myeloablative conditioning with allogeneic blood progenitor cell transplantation ... mediastinal mass treated with radiation therapy alone have at least a 50% ...
Annals of Oncology 13 (Supplement 1): 112–116, 2002 DOI: 10.1093/annonc/mdf624
Symposium article
Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin’s disease A. Josting1*, A. Engert1, V. Diehl1 & G. P. Canellos2 1
Department of Internal Medicine I, University Hospital Cologne, Germany, and the German Hodgkin Lymphoma Study Group (GHSG); Department of Adult Oncology, Dana Faber Cancer Institute, Boston, MA, USA
2
Introduction Depending on stage and risk factor profile, up to 95% of patients with Hodgkin’s disease (HD) at first presentation reach complete remission (CR; disappearance of all detectable clinical and radiographic evidence of disease) after standard treatment [1]. Depending on their initial treatment, those patients relapsing have different treatment options, including radiotherapy for localized disease in previously non-irradiated areas, conventional salvage chemotherapy, or high-dose chemotherapy (CT) followed by autologous stem cell transplantation (autoSCT) [2, 3]. Conventional CT is the treatment of choice for patients relapsing after initial radiotherapy for early stage HD. The survival of these patients is at least equal compared with advanced-stage patients initially treated with CT [4]. In contrast, patients with relapsed HD after primary CT generally have a poorer prognosis. The therapeutic options include salvage radiotherapy, salvage CT, and high-dose CT with autoSCT. More recently, new approaches such as sequential highdose CT, tandem high-dose CT, allogeneic (allo) SCT, or nonmyeloablative conditioning with allogeneic blood progenitor cell transplantation (‘mini-transplants’) have been investigated in relapsed HD [4–6]. Since more aggressive approaches are associated with increased toxicity, an accurate pretreatment prognostic assessment of patients is required to help selection of the most appropriate therapeutic regimen.
Prognostic factors in patients relapsing after primary radiotherapy Primary radiotherapy is now used less often in the treatment of localized HD. It has been replaced by combined modality therapy, where various numbers of cycles of combined CT are given prior to lower dose radiotherapy, which is limited to the involved field rather than being extensive, as in the past. Combined modality therapy has reduced the relapse rate to 40 or 50 years), stage at relapse and the type of therapy used for the treatment of relapse, i.e. CT alone or CT and radiation (Table 1). In some serious mixed cellularity or lymphoid-depleted history were also negative prognostic factors. Second-line therapy for radiation relapse has been quite successful in most series with long-term follow-up, demonstrating a 10-year relapse-free survival of 60% (Table 1). The overall salvage of unirradiated nodal-only relapse is superior to symptomatic disseminated recurrence [7, 10]. Royal Marsden Hospital series indicated that age, histology and nodal versus extranodal relapse determined the sucess of second-line treatment. In that series, the relapse-free survival at 10 years was 63%; however, nodal recurrence had a 10-year survival rate of 74% compared with 51% for those with an extranodal relapse [7]. With relatively small numbers, the Stanford series suggested that combined modality therapy has a better 10-year progression-free rate than CT alone (62% versus 37%),
113 Table 1. Prognostic factors: salvage after relapse from radiotherapy (multivariate analysis) Series
Significant factors
10-year survival from relapse (%)
Royal Marsden (473 patients) [7]
Age (>40 years), unfavorable histology, extranodal relapse
63
Stanford (109 patients) [10]
Age (>50 years), stage II, IIIA/B or IV, treatment (CMT versus CT)
57
Harvard Joint Center (138 patients) [11]
Unfavorable histology
62
CMT, combined modality treatment; CT, chemotherapy.
