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© 2000 American Society for Clinical Oncology Gemcitabine in the Treatment of Refractory Hodgkin’s Disease: Results of a Multicenter Phase II StudyFrom the Istituto Clinico Humanitas, Rozzano-Milano; Istituto Nazionale Tumori, Milano; Eli Lilly Co, Sesto Fiorentino, Italy; Innere Medizinische Universitaetsklinik, Cologne; Klinikum Kuechwald, Chemnitz; and Buergerhospital, Stutgart, Germany. Address reprint requests to Armando Santoro, MD, Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano-Milano, Italy; email armando.santoro{at}humanitas.it
PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin’s disease. PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m2, was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1,250 mg/m2 to 1,500 mg/m2. RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients’ main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study. CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin’s disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.
ALTHOUGH THE majority of patients with Hodgkin’s disease are cured by first-line therapy,1-12 a consistent number of patients require secondary treatment because of disease progression during or relapse after first-line therapy.13-16 Treatment with conventional-dose salvage chemotherapy can provide a cure for a fraction of relapsing patients, particularly those with late relapses.15-18 For patients with disease progression during or early recurrence after induction chemotherapy and for those with poor prognostic factors at relapse, high-dose chemotherapy with autologous bone marrow transplantation or peripheral stem-cell support has been considered the treatment of choice.14,16,19-23 However, a comparative analysis, conducted by a Stanford group,24 of patients who were matched for duration of first remission and treated with conventional-dose chemotherapy compared with high-dose chemotherapy did not show a clear advantage in terms of overall survival by the intensive approach, especially in patients who relapsed after more than 12 months. Nonetheless, only a limited number of patients with refractory Hodgkin’s disease are cured by either conventional-dose or high-dose chemotherapy.14-24 More effective salvage regimens are, therefore, required for this subset of patients to increase the percentage of chemosensitive cases before high-dose chemotherapy as well as to manage those patients who are not suitable candidates for such therapy. The needs of this subset of patients with Hodgkin’s disease dictate that the development of a new active drug is necessary. Gemcitabine, an analog of cytarabine, is a pyrimidine antimetabolite that has been found to demonstrate a broad spectrum of activity in solid tumors as well as in non-Hodgkin’s lymphomas.25-38 Additionally, gemcitabine has a favorable toxicity profile compared with many other cytotoxic agents regarding myelosuppression, alopecia, and vomiting.39 To evaluate the efficacy and safety of gemcitabine in resistant Hodgkin’s disease, a multicenter phase II study was initiated in Italy and Germany.
Study Design Patients with relapsing or refractory Hodgkin’s disease were enrolled onto a phase II study that evaluated the activity and toxicity of gemcitabine as single-agent chemotherapy. The study was conducted according to the Guidelines for Good Clinical Practice and was approved by local ethic committees. All patients gave their written informed consent.
Histologic diagnosis was confirmed in all cases. To be enrolled onto this phase II study, patients had to meet the following criteria: evidence of refractory or relapsed Hodgkin’s disease; more than one previous chemotherapy regimen; no prior chemotherapy for at least 3 weeks before enrollment; bidimensionally measurable disease; life expectancy
Therapy
Dose reductions were based on blood counts and nonhematologic toxicity before infusion. If patients had blood counts within the specified ranges, doses were reduced according to the following parameters: 25% for leukocytes less than 2.0 x 109 cells/L and
Patient Monitoring and Toxicity Assessment
Disease Monitoring
Statistics
Patient Characteristics Twenty-three patients with relapsing or refractory Hodgkin’s disease were enrolled onto this multicenter phase II study (Table 1). The majority of patients were males (74%), and the median age was 35 years (range, 19 to 58 years). The median time from diagnosis to gemcitabine treatment was 42 months (range, 10 to 157 months). Most patients had nodular sclerosis histology and an extranodal extent of disease. The numbers of prior chemotherapy regimens patients had received were as follows: 12 patients had received two, nine had received three, and two had received more than three. All patients had been previously irradiated. Fifteen patients were considered chemosensitive because of a partial or complete remission disease state with their last chemotherapy regimen; conversely, eight patients were classified as chemoresistant because they showed no response to their last prior chemotherapy. No patients had received previous high-dose chemotherapy with either autologous bone marrow transplantation or peripheral stem-cell support for patient refusal or single-institution policy in the management of patients with more than one relapse.
Drug Delivery The details of gemcitabine administration are reported in Table 2. Of the 300 scheduled infusions of gemcitabine, 167 (56%) were given at the assigned dose of 1,250 mg/m2, 12 (4%) were escalated to 1,500 mg/m2, and 83 (28%) were reduced. Leukopenia and thrombocytopenia were the primary reasons for dose reductions. Dose delays and omissions occurred in seven (2%) and 31 infusions (10%), respectively. Overall, seven patients received three or fewer cycles of gemcitabine, 12 received from four to six cycles, and four received more than six cycles. The median number of cycles was four, with a range of one to 11.
