Annals of Oncology 13:1650-1655, 2002
© 2002 European Society for Medical Oncology
Original Paper |
Long-term results of conventional-dose salvage chemotherapy in patients with refractory and relapsed Hodgkin’s disease (Croatian experience)
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alek-Razumoviantek-MarkulinDepartment 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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 Top Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Background:
The aim of this study was to analyze outcome of patients with Hodgkin’s 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, Hodgkin’s disease, mustine/vincristine/procarbazine/prednisone, refractory, relapsed
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Although Hodgkin’s disease (HD) is considered a highly curative neoplasm, about one-third of all patients fail to respond to conventional chemotherapy alone or combined with radiotherapy. A similar treatment failure rates occurs after mustine/vincristine/procarbazine/prednisone (MOPP), doxorubicin/bleomycin/vinblastine/ darcarbazine (ABVD) or hybrid regimens [1–5]. There are three types of failure: primary refractory disease, early relapse (remission lasts less than 12 months) and late relapse (remission lasts more than 12 months). Salvage standard-dose chemotherapy produces satisfactory durable remission rates only in the latter group of patients (10-year relapse-free survival 30–40%), but overall survival (OS) is reduced by second malignancies and other treatment-related complications. In contrast, treatment results in patients with initially progressive disease and early relapse are extremely poor with long-term relapse-free survival in 0–20% of patients [6, 7]. Recently, high-dose chemotherapy with autologous stem cell transplantation has become established as the first choice of salvage therapy. Many patients who underwent such treatment achieved long-term disease-free survival despite being resistant to multiple conventional-dose chemotherapy regimens [8–10].
The aim of this retrospective study was to analyze outcome of conventional-dose salvage chemotherapy in patients with stages II–IV HD in whom first-line chemotherapy with MOPP failed.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Between January 1982 and December 1989, 210 newly diagnosed patients with HD stages II–IV were treated with eight cycles of MOPP followed by irradiation of initial bulky sites or residual masses. Sixty-five patients who were primary refractory to or relapsed from complete remission (CR) were eligible for retrospective analysis of second-line treatment outcome. Twenty-four patients received radiotherapy as a part of initial treatment. They received 40–44 Gy on involved fields. Patients were required to be 15 years or older at progression with adequate renal, hepatic and bone marrow functions. The relapse had to be measurable and documented histologically. The extent of disease at relapse was determined by complete physical examination, chest radiography and computed tomography. Other staging procedures were performed as clinically indicated. Clinical staging was performed according to the guidelines of the Ann Arbor Conference [11].
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 40–44 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.
Fisher’s exact test was used for comparisons of patients’ characteristics and response rates. Survival rates were calculated according to the Kaplan–Meier 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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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Patients’ characteristics
The clinical characteristics of the 65 patients with primary refractory or relapsed HD are given in Table 1. The median age of the patients at relapse was 33 years (range 16–77). There were 34 males (52%) and 31 females (48%). The histological subgroups included 31 cases of nodular sclerosis (48%), 28 mixed cellularity (43%) and six lymphocyte depleted (9%). Stage II according to Ann Arbor criteria was registered in 12 patients (18%) and stages III/IV in 53 patients (82%). B symptoms (Ann Arbor classification) were present in 30 eligible patients (46%). Fifteen patients (23%) had extranodal disease. Twenty-four patients (37%) received radiotherapy as part of initial treatment.
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Treatment outcome
Table 2 summarizes the results of our investigation. Out of 65 patients who were primary refractory or relapsed after induction treatment, CR was achieved in 51%. The rates of complete response for the patient subgroups were: 75% for patients who relapsed more than 12 months after the initial treatment; 55% for those who relapsed within 12 months; and 35% for the group of primary refractory patients. Fifty-five percent of patients younger than 35 years and 45% of patients older than 35 years achieved a second CR. Median of second remission duration was 13 months. Tumor burden and extranodal disease were demonstrated to be adverse prognostic factors. Patients with stage II disease achieved CR in 76% compared with 46% of stage III/IV. Only 19% of patients with extranodal disease achieved CR. In contrast, patients with nodal disease had a significantly more favorable outcome with 65% achieving CR. Histological features did not influence the response.
