Treatment of favorable 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, 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 clinically staged (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)

• A favorable prognostic group was defined in the H7 and H8 trials as age 50 or under; without large mediastinal adenopathy; an ESR of less than 50/h and no B symptoms or an ESR of less than 30 mm/h with B symptoms; and disease limited to one to three regions of involvement.

• An unfavorable prognostic group was defined in the H7 and H8 trials as those having any one of the following features: large mediastinal adenopathy; four or more sites of involvement; B symptoms and an ESR over 30 mm/hour; an ESR over 50 mm/hour without B symptoms; or age over 50.

The treatment of favorable prognosis stage I-II Hodgkin's disease will be reviewed here.

RANDOMIZED TRIALS — Significant advances in the treatment of early stage Hodgkin's disease have been derived from information obtained from clinical trials. These trials were first organized in the 1960s at Stanford and the EORTC; later meta-analyses of randomized trials evaluated the influence of radiation field size and the impact of adjuvant chemotherapy. Early Hodgkin's disease in these trials was defined as patients with clinically or laparotomy staged I-II disease, although some studies included patients with stage III disease. Patients with unfavorable prognostic signs (B symptoms and extensive thoracic disease) were also included.

The randomized trials have consisted of two groups: those that compared more extensive radiation therapy to less extensive radiation therapy; and those that compared multiagent chemotherapy and radiation therapy to radiation therapy alone . Trials evaluating more specific issues such as radiation dose and field size, the optimal chemotherapy regimen when given with radiation therapy, and the efficacy of chemotherapy alone compared to radiation alone or combined therapy are discussed separately.

What follows are data from the meta-analysis, rather than an evaluation of each of the individual studies. There are a number of potential criticisms of the meta-analysis format. The quality of the data, including the details of cause of death and the length of follow-up, vary from center to center, definitions (eg, the size of radiation therapy fields), and the extent of staging were not always consistent between studies.

Despite these concerns, the analysis is a powerful and important tool in addressing the general question of how the extent of treatment affects the disease-free and overall survival of patients. The meta-analysis revealed one consistent observation: more extensive treatment resulted in fewer recurrences, but did not affect long-term survival in stage I-II Hodgkin's disease.

More versus less extensive RT — Eight trials in the meta-analysis evaluated treatment with larger versus smaller radiation field sizes. Larger fields generally included subtotal nodal (mantle and upper abdomen) or total nodal irradiation; smaller fields included involved fields or in some cases a mantle field. Larger field irradiation was associated with a significant advantage in disease-free survival in approximately one-half of the trials. Analysis of all combined data revealed a 10-year recurrence rate of 31 versus 43 percent with less extensive radiation (p<0.00001). However, no survival differences were seen in any of the trials (10 year survival 77 percent in both groups with analysis of all combined data) These findings were seen in subgroup analyses by stage, by use of staging laparotomy, by age at diagnosis, and by gender.

The lack of a survival difference suggests that salvage chemotherapy for relapse after initial radiation therapy is sufficiently effective to minimize the impact of the increase in relapse on survival. It has been presumed that any rise in mortality from recurrent Hodgkin's disease in patients receiving smaller field irradiation is balanced by an enhanced mortality from treatment-related causes (eg, cardiac disease, second tumors) in patients receiving more extensive radiation therapy. Data from the meta-analysis supported this hypothesis as there was a slight increase in death from causes other than Hodgkin's disease in the more extensive radiation group.

Chemotherapy plus RT versus RT alone — Thirteen trials evaluated treatment with multiagent chemotherapy plus radiation therapy to radiation therapy (RT) alone for early stage Hodgkin's disease. Combined therapy was associated with a significant advantage in disease-free survival in approximately one-half of the trials. Analysis of all combined data revealed 10-year recurrence rates of 16 versus 33 percent for combined treatment versus RT alone, respectively; however, there were no differences in any of the trials in terms of overall survival (10-year survival 79 versus 77 percent in both groups with analysis of all combined data) or cause-specific survival (ie, only scoring deaths from Hodgkin's disease; 88 versus 85 percent at 10 years). The findings were similar in different subgroups (eg, stage IA and IIA).

There were two reasons for the lack of survival differences in these trials:

• Patients who relapsed after treatment with radiation therapy alone were frequently salvaged successfully with combination chemotherapy (with or without additional radiation).

• Patients who were treated initially with combined modality therapy had a greater likelihood of mortality from treatment-related causes compared to patients treated initially with radiation therapy alone.

