Stage Hodgkin's Disease Research Articles

Radical radiotherapy as salvage treatment for relapse of Hodgkin's disease initially treated by chemotherapy alone: Prognostic significance of the disease-free interval

Purpose : A study was performed to determine the effectiveness of radical radiation therapy (RT) in the treatment of patients with Hodgkin's disease who relapsed following initial treatment with chemotherapy alone. Methods and Materials : A retrospective review of patients treated at City of Hope National Medical Center between 1970 and 1987 revealed a total of 10 patients who received radical RT with curative intent as salvage therapy. Results : Complete remission was achieved in eight of the ten patients. Patients had an overall 5-year actual survival of 60% and 10-year actuarial survival of 38%. Relapse-free survival was 30% at 5 years and at 10 years. For the five patients with a. disease-free interval (DFI) of at least 12 months prior to radical RT, overall actual survival at 5 years was 100% and relapse-free survival was 60%. Three of the ten patients, all with a DFI > 12 months and in first relapse when undergoing radical RT, were long-term relapse-free survivors. Conclusion : Radical RT is an effective salvage regimen for select patients with advanced stage Hodgkin's disease who relapse following initial treatment with chemotherapy alone provided that relapse is limited to sites which can be encompassed by radical RT fields and the DFI is greater than 12 months. Review of other published series supports DFI > 12 months as a favorable prognostic factor. Comparison to other salvage regimens such as autologous bone marrow transplantation is limited. Reviews of other treatment modalities should perform subset analysis on patients with similar presentations to compare the relative effectiveness of various salvage approaches.

Treatment of early and intermediate stages of supradiaphragmatic Hodgkin's disease: The Swedish National Care Programme Experience

Since 1985 a Swedish National Care Programme has provided tailored principles for the staging, treatment and follow-up of patients with Hodgkin's disease (HD). This report presents treatment results for all patients below 60 years of age who were diagnosed with early and intermediate stages, between 1985 and 1989. During that period, 210 patients with supradiaphragmatic HD in clinical (CS) and pathological (PS) stages IA+IIA, PS IB+IIB, and PS III1 A were diagnosed in five Health Care Regions in Sweden. In patients with CS IA, staging laparotomy was not recommended provided that the radiological assessment of the abdomen was adequate, whereas this procedure was recommended in stages CS IB, IIA and IIB in order to minimize treatment. In the absence of bulky mediastinal disease, patients with CS+PS IA and PS IIA were treated with mantle (occasionally mini-mantle) irradiation alone, while patients with bulky disease, as well as those with stages PS IB+IIB+III1 A, were treated with one cycle of MOPP/ABVD prior to mantle (PS III1 A sub-total nodal) irradiation. Full chemotherapy followed by radiotherapy to initial sites with bulky disease was recommended for patients with CS IIA who did not undergo laparotomy. After a median follow-up in excess of five years, treatment results are 'favourable' for all stages, provided the recommendations were followed. In patients with CS+PS IA treated according to the recommendations, recurrence rates were 14% (9/65) with all but one patient (64/65, 98%) remaining in continuous first or second remission. These figures were worse in patients treated inadequately (9/26 [35%] and 22/26 [85%], respectively). In PS IIA, adequately-treated patients had a recurrence rate of 13% (7/52) whereas 5/7 (71%) of those with bulky disease who received only mantle irradiation developed recurrences. Similar patterns also emerged in patients with CS IIA, PS IB+IIB and PS III1 A. The tailored principles, which usually entail less staging and/or treatment than is generally the case, produced favourable results when applied to an entirely unselected group of patients with early and intermediate stages of HD.

A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated hodgkin's disease

Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.

