Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group

T. Baetz1, A. Belch1, S. Couban1, K. Imrie1, J. Yau1, R. Myers1, K. Ding1, N. Paul1, L. Shepherd1, J. Iglesias2, R. Meyer1 and M. Crump1,+

1 National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario; 2 Eli Lilly, Toronto, Ontario, Canada

Received 24 June 2003; accepted 12 August 2003


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

Gemcitabine (difluorodeoxycytidine) is active as a single agent in Hodgkin’s disease and has been used successfully in combination with cisplatin to treat a variety of solid tumors.

Patients and methods:

We evaluated the combination of gemcitabine/dexamethasone/cisplatin (GDP) as salvage chemotherapy in 23 patients with relapsed or refractory Hodgkin’s disease (median age 36 years, range 19–57). Treatment consisted of gemcitabine 1000 mg/m2 intravenously on days 1 and 8, dexamethasone 40 mg orally days 1–4 and cisplatin 75 mg/m2 on day 1, every 21 days as an outpatient. Response was assessed following two cycles of treatment.

Results:

There were four complete responses and 12 partial responses for a response rate of 69.5% (95% confidence interval 52% to 87%); the remaining seven patients had stable disease and no patient progressed on treatment. All patients had successful stem cell mobilization and underwent transplantation with a median 10.6 x 106 CD34+ cells/kg. Hematological toxicity from GDP was mild (grade 3 neutropenia 8.6%, grade 3 thrombocytopenia 13%).

Conclusions:

In summary, GDP is an active regimen for patients with relapsed or refractory Hodgkin’s disease. The response rate is similar to the rates of other current salvage regimens, it can be given to outpatients with tolerable toxicity and it does not inhibit the mobilization of autologous stem cells.

Key words: gemcitabine, Hodgkin’s disease, salvage chemotherapy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The majority of patients with Hodgkin’s disease will be cured with primary treatment. However, among those with advanced-stage disease, 10–20% will not achieve a complete response (CR) and 20–30% will relapse following completion of initial therapy [1]. Standard treatment for patients with newly diagnosed advanced-stage Hodgkin’s disease is with doxorubicin (Adriamycin®)/bleomycin/vinblastine/dacarbazine (ABVD) [2, 3]. The use of other more intensive chemotherapy regimens for patients with adverse prognostic factors is currently being evaluated in clinical trials [4].

Second-line or salvage chemotherapy followed by autologous stem cell transplantation is the treatment of choice for patients with Hodgkin’s disease who have relapsed from, or are refractory to, initial chemotherapy [5, 6]. Two randomized trials comparing autologous transplantation with standard-dose second-line therapy have been conducted, both detecting longer progression-free survival in the groups of patients randomized to stem cell transplantation [7, 8]. Many second-line regimens have been reported [915], with several of these including a platinum compound such as cisplatin or carboplatin [1215]. While these regimens are associated with response rates (RRs) of 60–89%, they can produce substantial hematological and non-hematological toxicity, and hospitalization may be required either to administer the therapy or to manage resulting complications. New regimens providing sufficient disease control to permit successful autologous transplantation and a reduced risk of treatment-related toxicity are needed.

Gemcitabine (difluorodeoxycytidine) is an analog of cytarabine that has more effective cellular kinetics, including intracellular incorporation, phosphorylation and retention [16]. In comparison with many other cytotoxic agents, gemcitabine has a favorable toxicity profile and is now commonly used in treating patients with solid tumors such as those of pancreas, bladder and lung [1719]. Single-agent gemcitabine has shown activity in Hodgkin’s disease [20, 21] and a variety of histological subtypes of non-Hodgkin’s lymphoma [2225]. The addition of cisplatin to gemcitabine has shown synergistic activity in vitro [26, 27], and the combination of cisplatin and gemcitabine has become standard in the treatment of advanced bladder and non-small-cell lung cancer [1719]. Given the encouraging single-agent activity of gemcitabine seen in patients with Hodgkin’s disease, and the relatively moderate toxicities observed with gemcitabine and cisplatin combinations in patients with solid tumors, we chose to evaluate gemcitabine and cisplatin together with dexamethasone in the dose used in the DHAP (dexamethasone/cisplatin/cytarabine) regimen [15]. This phase II trial was designed to provide estimates of the efficacy and toxicities of gemcitabine/dexamethasone/cisplatin (GDP) used to treat patients with Hodgkin’s disease who had not responded to or suffered progressive disease while receiving, or relapsed after receiving, first-line therapy.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility and evaluation of patients
This multicenter phase II trial was completed by the National Cancer Institute of Canada Clinical Trials Group. Patients were eligible for participation in this trial if they had a histological diagnosis of Hodgkin’s disease and had relapsed after or were refractory to one prior chemotherapy regimen. A reference pathologist at each center confirmed the histological diagnosis of Hodgkin’s disease by reviewing initial biopsy material and/or biopsies obtained at the time of disease relapse or progression.

