect and better tolerance, the authors favor ESHAP instead of DHAP to be used in refractory/relapsed NHLs.

In contrast to the study conducted by Velasquez et al., in 1993 Johnson et al. (12) reported on 28 patients with refractory NHLs who received ESHAP. In that study, no objective responses were found although five patients had a transient reduction in tumor size. Median TTF was only 2.5 months and median survival was 7 months from the start of ESHAP. The authors considered that the reason why their results were markedly different to those reported by Velasquez et al. is possibly due to different patient selection. In Johnson et al.'s study, 22 patients had previously been heavily treated with etoposide. However, the authors concluded that ESHAP shows strictly limited efficacy but marked toxicity in patients with refractory NHLs.

More recently, Rodriguez et al. (13) introduced the MINE-ESHAP regimen, which consists of mesna, ifosphamide, mitoxantrone (novantrone) and etoposide up to maximum response, followed by ESHAP consolidation. In the authors' experience, this strategy was associated with a higher response rate and a superior failure-free survival compared with the ESHAP and DHAP. The overall and complete response rates of MINE-ESHAP were 69 and 48%, respectively. The median survival was 24 months and the median TTF was 12 months, which were much longer than with ESHAP and DHAP. However, the differences between MINE-ESHAP, ESHAP and DHAP were compared historically; a prospective, randomized study would be useful to determine which one is better. Furthermore, the follow-up of MINE-ESHAP was shorter and one cannot determine the exact proportion of patients cured by this treatment.

Table 2. Non-myeloid toxicities (WHO criteria, graded)
Toxicity Grade 1 Grade 2 Grade 3 Grade 4
Nausea/vomiting 9 12 7 -
Stomatitis 2 8 9 4
Alopecia 5 9 7 -
Skin 1 2 - -
Cardiac - - - -
Hepatic 2 1 - -
Renal 1 2 1 -
CNS 1 - - -
Infection - 6 8 4
Conjunctivitis - 1 - -
CNS, central nervous system.

Table 3. Previous reports of salvage regimens for refractory/relapsed non-Hodgkin's lymphoma
Regimens Cases CR (%) OR (%) TRD OS (months) Ref.
HDARAC/mitox. 31 7 (23%) 21 (68%) 2 6 14
DHAP 90 28 (31%) 50 (55%) 7 6 10
EPOCH 70 19 (27%) 61 (87%) 10 16 16
MINE-ESHAP 92 44 (48%) 63 (69%) 2 24 13
ESHAP 122 45 (37%) 78 (64%) 6 14 7
ESHAP 26 7 (27%) 18 (69%) 0 6.3 8
ESHAP 28 0 0 0 7 12
ESHAP 32 10 (31%) 17 (53%) 1 8.6 This study
CR, complete remission; OR, overall response; HDARAC, high-dose ara-C; mitox., mitoxantrone; DHAP, dexamethasone, high-dose ara-C, cisplatin; EPOCH; etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, solumedrol, high-dose ara-C, cisplatin; MINE-ESHAP, mesna, ifosphamide, mitoxantrone (novantrone) and etoposide, followed by ESHAP; TRD, treatment-related death; OS, median overall survival.

In addition to ESHAP and DHAP, many other clinical studies have applied high-dose ara-C to patients with refractory lymphoma and shown considerable efficacy. In 1990 Ho et al. (14) reported 31 patients with relapsed NHL who were treated with ara-C 3 g/m2/day for two doses and mitoxantrone 10 mg/m2/day also for two doses. CR was obtained in seven patients (23%, 95% CI 8-37%) for a median of 7 months with tolerable toxicities. In contrast to the study conducted by Ho et al., in 1997 Wang et al. (15) reported 16 Chinese patients with refractory NHL treated with high-dose ara-C and mitoxantrone. In their study, five out of 16 (31%) patients died of treatment-related complications. The authors suggested that the regimen was too toxic to be acceptable as salvage therapy for refractory NHL. Wilson et al. (16) reported a regimen containing no ara-C and demonstrated a considerable response with tolerable toxicity. They combined etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin (EPOCH) in 74 patients with relapsed lymphoma and attained a CR rate of 27% and a PR rate of 60%. In that study, the incidence of febrile neutropenia was only 17%. Comparing the data for these regimens, our study revealed a similar CR rate (31.3%) in these poor-risk NHL patients (Table 3).