Chemotherapy regimen — Most patients in the trials reviewed in the meta-analysis received alkylating agent chemotherapy, usually MOPP (mechlorethamine, vincristine, procarbazine, prednisone) or an equivalent. It is therefore possible that the above findings do not apply to current practice in which MOPP has been replaced by more effective treatment regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Early results suggest that ABVD plus involved field irradiation in stage I-II Hodgkin's disease may be more effective and less toxic than alkylating agent regimens and radiation therapy

Mortality — The treatment of early stage Hodgkin's disease has become so successful that at 15 to 20 years posttreatment, the overall mortality rate from causes other than Hodgkin's disease may exceed that seen from Hodgkin's disease. In one series of 794 patients, for example, 124 died at a mean follow-up of 11 years: 56 from Hodgkin's disease, 36 from second malignancies, 15 from cardiac disease, and eight from other causes. Deaths from Hodgkin's disease primarily occurred in the first five to ten years, with almost no Hodgkin's-related deaths after 15 years; in comparison, deaths from second malignancy primarily occurred after ten years and continued to increase with time. The estimated excess risk of mortality was approximately 1 percent per year over the first 20 years.

Second malignancy — The estimated risk of a second cancer is approximately 13 percent at fifteen years after treatment of Hodgkin's disease. The most common second malignancies are acute nonlymphoblastic leukemia (which primarily occurs in the first ten years and develops much more often after chemotherapy than radiation), non-Hodgkin's lymphoma, and solid tumors (which account for about 75 percent of second malignancies and occur after both chemotherapy and radiation)

Cardiac disease — A variety of complications related to cardiac irradiation (arrhythmias, myocardial infarction and coronary artery disease, pericarditis, myocarditis, pericardial effusion and tamponade, and cardiac death) have been carefully documented after radiation therapy to the mediastinum

In many of the initial studies, cardiac complications related to treatment techniques that resulted in a high radiation dose to the anterior mediastinum and heart. Current practice, which restricts the dose to the whole heart, blocks the subcarinal region part way into treatment, and limits exposure to cardiac toxins such as doxorubicin, has lowered this risk. A retrospective study of 2232 survivors of Hodgkin's disease treated at Stanford and followed for an average of 9.5 years found that 3.9 percent died from cardiac disease (myocardial infarction, heart failure, radiation pericarditis or pancarditis, cardiomyopathy, or valvular heart disease); the relative risk of death from heart disease was 3.1. This risk was increased only in those patients who received more than 30 Gy to the mediastinum. Blocking to limit cardiac exposure did not alter the risk of myocardial infarction, but did reduce the relative risk for other cardiac diseases from 5.3 to 1.4. The lack of protection against infarction may reflect exposure of the proximal portion of the coronary arteries to the full dose of radiation regardless of the amount of blocking used.

In a study from Stanford University to determine long-term cardiac effects, 294 asymptomatic patients treated with mediastinal irradiation for Hodgkin's disease underwent electrocardiography and echocardiography screening at a median time of 15 years following initial treatment. In this study, the prevalence of valvular abnormality increased significantly with increasing follow-up time. For patients who were more than 20 years post-RT, >60 percent had at least one pathologic valvular abnormality (eg, aortic stenosis or regurgitation, mitral regurgitation or stenosis). Less than 10 percent of these patients had an audible murmur on examination.

These results demonstrate the usefulness of screening echocardiogram in identifying patients with valvular disease who might benefit from endocarditis prophylaxis. The number needed to screen with echocardiography to identify a candidate for endocarditis prophylaxis decreased dramatically with time following irradiation: 13 for patients at 2 to 10 years, 4 for patients at 11 to 20 years, and 1.6 for those beyond 20 years following initial Hodgkin's disease therapy.

Recurrent disease — Most relapses of early stage Hodgkin's disease occur within the first two to three years. In one series of 1044 patients in remission after therapy for early stage Hodgkin's disease, 32.6 percent relapsed; only 3.5 percent of these relapses occurred after five years

Patients who relapse are more likely to be cured with combination chemotherapy if they were initially treated with radiation therapy alone as opposed to chemotherapy alone or combined radiation therapy and chemotherapy. The following observations are pertinent in this regard:

• The 10-year actuarial survival rate after relapse in patients who were initially treated with radiation therapy alone and then received multiagent chemotherapy for relapse is 57 to 62 percent. Most of the patients in these studies received MOPP for relapse; current treatment with ABVD is likely to yield a better 10-year survival given the enhanced efficacy of ABVD compared to MOPP in patients with advanced stage Hodgkin's disease or relapse after initial radiotherapy

• However, a later study reported a 10-year actuarial freedom from second recurrence rate of 70 percent with chemotherapy following initial relapse after radiation therapy alone . MOPP and ABVD were equally effective.

