E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma

Annals of Oncology 5: 453-456, 1994. O 1994 Kluwcr Academic Publishers. Printed in the Netherlands.

Original article E-SHAP: An effective treatment in selected patients with relapsed non-Hodgkin's lymphoma A. A. Ezzat, F. Khalifa, J. Berry, B. Khan, M. A. Raja & A. Abdel-Warith Departments of Oncology and Biostadstics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

statistically significant improvement in median relapse-free survival in patients who had previously achieved CR (p =• Background: The optimal treatment of relapsed or refractory 0.0012), no bulky disease (P - 0.0006) and no B-symptoms non-Hodgkin's lymphoma is unknown. The reported encour- (P = 0.0004). The toxicity was acceptable: 8 instances of aging results of a salvage regimen, E-SHAP (etoposide 40 febrile neutropenia, 2 of reversible renal impairment and 2 mg/m2/day x 4, methyl prednisolone 500 mg daily x 4, cyto- symptomatic electrolyte abnormalities. No fatal toxicities sine arabinoside 2 gm/m2 one dose and cisplatinum 25 mg/ were encountered. The median time to treatment failure was m2/day x 4), at the MD. Anderson Hospital in Texas, which 191 days and median overall survival was 190 days. resulted in a 65% response rate, could not be reproduced in Conclusions: E-SHAP is an active combination chemothe United Kingdom (0% response). therapy when used as a salvage regimen or for remission Patients and methods: Twenty-six patients with relapsed induction before bone marrow transplantation in selected (n — 16) or refractory (n - 10) non-Hodgkin's lymphoma patients with relapsed non-Hodgkin's lymphoma. Patients were treated at our Centre by a modified E-SHAP regimen who previously achieved CR, with low tumour burden and (cytosine arabinoside 1 gm/m2 one dose). The treatment was no B-symptoms are the best candidates for this treatment. It intended as remission induction before BMT (n - 16), as sal- has a limited palliative effect. vage by itself (n — 5) and for palliation of symptoms (n — 5). Results: The overall response rate was 72% (CR = 7 and Key words: non-Hodgkin's lymphoma, salvage chemotherPR — 11). A comparison of Kaplan-Meier curves showed a apy, etoposide, cisplatinum Summary

Introduction The development of curative combination chemotherapy for patients with advanced aggressive nonHodgkin's lymphoma (NHL) has been one of the major innovations in cancer therapy during the past two decades [1-3]. Such success using primary combination chemotherapy in intermediate or some high-grade NHL can result in an approximately 50% cure rate [4-9]. The prognosis remains poor for patients who relapse or do not respond to such treatment, regardless of any further therapy [3, 10]. Salvage regimens using standard-dose combination chemotherapy in this setting can lead to complete remission, though only 5% to 10% of patients survive for a long period of time [1015]. High-dose chemotherapy and autologous bone marrow transplantation (ABMT) can sometimes cure these patients [16,17], but there are no published randomized trials in which this approach has been proven superior to standard salvage regimens. The experience at the MX). Anderson Hospital with E-SHAP in relapsed and refractory lymphoma has been updated by Velasaquez et al. [13]. It showed a 65% response rate and a four-year disease-free survival of 10% in 122 patients treated. The poor results report-

ed recently by Johnson et al. [18] from the United Kingdom using the same regimen prompted an analysis of our experience at this stage.

Methods Patient characteristics Between October 1991 and August 1993, 26 consecutive patients less than 60 years old with relapsing (N - 16) or refractory (n - 10) intermediate- or high-grade NHL (NHL) were treated with a modified E-SHAP regimen at King Faisal Specialist Hospital and Research Centre. Details of previous treatments are shown in Table 1. The only criteria for exclusion from this treatment were poor performance status (ECOG > 3) and patient wish for no further therapy. Pre-treatment evaluation included history, physical and hematology examinations, multichemistry screening profile, chest X-ray, computer axial tomography or ultrasound of the abdomen and unilateral bone marrow aspiration and trephine biopsy. Patient characteristics prior to starting E-SHAP are shown in Table 2. None of the lymphomas were related to HIV infection. Immunophenotyping was available for 18 patients: 10 had B cell lineage, 6 T-cell, one had B-cell with excess T, and one had null cell. Extranodal involvement was common, involving bone marrow in four cases, liver in four, bone in two, gastrointestinal tract in four, central nervous system in two, eye in two and kidney, testis, parotid in one each. Bulky disease was seen in 16 cases and B-symptoms in 15. LDH values above nor-

454 Table I. Patient characteristics: Prior treatment. Stage at presentation

I II

in

rv Number of recurrences

Number of previous chemotherapies Previous radiation therapy Previous autologous BMT Best previous response Previous longest remission duration (months) Previous anthracycline Previous etoposide Previous cisplatin Previous cytosine arabinoside