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Ten patients were treated with irradiation at relapse. Two of them received radiotherapy at previously irradiated sites because of the progression in a previously irradiated area. CEP regimen (CCNU/etoposide/prednimustin) or EVAP regimens (etoposide/vinblastine/doxorubicin/prednisone) were used as third-line treatment. Only one patient was treated with autologous bone marrow transplantation at second relapse. He stayed alive for 2 years after transplantation.
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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There were three second malignancies in this group of patients. Acute myeloblastic leukemia [M1 according to FAB (French–American–British) classification] occurred in one patient 9 years after HD was diagnosed. He was initially treated with eight cycles of MOPP and achieved CR. Ten months later relapse occurred and the patient received eight cycles of ABVD. He did not received any radiotherapy. The patient died during induction therapy for acute leukemia. A case of lung adenocarcinoma was documented in a young woman 7 years after chemotherapy and radiotherapy for HD. She received eight cycles of MOPP chemotherapy plus involved field radiotherapy with 44 Gy and achieved CR. She relapsed 18 months later and was treated with eight cycles of ABVD. After palliative lung resection, she received chemotherapy (cyclophosphamide/doxorubicin/vincristine/etoposide) and died 6 months after the lung cancer diagnosis. The third patient developed aggressive B-cell non-Hodgkin’s lymphoma and died within 2 months of progressive disease. He was treated with six cycles of MOPP and irradiation, but experienced early relapse. After the six cycles of ABVD he achieved second remission and developed non-Hodgkin’s lymphoma 3 years after the diagnosis of HD was established.
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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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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The results of our investigation correlate with previous observations. Conventional-dose salvage regimens are incapable of producing significant response in refractory patients. Patients with primary refractory HD or early relapse (CR <12 months) represent extremely unfavorable prognostic groups. In our series the 10-year OS is 0% and 15% respectively and 10-year freedom from second progression (FFSP) 0% and 10% respectively. The most favorable group consists of patients whose first remission lasted over 12 months. The 10-year FFS and OS rates were 44% and 18% respectively. Longo et al. [7] reported long-term results from patients who relapsed after MOPP therapy and were retreated with MOPP. OS at 11 years was 24% and 11% in patients with long and short initial remissions, respectively. Age less than 30 years was also recognized as a factor with positive influence on survival. A Stanford series [12] that used AVBD as a salvage regimen after MOPP reported 71% overall response rate. The CR was 38% with median CR duration of approximately 2 years. The Cancer and Leukemia Group B (CALGB) reported results of second-line use of ABVD following MOPP as a part of a prospective randomized trial comparing MOPP with ABVD for advanced HD. The CR rate was 35% and 5-year progression-free survival was 15% [5]. With an intention to substitute ABVD in patients with HD who relapsed from or were refractory to MOPP, CALGB conducted a trial using EVA regimen (etoposide/vinblastine/doxorubicin). This regimen showed a 73% overall response rate and 29% FFS at 3 years. Survival rates were significantly better in patients with late relapse without B symptoms compared with patients who failed induction therapy within 1 year and had B symptoms at relapse [13]. The Milan group [6] reported analysis of 115 patients who were refractory to or relapsed after alternating or hybrid MOPP–ABVD. They used CEP regimen (CCNU/etoposide/prednimustin) as salvage therapy for induction failure and early relapse. Patients with late relapse were retreated with MOPP–ABVD. An overall response rate was 74% (CR 64% and partial remission 10%). At 8 years, OS was 27% and FFSP 22%. These results do not confirm concern that an eight-drug regimen bears a higher risk of resistant disease at relapse in uncured patients [6].
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 [15–17]. Several authors demonstrated an increased risk for development of solid cancers after treatment for HD, and the risk was related to radiotherapy [15–19]. 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 [20–36]. Autologous bone marrow transplantation or peripheral stem cell transplantation seem to provide a better chance for this group of patients [37–40]. 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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+ Correspondence to: Dr B. Labar, Department of Internal Medicine, Division of Hematology, Clinical Hospital Center Rebro, Kispaticeva 12, Zagreb, Croatia. Tel: +385-1-23-88-644; Fax: +385-1-24-21-892; E-mail: boris.labar{at}inet.hr
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References |
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