Clinical evaluation of efficacy of chemoradiotherapy for Hodgkin's disease

Patients with stage III (A,B) Hodgkin's disease (366) received chemoradiotherapy consisting of 2-4 courses of combined modality treatment followed by total or subtotal irradiation of lymph nodes. Overall 10-year (84%) and 15-year (79%) and relapse-free 10-year (85%) and 15-year (82%) survival was reported in stage IIIA cases. Subtotal exposure proved relatively more effective in such patients without iliac and inguinal lymph node involvement. If, following combined modality therapy, intoxication symptoms were aborted in stage IIIB patients; fairly good results were obtained after total and subtotal irradiation of lymph nodes or involved areas (10-year (70%) and 15-year (65%) overall and 10-year (75%) and 15-year (75%) relapse-free survival.     

Prognostic factors in Hodgkin's disease

Hodgkin's disease (HD) is a curable tumoral disease. However, there are groups of patients who suffer relapse and the identification of prognostic factors and the adaptation of treatments to individual risk is one the lines of investigation in this disease. A study was performed on 526 patients diagnosed of HD in our hospital between January 1967 and September 2001. An analysis was made of the most important variables in terms of both disease-free and overall survival. Overall survival in this series of patients was 94% at 2 years, 86% at 5 years, 76% at 10 years and 72% at 15 years. Median survival was 249 months. Factors influencing poor prognosis in the overall survival were: male gender (P < 0.0001), lymphocyte depletion (P < 0.0001), stages III and IV (P < 0.0001), B symptoms (P < 0.0001), spleen involvement at diagnosis (P = 0.003), no complete remission after first line treatment (P < 0.0001), and more than 30 years-of-age (P < 0.0001). Disease free survival was 83% at 2 years and 68% at 5 years although without reaching the mean follow-up. The disease free survival study revealed the following risk factors: male gender (P = 0.02), lymphocyte depletion (P < 0.0001), stages III and IV (P < 0.001), B symptoms (P < 0.001), extranodal or splenic involvement (P < 0.05), and no complete remission after first line treatment (P < 0.0001). The result of treatment optimization is that some factors that were considered to indicate a poor prognosis have disappeared, and that others which are useful have appeared and allow us to establish groups with differing risks of relapse and who could be candidates for differentiated treatments.     

Prognostic factors in Hodgkin's disease.

The clinical records and treatment results of 163 patients with Hodgkin's disease, who were seen at Ellis Fischel State Cancer Hospital (EFSCH) between 1940 and 1971, were reviewed and analyzed. More than 200 clinical and histological variables were recorded for each case of Hodgkin's disease, including details of radiotherapy and chemotherapy. Statistical studies were carried out in order to evaluate the independent prognosis significance of each of these factors. All of the lesions were reclassified according to the Lukes proposal which was modified and recommended at the 1965 Rye classification (except for hepatomegaly which was included in Stage IV). This is a retrospective study, and the modern techniques of staging were rarely used in pretreatment studies (since 1965, only ten patients have had an abdominal exploration). The basic work-up consisted of a complete blood count, urinalysis, blood type, chest X ray, and EKG. Lymphangiogram and radioisotope liver scans were used on less than 10% of the patients. About 30% of the patients had gastrointestinal X rays and 70% had IVP. Bone marrow biopsies -- the majority of which were done by needle aspiration -- were obtained for approximatley 50% of the patients. Clinical stage, histological type, and presence of absence of systemic symptoms appeared to be themost significant prognostic factors. The classification of systemic symptoms according to the criteria of either the Rye or Ann Arbor conferences showed no particular difference in determining the survival rate. Among the systemic symptoms, fever appeared to be the most important for survival rate. Survival rates were higher in nonanemic and nonlymphocytopenic patients. Eosinophilia, blood group, and Rh factor had no prognostic significance. The relapse-free interval was an important indicator of long-term prognosis. The unfavorable influence of relapse in ultimate prognosis was clearly seen; however, the extent of the relapse site was shown to have no significant influence on survival.     

Risk factors for bone marrow involvement in Hodgkin's disease

The significant factors of risk for bone marrow involvement in Hodgkin's disease included age over 40 yrs, such unfavorable histological features as lymphoid exhaustion and nodular sclerosing stage II, symptoms of intoxication, an ESR of more than 50 mm/h, increased fibrinogen (> 5.0 g/l), blood-plasma alkaline phosphatase (> 130 units), leukocyte concentration (> 10,000 per min) and decreased hemoglobulin (< 100 g/l). Despite the reliable correlation between bone marrow involvement and said factors, relevant data did not provide a similarly reliable basis for accurate prognosis of tumor dissemination. However, our findings pointed to two categories of Hodgkin's disease patients characterized by minimal risk of tumor dissemination--patients under 20, with stage I-II AB and IIIA tumors,--and patients with similar tumors and such favorable histological patterns of major pathology as high lymphocytic ratio and nodular sclerosing stage I.     

