Analysis of supradiaphragmatic clinical stage I and II Hodgkin's disease treated with radiation alone.

Patients with clinical Stage I and II Hodgkin's disease have been managed at the Princess Margaret Hospital for over 20 years, without the use of routine staging laparotomy. Our experience identified as adverse prognostic factors presence of a large mediastinal mass, B symptoms, and advanced age in presence of unfavorable histology (20). We had suggested previously that the use of extended field radiation therapy (XRT) was associated with a lower risk of relapse than involved field XRT or mantle XRT. There has been a trend over the past decade to select those patients with favorable prognostic factors for treatment with XRT alone and to use mantle plus upper abdominal XRT (extended field XRT) to treat them. A retrospective study of patients with clinical Stage I and II Hodgkin's disease treated at the Princess Margaret Hospital between 1978 and 1986 was conducted to determine the impact of patient selection and extended field radiation on outcome. The study involved 250 patients with supradiaphragmatic disease selected for treatment with radiation alone on the absence of adverse prognostic factors. Radiation techniques included involved field radiation in selected patients (those with upper neck involvement), mantle radiation in the earlier years, and mantle plus upper abdominal radiation in the later years of the study. Actuarial survival was 83.3% at 8 years; cause-specific survival was 90.1% and the relapse-free rate 71.6%. Local tumor control was 94.6%; only two patients had true infield failure. Multivariate analysis showed that significant prognostic factors included age, histology, and erythrocyte sedimentation rate. Extent of the radiation treatment volume was significant and influenced the risk of relapse, particularly out-of-field relapse, independently of other factors. A dose of 35 Gy was found to be sufficient for control of clinical disease. This study validated a previously developed model for the selection of clinically staged patients with Stage I and II Hodgkin's disease for treatment with radiation alone. Careful selection of these patients can yield excellent results without requiring that staging laparotomy be routinely performed or the use of systemic chemotherapy as the initial treatment.     

Wide-field radiation therapy alone or with chemotherapy for Hodgkin's disease in relapse from combination chemotherapy

Nineteen patients with Hodgkin's disease who relapsed primarily in nodal sites after intensive combination chemotherapy were retreated with wide-field radiation therapy alone or with additional chemotherapy between January 1971 and December 1984. Six patients presented in second relapse and 13 patients in first relapse. Seven patients were treated with combination chemotherapy and radiation therapy and twelve patients were treated with radiation therapy alone. Radiation therapy field sizes and doses were similar to those recommended for early-stage Hodgkin's disease patients treated with radiation therapy alone. The 5-year actuarial freedom from relapse (FFR) and survival following retreatment were 48% and 69%, respectively. Twelve patients are currently disease-free 12 to 172 months following retreatment. Wide-field radiation therapy alone or with additional chemotherapy should be considered for patients with advanced Hodgkin's disease who relapse in nodal sites after initial combination chemotherapy.     

Mantle irradiation alone for pathologic stage I and II Hodgkin's disease: long-term follow-up and patterns of failure.