Eligibility criteria required that patients be >=16 years of age and have an Eastern Cooperative Oncology Group performance status [28] of 0–2. At least one site of bi-dimensionally measurable tumor as assessed by clinical examination, computed tomography (CT) or magnetic resonance imaging had to be identified. Additional eligibility criteria included: normal bone marrow function (absolute neutrophil count >1.5 x 109/l, platelets >100 x 109/l); serum creatinine <140 mmol/l; serum aspartate or alanine aminotransferase <2.5 x upper limit of normal (ULN); and bilirubin <1.5 x ULN. Patients were ineligible if they had central nervous system involvement by lymphoma, human immunodeficiency virus infection, or a serious intercurrent illness or medical condition such as active uncontrolled infection or significant cardiac dysfunction that would preclude safe administration of the protocol treatment. Prior treatment with gemcitabine, cisplatin or high-dose chemotherapy and stem cell transplantation was also an exclusion criterion. The Human Experimentation Committee or the Research Ethics Board of each participating center approved this study, and all patients provided written informed consent.

Treatment plan
Before entry into this study, patients underwent a complete history and physical examination, including evaluation of performance status, and assessment for the presence of constitutional symptoms and concurrent co-morbid conditions. Laboratory studies included a complete blood count (CBC) with white blood cell differential count, biochemistry profile (including albumin and lactate dehydrogenase), and bone marrow aspiration and biopsy. Radiological examinations, including a chest radiograph and CT scanning of the chest, abdomen and pelvis, were required within 3 weeks of starting treatment. Gallium scanning was recommended but not required.

Patients received GDP in an outpatient setting with treatment cycles scheduled every 21 days. Chemotherapy in this study consisted of gemcitabine 1000 mg/m2 intravenously (i.v.) over 30 min on days 1 and 8, dexamethasone 40 mg orally in divided doses on days 1–4, and cisplatin 75 mg/m2 i.v. over 60 min, usually following gemcitabine. One or more of the dexamethasone doses could be administered i.v. before chemotherapy to prevent emesis, and the oral protocol treatment dose reduced accordingly.

In order to reduce the risks of cisplatin-related nephrotoxicity, a specific hydration protocol was recommended, consisting of pre-hydration with 250 ml 5% dextrose in saline given i.v. over 30 min, and 250 ml 20% mannitol in normal saline i.v. over 1 h given concurrently with the administration of cisplatin. Cisplatin was mixed in 500 ml normal saline and administered over 1 h. An additional 500 ml normal saline were given after cisplatin. Patients were asked to drink six to eight glasses of fluid over the rest of the day following completion of the cisplatin infusion. An antiemetic protocol appropriate for highly emetogenic chemotherapy was suggested (e.g. ondansetron or dolasetron in addition to dexamethasone). While on study, patients were not permitted to receive other cytotoxic, monoclonal antibody or radiation therapy.