Second solid tumors and leukemia after treatment for Hodgkin's disease: An analysis of 1121 patients from a single institution

Purpose : To define the risk of having a second malignant neoplasm (ST) in different subsets of Hodgkin's disease patients and possibly to identify potentially avoidable therapeutic behaviors, linked with an increased second tumor probability. Methods and Materials : Cumulative probability of having a ST has been calculated for the different clinical and therapeutic subgroups of a population of 1121 patients consecutively treated (1960–1988) for Hodgkin's disease. Age groups at diagnosis were as follows: <20 years, 18%; 2040, 48%; 41–60, 26%; >60, 8%. Initial treatment consisted of radiation alone (67%), combined modality treatment (24%), chemotherapy alone (9%). Treatment for relapse was also coded, and the occurrence of ST was related both to initial treatment (considering relapsed patients as censored at relapse) and to the “overall” treatment burden, without censoring at relapse. Results : An increased ST risk has been observed in patients older at HD diagnosis. Second tumors cumulative probability rates were significantly higher in patients initially treated with chemotherapy, especially when associated with subtotal or total nodal irradiation (relative risks of 3.1 and 4.1, p = .03 and .005, respectively, when compared to involved field radiotherapy alone). The same trend was observed for second solid tumors. Acute leukemia was more frequent in patients initially given chemotherapy alone or associated with radiotherapy ( p = .01), and in those treated with an increasing number of cycles ( p = .004). “Salvage” chemotherapy after radiation alone at presentation does not seem to be linked with an increased risk of leukemia. Conclusion : The 15-year cumulative ST probability (11%) should be evaluated in the context of the very good cure rates achieved for Hodgkin's disease. The use of chemotherapy, particularly when associated with subtotal or total nodal irradiation, entails an increased risk of second malignancies and might be inappropriate in early stage Hodgkin's disease patients.

Controversies in the management of early stage Hodgkin's disease [see comments

Controversies in the management of early stage Hodgkin's disease [see comments

Yttrium 90 polyclonal antiferritin therapy in patients with refractory end stage Hodgkin's disease

Yttrium 90 polyclonal antiferritin therapy in patients with refractory end stage Hodgkin's disease

Radiotherapy in early stage Hodgkin's disease.

Ninety-nine patients with "standard risk" Stage IA-IIA Hodgkin's disease observed between January 1983 and December 1990, received radiotherapy only. The complete response rate was 98% (97/99). Twenty-one patients (21%) relapsed, 17 of whom (81%) obtained a second complete remission. The projected 9-year overall survival and disease-free survival were 95% and 78%, respectively. In this study our goals were to reduce the irradiation volumes, to decrease the number of splenectomies performed at diagnosis, and to utilize radiotherapy alone in these patients. We were able to reduce the irradiation volumes in over 50% and 80% of the patients with disease in the upper torso and subdiaphragm, respectively. Furthermore, this therapeutic approach permitted us to reduce the acute and long-term toxic effects related to splenectomy and combined modality treatment.

How relevant is secondary leukaemia for initial treatment selection in hodgkin's disease?

Specific tools of decision analysis, a set of mathematical rules for simplifying complex decisions, were applied to evaluate the impact of secondary leukaemia on the selection of initial treatment in Hodgkin's disease (HD). For this purpose, a combined ‘expected utility’ considering survival, relapse free survival, and secondary leukaemia was determined for different treatment strategies. Our analysis revealed that considerations of secondary leukaemia for initial therapy should include the a priori estimation of all possible events which may occur after initial treatment, e.g. the probabilities of recurrence and success of salvage therapy. In early and intermediate stage HD, for example, the minimal risk of leukaemia after successful radiotherapy (RT) must be weighed against the increased risk after treatment failure and subsequent salvage therapy. Thus, the difference of expected risk of leukaemia between RT and combined modality treatment (CMT) is within 4% for HD, stage II B and near to 0% in stage III A. In advanced stage HD, the addition of RT to chemotherapy has no adverse effect on the expected utility of initial treatment. These conclusions are only marginally affected by reported differences in rates of recurrence, salvage success, and secondary leukaemia. Subjective quality of life considerations, such as the latency period between treatment and leukaemia and patients' attitudes towards the occurrence of leukaemia, did not significantly affect expected utilities. In summary, our results strongly suggest that presently there is no sound basis for reducing the intensity of initial treatment in HD to avoid secondary leukaemia.

Is Hodgkin's disease an infectious disease?

