Treatment of unfavorable prognosis stage I-II Hodgkin's disease INTRODUCTION — Once the diagnosis of Hodgkin's disease has been established, subsequent therapy and prognosis are based upon the stage of the disease, as currently defined by the Cotswolds classification. Among patients with stage I-II disease, there is subsequent stratification into favorable and unfavorable prognosis disease based upon the presence or absence of certain clinical features, such as age, number of regions involved, B symptoms, and large mediastinal adenopathy. The clinical use of these features can be illustrated by the European Organization for the Research and Treatment of Cancer (EORTC). Patients with any one of the following adverse factors are considered to have unfavorable prognosis clinical stage (CS) I-II disease: large mediastinal adenopathy; involvement of four or more lymph node regions; age over 50 at diagnosis; or a defined combination of B symptoms and elevated erythrocyte sedimentation rate (ESR)
TREATMENT REGIMENS — There are no randomized studies indicating improved survival with combined modality therapy compared to irradiation alone. However, when one considers the improved freedom-from relapse and expected lower rate of long-term toxicity, combined modality therapy has become the treatment of choice for most of these patients. Data from a number of studies indicate that radiation fields can be safely limited to involved regions (variably defined) in most combined modality programs and that the radiation dose can be reduced to 30 to 36 Gy. The evolution of clinical trials to identify the best chemotherapy combination for unfavorable prognosis, early stage Hodgkin's disease has paralleled studies to identify the best chemotherapy in advanced Hodgkin's disease. Early studies compared MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) to MOPP-like combinations, later trials compared MOPP or MOPP-like combinations to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in an attempt to both enhance efficacy and reduce toxicity by limiting exposure to alkylating agents, and the most recent trials compared ABVD to novel intense chemotherapy combinations. RT alone versus combined modality therapy — The issue of radiation therapy alone versus combined modality approaches in patients with unfavorable prognosis early stage Hodgkin's disease was primarily addressed in trials performed between 1968 and 1982. In addition, some more recent studies that included patients with both favorable and unfavorable disease can be analyzed with respect to the outcome of patients with unfavorable prognostic factors. Combined modality therapy has usually been associated with an improvement in relapse-free survival but not overall survival The EORTC was one of the first to stratify
patients with clinical stage (CS) I-II disease into favorable and unfavorable groups based
upon initial disease characteristics [3].
Patients were entered into the H5U (unfavorable) trial if they had any of four
characteristics: age 40 years or older, ESR Virtually identical findings were noted in another trial in which 115 patients with supradiaphragmatic, laparotomy (pathological) staged (PS) IA-IIB Hodgkin's disease were randomly assigned to receive treatment with mantle radiotherapy alone or followed by adjuvant treatment with nitrogen mustard, vinblastine, prednisolone, and procarbazine (MVPP). Combined modality therapy was associated with no difference in overall survival at ten years (95 versus 90 percent with radiation alone) but a significant advantage in relapse-free survival (91 versus 67 percent). In a third study, total lymphoid irradiation was given either alone or with MOPP to patients with PS I-II disease and B symptoms . There was no advantage to the combined modality approach in terms of either overall or relapse-free survival. Chemotherapy alone versus combined modality therapy — One prospective trial has compared chemotherapy alone versus combined modality therapy in unfavorable prognosis stage I-II . In this study, 104 patients with CS I-II Hodgkin's disease with unfavorable features (older age, more than two sites of involvement, or bulky disease) were randomly assigned to treatment with six cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (CVPP) alone or six cycles of CVPP sandwiched around involved field irradiation (30 Gy). Patients treated with combined modality therapy had a higher rate of disease-free survival (75 percent versus 34 percent for CVPP alone, p<0.001) and a trend toward a higher rate of overall survival (84 versus 66 percent). Choice of chemotherapy regimen — Studies that have evaluated different chemotherapeutic regimens in unfavorable prognosis stage I-II disease generally have not identified important differences in overall survival. Nevertheless, ABVD is usually considered the treatment of choice because of superior outcomes in trials of patients with advanced Hodgkin's disease and reduced late toxicity ABVD
versus MOPP and MOPP-like regimens — In an EORTC trial, H6U, patients were
entered into the unfavorable group with any of the following characteristics: an ESR
>50 mm/h; an ESR >30 mm/h in the presence of B symptoms; a mediastinal mass