PURPOSE: We performed a retrospective study to determine the long-term outcome, patterns of failure, and prognostic factors for patients with pathologic Stage I or II Hodgkin's disease (HD) who were treated with mantle irradiation alone. METHODS AND MATERIALS: The medical records of 145 patients with pathologic Stage I or II supradiaphragmatic Hodgkin's disease treated with mantle irradiation alone between June 1967 and June 1991 were reviewed. Patterns of failure, overall survival (OS) rate, and progression-free survival (PFS) rate were determined. Univariate and multivariate analyses were performed to identify adverse prognostic factors for OS and PFS. The number of adverse prognostic factors per patient was counted, and a prognostic score was assigned to each patient. The log-rank test was used to compare the OS or PFS rates among patients with prognostic scores 0, 1, and 2. RESULTS: The median patient age was 27 years (range 10-66), with almost even male to female distribution. Every patient had splenectomy and negative laparotomy (LAP). Fifty-one patients had Stage I disease (IA-49, IB-2) and 94 Stage II (IIA-89, IIB-5). The histologic subtypes were nodular sclerosing in 110, mixed cellularity in 28, lymphocyte predominance in 5, lymphocyte depleted in 1, and unclassified in 1. Twelve patients with Stage II disease had >/= 3 sites of nodal involvement. Fifty-four patients had a prognostic score of 0, 70 of 1, and 21 of 2. The median follow-up time for the 109 surviving patients was 146 months (range 25-381). The 10- and 20-year actuarial OS rates for the whole group were 87.6% and 65.3%, respectively. The corresponding actuarial PFS rates were 75.3% and 74.2%, respectively. Thirty-six patients (9 Stage I, 27 Stage II) had relapses in a total of 41 sites. Failures by histology were 29 patients with nodular sclerosing, 6 with mixed cellularity, and 1 with lymphocyte predominance. Failures by sites were: trans-diaphragmatic, 22 (para-aortic nodes, 15; as the only site of progression in 12; visceral, 7; as the only site of progression in 5); within radiation field, 8; marginal miss, 8 (as the only site of failure in 2); and unknown, 3. The majority of the failures occurred within 5 years of diagnosis. Long-term side effects of radiation included cardiac complications in 30 patients, with 10- and 20-year actuarial cardiac complication rates of 12.6% and 35.1%, respectively; secondary solid tumors in 14, with 10- and 20-year actuarial rates of 2.3% and 25.7%, respectively; leukemia in 4; non- Hodgkin's lymphoma in 4, with the 10- and 20-year actuarial rates for leukemia and non-Hodgkin's lymphoma of 4.0% and 13.9%; and hypothyroidism in 38. Four adverse prognostic factors were identified for PFS: age > or = 40 years, > or = 3 sites of involvement, male sex, and constitutional symptoms. The prognostic score correlated with patients' outcome as indicated by PFS and OS rates. Patients with a prognostic score of 0 did significantly better than those with a score of 1 or 2. CONCLUSION: In this select group of patients with pathologic Stage I and II Hodgkin's disease treated with mantle irradiation alone, the OS and PFS rates at 10 and 20 years were comparable to those reported in the literature. The major pattern of disease progression was relapse below the diaphragm, therefore close surveillance of the abdomen is warranted. The prognostic score used in our series may predict the patient's outcome, and might be worth testing in a prospective trial. In our series, patients with a prognostic score of 0 had excellent long-term survival, indicating adequate treatment with mantle irradiation alone. Late complications of the treatment pose a significant threat for the patient's survival with long-term follow-up.     

Management of stage I and II Hodgkin's disease

Early stage Hodgkin's disease is highly curable with radiation therapy alone. Some prognostic factors are associated with increased risk of relapse and may require combined modality treatment. The evolution of treatment of stage I and II Hodgkin's disease is presented.     

Pathologic stage I and II Hodgkin's disease, 1968--1975: relapse and results of retreatment.

Sixty-seven previously untreated patients with Hodgkin's disease, pathologic stages I and II, seen during a 7-year period were evaluted with respect to initial staging and treatment, as well as relapse and retreatment results. The initial treatment consisted of radiation therapy (RT) to an involved field (IF) or an extended field (EF) for patients with stages IA and IIA, or RT and, in recent cases, combination chemotherapy [cyclophosphamide, Oncovin, procarbazine, and prednisone (COPP)] for patients with stages IB and IIB. Nineteen of the 67 patients relapsed (28%), including 11 of 56 patients with stages IA and IIA (20%) and 8 of 11 patients with stages IB and IIB (73%). Seventeen of the 19 relapses occurred within 24 months after completion of the initial therapy (89%). The relapse-free survival at 5 years was 75% for the A patients and 25% for the B patients. The actuarial survival of stage IA and stage IIA patients at 5 years was 91%; there was no significant difference between patients treated initially with either IF or EF. The actuarial survival at 5 years for the patients with stages IB and IIB was 88%, as most responded to a second program of induction therapy. No correlation could be found between the pattern of relapse and the initial pathologic stage or the mode of treatment.     

The management of stage I-II supradiaphragmatic Hodgkin's disease with chemotherapy alone

The treatment of choice for patients with early stage Hodgkin's disease (HD) has been extended field or subtotal nodal irradiation. Remission rates of over 95% have been obtained, however, about 5% of stage I and II patients will suffer from progressive disease while on therapy and an additional 15-20% will relapse. Chemotherapy (Ch) alone has not been adequately tested in early-stage HD. In this study, all HD stage I and II patients treated with Ch alone in the University Hospital "Clínica Puerta de Hierro" between 1980 and 1997 were reviewed. Thirty-five patients were treated between 04/80 and 12/97. All patients achieved complete remission. The median follow-up was 119 months (range 21-240 months), no patients were lost at follow-up. Overall survival (OS) was 97% (IC 95%, 92-100) at 5 years and 88% (IC 95%, 75-100) at 10 years. Failure free survival (FFS) was 93% (IC 95%, 83-100) at 5 years and 66% (IC 95%, 47-86) at 10 years. Three (8.5%) patients died: two due to a second tumour (non-Hodgkin's lymphoma and myeloid acute leukaemia) and the other due to sepsis post-Ch. Univariate and multivariate analysis only associated histology subtype relative risk (RR) 4.0 nodular sclerosis (95% IC, 1.0-5.5; p:0.02) with higher relapse. Other prognostic factors did not reveal significant differences with respect to failure free or OS. In conclusion, we believe that death from HD in early-stage patients is unusual and mortality from causes other than HD occurs many years later. Outside clinical trials due to the lack of clear prognostic factors, with the exception of specific situations, patients should be informed of all the possible alternatives as well as the consequences of the treatments employed. In our experience, it appears that using Ch alone in the initial stages does not jeopardize overall patient survival, with similar results being achieved.     