Several lines of evidence question the concept of Hodgkin's disease (HD) starting as a true malignant disorder of the lymphatic system: (i) In early stages HD exerts pronounced clinical and biological features of an atypic immune response. (ii) Despite extensive investigations, the Hodgkin/Reed-Sternberg (H/RS) cells have not been unequivocally determined as the definite malignant cell population in HD. (iii) The epidemiological pattern of HD strongly resembles that of an infectious disease. (iv) About 50% of HD cases can be linked to infection with Epstein-Barr virus. Hodgkin's disease in early stages might thus be understood as the unsuccessful attempt of the organism to eliminate a cell expressing a putative (cellular or viral) target antigen. A stepwise transformation of this antigen-carrying cell, possibly triggered by an inherent genetic instability, might then lead to outgrowth of a malignant cell clone in late stages of the disease.

Treatment of early Stage Hodgkin's disease

Current trends in the treatment of patients with Stages I and II Hodgkin's disease are discussed in this review. Recommendations for staging procedures and the updated staging classification are described. Long-term results with extended field radiation therapy overall and in subgroups of patients are detailed. As follow-up and numbers of patients treated with extended field radiation therapy have accrued, prognostic factors, predictive of outcome, have emerged. The evolution of combined modality treatment with chemotherapy and radiation therapy and, more recently, chemotherapy alone for early stage patients is reviewed. Discussion is made of recent programs in various centers to reduce toxicity while maintaining good results. Long-term potential toxicities are described, and recommendations are made for long-term follow-up monitoring.

Late relapse in early-stage Hodgkin's disease patients enrolled on European Organization for Research and Treatment of Cancer protocols.

The great majority of relapses after the treatment for early-stage Hodgkin's disease are observed within 4 to 5 years after treatment completion. This study describes the characteristics and outcome of patients who had late relapses, which was defined as relapses that occurred 5 or more years after initial treatment start. A total of 1,082 adult patients with early clinical stage Hodgkin's disease were enrolled on three consecutive European Organization for Research and Treatment of Cancer (EORTC) protocols (H1, H2, and H5 trials) from 1964 to 1981. Of these, 1,044 patients satisfied the eligibility criteria with a supradiaphragmatic localization, age greater than 15 years, and initial complete remission. Overall, 341 patients (32.6%) relapsed, 304 (29.1%) early and 37 (3.5%) late. For each of these 37 late relapsers, questionnaires were sent to the participating centers and detailed information for 34 relapses was obtained. Cumulative probabilities for developing a late relapse were estimated using the Kaplan and Meier method. Quantification of the relationship between late relapse and several confounding variables was performed using the Cox's proportional hazards model. The 10- and 15-year cumulative probabilities of late relapse in patients who were disease-free at 5 years were 4.8% and 8.3%, respectively. Patients treated on more recent protocols had a higher incidence of late relapse, possibly due to an attempt to tailor therapy to the specific prognostic factors (10-year cumulative probabilities, 4.6%, 2.6%, and 7.5% in trials H1, H2, and H5, respectively). Incidence of late relapses significantly correlated with male sex, B symptoms, mediastinal involvement, and treatment modality. Salvage treatment induced a complete response in 27 patients (79%) and a prolonged complete remission in 24 patients (71%). Twenty years after initial treatment start, similar overall survival rates were observed for late relapsing (72%) and nonrelapsing patients (75%). Late relapses of Hodgkin's disease are uncommon, but may be more frequent with recent protocols tailored to specific prognostic factors. If treated, their outcome is favorable. Late relapse is therefore another factor indicating that careful, long-term follow-up is needed for patients with Hodgkin's disease.

Early stage Hodgkin's disease: Ten-year results of a non-randomised study with radiotherapy alone or combined with MOPP