Response Evaluation Twenty-two of the 23 enrolled patients were assessable for response; all 23 patients were included in the efficacy analyses. As reported in Table 1, the disease status for two patients (9%) reached a state of complete remission and seven patients (30%) experienced a partial remission; the overall response rate was 39% (95% confidence interval, 19.7% to 61.5%). Ten patients had stable disease, and only three patients had their disease status progress. No patients received high-dose chemotherapy followed by stem-cell rescue after exposure to gemcitabine. The predilection of positive response to gemcitabine therapy did not seem to be related to the main pretreatment characteristics (Table 1). In particular, response to the last prior chemotherapy, as well as disease extent and number and type of previous chemotherapy regimens, did not influence the incidence rate of complete or partial responses to gemcitabine. Median duration of remission was 6.7 months (range, 3.7 to 33+ months) for partial responders and 14 months (range, 2 to 26+ months) for complete responders; median overall survival time was 10.7 months (range, 4 to 34.7+ months).
Toxicity
Few grade 3 toxicities were reported: five patients experienced a decrease in hemoglobin and platelet levels, two experienced infection, two experienced nausea and vomiting, one experienced myocardial alteration, and one experienced pulmonary toxicity. No RBC or platelet transfusions were required.
Because of the major improvement in the treatment of Hodgkin’s disease in the last two decades, the majority of patients with early1-3 or advanced disease5-9 can anticipate long-term disease-free survival and a possible cure from a combined chemoradiotherapy approach. These achievements in the treatment of Hodgkin’s disease will most likely take place soon with the introduction of new, more aggressive chemotherapy regimens such as bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone,10 Stanford V,11 and epidoxorubicin, cyclophosphamide, vinorelbine, bleomycin, and prednisone.12 Despite these successful treatment options and the promise of new therapies, approximately 20% of all patients with Hodgkin’s disease are primary-therapy resistant or relapsing after induction chemotherapy and require a salvage approach therapy.9,13-16 Second-line treatment may effect a cure in some patients; successful salvage therapy is influenced by some pretreatment characteristics, including response to and duration of remission from first-line therapy, as well as the bulk of disease at relapse.13-16 Salvage cure can be obtained with conventional-dose chemotherapy in some patient subgroups, such as those who experience late relapses.15,17,18 However, high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support has been considered the standard approach for the majority of patients with refractory or relapsing Hodgkin’s disease.14,16,19-23 This standard of treatment remains despite a competitive retrospective matched analysis24 of conventional salvage therapy versus high-dose chemotherapy; this analysis failed to show a significant advantage for the intensive approach, excluding a selected subset of patients who failed induction therapy. Only approximately one third of truly resistant patients may be cured by this approach, and still fewer patients may be cured by a conventional chemotherapy salvage regimen. Consequently, the development of new drugs with activity in refractory Hodgkin’s disease, including such new drugs that improve the efficacy of first-line treatment, salvage treatment, and pretransplantation conditioning regimens, is of major interest when outlining chemotherapy combinations. Only a few new drugs40,41 or chemotherapy regimens,42,43 however, have been studied in recent years. This study is the first to evaluate the activity of gemcitabine in patients with previously treated Hodgkin’s disease. The incidence of complete and partial responses is promising and strongly suggests a possible role of this drug in the management of Hodgkin’s disease. Additionally, gemcitabine-induced toxicity is mild, which thus increases the possibility of using gemcitabine in tandem combinations with other drugs, such as vinorelbine41,42 and ifosfamide,43 that have already been proven to demonstrate activity in refractory Hodgkin’s disease. Obviously, the inclusion of gemcitabine in an earlier phase in the management of Hodgkin’s disease remains to be established, but the potential for such a treatment regimen holds much promise.
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Yuen AR, Rosenberg SA, Hoppe RT, et al: Comparison between conventional salvage therapy and high-dose therapy with autografting for current or refractory Hodgkin’s disease. Blood 89:814-822, 1997 25. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical pharmacology and mechanism of action. Semin Oncol 23:3-15, 1996[Medline] 26. Bouffard DY, Momparler LF, Momparler RL: Comparison of antineoplastic activity of 2', 2'-difluorodeoxycytidine and cytosine arabinoside against human myeloid and lymphoid leukemic cells. Anticancer Drugs 2:49-55, 1991[Medline] 27. Csoka K, Liliemark J, Larsson R, et al: Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol, 22:47-53, 1995 28. Bouffard DY, Momparler RL: Comparison of the induction of apoptosis in human leukemic cell lines by 2',2'-difluorodeoxycytidine (gemcitabine) and cytosine arabinoside. Leuk Res 19:849-856, 1995[Medline] 29. Moore M: Activity of gemcitabine in patients with advanced pancreatic carcinoma: A review. Cancer 78:633-638, 1996[Medline] 30. Steward WP: Combination studies with gemcitabine in the treatment of non-small cell lung cancer. Br J Cancer 78:15-19, 1998 (suppl 3) 31. Stadler WM, Kuzel TM, Raghavan D, et al: Metastatic bladder cancer: Advances in treatment. Eur J Cancer 33:23-26, 1997 (suppl 1)
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
12 weeks; performance status (Karnofsky scale) 
2 and Mann-Whitney U tests were used to compare different groups of patients for categorical and continuous variables, respectively. The medians for time to best response, time to progression, and survival were determined using the Kaplan-Meier method. The log-rank test was used to compare curves for time to progression and survival between different groups of patients. Statistical analysis was performed using SPSS 8.0 for Windows (SPSS, Inc, Chicago, IL). 