During treatment, all patients had a CBC including white blood cell differential count, serum creatinine, aspartate aminotransferase or alanine aminotransferase, alkaline phosphatase and serum bilirubin on day 1 of each treatment cycle; the CBC and differential count were repeated on day 8. Treatment cycles were delayed by 1 week for granulocytopenia of <1.0 x 109/l or thrombocytopenia of <100 x 109/l. An attenuation schedule was also implemented for the day-8 dose of gemcitabine if granulocytopenia and/or thrombocytopenia were observed on that day. If the day-8 granulocyte count was <0.5 x 109/l or the platelet count <=50 x 109/l, the physician had the choice of omitting this gemcitabine dose, or delaying treatment and administering this dose 1 week later provided the granulocyte count was then >0.5 x 109/l and the platelet count >50 x 109/l. If isolated granulocytopenia of 0.5–0.9 x 109/l was observed on day 8, the physician had the choice of administering the full dose of gemcitabine and initiating therapy with filgrastim, or administering gemcitabine with a dose reduction of 25%. If isolated thrombocytopenia of 50–99 x 109/l was observed on day 8, the dose of gemcitabine was administered with a dose-reduction of 25%. Primary prophylaxis with colony-stimulating factors was not permitted. After one dose delay, patients were to receive filgrastim with subsequent treatment cycles in order to maintain dose intensity. Filgrastim was also recommended for patients who suffered an episode of febrile neutropenia with a previous treatment cycle.

Toxicities were graded using the National Cancer Institute Common Toxicity Criteria Version 2.0. Doses of cisplatin and gemcitabine were reduced by 25% if any grade 3 non-hematological toxicities (excepting nausea, vomiting and alopecia) were observed. Doses of cisplatin were reduced by 25% if serum creatinine was between 140 and 199 µmol/l. Protocol therapy was discontinued with the occurrence of any grade 4 non-hematological toxicities or for elevations of serum creatinine to >=200 µmol/l.

Assessment of outcomes
The primary end point of this study was response rate (RR) following two cycles of GDP. All patients underwent disease reassessment by physical examination and CT scan of the chest, abdomen and pelvis. Other scans or X-rays were performed as indicated. Bone marrow biopsy was repeated after cycle 2 if the marrow was involved by disease at baseline. Antitumor response was categorized according to the International Workshop Criteria [29] and toxicity graded according to the National Cancer Institute Common Toxicity Criteria Version 2.0. Following two cycles of GDP, patients who had CR, an unconfirmed CR (CRu), partial response (PR) or stable disease (SD), and who were considered by their treating physician to be candidates for high-dose chemotherapy with stem cell transplantation, were taken off study and proceeded to stem cell mobilization. Those with progressive disease were removed from the study. Patients achieving a CR, CRu or PR who were not candidates for autologous transplantation could receive up to six cycles of GDP.

Statistical methods
The primary end point of the study was treatment efficacy after two cycles measured by the objective RR (CR + CRu + PR) as defined by the International Workshop to Standardize Response Criteria for Non-Hodgkin’s Lymphoma [29]. It was assumed that this regimen would not be of further interest, and additional phase III testing not warranted, if the observed RR was <50%. In order to minimize the average sample size and ensure that we would continue to a phase III trial with high probability if the true RR is >60%, and with lower chance to a phase III trial if the true RR is <40%, a two-stage design was used for patient accrual in this trial [30]. In the first stage, 22 patients were to be entered; if fewer than 10 responses were observed, the study would be stopped and the conclusion drawn that GDP was not sufficiently active and unlikely to be of further interest. If 15 or more objective responses were seen, the study would be considered positive and further testing of GDP would be warranted. If between 10 and 14 responses were observed, then another 22 patients would be enrolled to a total of 44. If 24 or more responses were then observed (i.e. an RR of >=55%), it would be concluded that GDP is an active regimen in this patient population, with a power of 80% and a type 1 error of 3.7%.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between January 2001 and July 2002, 24 patients with relapsed or refractory Hodgkin’s disease from seven different centers in Canada were registered onto this trial. One patient was found to have non-Hodgkin’s lymphoma on pathology review following the start of treatment and therefore was excluded; the remaining 23 patients are included in this analysis. The baseline characteristics of the patients are described in Table 1. The median age of the patients was 36.5 years (range 19–57), and 21 (91%) had nodular sclerosis histology. The clinical features of the group were generally unfavorable: in six patients (26%) ABVD had either failed to achieve a remission, or there had been a relapse within 3 months of completing therapy. Only nine patients (39%) had achieved a remission of >12 months duration. According to the prognostic score for relapsed Hodgkin’s disease described by Josting et al. [31], 10 patients (43%) had a prognostic score of >=2.