especially in patients with more advanced stages at relapse (stages IIA–IV) [10]. Isolated stage IA relapse has a markedly high salvage rate (∼90%) as opposed to patients in stage IIIB and IV, where the long term salvage rate is ∼30%. Differences between types of salvage therapy—mainly CT alone versus combined modality—have not been corrected for the patterns of relapse. It is understandable that nodal relapses might be better treated with combined modality therapy as opposed to disseminated IIIB or IV recurrences, where the addition of radiotherapy might not be an advantage. Patients with a bulky mediastinal mass treated with radiation therapy alone have at least a 50% recurrence rate, compared with patients without mediastinal bulk, who have much more favorable freedom from progression. However, it is noteworthy that in most series the OS is similar, attesting to the potential value of systemic CT alone in the setting of relapse at this bulky site. The second-line combination CT used initially was the classical MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) or its variant MVPP (with vinblastine instead of vincristine) [12–14]. A high rate of CR was achieved in the range of 70–85%. There were, however, some secondary leukemias resulting from the alkylating agents contained in these regimens [14, 15]. The introduction of ABVD (doxurubicin, bleomycin, vinblastine, dacarbazine) as a primary systemic treatment for newly diagnosed advanced disease or disease in relapse from primary radiation demonstrated equivalence to MOPP. ABVD is associated with fewer secondary leukemias, resulting in its widespread use [1]. In the Milan series, a historical comparison of doxurubicin-containing regimens suggested that they were superior to MOPP in the setting of radiation relapse [16]. In most series, CT regimens have not been compared prospectively in the setting of relapse from primary radiation therapy. Although ABVD has generally replaced MOPP as the salvage CT of choice, some caution is indicated in patients with prior extensive thoracic irradiation requiring special attention to cardiac and pulmonary function. Patients who relapse from second-line therapy are often candidates for high-dose CT with stem-cell support. The salvage of relapsing patients is likely to get better than the 60% level with the potential for earlier diagnosis with
more sensitive diagnostic techniques such as PET scans. In addition, for those who fail conventional-dose salvage CT, high-dose therapy can still result in long-term disease-free survival in a further 30–50%.
Prognostic factors in patients relapsing after primary CT It was first noted in 1979 that the length of remission after first-line CT had a marked effect on the ability of patients to respond to subsequent salvage treatment [17]. In 1992 the National Cancer Institute (NCI) updated their experience with the long-term follow-up of patients who relapsed after polychemotherapy [18]. Derived primarily from investigations involving failures after MOPP and MOPP variants, the conclusions are relevant to other CT programs. On this basis, CT failures can be divided into three subgroups: • Primary progressive HD (∼10% of all cases), i.e. patients who never achieved a CR • Early relapses within 12 months of CR (∼15% of all cases) • Late relapses after CR lasting >12 months (∼15% of all cases) Using conventional CT for patients with primary progressive disease, virtually no patient survives >8 years. In contrast, the projected 20-year survival for patients with early relapse or late relapse was 11 and 22%, respectively [18].
Primary progressive HD Patients with primary progressive HD, defined as progression during induction treatment or within 90 days after the end of treatment, have a particularly poor prognosis. Treatment of patients with primary progressive HD has consisted of salvage CT, radiotherapy, and high-dose CT with autoSCT. Conventional salvage regimens have given disappointing results in the vast majority of patients: response to salvage treatment is low and the duration of response is often short. The 8-year OS ranges between 0 and 8%. Freedom from treatment failure (FFTF) in second remission is 0% at 4–8 years in small series reported [18, 19]. Extensive disease often limits the use of radiotherapy. The German Hodgkin’s Lymphoma Study Group (GHSG) retrospectively analyzed 206 patients with progressive disease to determine outcome after salvage therapy and identify prognostic factors [20]. The 5-year freedom from second failure (FF2F) and OS for all patients was 17 and 26%, respectively. As reported from transplant centers, the 5-year FF2F and OS for patients treated with high-dose CT was 42 and 48%, respectively, but only 33% of all patients received high-dose CT. A high proportion of those patients will rapidly succumb to progressive disease. Life-threatening severe toxicity upon salvage treatment occurred in 11% of patients. Insufficient stem-cell harvest, poor performance status and older age also contributed to ineligibility for high-dose CT. In a multivariate
114 analysis, Karnofsky performance score at progress (P