Hodgkin's disease: combination chemotherapy for relapse following radical radiotherapy.

The results of Mustine, Vinblastine, Procarbazine, Prednisolone (MVPP) combination chemotherapy for relapsed Hodgkin's disease in 33 patients who were treated initially by definitive radiotherapy are analyzed. Twenty three of 27 (85%) who received chemotherapy at first relapse achieved complete remission (CR); 20 of these remained in remission at periods of 13–96 months (median 53 months) from treatment. Six patients were retreated by irradiation at first recurrence and all suffered further relapse within 14 months. Only 3 (50%) of this group achieved CR with subsequent chemotherapy. The results of radiotherapy for early stage Hodgkin's disease are improving now that certain presentations that are associated with high risk for relapse when treated by irradiation alone are recognized. The high CR rate obtained with MVPP in patients with recurrence following radiotherapy suggests that chemotherapy may reasonably be withheld in the initial management of localized disease, thus reducing the risk of iatrogenic complications associated with combined modality therapy.     

Extended mantle radiation therapy for pathologic stage I and II Hodgkin's disease

Between 1968 and 1983, 135 patients with pathologic stage (PS) I and II Hodgkin's disease were treated with extended mantle radiation technique (EMRT) at Michael Reese Hospital and the University of Chicago Center for Radiation Therapy. EMRT combines both standard mantle and para-aorta fields (M-PA) in one port. Actuarial disease-free survival at 5 and 10 years was 82.5%. Actuarial overall survival was 96% and 83% at 5 and 10 years, respectively. Acute complications were evaluated in 112 patients available for analysis. Severe nausea and vomiting occurred in 13%, weight loss of greater than 10% of body weight in 19%, and acute hematologic toxicity in 4% of patients. Bone marrow suppression was transient and did not interfere with subsequent delivery of salvage treatment with either chemotherapy or radiation therapy in 22 patients who relapsed. The cost of EMRT is 40% lower than the cost of treatment with M-PA. The median treatment time was 38 days, 33% less than the 56 days for M-PA field assuming no interruptions. These results suggest that the EMT is a safe and effective treatment tolerated by most patients. The advantages of this method are eliminating the possibility of technical error of matching between mantle and para-aortic field, decreasing overall treatment time, and reducing the cost.     

High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following first relapse after chemotherapy

Background: The best results of conventional-dose salvage chemotherapyfor Hodgkin's disease have been reported after first relapse.We evaluated the results of high-dose chemotherapy and autologoushematopoietic rescue for Hodgkin's disease patients who hadrelapsed from an initial chemotherapy-induced complete remission. Patients and methods: Eighty-five patients received high-dosecyclophosphamide, carmustine, and etoposide (CBV) followed byautologous bone marrow or peripheral blood stem cell transplantation. Results: Actuarial survival at five years was 51%, and failure-freesurvival was 40%. Failure-free survival at five years was 90%for patients who received no conventional-dose salvage chemotherapyprior to CBV. Failure-free survival of patients treated initiallywith a four-drug regimen was not significantly different thanpatients treated with seven/eight-drug regimens. Conclusion: These results appear to be better than those reportedfor conventional-dose salvage chemotherapy. High-dose therapyfollowed by autologous bone marrow or peripheral blood stemcell transplantation should be considered for any patient withrelapsed Hodgkin's disease, regardless of the length of initialremission, or type of initial chemotherapy. Certain patients,especially those with minimal disease, may benefit by proceedingdirectly to transplantation after relapse, without first receivingconventional-dose salvage chemotherapy. bone marrow transplantation, drug therapy, hematopoietic stem cell transplantation, Hodgkin's disease     