From September 1976 to June 1982, 201 consecutive patients with stage I (A and B)-IIA Hodgkin's disease were stratified in two groups according to prognostic factors. The F group included 116 patients with favourable presentation: they were staged with laparotomy and treated with subtotal or total nodal radiotherapy alone. The U group included 85 cases with unfavourable presentation who were staged by laparoscopy and treated with 3MOPP (mechlorethamine, vincristine, procarbazine, prednisone)-radiotherapy-3MOPP. At 10 years the F group showed a freedom from progression (FFP) of 71%, with significant difference between stage I and II (85% vs. 59%; P=0.003) and an overall survival of 84%. The results of the U group were: FFP 83%, overall survival 74%, and the findings were not influenced by stage. FFP in patients with bulky vs. not bulky lymphoma was 70% vs. 87% ( P=0.04). No secondary acute non-lymphocytic leukaemia developed among patients treated with radiotherapy and in continuous complete remission, while acute leukaemia occurred in the F group patients who received salvage chemotherapy (4 of 31 cases) and in the U group (3 of 85 cases). Present results confirm the usefulness of radiotherapy alone in favourable pathological stage IA. All other disease stages will require a different strategy that should consist of radiotherapy combined with short-term effective regimens, such as ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or VBM (vinblastine, bleomycin and methotrexate) to reduce the incidence of MOPP-associated gonadal dysfunction and leukaemogenesis.

Chemotherapy Dose and Survival in Advanced Hodgkin’s Disease

We analysed the effect of chemotherapy dose reductions on survival in 35 patients with Hodgkin's disease stage IIIB or IV treated at our institution by three double courses of C-MOPP/ABVD chemotherapy followed by either one further course or by involved-field radiotherapy. Patients receiving reduced doses of alkylating agents had markedly slower responses and worse survival than those not requiring dose reductions. This experience with a very limited number of cases suggests that dose intensity may be an important prognostic factor in advanced Hodgkin's lymphoma, although dose reductions might have been necessary in patients with an intrinsically poor prognosis. Prospective randomized trials comparing standard chemotherapy with intensified protocols supported by hematopoietic growth factors are needed and are being conducted to determine the role of total chemotherapy dose and delivery time in the cure of Hodgkin's disease.

Radiotherapy versus combined modality in early stages

In early stage Hodgkin's disease the optimal choice of treatment for the individual patient is still an unresolved issue. So far, twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out worldwide. The preliminary results of a global metaanalysis of these trials indicate that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front improves survival. Arguments in favour of the addition of chemotherapy up front are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against the use of chemotherapy up front is: that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone. The results of these trials are however conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for general clinical use.

Immunoscintigraphy in Hodgkin's disease and anaplastic large cell lymphomas: results in 18 patients using the iodine radiolabeled monoclonal antibody HRS-3.

Immunoscintigraphy (IS) using the HRS-3 Hodgkin associated monoclonal antibody (MoAb) was performed in 18 patients with Hodgkin's Disease (HD) at staging or restaging. Either F(ab')2 fragments (14 patients) or whole HRS-3 (4 patients) labeled with 77-260 Mbq 131-I were used. Whole body images, including anterior and posterior views, were taken from a digital gamma camera, within 4 to 8 hours after injection and then daily for 5 days. In one patient IS was discontinued due to iodine intolerance. Seventeen patients were evaluable: 14 showed a true positive result including 2 cases which were reviewed as anaplastic large cell lymphoma (ALCL). Nodal, splenic, bone marrow and muscle involvements were imaged, many of these sites were previously unsuspected. In 7 patients with true positive findings the Pressman Specificity Index, as measured from biopsied material, ranged from 1.5-3 in 4 patients and from 5 to greater than 100 in 3 patients. Imaging was equivocal or failed in 1 patient (lymph nodes). In 2 patients, IS imaging was truly negative due to the absence of active HD, and a false negative result occurred once (inguinal node). In none of the patients a false positive image was observed. In order to rule out non-specific iodine uptake a control, anti-ACE MoAb, labeled with 125-Iodine was injected simultaneously in 10 patients. The evaluation of the study gave a sensitivity of 87% and a good specificity. IS using radioiodine labeled MoAbs is feasible and represents a reliable non-invasive diagnostic method for the staging and follow-up of HD and ALCL.

Reducing the toxicity of the combined modality therapy of favourable stage Hodgkin's disease

Cancer Institute and Brigham and Women’s Hospital experience Acknowledgements-We thank the Finnish National Mesothelioma over 2 decades 1%5-198S.J Clin Oncoll988,6,147-153. Pathology Panel (Eero Taskinen, Sisko Anttila and Tauno Ekfors) and 29. Spirtas R, Connelly RR, Tucker MA. Survival patterns for maligthe EORTC Lung Cancer Cooperation Group Mesothelioma Pathology nant mesothelioma: The SEER experience. ZntJ Cancer 1988,41, Panel (Dr H. Planteydt) for classifying the tumours and Anne Hand for 525-530. linguistic revision. Supported by the Finnish Cancer Society. 30. Law MR, Ward FG, Hodson ME, Heard BE. Evidence for longer survival of patients with pleural mesothelioma withour asbestos exposure. Thorax 1983,38,744-746.