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Table 1. Patient characteristics
 
Treatment received
Twenty-two patients received two cycles of GDP and one patient received three cycles, resulting in a total of 47 treatment cycles. Fourteen cycles (30%) were modified, including four dose reductions, one dose elimination and nine dose delays. Hematological toxicity was the most common cause for a dose modification, accounting for three dose reductions and five dose delays. Growth factors were not given as primary prophylaxis to any patient; six patients received filgrastim because of low treatment-day granulocyte counts.

Treatment response
Four patients (17.3%) had a CR and 12 (52.2%) had a PR following two (22 patients) or three cycles (one patient) of GDP, giving an overall RR of 69.5% (95% CI 52% to 87%). Seven patients had SD and no patients progressed on this treatment. All patients proceeded to stem cell mobilization and autologous stem cell transplantation.

Treatment-related toxicity
Toxicity associated with GDP chemotherapy is summarized in Table 2. No patients died while receiving study treatment. There were no episodes of febrile neutropenia and no patient required a platelet transfusion. Four patients required a red blood cell transfusion. Among the non-hematological toxicities, the most commonly observed problem was vomiting, with three patients (13%) experiencing vomiting of grade 3 severity. One patient who had previously received mediastinal radiation suffered a myocardial infarction with an associated iliac artery embolism 6 days after commencing his second cycle of GDP. The day-8 dose of gemcitabine was held and, after recovering from his infarct, the patient proceeded to stem cell harvesting and transplantation. Subclavian deep venous thrombosis was diagnosed in a second patient during cycle 2. No significant renal or ototoxicity was reported.


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Table 2. Toxicity of gemcitabine/dexamethasone/cisplatin (n = 23)
 
Four patients (17%) required hospitalization that resulted in a total of 13 hospital days. Reasons for hospitalization included management of non-neutropenic fever (one admission for 3 days), tumor lysis syndrome (one admission for 3 days), transportation concerns with first therapy (one admission for 1 day) and the myocardial infarction of the previously described patient (6 days).

Transplantation
Following GDP, all patients received high-dose chemotherapy and autologous stem cell transplantation. The protocols for stem cell collection and high-dose therapy were left to local policy. A variety of mobilizing regimens were used to collect stem cells following GDP, with the most common practice including a combination of chemotherapy and growth factor. Stem cell collections were adequate in all patients; the median number of CD34+ cells collected was 10.8 x 106/kg body weight (range 2.0–49.3x 106). Hematopoietic engraftment after transplantation was consistent with expectations. The median number of days to an absolute neutrophil count >0.5 x 109/l was 11 (range 9–13) and the median number of days to platelet count of >20 x 109/l was also 11 (range 8–19).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this multicenter phase II study demonstrate that GDP is an active and well-tolerated regimen in patients with relapsed or refractory Hodgkin’s disease. Treatment was given on an outpatient basis and was associated with a low risk of subsequent hospitalization or need for blood product support. The sample size of this trial was determined to ensure that an objective RR of at least 60% would be detected. When responses were observed in 16 of the first 23 patients evaluated (RR 69.5%), the study was closed to further accrual, as these results satisfied our pre-defined criterion for antitumor activity that would warrant possible phase III testing. The toxicity profile of GDP appeared favorable compared with previous experience with second-line treatment regimens in Hodgkin’s disease or aggressive lymphoma. Finally, all patients proceeded to autologous stem cell transplantation; adequate numbers of stem cells were harvested in all patients and hematopoietic recovery after transplantation was rapid.

Following reports by Santoro et al. [20] and Zinzani et al. [21] of single-agent activity of gemcitabine in Hodgkin’s disease, we chose to evaluate this agent in combination with cisplatin and dexamethasone in patients with Hodgkin’s disease who required second-line therapy. The addition of cisplatin to gemcitabine was based on the observation of synergy between the two drugs in vitro [26] and the high RR and manageable hematological and non-hematological toxicity of this combination in patients with solid tumors [17, 32]. High-dose dexamethasone is a component of a number of active second-line regimens for Hodgkin’s disease [9, 15], and in addition is important in preventing delayed nausea and vomiting from moderate or high-dose cisplatin.