Comparative evaluation of the efficacy of chemotherapy and chemoradiotherapy of stage IIIB Hodgkin's disease

The results of treatment of 92 cases of stage IIIB Hodgkin's disease were evaluated. Combined treatment (46) included 3-4 courses of MOPP (embichin, vincristine, natulan and prednisolone) followed by radical radiotherapy 2-4 weeks later. Complete remission was recorded in 36 (78.3%) out of 46 patients. Overall 5-year survival in that group was 75.3 +/- 7.8% matched by 95.8 +/- 4.2% in those in complete remission (36). No signs of recurrence were observed in 68.0 +/- 11.1% in the latter group during the 5 years of follow-up. Combination chemotherapy (MOPP) alone was given to 46 patients. Complete remission was registered in 43.5% of those patients which was significantly less frequent than in the combined therapy group (78.3%). Overall 5-year survival was 53.8 +/- 8.6% and recurrence-free course--in 58.1 +/- 11.7%. Overall survival and complete remission rate in the combined treatment group were shown to be significantly higher than in the patients who had received 5-6 courses of MOPP alone.     

Prognostic factors in patients with subdiaphragmatic Hodgkin's disease

Between April 1969 and December 1980, 329 patients with pathologically staged IA-IIB Hodgkin's disease were treated at the Joint Center for Radiation Therapy. Twenty-five (7.6 per cent) of these patients presented with inguinal-femoral or superficial iliac adenopathy and had disease limited to below the diaphragm. In addition 11 patients presented with intra-abdominal masses and Hodgkin's disease was diagnosed on laparotomy. The median age, histologic subtypes, and actuarial relapse free and overall survival of patients with peripheral adenopathy limited to below the diaphragm were similar to patients with supradiaphragmatic Hodgkin's disease. Patients with disease limited to the pelvic or inguinal-femoral nodes were treated with pelvic and para-aortic irradiation alone. Staging laparotomy identified those patients with para-aortic or splenic involvement and these patients were treated with total nodal irradiation or combined modality treatment. The small group of patients who presented with intra-abdominal disease without peripheral adenopathy was older, had a predominance of lymphocyte depleted histology, and had a worse prognosis than the other patients described.     

Prognostic factors in decision-making in the clinical management of Hodgkin's disease

At the beginning of this conference, Dr Ford asked whether or not Hodgkin's disease was a malignancy. Most physicians would agree that, regardless of whether this question can be answered on a molecular level, Hodgkin's disease certainly behaves like a malignancy, and clinically fits criteria necessary to call it one. It grows without control locally, comprising vital organs. It 'metastasizes', infiltrates organs, and causes organ dysfunction. Patients afflicted with the disease have a shortened life span without proper therapy, as demonstrated by DeVita in his original publication describing the benefits of MOPP chemotherapy (nitrogen mustard, vincristine, procarbazine, prednisone) (DeVita et al., 1970). However, it can progress very slowly, with 50 per cent of untreated patients with stage III or IV disease dead at one year, but 10 to 15 per cent alive at five years. Therefore, in its clinical behaviour, Hodgkin's disease certainly qualifies as a malignant disorder, despite the fact that we do not have the molecular means of calling it one.     

Prognostic factors for positive surgical staging in patients with Hodgkin's disease

Staging laparotomy was performed as part of the routine recommended diagnostic evaluation following clinical staging (CS) in 692 patients presenting with supradiaphragmatic Hodgkin's disease (HD). Various clinical factors were analyzed by multivariate analysis for prediction of abdominal involvement. Factors that were statistically significant for predicting disease below the diaphragm included CS III-IV disease (P less than .001), B symptoms (P less than .001), mixed cellularity (MC) or lymphocytic depletion (LD) histology (P = .017), number of supradiaphragmatic sites greater than or equal to 2 (P = .001), male sex (P = 0.034) and age greater than or equal to 40 years (P = .004). Separate analyses were performed for various subgroups of CS IA-IIA, CS IB-IIB, CS IIIA-IVA, and CS IIIB-IVB patients. Upstaging was seen in 0% to 55% of CS I-II patients based on subgroup. Male sex, B symptoms, and number of sites above the diaphragm greater than or equal to 2 all independently predicted for positive surgical staging in CS I-II patients. Sixty-four percent of CS I-II patients who were upstaged had extensive abdominal disease by positive lower abdominal nodes or multiple splenic nodules (greater than or equal to 5). Downstaging (to pathological stage [PS] I-II) was seen in 9% to 68% of patients with CS III-IV disease based on subgrouping. Age greater than or equal to 40, MC or LD histology, and B symptoms all independently predicted for positive surgical staging in CS III-IV patients. Downstaging was more frequently seen in CS IIIA-IVA patients (55%) than in patients who were CS III-IVB (22%). Four subgroups of patients who had a low probability (less than 10%) of stage or treatment change following laparotomy were identified. These included CS IA female patients, CS IA male patients with lymphocyte predominance histology or high neck presentations, and patients with CS IIIB-IVB disease and account for 21% of the study population. Staging laparotomy altered the stage and treatment of a significant number of the remaining 79% patients and should continue to be recommended for this group of patients.     

Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkin's disease

Prognostic factors were analyzed retrospectively in 109 patients who relapsed after treatment with radiation only for Hodgkin's disease. Factors analyzed included initial stage, age, time to first relapse, histology, sex, extent of initial irradiation, sites of relapse, relapse stage (RS), average relative dose intensity (ARDI) of chemotherapy, and type of salvage therapy. Ninety-three percent of the patients received either standard or modified mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). With a median follow-up of 8.3 years, the actuarial survival and freedom from second relapse (FF2ndR) was 57% at 10 years. The extent of disease at the time of relapse, or so-called RS was found to be the single most important prognostic factor. Nearly 90% of patients with RS IA or IEA (favorable group) were disease free, and nearly 60% of patients with RS IIA, IIEA, or IIIA (intermediate group) were disease free compared with only 34% of patients with B symptoms or stage IV disease (unfavorable group). In a subset analysis, the use of combined modality therapy (CMT) was associated with an improved FF2ndR and survival in patients from the intermediate and unfavorable relapse groups. Age greater than 50 years was associated with an increased risk of second relapse and a lower survival. The other factors analyzed appeared to be of no independent prognostic value.     

An analysis of prognostic factors in early stage Hodgkin's disease

An analysis of prognostic factors has been carried out in 398 patients presenting with clinical Stage I and II Hodgkin's disease treated between 1963 and 1979. By life table analysis older age, lymphocyte depletion histology, systemic symptoms, mediastinal node bulk, and erythrocyte sedimentation rate (ESR) greater than 40 mm/h were associated with a significantly worse survival probability. On multiple factor regression analysis only age and stage were independent prognostic variables for survival, with systemic symptoms having borderline significance. Using this information, together with other analyses of prognosis in early Hodgkin's disease three groups of patients are defined. The first with a predicted 5-year survival of 78% would include patients possessing at least one of the following features; age greater than 60, lymphocyte depletion, greater than 3 sites involved, systemic symptoms, mediastinal/thoracic ratio of greater than 1/3. The second groups present with at least two of the following factors; ESR greater than 40 mm/h, male sex, 3 involved sites, or mixed cellularity histology, and the 5 year survival probability is 84%. The remaining Stage I and II patients would constitute a good prognosis group with a predicted 5-year survival of 92%.     

New prognostic factors in the treatment of patients with stage-III Hodgkin's disease

Our data are presented on evaluation of chemoradiotherapy of 365 patients with stage III Hodgkin's disease. Patients with stage IIIA tumors revealed the following significant differences of overall and relapse-free survival (p < or = 0.00001): 15-year overall survival (nodular sclerosis G1) - 95% vs.G2 - 45%; 15-year relapse-free survival: G1 - 86%, G2 - 32%. In stage IIIB group, overall survival (50%) was significantly lower as compared with 70%. Involvement foci significantly regressed by less than 75% (p = 0.044) after 2-4 cycles of preliminary combination chemotherapy. Our results suggest that differentiated criteria be used for prognosis of stage III Hodgkin's disease treatment.     

Costs and effectiveness of staging and treatment options in early-stage Hodgkin's disease.

PURPOSE: Using a cost-effectiveness analysis, to weigh the costs and benefits of the different staging and treatment options in early-stage Hodgkin's disease. METHODS: We constructed a decision-analytic model for a hypothetical cohort of 25-year-old patients with early-stage Hodgkin's disease. Markov models were used to simulate the lifetime costs and prognosis of each staging and treatment strategy. Baseline probabilities and cost estimates were derived from published studies and bills of relevant patient cohorts. RESULTS: Among the six management strategies considered, the incremental cost-effectiveness ratio of laparotomy and tailored treatment compared with mantle and para-aortic-splenic radiation therapy in all clinical stage I-II patients was $24,100/quality-adjusted life year, while that of the strategy of combined modality therapy in all clinical stage I-II patients compared with laparotomy was $61,700/quality-adjusted life year. All the remaining strategies were dominated by one of these three strategies. Sensitivity analysis showed that the cost-effectiveness ratios were driven predominantly by the effectiveness rather than the cost of each strategy. In particular, the analysis was heavily influenced by the utility of the post-laparotomy health state. CONCLUSIONS: In considering the various alternative management strategies in early-stage Hodgkin's disease, even very small gains in effectiveness were enough to justify the additional costs of more expensive treatment options.     