exceeding 0.35 of the intrathoracic diameter at T5-6 (ie, MTR The degree of benefit has been less in other trials . The Stanford C2-3 studies, for example, included patients with large mediastinal masses or multiple E-lesions treated with split course chemotherapy (either ABVD or a MOPP-like regimen) and mantle radiation. At fifteen years, ABVD was associated with a trend toward improvement in both overall survival and the rate of freedom from relapse. The failure of ABVD-containing regimens to show a convincing survival advantage over MOPP or MOPP-like combinations in these studies is in contrast to the results observed in trials of chemotherapy alone for patients with advanced Hodgkin's disease. As an example, a Cancer and Leukemia Group B trial of patients with advanced Hodgkin's disease or relapse after initial radiotherapy found significant advantage for ABVD compared to MOPP, both of which were given for six to eight cycles: a higher rate of initial complete response (82 versus 67 percent, p = 0.006); less hematologic toxicity; and a better outcome after relapse [14]. Patients with recurrent disease after ABVD subsequently received MOPP and 61 percent achieved a second remission; in comparison, only 35 percent of those who suffered relapse after MOPP responded to ABVD. Two factors may explain the inability to demonstrate these advantages in patients with unfavorable prognosis stage I-II disease: patients with stage I-II disease are also treated with irradiation, which may obscure differences seen with chemotherapy alone; and the number of patients in these trials may have been inadequate to demonstrate a true difference. Alternative regimens — The German Hodgkin's Lymphoma Study Group Trial HD5 randomly assigned patients with stage I or II disease and at least one adverse risk factor to receive either two cycles of COPP/ABVD or COPP/ABV/IMEP (IMEP: ifosfamide, methotrexate, etoposide, prednisone), followed by extended field radiation therapy . There were no significant differences between the two treatment arms in rates of complete remission, freedom from treatment failure, overall survival at seven years, serious infections, toxic deaths, or second malignancies. Several nonrandomized trials also have evaluated other chemotherapy regimens. These include brief chemotherapy (two cycles of CVPP) followed by extended field irradiation; three cycles of novantrone, vincristine, vinblastine, and prednisone (NOVP) combined with involved field irradiation ; and the Stanford V regimen (nitrogen mustard, doxorubicin, vincristine, vinblastine, etoposide, bleomycin, and prednisone) given for three months, followed by involved field radiation therapy These regimens all appear to be effective but no comparative studies with ABVD or MOPP have been published. Currently, Stanford V is being compared to ABVD in the Intergroup 2496 trial. This study includes patients with stage II disease and large mediastinal adenopathy as well as those with stage III-IV disease. Less toxic regimens — Less toxic chemotherapy regimens that have been effective in combined modality programs for favorable prognosis stage I-II Hodgkin's disease do not appear to be effective in unfavorable prognosis or bulky disease Optimal number of chemotherapy cycles — Several randomized trials have addressed the issue of the number of cycles of chemotherapy necessary in combined modality programs for unfavorable prognosis stage I-II disease. In one study, conducted between 1972 and 1975, patients with stage I-II disease who had B symptoms, more than two sites of disease, or extranodal involvement were assigned to either staging laparotomy followed by three cycles of MOPP plus mantle irradiation or to six cycles of MOPP followed by staging laparotomy plus mantle irradiation . Patients with large mediastinal masses were not specifically included in this trial. Among the 46 patients with B symptoms, overall survival at four years was 100 percent and the disease-free survival among complete responders was 93 and 96 percent after three or six cycles of chemotherapy. A three-arm EORTC H8U trial compared the hybrid MOPP/ABV regimen for four versus six cycles and the radiation field size for involved versus extended fields. At four years of follow-up with 995 patients analyzed, there were no differences in failure-free or overall survival. An ongoing EORTC trial, H9U, has randomly assigned patients to receive either four or six cycles of ABVD Other, nonrandomized studies have used less than four cycles of chemotherapy in patients with large mediastinal masses and in patients with other unfavorable factors. Among patients with large mediastinal masses, the chemotherapy regimens included two cycles of MOPP and three cycles of ABVD or another ABVD regimen in which vindesine was substituted for vinblastine . The three cycle classic ABVD regimen has been associated with ten year overall survival and freedom from relapse or progression rates of 70 to 78 percent and 63 to 74 percent, respectively. These values are lower than those described in the EORTC H6U trial that used the full six cycle regimen. Alternatively, among patients with unfavorable prognostic factors other than bulky disease, several small retrospective studies have suggested that reduced cycles of therapy can produce excellent outcomes In summary, these data suggest that patients with unfavorable disease by virtue of age, histology, number of sites of disease, or B symptoms perhaps can be treated adequately in combined modality programs with as few as three months of conventional chemotherapy. However, the randomized EORTC H8U trial using four cycles of chemotherapy provides the most complete evidence to date. For patients with large mediastinal masses, at least four months of chemotherapy appears to be required. Optimal timing of chemotherapy — There have been no randomized trials evaluating the optimal timing of chemotherapy and irradiation. In initial studies, many patients were treated with radiation therapy followed by adjuvant chemotherapy. In later studies, the advantages of initial