• Although most of the data are from patients with advanced Hodgkin's disease, the survival rates may also be significantly worse in patients with early stage disease who relapse after chemotherapy alone or combined with radiation therapy. Treatment with similar or alternative chemotherapy regimens after relapse from chemotherapy alone has been associated with complete response rates of 35 to 45 percent and 5-year to 10-year survival rates of only 20 to 32 percent, most of which occurred in complete responders

The difference between the type of initial therapy for early stage Hodgkin's disease and survival after relapse was illustrated by an Italian study in which 89 patients with PS IA-IIA disease were randomized to initial therapy with radiation alone or MOPP. Twelve relapses occurred in each group; induction of a second complete remission (92 versus 50 percent) and survival at 80 months from the time of relapse (85 versus 15 percent, p = 0.02) were both higher in the patients initially treated with radiation therapy.

In summary, current information suggests that, when chemotherapy is used as part of definitive treatment for early stage Hodgkin's disease, the regimen should be designed to minimize relapse. This can be best accomplished by the use of both chemotherapy and radiation therapy rather than chemotherapy alone. Because of the poor outcomes after relapse, the majority of patients who relapse after chemotherapy alone or when combined with radiation are now considered candidates for high dose chemotherapy and autologous bone marrow rescue.

RECOMMENDATIONS — Standard care currently provides a number of treatment options for patients with early stage, favorable prognosis Hodgkin's disease. The preferred option is the use of combination chemotherapy and radiation therapy, often with a modified number of cycles of chemotherapy and some modification of radiation field sizes and doses. Other options include the use of mantle irradiation alone for selected patients with negative laparotomy staging, mantle- paraaortic and splenic irradiation without laparotomy staging, and chemotherapy alone. The latter option is currently in clinical trials. All these options result in the same probability for long-term survival, but are associated with different recurrence rates and treatment related morbidity and mortality rates.

What follows is our general approach to the therapy of favorable prognosis stage I-II disease, which includes one of the following options. Although there are differences in relapse rates, there has been no demonstrable difference in overall survival.

• No laparotomy, ABVD for three to six cycles, followed by involved field irradiation with 30 Gy with an optional boost of 6 Gy to individual nodes of concern. This approach has the lowest relapse rate (10 to 15 percent) but requires a longer total treatment time than radiation alone.

• No laparotomy, mantle irradiation to 30 Gy with a total dose of 36 to 40 Gy to regions of initial involvement, followed by paraaortic and splenic irradiation to 30 Gy. This regimen has a relapse rate of 20 to 25 percent but is easier to salvage after first relapse than the above regimen. However, the risk of second malignancies is increased with these large radiation fields.

• Negative laparotomy followed by mantle irradiation to 30 Gy with a total dose of 36 to 40 Gy to regions of initial involvement. Selected patients may not require the laparotomy (see above). This regimen is particularly attractive for CS/PS I patients where the risk of recurrence is only 10 to 15 percent. With this regimen, it is easier to salvage after first relapse, and it should be associated with a lower risk of second malignancy than the second regimen.

• Full dose chemotherapy alone is under investigation in clinical trials. Limited data suggest that the risk of recurrence is higher than with combined chemotherapy and radiation therapy.

In an attempt to compare these approaches, a decision analysis was performed for a hypothetical cohort of 25-year-old patients with clinical stage I-II, favorable prognosis Hodgkin's disease using studies published in the modern era. Two general conclusions were reached. Among patients with pathologic stage I to II disease, mantle and paraaortic radiation therapy was preferred to mantle irradiation alone, chemotherapy alone, or combined modality therapy. Among patients with clinical stage I to II disease, it was not possible to distinguish between the two options noted above: mantle irradiation followed by paraaortic and splenic irradiation and combined modality therapy.

Despite the increasing availability of guidelines for the treatment of Hodgkin's disease, there must remain room for individualization of treatment. In particular, patient preference must be considered with different treatment options, some of which result in a higher recurrence risk at the gain of less toxic initial treatment (without any difference in long-term survival). Treatment should also be individualized when a particular approach might result in a higher risk of a serious late complication (eg, the use of large radiation fields and the risk of late breast cancer in young females and of lung cancer in smokers).

FUTURE DIRECTIONS — Death from favorable prognosis early stage Hodgkin's disease is unusual and mortality from causes other than Hodgkin's disease occurs many years later. Thus, survival is not a useful parameter to evaluate the results in early stage Hodgkin's disease. Efficacy must be judged by freedom from first recurrence rates, acute and chronic morbidity, and by new criteria such as quality of life and perhaps cost-effectiveness . However, even those regimens that provide the highest freedom from first recurrence may not be optimal, since, depending on the regimen used, treatment- related mortality at 10 to 20 years may exceed Hodgkin's disease mortality in patients with favorable early stage disease

Accordingly, current clinical trials are evaluating the use of alternative chemotherapy combinations, shortened courses of chemotherapy, chemotherapy with smaller radiation fields and/or lower radiation doses, and chemotherapy without radiation therapy.