Abstract
OBJECTIVE Thus far there is no standard salvage regimen for patients with recurrent and refractory intermediate and high grade non-Hodgkin’s lymphoma (NHL). This study intends to investigate the therapeutic efficacy of the DICE (dexamethasone, isofosfamide, cisplatin and etoposide) regimen on the recurrent and refractory NHL, and to observe the related adverse effects.
METHODS Clinical records of 22 patients with recurrent and refractory NHL, who failed to achieve a remission from the CHOP [cyclophosphamide, hydroxydaunomycin/doxorubicin (adriamycin), oncovin, prednisone] regimen within 2 to 6 cycles of treatment, were reviewed. DICE, as a salvage regimen with a median course of treatment of 4 cycles (ranging from 2 to 7 cycles), was now used, and evaluation of the therapeutic efficacy and adverse effect of DICE was conducted in all the patients. Of the 22 NHL cases, 8 were of T-cell origin and the other 14 B-cell origin. Salvage treatment was performed in the patients, with appraisal, prevention and treatment of the toxic reactions.
RESULTS Following DICE treatment in the 22 patients, the total effective rate of the regimen was 63.6%, and the complete remission (CR) rate was 40.9%. The effective rates of DICE on the T and B-cell sourced NHL were 75.0% and 57.1%, and the CR rate were 37.5%, 42.9%, respectively (P > 0.05). An increase of the lactate dehydrogenase (LDH) level accompanied by a giant lump was the short-term effect on patients with recurrence (mean P < 0.05) who were drug resistant. Myelosuppression, digestive system reaction and alopecia were the commonly-seen complications in the patients who received DICE regimen. All patients recovered after treatment, and no chemotherapy-related death occurred.
CONCLUSION DICE regimen is effective in treating refractory and recurrent NHL.
keywords
Introduction
Chemotherapy is the recommended first-line treatment for treating the intermediate and high grade non-Hodgkin’slymphoma (NHL). Intermediate and high grade NHL patients who initially receive an standard CHOP regimen of cyclophosphamide, hydroxydaunomycin/doxorubicin (adriamycin), oncovin and prednisone have an effective rate of 60% to 80%[1]. However, failure of the CHOP regimen, or relapse after the chemotherapy, is a difficult problem for clinical treatment of the NHL. The remission rate of the commonly used salvage treatment plans, such as DICE, MINE and EPOCH etc., ranges from only 30% to 70%. In our study, during a period from January 2006 to December 2007, DICE regimen was used to treat the patients with recurrent or refractory intermediate and high grade NHL who underwent a failure of the CHOP or CHOP-alike chemotherapeutic regimen, and the efficacy and safety of DICE were observed. The results of our study are reported as follows.
Patients and Methods
Patients
From January 2006 to December 2007, 22 patients with recurrent or refractory intermediate and high grade NHL, confirmed by pathology and immunohistochemistry, were admitted to the Department of Medicine, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu, China, with appraisable lesions, from 0 to 3 scores of Karnofsky performance status (KPS) scale (eastern cooperative oncology group, ECOG). The peripheral white blood cell counts of the patients were over 3.5 × 109/L; blood platelets were 100 × l09/L, and the hepatic and renal functions were normal. Bone marrow examination was conducted on all patients before the chemotherapy, plus chest and superior abdominal CT scan. The potential survival time was ≥ 3 months. The bases of the observation indices were type-B ultrasonic, X-ray, CT scan or MRI, and distribution and size of the lymphoma at the body surface and in the abdominal and thoracic cavities were determined. Direct measurement was used for measuring the size of the tumor on the surface of the body. For the general state of health and patient clinical data are shown in Table 1.
Clinical features of 22 patients with non-Hodgkin’s lymphoma (NHL).
The age of the patients ranged from 20 to 81, with a median age of 46. In the 22 patients, there were 13 males and 9 females. All patients underwent 2 to 6 cycles of CHOP chemotherapeutic regimen. Of the NHL cases, 13 were refractory, and no remission was found in these patients after 3 courses of CHOP treatment. There were 9 recurrent NHL cases in the total, and the marcellomycin included adriamycin, pharmorubicin and pirarubicin. Adjunct radiotherapy was given in 12 of the total 22 cases (54.5%).