Risk factors for nodular sclerosis and other types of Hodgkin's disease.

The age-adjusted incidence rates of nodular sclerosis in Los Angeles County from 1972 to 1975 were 58% lower in Mexican-Americans and 42% lower in blacks than in other whites. They were the same for each sex among other whites and the curve of age-specific incidence peaked in young adulthood. The incidence of nodular sclerosis was directly associated with social class. In contrast, the rates for other histological varieties of Hodgkin's disease (lymphocyte predominance, mixed cellularity, lymphocyte depletion) were only 12% lower in Mexican-Americans but 34% lower in blacks. In other whites, the rates were 92% higher in men and increased gradually with age while there were no clear trends with social class. These characteristics support the hypothesis that, at least for purposes of etiology, the nodular sclerosis form of this disease should be considered a distinct entity. Self-administered questionnaire were completed by 218 of the 1972 to 1973 Hodgkin's disease patients and 218 individually matched neighbourhood controls. Significantly high risk ratios for Hodgkin's disease were found for prior appendectomy (risk ratios = 1.9, p = 0.01) and for past amphetamine use (risk ratios = 3.0, p = 0.01). The elevated risk associated with amphetamine use had been found in a previous study.     

A multivariate analysis of prognostic factors in early stage Hodgkin's disease

A multivariate analysis of the prognostic factors was carried out with a Cox model on 1,139 patients with clinical Stage I + II Hodgkin's disease included in three controlled clinical trials. The following indicators had been prospectively registered: age, sex, systemic symptoms, erythrocyte sedimentation rate (ESR), number and sites of involved lymph node areas, histologic type, clinical stage, pattern of presentation, results of staging laparotomy when performed, as well as the date and type of treatment. A linear logistic analysis showed that most of the indicators are interrelated. This emphasizes the necessity of a multivariate analysis in order to assess the independent influence of each of them. The two main prognostic indicators for relapse-free survival are systemic symptoms and/or ESR and number of involved areas. The only significant factor for survival after relapse is age. Sex has a small but significant influence on relapse-free survival. The relative influence of each indicator varies with the type of treatment and these variations may help in understanding the biologic significance of the indicators.     

Radiotherapy for Hodgkin's disease in pregnancy

Hodgkin's disease diagnosed during pregnancy poses a dilemma as there are risks of abortion and fetal malformation with the use of radiotherapy and chemotherapy. A patient with Hodgkin's disease during pregnancy treated with radiotherapy is presented.     

Prognostic factors for children with Hodgkin's disease treated with combined-modality therapy.

PURPOSE: Evaluation of pretreatment factors to identify children at high risk for relapse after combined-modality therapy for Hodgkin's disease. PATIENTS AND METHODS: From 1990 to 2000, 328 pediatric patients with clinical stage I to IV Hodgkin's disease were treated with chemotherapy and low-dose involved-field radiotherapy on prospective, collaborative, risk-adapted protocols at three institutions. Pretreatment factors were analyzed by univariate and multivariate analysis for prognostic significance for 5-year disease-free survival (DFS) and overall survival (OS). RESULTS: With a median follow-up of 59 months (range, 8 to 125 months), the 5-year DFS and OS for all patients were 83% and 93%, respectively. Several factors were associated with inferior DFS and OS by univariate analysis. By multivariate analysis, male sex; stage IIB, IIIB, or IV disease; bulky mediastinal disease; WBC more than 13.5 x 10(3)/mm3; and hemoglobin less than 11.0 g/dL were significant for inferior DFS. A prognostic index was developed incorporating the five significant factors from the multivariate analysis, assigning each a score of 1. The 5-year DFS and OS for children with a prognostic score of 0 to 1 were 94% and 99%; score 2, 85% and 96%; score 3, 71% and 92%; and score 4 or 5, 49% and 72%, respectively. There was a significant difference in DFS among each of these groups, with significantly worse OS in those with a score of 4 to 5. CONCLUSION: A prognostic index that was based on five pretreatment factors correlated with inferior DFS by multivariate analysis stratified patients by outcome; this may be useful in assigning children with Hodgkin's disease to risk-adapted therapy.