Combination chemotherapy for the treatment of Hodgkin's disease in relapse

Vindesine (desacetyl vinblastine amide sulfate, DVA) was used in combination with CCNU (lomustine) and melphalan (Alkeran) (CAD) to treat 15 heavily pretreated patients with Hodgkin's disease in relapse. The patients were treated with up to six cycles, depending upon their response. Two patients (13%) achieved a complete remission (CR) and five (33%) patients a partial remission (PR). The major toxicity was prolonged thrombocytopenia, which was decreased by a reduction in the initial drug doses for patients who had received extensive prior chemotherapy and radiotherapy (RT). The CAD regimen was then alternated with nitrogen mustard or cyclophosphamide, vincristine, procarbazine, and prednisone (MOPP, C-MOPP) and doxorubicin (Adriamycin), bleomycin, and vinblastine (ABV) for a total of nine cycles in 25 patients with Hodgkin's disease in relapse with somewhat more favorable prognostic features. Two patients also received low-dose RT to areas of bulky nodal disease. Eleven patients (44%) achieved a CR and seven (28%) a PR. Of the 11 CR patients, six remain in remission. The serious toxicity was comparable to that seen with other combination chemotherapy regimens. These results indicated that the CAD/MOPP/ABVD regimen is as active as other so-called 'salvage' regimens for Hodgkin's disease in relapse, and suggest that it might be useful for newly diagnosed Hodgkin's disease.     

Hodgkin's disease stage I and II. A comparison between two different treatment policies.

A retrospective analysis was performed on 145 patients with Stage I and II Hodgkin's disease treated over an 11-year period. Sixty-two patients (Group I) received a mantle field without systematic irradiation of the para-aortic lymph nodes. Eight-three patients (Group II) received radiotherapy according to the folowing policy: all Stage IB and IIB and all mixed cellularity and lymphocytic depletion types received total nodal irradiation while stage IA and IIA nodular sclerosing and lymphocytic predominance cases received irradiation to a mantle field and to the para-aortic lymph nodes. The characteristics of the two groups were roughly comparable in age range, sex, staging, histopathologic subtypes and total irradiation doses. All patients had lymphangiograms although not all underwent staging laparotomies. The staging laparotomy did not appear to have an influence within each group. The extent of irradiation did significantly affect both the incidence of further manifestation of disease as well as survival rates. The frequency of lymph node extension, organ extension and local recurrence for Group I was 24%, 14%, and 3%, while for Group II it was 4%, 6%, and 6%, respectively. The seven-year absolute survival rate for Group I was 57% while for Group II it was 93%.     

Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study.

BACKGROUND: Chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine and darcarbacine) schedule is the standard treatment for advanced Hodgkin's lymphoma. Certain facts, including a low toxicity compared with MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin and vinblastine) and minimal potential for inducing second neoplasias or patient sterility, support the use of ABVD to treat early disease stages. In the present study, we prospectively evaluated the long-term efficacy and toxicity of six cycles of ABVD as treatment for early-stage Hodgkin's lymphoma. PATIENTS AND METHODS: From January 1990 to June 2002, 95 patients with stage I and II Hodgkin's lymphoma were treated with six ABVD cycles. Fifteen patients who met the criteria for mediastinal bulky disease also received further radiotherapy on the mediastinum. RESULTS: After six cycles, 89 patients (94%) showed a complete response (CR) and six patients (6%) showed a partial response (PR). These PRs became CRs after radiotherapy. After a median follow-up of 78 months, 14 patients had relapsed and three had died. Overall survival and progression-free survival rates at 7 years were 96% and 84%, respectively. For patients with stage IA and IIA without mediastinal bulky disease, the survival rates were 97% and 88%, respectively. CONCLUSIONS: The administration of six ABVD cycles is an effective and safe treatment in patients with stage I and II Hodgkin's lymphoma.     

New assessment of the prognostic significance of histopathology in Hodgkin's disease for laparotomy-negative stage I and stage II patients.

This paper describes preliminary radiotherapy results in 90 patients with Stage I and II Hodgkin's disease who were evaluated by laparotomy, including splenectomy, and liver and bone marrow biopsies. As a result of selection by laparotomy, the estimated five-year survival rate for these patients was 96%. No statistically significant differences were detected in the disease-free survival for patients with mixed cellularity, nodular sclerosis, and lymphocytic predominance disease. Since only one patient with lymphocytic depletion was in this series, no statement can be made regarding this rare histopathology. Patterns of new disease differed for Stage I and II patients. The major difference was that patients with nodular sclerosing Stage II presentations involving the mediastinum were at considerable risk of developing subsequent disease in the pulmonary parenchyma or the pleura. This finding, together with the demonstration that a histologic diagnosis of mixed cellularity did not carry an inferior prognosis, indicates the need for reassessment of the appropriateness of applying treatment programs based on results of lymphangiographically staged patients to Stage I and II patients evaluated by laparotomy.     

Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease.

BACKGROUND: The aim of this study was to determine salvage outcome in patients with Hodgkin's disease who relapse after radiation therapy, and to compare the efficacy of mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) versus Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) as salvage treatment. PATIENTS AND METHODS: One hundred patients with Hodgkin's disease (97 with stage I-II disease at presentation) who relapsed after radiation therapy alone were salvaged with either MOPP or ABVD. Freedom from second relapse (FFSR) and overall survival (OS) were determined, and prognostic factors for salvage outcome were evaluated. RESULTS: The median follow-up time since salvage therapy was 12 years. The 10-year FFSR and OS rates were 70% and 89%, respectively. Forty-one patients were salvaged with MOPP and 59 received ABVD. The type of salvage chemotherapy did not significantly influence FFSR or OS. Age >50 years at initial diagnosis was the only significant predictor for an inferior FFSR and OS on both univariate and multivariate analyses. CONCLUSIONS: The two salvage regimens of MOPP and ABVD had similar efficacy in this group of patients with predominantly early-stage disease at initial radiation therapy. The inferior salvage outcome in patients aged >50 years is a contributing factor to the overall poor prognosis of patients presenting with Hodgkin's disease at an older age.     

Late pulmonary effects in favorable stage I and IIA Hodgkin's disease treated with radiotherapy alone

Radiotherapy (RT) in patients with favorable-stage Hodgkin's disease can induce clinical and subclinical evidence of pulmonary damage lasting over the years. In this study, we monitored 36 patients with stage IA-IIA Hodgkin's disease treated with subtotal nodal RT. The planned dose of RT was 40 Gy to 44 Gy to the involved areas and 36 Gy to the adjacent uninvolved areas. Pulmonary function was evaluated by chest radiograph, spirometric parameters, arterial blood gas analysis, and single-breath CO transfer factor (DLCO). The tests were performed before and at the end of irradiation, and during the follow-up 1 and 3 to 5 years after the treatment. At the end of RT, we found a significant decrease of total lung capacity, vital capacity, forced expiratory volume in 1 second, residual volume, and DLCO. Spirometric parameters improved during the follow-up period, whereas the decline of DLCO (-6.4%) was persistent. No correlation was found between mantle RT dose and DLCO changes. Four patients showed a decline of DLCO of >20% from pretreatment values but only one was symptomatic. Our study confirms that RT induces a pulmonary-restrictive disease at a subclinical level that seems to be reversible in the majority of patients.     

The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after a chemotherapy relapse.

PURPOSE: The optimal sequence of salvage chemotherapy (SC) and autologous bone marrow transplantation (ABMT) for Hodgkin's disease (HD) patients who relapse after primary chemotherapy is unknown. We created a decision analysis model to determine the optimal treatment strategy and the most cost-effective approach. METHODS: The decision tree simulated a 25-year-old HD patient who relapsed less than 12 months after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. Four strategies used ABMT in some sequence with SC; the final strategy considered SC alone. Clinical data were derived from 17 published reports chosen by explicit criteria. Costs of care were estimated from the published literature and institutional experience. RESULTS: The optimal strategy was ABMT in second relapse, which was superior to the SC-only option by 1.9 years at an incremental cost of $26,200 per each year of life saved. When the probabilities of complete remission and disease-free survival were reduced for SC, similar to the clinical expectation of SC after a seven- or eight-drug regimen like MOPP/doxorubicin, bleomycin, and vinblastine with or without dacarbazine (MOPP/ABV[D]), ABMT in first relapse was the preferred strategy and provided 6 additional months. However, when the data from favorable (or unfavorable) SC and ABMT reports were compared head-to-head in this model, SC followed by ABMT in second relapse was always optimal. CONCLUSIONS: All relapsed HD patients should plan to use ABMT in some sequence with SC, if necessary. In most situations the optimal strategy is ABMT in second relapse. This analysis will assist clinicians in planning treatment for relapsed HD patients. It could be refined if historical series were updated to report the incidence and outcomes of SC relapse from seven- or eight-drug regimens.     

Late relapse of Hodgkin's disease after 25 years

This short report documents a late relapse of Hodgkin's disease 25 years later after initial complete remission. The case represents the second longest ever reported disease-free survival that was followed by late recurrence. Data about late occurrence in Hodgkin's disease of relapses are reviewed. The biological and clinical significances of those events of late relapses are emphasized.