The EORTC trials for limited stage Hodgkin's disease

SINCE 1964, all the efforts of the Lymphoma Group of the EORTC (European Organisation for Research and Treatment of Cancer) have been devoted to the task of tailoring treatment to the presentation of Hodgkin’s disease (HD) for any given patient [l-12]. We will first briefly review the results of the four controlled studies conducted by the group from 1964 to 1988 for stages I and II HD. We will then present in detail the designs of the on-going H7 randomised trials for these same subsets of Hodgkin’s disease patients.

Duration of the preclinical phase of chronic myelogenous leukemia: a case report

The molecular events that allow for clonal expansion of the malignant population in chronic myelogenous leukemia (CML) are poorly understood. Recent experiments in transgenic mice suggest a close temporal relationship between expression of the aberrant protein and manifestation of a hematologic neoplasm that resembles CML; tracing the same phenomenon in humans has not been possible. We studied a patient who underwent autologous bone marrow harvest after completion of chemotherapy and radiation therapy for advanced stage Hodgkin's disease. At the time of harvest his peripheral blood counts and bone marrow were morphologically normal. Sixteen months later he developed the clinical manifestations of CML. Detailed molecular evaluation of the harvested marrow showed that a small number of cells contained the Philadelphia chromosome. The time interval required for expansion of the malignant clone, as suggested by this particular patient, was at least 16 months although it is recognized that this figure may be variable.

Ultrasonography of spleen and liver in staging Hodgkin's disease

Ultrasound (US) findings and accuracy in detecting splenic and hepatic involvement were analysed in 137 unselected, untreated patients with Hodgkin's disease. Histology was available from the spleens of 61 patients and the livers of 59 patients. In 20 patients the spleen appeared abnormal at US; containing focal hypoechoic lesions in 14, being enlarged in 13 and inhomogeneous in 2 patients. Most focal lesions were < 10 mm. The sensitivity of US in detecting involvement of the spleen was 54% and the specificity 100%; the ability of US to detect hypoechoic splenic lesions improved during the study period. Focal hypoechoic hepatic lesions were found in three patients; histological examination of these showed benign changes in one and suspicious finding in the second. In the third the lesion disappeared during chemotherapy. In three cases with definitive histological evidence of liver involvement, US results were false-negative. The results indicate a higher diagnostic efficacy for US in the detection of splenic than hepatic involvement by Hodgkin's disease.

Radiation therapy in the management of early stage Hodgkin's disease presenting in later life

This study examined the contention that although elderly patients with Hodgkin's disease have a worse prognosis overall than younger patients, a subgroup of older patients fit enough to be managed like younger patients can fare just as well. A retrospective analysis was made on 29 patients older than 60 years of age with Stage I and II Hodgkin's disease treated by radiation therapy alone. Fourteen of these patients were managed optimally, i.e., were adequately staged (defined by one or more of the following: laparotomy, computed tomography [CT] scan, and/or lymphangiogram), followed by radical radiation therapy (mantle or inverted-Y). The remaining 15 patients, because of their general medical condition, were managed suboptimally with limited staging and/or involved-field irradiation. None of the 14 patients managed optimally relapsed over a median of 4.75 years of follow-up compared with 10 of 15 patients in the suboptimal group. For the optimally managed versus suboptimally managed groups, the actuarial 5-year disease-free survival rates were 61% and 6%, respectively; the actuarial overall survival rates (death from all causes) were 61% and 19%, respectively; and the disease-specific survival rates were 100% and 39%, respectively. Only three of the patients irradiated radically had acute complications severe enough to warrant a break in treatment. In the opinion of the authors, those elderly patients able to tolerate adequate staging and radical radiation therapy can anticipate a high likelihood of cure.