Therapeutic regimen
DICE regimen: i.v. drip of 10 mg/m2 Dexamethasone, added in 250 ml sodium chloride, at day 1 to 4; i.v. drip of 1.2 g/m2 isophosphamide, added in 250 ml of sodium chloride, at day 1 to 4, with 40 drops per min; i.v. drip of Mesna 400 mg, added in 40 ml of sodium chloride, at 0, 4, 8 h after administration of each day, respectively; i.v. drips (shielded from light) of 25 mg/m2 cisplatin, with addition of 500 ml of sodium chloride, at day 1 to 4, with 40 drops per min; i.v. drip of 60 mg/m2 etoposide, with addition of 250 ml of sodium chloride, at day 1 to 4, and 40 drops per min, with 21 days per cycle.
Hydration and alkalinization before chemotherapy were given to prevent crystal clogging in the renal tubule, and hydroxytryptamine (5-HT) receptor antagonist was given through i.v. to prevent vomiting. A grade-III and above bone marrow depression (BMD) after the chemotherapy was treated with granulocyte colony stimulating factor (G-CSF), and as a conventional medication, allopurinol was administered to prevent hyperlithuria. Following the chemotherapy routine reexaminations of the heart, hepatic and renal functions, as well as of electrolyte balance, were conducted, with a timely symptomatic treatment and follow-up by either a visit to a clinic or phone consultation with the patients undergoing the chemotherapy.
Standard of curative effect evaluation and appraisal of adverse effects
To set up the standards for evaluating the objective efficacy of solid tumor treatment, the follow-up visits at a clinic or by phone call of all the patients were conducted until March 2008 based on the evaluation standards of WHO (1981). The therapeutic effects were classified as: complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). CR + PR were considered effective. For evaluating the adverse reaction, the standard of WHO anticancer drug toxicity grade (grade 0 to IV) was used.
Statistical analysis
State 8.0 software was used for a statistical analysis of the data that was input into the data bank. The statistical method mainly included the χ2 Fisher test. The value of P < 0.05 was considered as a statistically significant difference.
Results
Therapeutic efficacy
A 2 to 7-cycle DICE regimen salvage treatment was conducted in all the 22 patients, with a total effective rate of 63.6% and a CR of 40.9 %. The effective rate of T-cell NHL treatment was 75.0% (6/8), CR 37.5% (3/8), PR 37.5% (3/8), SD 12.5% (1/8), and PD 12.5% (1/8). The effective rate of B-cell NHL was 57.1% (8/14), CR 42.9% (6/14), PR 14.3% (2/14), SD 28.6% (4/14), and PD 14.3% (2/14). In the comparison of the CR in the patients with the T and B cell-originated NHL, the value of P was less than 0.05, which had no statistical significance (Table 2).
Therapeutic effect of the DICE regimen on various kinds of NHL.
Grouping of all the 22 patients was based on the following situations, i.e. whether the LDH and β2-MG were normal, if the NHL symptoms were accompanied by giant lump, or present the Group-B symptom. The patients with LDH > 211 μ/L or giant lump (lump > 10 cm or the biggest transverse diameter of the mediastinal lump ≥ 1/3 of the biggest inner diameter of the thoracic skeleton) had a poor curative effect (P = 0.008 and 0.035). There was a statistical significance between the two. The patients with β2-MG ≤ 4 μg/ml and without Group-B symptom showed a better therapeutic effect, but it had no statistical significance (P > 0.05). Therefore, rising of the LDH level and an accompanying giant lump are the high-risk factors that affect the near-term efficacy of the drug-resistant patients with recurrence. Statistics of the prognostic analysis is available because of a short follow-up time (Table 3.)
Relationship between Short-term efficacy of DICE regimen and Clinical parameters (n).
Adverse effects
After a DICE regimen salvage treatment in all the patients, BMD, digestive-tract reaction, and alopecia were commonly seen as adverse reactions. The incidences of the Grade-I to II and the Grade-III to IV granulocytopenia were 54.5% (12/22) and 22.7% (5/22), and that of the Grade-I to II and the Grade-III to IV thrombocytopenia were 59.1% (13/22) and 9.1% (2/22), respectively. Most of the Grade-IV BMD occurred at the first cycle, and usually the patients could smoothly complete the treatment after support of the colony stimulating factor (CSF) and/or adjustment of a corresponding dose. Grade-I to II nausea and vomiting occurred in 59.1% of the cases (13/22), and the incidence rates of the Grade-I to II and the Grade-III to IV alopecia were 45.5% (10/22) and 13.6%, respectively (3/22). Granulocytopenic fever was found in 2 patients, accounting for 9.1% of the total cases. Grade-I skin rash was found in 1 patient and Grade-I peripheral neuritis in 2, without finding out Grade-III to IV hepatic and renal toxicity. No treatment-related death occurred in the group (Table 4).