Primary resistance 1 2 4 1 2 >3 6 1 1 Complete response Failure Range Median 26 14 9 1

Treatment

3 6 6 11 8 16 1 1 18 6 2

involved field TBI 18 8 3-21 months (8.6 months) 14 responded 8 responded 8 responded responded

Table 2. Patient characteristics: At start of E-SHAP N - 26. Age Range Median Performance status (ECOG) <2 3 Histology (working formulation) D G H I Stage I

n

in

rv

B-symptoms Bulky disease LDH above normal

The intent of treatment with E-SHAP was to induce remission before BMT (n - 16), as a salvage regimen by itself (n - 5) and in 5 patients to palliate symptoms. BMT was considered in patients <50 years of age with ECOG performance status < 1 who achieved at least PR. Patients were hospitalized to undergo the treatment after giving their signed consent On days 1 to 4 methylprednisolone 500 mg was given in a 100 ml infusion over 15 minutes, followed by etoposide 40 mg/m2 infused in 250 ml over 2 hours. Cisplatinum 25 mg/ mVday in 1000 ml was given as a continuous infusion on days 1 to 4. On day 5, cytosine arabinoside 1 gm/m2 (23 patients) or 2 gm/m2 in 3 patients was given as a 3-hour infusion in 500 ml. The treatment was repeated every 3—4 weeks provided hematological recovery had occurred with absolute neutrophils above 1.0 x 10VL and platelet counts were above 100 x 109/L. Dose adjustments were made in accordance with renal function and degree of myelosuppression. WHO grades 3 or more for nausea, vomiting, mucositis, hematological and neurotoxicity called for a 25% reduction of all drugs except methylprednisolone. Renal function was assessed by monitoring serum creatinine and the dose of cisplatinum was reduced by 50% if the creatinine increased, and withheld completely if it exceeded twice normal. A total of 69 cycles were given, 46 at full dose and 23 with a 25% dose reduction of cisplatinum, etoposide and cytosine arabinoside. Reassessment by clinical examination and/or computer axial tomography scanning and/or bone marrow was planned after two cycles of treatment unless there was overt disease progression. At least a PR was required for continuation of treatment or considering BMT for eligible patients.

18-57 years (38 years) 25 1 1 20 4 1 3 4

5 14 15 16 18

Statistical analysis Statistical Analysis System (SAS) was used to analyse the data. Kaplan-Meier (KM) curves were drawn to study the survival patterns (20]. The log-rank test was used to check statistical significance between two curves. A p value of less than 0.05 was considered significant.

Results Response to E-SHAP

Twenty-five patients were evaluable for response (one refused further treatment after one cycle of E-SHAP because of WHO grade 2 nausea and vomiting). Objective responses were observed in 18/25 (72%) patients, of whom 7 had CR, and 11 PR. The other 7 patients mal were observed in 18 patients. Histology was classified according had progressive disease before receiving their second to the Working Formulation [19]. cycles of E-SHAP despite transient initial response. None of the patients who achieved CR had B-sympDefinitions toms or bulky disease and all had achieved CR to previous chemotherapy for a median time of 8 months Standard WHO criteria were used to categorize response: complete response (CR) was defined as the absence of all evidence of lym- (range 3-21 months). For this group, the median phoma, and partial response (PR) as >50% reduction in measurable relapse-free time for E-SHAP was not reached, but disease or reduction to minimal size of evaluable lesions for four 75% were disease free for at least 319 days and 75% weeks. The duration of response was measured from day of docu- have survived for at least 331 days. mentation of a response to the day of progression and/or recurAmong the 11 patients who attained PR, 6 had rence. Bulky disease was defined as > 10 cm in maximum transverse diameter of nodal disease or involvement of two or more extranodal B-symptoms, 3 bulky disease, 3 had refractory lymsites. Refractory lymphoma was defined as lymphoma that failed to phomas, and 8 had previous CR for a median of 7 achieve CR to first-line therapy. months (range 4-15 months). In this group the median

455

relapse-free time to E-SHAP was 119 days, while the median survival was 190 days. All 7 patients with progressive disease on E-SHAP had B-symptoms, high tumour burden and refractory lymphomas; their median survival time was only 73 days.

showed statistically significant median relapse-free survival in patients who achieved previous CR vs. no previous CR (10.6 months vs. 1.3 months, P - 0.0012), no bulky disease vs. bulky disease (10.6 months vs. 1.9 months, P - 0.0006) and patients without B-symptoms vs. those with B-symptoms (10.6 months vs. 2 months, P-0.0004).