treatment with chemotherapy became apparent. These included the opportunity to treat all involved and occult sites of disease at the outset, and the ability to use more restricted (and less toxic) radiation fields by taking advantage of tumor shrinkage secondary to chemotherapy. Some studies, which incorporated six months of conventional chemotherapy, used a "split course" or "sandwich" approach, with an initial three months of chemotherapy, followed by irradiation, and then completion of the chemotherapy Use of a split course approach meant that the delay from the start of treatment to the initiation of irradiation was never longer than three months. However, issues related to dose intensity of chemotherapy have been raised because there may be a need for reduced chemotherapy doses after irradiation is given. As a result, the majority of clinical trials now include the entire course of chemotherapy before the start of irradiation. This is particularly true for regimens with only three to four monthly cycles of chemotherapy. Radiation therapy volume — Several randomized trials have addressed the question of radiation therapy volumes in combined modality programs. One study, for example, treated 209 patients with stage I-II Hodgkin's disease and a variety of unfavorable factors with six cycles of MOPP sandwiched around either involved field (40 Gy) or extended field (40 Gy) irradiation. The six-year disease-free survival rates were not different in the two groups (87 versus 93 percent). Similar findings were noted in another trial in which 133 patients, 20 percent of whom had bulky disease, were treated with four months of chemotherapy (ABVD), followed by involved field (36 Gy) or subtotal nodal irradiation (STNI) (30 to 36 Gy) The five-year freedom from progression rate (93 versus 96 percent with STNI) and overall survival (96 versus 100 percent) were similar in the two groups. This observation has also been confirmed by the German Hodgkin's Lymphoma Study Group in its HD8 trial that randomly assigned 1,204 patients to receive involved or extended field irradiation after four cycles of COPP/ABVD. At a median observation period of 4.5 years, there was no difference in freedom from treatment failure or overall survival between the two treatment groups. Acute side effects (eg, leukopenia, thrombocytopenia, nausea, gastrointestinal and pharyngeal toxicity) were more frequent in those treated with extended field irradiation. The evidence from these randomized trials plus similar observations in nonrandomized studies suggest that radiation fields can be safely limited to involved regions (variably defined) in most combined modality programs. Radiation therapy dose — The initial studies of combined modality therapy generally used radiation doses that were similar to those used for radiation treatment alone (36 to 44 Gy). A later report combined patients with unfavorable disease from two studies of the German Hodgkin Study Group (GHSG), HD1 and HD5. Treatment consisted of two double cycles of COPP/ABVD and extended field irradiation using three different doses: 20, 30, and 40 Gy. Bulky sites (>5 cm in any axis) were always irradiated to 40 Gy. The four year survivals were not different in the three groups (93, 94, and 88 percent, respectively). The newest trial of the GHSG (HD11), which is a four arm randomization, evaluates involved field doses of 30 versus 20 Gy following four cycles of either ABVD or 4 BEACOPP. Bulky sites will not be boosted to 40 Gy. It will be particularly important to evaluate the outcome of this trial according to the presence of bulky disease. SUMMARY AND RECOMMENDATIONS — The outcome for patients with unfavorable prognosis stage I-II disease has improved dramatically in the past three decades with the use of combined modality therapy. This approach permits the elimination of staging laparotomy, and may allow reductions in the duration of chemotherapy and in radiation field doses, especially to minimally involved regions. In addition, although overall survival is not enhanced, combined modality therapy is associated with significantly higher freedom from relapse at 10 years than radiotherapy alone (approximately 90 versus 65 percent) The randomized trials and nonrandomized retrospective studies mentioned above have led to the following general principles in the therapy of unfavorable prognosis stage I-II Hodgkin's disease:
Patients considered to have unfavorable disease without large mediastinal adenopathy may be treated adequately with as few as three or four months of conventional chemotherapy, but four months is the general minimum for patients with bulky disease. Current combined modality management protocols for favorable prognosis disease may be adequate for these patients.
The use of more restricted fields may be especially beneficial in the young woman who does not have initial axillary adenopathy. The elimination of axillary irradiation in this setting may markedly reduce the risk for developing subsequent breast cancer. |
70 mm/h; mixed cellularity or lymphocyte
depletion histology; and CS II without mediastinal involvement. Two hundred and ninety-six
patients were randomized to treatment with nodal irradiation alone or combined modality
therapy with split-course MOPP and mantle irradiation given between the third and fourth
cycles of chemotherapy. At 15 years, the overall survival rate was 69 percent in both arms
but relapse-free survival was higher with combined modality therapy versus radiation
therapy alone (84 versus 65 percent).
0.01)
and produced significantly less hematologic and late gonadal toxicity, but more pulmonary
toxicity.