The RR of 69.5% in our study demonstrates that GDP compares favorably with other published salvage regimens [815], as listed in Table 3. While the results of many second-line or salvage regimens for the treatment of patients with relapsed or refractory Hodgkin’s disease have been reported, no single regimen has emerged as the accepted standard. Because no randomized trials have been published that directly compare the efficacy, toxicity or quality of life associated with the various regimens, assessment is limited to a comparison of generally small phase II studies [815]. As shown in Table 3, the RR associated with the use of GDP is similar to those described with most other regimens, and treatment-related toxicity appears to be reduced. As the patient populations evaluated in these trials probably have differing prognostic features, randomized trials are required to permit a direct comparison of the efficacy and toxicities of the different salvage regimens.


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Table 3. Comparison of published salvage regimens for Hodgkin’s disease. Toxicity grading according to individual trial criteria
 
In order to facilitate a description of the prognosis of the patient populations included in trials of second-line therapy, Josting et al. [31] described a prognostic index that predicts for freedom from second treatment failure and overall survival in patients with relapsed or refractory Hodgkin’s disease. In this analysis, three factors were found to predict for poorer outcomes in patients who relapse after chemotherapy: anemia (hemoglobin <105 g/l in females and <120 g/l in males), stage III or IV disease at relapse, and time to relapse (<12 months). Although the authors did not use these variables to predict response to second-line therapy, freedom from second treatment failure at 12 months was clearly different between patients with no risk factor (~80%), and one (68%), two (50%) or three of these risk factors (35%). In our cohort, 43% of patients had at least two adverse risk factors, indicating that the group studied is probably representative of the broad population of patients who have experienced disease progression after ABVD. Other studies evaluating prognosis in patients with relapsed or refractory Hodgkin’s disease have observed that relapse or progression within 1 year of initial therapy is an adverse factor [33, 34]. In our cohort, 61% of patients experienced disease progression within 1 year of completing ABVD, again suggesting that our data are generalizable to a broader population.

Some currently used salvage regimens can produce severe and sometimes fatal toxicities that limit their use in patients with co-morbid conditions or poor performance status, and might prevent patients from proceeding to autologous stem cell transplantation. For example, Schmitz et al. [8] reported the results of using two cycles of dexa-BEAM in patients with first relapse of Hodgkin’s disease; responding patients were then allocated to receive additional therapy with dexa-BEAM or proceed to autologous stem cell transplantation according to a randomization process conducted before initial therapy. Among 144 evaluable patients who were to receive the initial two cycles of dexa-BEAM, eight patients (5.5%) suffered fatal treatment-related toxicities and five (3.5%) could not be randomized subsequently because of serious infections. In contrast, the toxicities with GDP were moderate. No renal or ototoxicity was observed; there were no episodes of neutropenic fever, and no patient required a platelet transfusion. Treatment was administered on an outpatient basis and hospitalizations for management of treatment-related toxicities accounted for only 13 days over a total of 47 treatment cycles. No toxicities, including cumulative myelosuppression, were observed that might subsequently impair the ability to harvest sufficient stem cells. Stem cell mobilization following salvage regimens containing carmustine or high-dose cytarabine, however, can be difficult [35].

In conclusion, this study demonstrates that GDP is an active outpatient treatment for patients with relapsed or refractory Hodgkin’s disease before high-dose chemotherapy and autologous stem cell transplantation. These results provide sufficient data to support comparative testing of GDP in a phase III trial.


    Footnotes
 
+ Correspondence to: Dr M. Crump, Princess Margaret Hospital, Department of Medical Oncology and Hematology, 610 University Avenue, Room 5-108, Toronto, Canada M5G 2M9. Tel: +1-416-946-4567; Fax: +1-416-946-6546; E-mail:michael.crump{at}uhn.on.ca Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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