Adverse effects of DICE regimen (n, %).
Discussion
The incidence of NHL ranks first in the solid tumors of hematological system[2]. Malignant lymphoma is a group of heterogeneous diseases. As there is great diversity within the manifestations as regards cytogenetics and molecular biology, clinical manifestations, therapeutic efficacy and prognosis, there is also considerably difficulty in the treatment of the NHL. Since 1976, the CHOP regimen has been regarded as the admittedly classical regimen of NHL treatment[1], however, a 50% of the NHL patients failed to heal after administering the anthracycline or marcellomycin such as the CHOP or CHOP-alike regimen, which was used as the first-line therapy. Primarily drug-resistance and relapsed progression were found in most of the patients, who ultimately died of their tumors[3,4]. Although studies on hematopoietic stem cell transplantation, or targeted therapy have made a satisfactory progress over the past a few years[5], a limited subject range and high cost restricted widespread use of the techniques. Therefore, the conventional salvage treatment is of vital significance. The theoretical foundation of the DICE regimen is mainly based on the following: i) to avoid producing as much as possible cross tolerance when combined with the regimen of the first-line drug (e.g. IFO is a broad-spectrum anticancer drug, with a long plasma half life. The antitumor activity of IFO is higher compared to cyclophosphamide, without cross tolerance between the two and with a relatively favorable curative effect); ii) considering the available drug tolerance and accumulative toxicity of marcellomycin to the heart; iii) DDP is one of the chemotherapeutic agents with top anticancer activity, and VP-16 is the type-II topoismerase suppressant. Animal experiments have shown that DDP combined with VP-16 has a high coordinated antitumous effect. Therefore, single administration, or drug combination of the medicines, such as isophosphamide, etoposide and cisplatin, will have less probability of tolerance to the NHL, or other relapsed tumors with drug resistance, resulting in a satisfactory therapeutic efficacy[6]; iv) a previous report showed that a continuous administration of VP-16 and DXM may reverse the drug tolerance caused by overexpression of the multi-drug resistance gene[7]. In this report, the effective rate of DICE regimen was 60% to 73% in the NHL cases which failed in CHOP therapy, with a complete remission (CR) rate ranging from 23% to 41%[8]. In our study, the total effective rate of the NHL cases was 63.6%, and CR rate was 40.9%, which was in accordance with the literature. It was also shown in the data from our study that LDH was abnormal (P = 0.035), and the accompanied giant lump (P = 0.008) was the high-risk factor affecting the short-term efficacy on the relapsed and drug-tolerant NHL patients. As DICE regimen was conducted, the commonly-seen adverse reactions included BMD, granulocytopenia, nausea and vomiting, and alopecia, the incidence rates of the Grade-III to IV granulocytopenia and thrombocytopenia were respectively 22.7% and 9.1%. CSF support and dose adjustment were needed from time to time, which was reported in the literature[9], and needed adequate attention during the treatment. The symptoms of digestive system and electrolyte disturbances of the patients were mainly caused by cisplatin[10]. Administration of 5-HT receptor antagonist before use of cisplatin may significantly reduce the digestive-system reactions caused by cisplatin-based chemotherapy, and all patients can recover after symptomatic treatment and the correction of electrolyte disturbances. All kinds of toxicity are tolerable and reversible, and no treatment-related death has occurred.
Our results in the study show that raising of LDH level and accompanied giant lump are the high-risk factors affecting the curative effect of salvage treatment of the relapsed or drug-resistant patients. DICE regimen is a safe and effective regimen for the salvage therapy in treating the relapsed or moderately to highly drug-resistant patients.
Footnotes
This work was supported by a grant from the Nantong Municipal Bureau of Science and Technology, China (No.2006[29]).
- Revision received July 10, 2008.
- Accepted January 6, 2009.
- Copyright © 2009 by Tianjin Medical University Cancer Institute & Hospital and Springer
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