Toxicity

The principal toxicity of E-SHAP was hematological; WHO grades 3 and 4 neutropenia and thrombocytopenia were seen in 11 and 4 patients, respectively. We encountered 8 episodes of febrile neutropenia requiring hospitalisan'on. All infection resolved with empiric antibiotics. There were no fatal toxic effects directly attributable to E-SHAP. Acute toxicity was manageable, and good anti-emetic control was possible using ondansetron and dexamethasone. Two patients developed transient falls in renal function. Mild peripheral neuropathy from cisplatinum occurred in 5 patients, and moderate to severe in one. Severe symptomatic hypocalcemia and hypomagnesemia requiring hospitalisation for replacement therapy occurred in two patients. One patient had severe colitis which presented as an acute abdomen requiring hemicolectomy.

W

if"1

sp

sT1

Fig. 1. Survival analysis for relapse time (days).

Outcome Discussion Fourteen of the 16 patients eligible for BMT responded to E-SHAP (CR n - 4 and PR n - 10). Six patients have had BMT after a median of 3 cycles. Two patients are scheduled to receive it; one left the country to receive allogenic BMT in an overseas centre (he had previously received autologous BMT in our centre). The reasons the other 8 patients did not receive BMT were: PD (n - 2) after one cycle of E-SHAP; leptomeningeal progression after an average of 3 cycles while PR was observed in the original site of disease (n = 2), progression while awaiting BMT after initial PR after a median of 3 cycles (n = 3). The eighth patient had severe symptomatic hypocalcemia and hypomagnesemia and achieved CR after 4 cycles of E-SHAP and was given involved field radiation to the site of original disease. Of the five patients who received the E-SHAP as a salvage regimen, 3 had CR and are currently alive with no disease at 3,4 and 16 months. One achieved PR and is alive at 2.5 months, and the fifth is the non-evaluable patient in this series. None of the five patients who were treated with palliative intent responded to E-SHAP, and symptomatic relief was short-lived (average 1-2 weeks). The median time to relapse for the group as a whole was 191 days (range 17-484 days) and the median overall survival was 190 days (range 26-484 days) (Fig. 1). When the response to E-SHAP was analyzed in relation to pre-treatment prognostic factors, refractory disease, tumour burden (bulk) and B-symptoms were seen as significant determinants. Univariate analysis

This review demonstrates that E-SHAP (with a single dose of cytosine arbinoside of 1 gm/m2) is capable of inducing an overall response in 18/25 (72%) evaluable patients with relapsed or refractory NHL. Although a significant number of our patients had already been exposed to some of the agents in E-SHAP, response was not compromised. Similar to the experiences at M.D. Anderson and Seattle, we confirm the activity of this regimen, and identified tumour burden, B-symptoms and previous CR as predictors of response. However, we did not achieve CR in any patients who had never previously achieved CR [13,15]. Our results are in marked contrast to those of Johnson et al. [18] from St. Bartholomew's Hospital, who obtained no objective response in 28 patients with refractory or relapsing lymphoma with E-SHAP. Prior treatments and bad prognostic factors in their series may in part explain such differences. The median age of our patients was 38 years vs. 46 in their series. Also, nearly all of their patients had extranodal, frequently high-grade, lymphoma, and >50% had bulky disease and B symptoms. Similar to other reports using comparable combination chemotherapy in this setting, myelosuppression was the major toxicity. We had a lower incidence of febrile neutropenia (11%) as compared to 31% and 28% reported by Velasquez and Press et al., respectively [13,15]. This could be explained by our use of a lower dose

456 of cytosine arabinoside (1 g/m2). No toxic death or tumour lysis syndrome resulted from E-SHAP. The observed renal, neuro-toxicity, and symptomatic hypocalcemia and hypomagnesemia were similar to those in previous reports with cisplatinum alone. The true test of any salvage combination chemotherapy in NHL is whether it induces a high response that can lead to an improved relapse-free time and/or survival. The long-term benefits in our series cannot be properly assessed due to the small number of the patients, short follow-up, and the goals of therapy: E-SHAP for remission induction prior to BMT in 16 patients, as a salvage regimen in 5 and for palliation in 5 patients. In conclusion, E-SHAP canot be recommended as a palliative treatment in refractory lymphoma; it does not change the outcome, is time-consuming, expensive and potentially toxic. However, when used in selected patients, previous responders who have ideally achieved CR, then E-SHAP, albeit even when the dose of cytosine arabinoside is decreased, is a useful regimen for testing sensitivity in preparation for BMT. It may have a role in salvaging patients who are not eligible for BMT but who nevertheless have a relatively favourable disease process: low tumour burden, absence of B-symptoms and a previous durable remission following primary therapy.

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Acknowledgements 16.

We thank Drs R. Wierzbicki, H. El-Solh and P. Ernst for reviewing the manuscript and J. McNeil and Patricia Baassiri for their secretarial assistance. 17.

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Received 9 December 1993; accepted 23 February 1994. Correspondence to: Dr Adnan Ezzat Department of Oncology King Faisal Specialist Hospital & Research Centre PO Box 3354 Riyadh 11211, Saudi Arabia