Department of Internal Medicine, Division of Hematology, Clinical Hospital Center Rebro, Zagreb, Croatia
Received 24 October 2001; revised 3 April 2002; accepted 25 April 2002
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Abstract |
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The aim of this study was to analyze outcome of patients with Hodgkins disease (HD) in whom first-line chemotherapy with mustine/vincristine/procarbazine/prednisone (MOPP) had failed.
Patients and methods:
From January 1982 to December 1989 among 210 patients treated with MOPP and radiotherapy to initial bulky sites, 65 patients were primary refractory to or relapsed after initial treatment.
Results:
Twenty-nine of 65 patients (44%) were primary refractory to initial chemotherapy, 20 relapsed within 12 months after complete remission (CR) and 16 relapsed after CR that lasted more than 12 months. Patients with primary refractory HD and early relapse (<12 months after CR) were treated with doxorubicin/bleomycin/vinblastine/darcarbazine. In patients with late relapse (>12 months after CR) MOPP was repeated. The median follow-up for all patients was 115 months. The overall response rate was 63%. Thirty-three patients (51%) achieved a second CR and eight patients (12%) partial response. Remission rate was greatest in patients with late relapse (CR >12 months) (75 versus 55% for early relapse versus 35% for primary refractory HD) (P <0.01). At 10 years, overall and failure-free survival rates were 21 and 16%, respectively. Patients who were in first remission longer than 12 months had a superior overall survival (37 versus 18% for early relapse) and failure-free survival (24 versus 10% for early relapse). No patient with primary refractory HD was alive beyond 52 months after initial treatment failure (P <0.01). Main prognostic factors were duration of the first remission and tumor bulk at relapse.
Conclusions:
Our results confirm previous observations that a significant proportion of patients with HD who experience induction treatment failure cannot be cured with conventional treatment and probably need more aggressive therapy.
Key words: doxorubicin/bleomycin/vinblastine/darcarbazine, Hodgkins disease, mustine/vincristine/procarbazine/prednisone, refractory, relapsed
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Introduction |
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The aim of this retrospective study was to analyze outcome of conventional-dose salvage chemotherapy in patients with stages IIIV HD in whom first-line chemotherapy with MOPP failed.
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Patients and methods |
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Primary refractory patients were treated with six to eight cycles of ABVD, as well as patients with CR that lasted <12 months. In patients who relapsed after 12 months of CR MOPP was repeated. Chemotherapy regimens MOPP and ABVD were administered as originally recommended [1, 2].
In patients who had not had previous radiotherapy, it was incorporated in the second-line treatment in case of bulky disease. Irradiation was also administered in previously irradiated patients with appearance of disease in new locations. Involved fields received doses of 4044 Gy, divided into daily doses of 2 Gy 5 days weekly.
CR was defined as disappearance of all measurable disease, and partial remission as a 50% or greater reduction in the sum of the largest perpendicular diameters of all measurable disease. Primary refractory HD was defined as progression during initial treatment or as partial or transient (<2 months) response to initial therapy.
Statistics
OS was measured from the time of entry into the study to the time of death from any cause. Failure-free survival (FFS) was defined as the interval from the entry into the trial to the time of progression, relapse after a CR, or death from any cause.
Fishers exact test was used for comparisons of patients characteristics and response rates. Survival rates were calculated according to the KaplanMeier method. The prognostic significance of various factors was tested by Cox regression analysis. A two-sided P value is used for all statistical tests.
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Results |
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Fifteen patients from the entire group were alive at 10 years (Figure 1). None of the primary refractory patients survived. Thirty-seven percent of patients whose remission lasted longer than 12 months after the initial treatment were alive at 10 years, compared with 20% survival rate in the more unfavorable group (Figure 2). There was statistically significant difference in survival rate between stage II and stage III/IV patients at diagnosis (P = 0.05) as determined by Cox regression analysis. None of the patients with extranodal disease survived 10 years. Age and histological features did not influence the survival rate. For the entire group, the rate of FFS at 10 years was 16% (Figure 1). Significant differences were observed in the group with CR <12 months (18% FFS), and CR >12 months (40%) (Figure 3). Age and histology did not influence 10-year FFS. Stage II and stage III/IV differ significantly in 10-year FFS. Forty percent of patients with nodal disease were failure-free after 10 years.
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Forty patients died of progressive HD, three of second neoplasm, five of cardiac and/or pulmonary complications caused by chemotherapy or radiotherapy and three of other causes.
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Discussion |
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The treatment of HD is associated with development of second malignancies. The risk of acute leukemia was found to be increased in the patients who received more than six cycles of MOPP chemotherapy but not in the patients who received combined chemotherapy and radiation [14]. The risk of lymphoma was also increased after treatment for HD [1517]. Several authors demonstrated an increased risk for development of solid cancers after treatment for HD, and the risk was related to radiotherapy [1519]. The incidence of second neoplasms in our group of patients was lower than in other series, probably because of the small number of long-term survivors [15].
Our results in long-term follow-up demonstrated that the significant proportion of patients with HD who experienced early relapse or had primary refractory disease probably needed more aggressive therapy than MOPP or ABVD. Many different salvage regimens were reported to be successful in this setting but large randomized trials are lacking [2036]. Autologous bone marrow transplantation or peripheral stem cell transplantation seem to provide a better chance for this group of patients [3740]. We had transplanted only one patient who survived 2 years after autologous bone marrow transplantation. The combination of high-dose chemotherapy and stem cell rescue is currently the favored treatment for patients with refractory disease and patients who experience early relapse. Our results indicate that conventional-dose salvage chemotherapy remains a possible treatment for the most favorable group of patients (i.e. those with relapse 12 months after CR and no adverse prognostic factors at progression). However, current therapeutic protocols still have unsatisfactory results, and novel regimens and chemotherapeutics should be developed.
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Footnotes |
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References |
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