Therapeutic toxicities in our study were similar to those in other reported series (7,8). The major complication of ESHAP was myelosuppression. In our study, all patients experienced grade 4 leukopenia and thrombocytopenia and all of them received G-CSF to reduce the period of severe leukopenia. However, grade 4 leukopenia (WBC <1000/µl) still lasted for an average of 12 days and one patient(3%) died within 4 weeks owing to profound myelosuppression with sepsis. Non-hematological toxicities, including stomatitis, dermatitis, impaired liver and renal functions, central nervous system toxicity and chemical conjunctivitis, are generally reversible and not life-threatening.

In our study, the median survival for all patients was short compared with the study conducted by Velasquez et al. (8.6 versus 14 months). The majority of the responders in our study relapsed within 2 years after starting ESHAP treatment with a median TTF of only 11.4 months. The reason why our patients had a poorer prognosis is possibly due to different patient selection. All our patients had intermediate- or high-grade NHLs. In Velasquez et al.'s study, 34 out of 122 patients were diagnosed as having low-grade NHLs.

In summary, our findings suggest that ESHAP is an active and tolerable regimen for treating relapsed/refractory lymphoma, but the duration of remission is brief and without significant impact on survival. Further studies are required to determine the optimum regimens for treating refractory non-Hodgkin's lymphoma.

Acknowledgment

This work was kindly supported by a grant from the Yen Tjing-Ling Medical Foundation.

References

1. Armitage JO. Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993;328:1023-30. MEDLINE Abstract

2. Cabanillas F, Hagemeister FB, Bodey GP, Freireich EJ. IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 1982;60:693-7. MEDLINE Abstract

3. Fisher RI, Stiff PJ. Treatment options for recurrent lymphomas. Semin Oncol 1990 (Suppl 4);17:63-7.

4. Philip T, Armitage JO, Spitzer G, Chauvin F, Jagannath S, Cahn JY, et al. High-dose therapy and autologous bone marrow transplantation after conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987;316:1493-8. MEDLINE Abstract

5. Armitage JO. Bone marrow transplantation in the treatment of patients with lymphoma. Blood 1989;73:1749-58. MEDLINE Abstract

6. Press OW, Livingston R, Mortimer J, Collins C, Appelbaum F. Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine and cisplatin before marrow transplantation. J Clin Oncol 1991;9:423-31. MEDLINE Abstract

7. Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, et al. ESHAP-an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169-76. MEDLINE Abstract

8. Ezzat AA, Khalifa F, Berry J, Khan B, Raja MA, Abdel-Warith A. E-SHAP: an effective treatment in selected patients with relapsed non-Hodgkin's lymphoma. Ann Oncol 1994;5:45-6. MEDLINE Abstract

9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457-81.

10. Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose ara-C and dexamethasone (DHAP). Blood 1988;71:117-22. MEDLINE Abstract

11. Rodriguez-Monge EJ, Cabanillas F. Long-term follow-up of platinum-based lymphoma salvage regimens. Hematol Oncol Clin N Am 1997;11:937-47.

12. Johnson PW, Sweetenham JW, McCallum P, Norton AJ, Rohartiner AZ, Lister TA. E-SHAP: inadequate treatment for poor-prognosis recurrent lymphoma. Ann Oncol 1993;4:63-7. MEDLINE Abstract

13. Rodriguez MA, Cabanillas FC, Velasquez W, Hagemeister FB, McLaughlin P, Swan F, et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 1995;13:1734-41. MEDLINE Abstract

14. Ho AD, Valle FD, Ruckle H, Schwammborn J, Schlimok G, Hiddemann W, et al. Mitoxantrone and high-dose cytarabine as salvage therapy for refractory non-Hodgkin's lymphoma. Cancer 1989;64:1388-92. MEDLINE Abstract

15. Wang WS, Tzeng CH, Chiou TJ, Liu JH, Hsieh RK, Yen CC, et al. High-dose cytarabine and mitoxantrone as salvage therapy for refractory non-Hodgkin's lymphoma. Jpn J Clin Oncol 1997;27:154-7. MEDLINE Abstract

16. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol 1993;11:1573-82. MEDLINE Abstract

Received July 30, 1998; accepted October 16, 1998
For reprints and all correspondence: Wei-Shu Wang, Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan
Abbreviations: NHL, non-Hodgkin's lymphoma; DHAP, dexamethasone, high-dose ara-C, cisplatin; EPOCH, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin; ESHAP, etoposide, solumedrol, high-dose ara-C, cisplatin; MINE-ESHAP, mesna, ifosphamide, mitoxantrone (novantrone) and etoposide, followed by ESHAP

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