Total Nodal Irradiation Research Articles

The decision between single- and combined-modality therapy in Hodgkin's disease

Using the technique of decision analysis to evaluate data on single-modality and combined-modality therapy in Hodgkin's disease, we have been able to determine which treatment gives the best chance for prolonged disease-free survival in given settings. Both the potential of combined-modality therapy for inducing secondary hematologic malignancies and the rate of salvage with MOPP following relapse after radiotherapy have been studied to observe the effect of different rates of these variables on the therapeutic decision. An analysis of patients with known pathologic stage endorsed the continued use of extended-mantle radiotherapy for Stages IA and IIA disease; under most of the conditions analyzed, combined-modality therapy appeared the best option for Stage IIIA disease. The results for Stages IB and IIB disease showed neither combined-modality therapy nor total nodal irradiation to have a conclusive advantage. We also analyzed management decisions for patients who had not had pathologic staging. For this, probabilities of each pathologic stage were derived from a large patient data base and were incorporated into the decision analysis. The results of this analysis indicated that, despite the mortality of laparotomy, treatment designated according to pathologic stage was more effective than immediate combined-modality therapy for most types of patients. For certain patients in whom the clinical features could be used to predict a high probability of advanced disease, the most effective management was immediate MOPP chemotherapy without staging laparotomy.

Second malignant neoplasms in patients treated for Hodgkin's disease with radiotherapy or radiotherapy and chemotherapy.

The incidence of second malignant neoplasms (SMN) was assessed in 248 patient with Hodgkin's disease (HD) treated by radiotherapy alone (XRT) or in combination with chemotherapy (XRT + C) between January/1960 and June/1977. Radiation therapy was categorized as less than extended field (less than EF), extended field (EF) or total nodal irradiation (TNI). Chemotherapy was scored as single agent (SAC) or multiagent (MAC). MAC consisted primarily of either nitrogen mustard, vincristine, prednisone and procarbazine (MOPP) or cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP). Ten metachronous malignancies occurred 1-21 years (median 10 years) after the diagnosis of HD. With a median follow-up of 6 years the observed-to-expected ratio (O/E) was 4.2 for XRT alone and 7.6 for XRT + MAC. For 46 patients with greater than or equal to 10 years follow-up (median 13 years) the O/E ratio was 16.1 for XRT and 26.5 for XRT + MAC. All SMN occurred in patients who had not had a splenectomy at or prior to the time of HD diagnosis. Only four of nine solid SMN were within treatment portals or near portal margins. The diagnosis of another malignant neoplasm was made prior to or simultaneous with the diagnosis of HD in four additional patients. This observation, and the occurrence of five of six SMN outside of the treatment field in the XRT alone group, suggest that there may be factor(s) associated with the incidence of SMN in HD in addition to treatment itself.

Survival of Patients With Localized Diffuse Histiocytic Lymphoma

Abstract Twenty-eight patients with previously untreated diffuse histiocytic lymphoma (DHL) were identified to be in pathologic stage (PS) I (11), IE (3), II (8), or IIE (6) by exploratory laparotomy and splenectomy. Six patients were treated with total nodal radiotherapy; 14 with an extended mantle; 5 with an inverted Y or whole abdomen; and 3 with an involved field. Twenty-six patients achieved a complete remission (93%) and 2 patients had persistent local disease. The median survival and disease-free survival and for the complete response group are 56 and 51.5 mo, respectively. Ten of the 11 stage I or IE patients had supradiaphragmatic lymph node disease. Patients with stage I or IE disease (n = 14) demonstrated a median survival of 72.5 mo and a median disease-free survival of 69.5 mo; there was 1 disease-related death. Patients with stage II or IIE disease (n = 14) demonstrated a median survival of 33 mo and median disease-free survival of 29.5 mo; there were 10 relapses or deaths. Patients in stages I, IE, II, or IIE with infradiaphragmatic disease (n = 7) had a median survival of 36 mo, while patients with supradiaphragmatic presentation (n = 21) demonstrated median survival of 68 mo (p = 0.37). The data indicate that patients with diffuse histiocytic lymphoma with stage I supradiaphragmatic lymph node disease are curable using radiotherapy alone, achieving a 93% 11-yr actuarial disease-free survival. Patients with stage II or IIE diseases are not readily curable with radiation therapy alone, achieving a 33% 11-yr actuarial disease-free survival; radiotherapy with adjuvant chemotherapy or chemotherapy alone should be considered for this group.

Survival of patients with localized diffuse histiocytic lymphoma

Twenty-eight patients with previously untreated diffuse histiocytic lymphoma (DHL) were identified to be in pathologic stage (PS) I (11), IE (3), II (8), or IIE (6) by exploratory laparotomy and splenectomy. Six patients were treated with total nodal radiotherapy; 14 with an extended mantle; 5 with an inverted Y or whole abdomen; and 3 with an involved field. Twenty-six patients achieved a complete remission (93%) and 2 patients had persistent local disease. The median survival and disease-free survival and for the complete response group are 56 and 51.5 mo, respectively. Ten of the 11 stage I or IE patients had supradiaphragmatic lymph node disease. Patients with stage I or IE disease (n = 14) demonstrated a median survival of 72.5 mo and a median disease-free survival of 69.5 mo; there was 1 disease-related death. Patients with stage II or IIE disease (n = 14) demonstrated a median survival of 33 mo and median disease-free survival of 29.5 mo; there were 10 relapses or deaths. Patients in stages I, IE, II, or IIE with infradiaphragmatic disease (n = 7) had a median survival of 36 mo, while patients with supradiaphragmatic presentation (n = 21) demonstrated median survival of 68 mo (p = 0.37). The data indicate that patients with diffuse histiocytic lymphoma with stage I supradiaphragmatic lymph node disease are curable using radiotherapy alone, achieving a 93% 11-yr actuarial disease-free survival. Patients with stage II or IIE diseases are not readily curable with radiation therapy alone, achieving a 33% 11-yr actuarial disease-free survival; radiotherapy with adjuvant chemotherapy or chemotherapy alone should be considered for this group.

Longitudinal studies of blood lymphocyte capacity in Hodgkin's disease.

Blood lymphocyte functional capacity and serum immunoglobulins were studied in 40 patients with Hodgkin's disease (HD) admitted to Radiumhemmet, Stockholm, before treatment and in complete remission 2-56 months following termination of radiotherapy (total nodal irradiation [TNI]; n = 29) or chemotherapy (MOPP; n = 11). Lymphocyte studies included determination of total lymphocyte and T-cell counts and evaluation of spontaneous DNA synthesis during the first day of culture and mitogen-(concanavalin A, pokeweed mitogen) and antigen (purified protein derivative, PPD)-induced activation on the third day. Blood lymphocyte and T-cell counts decreased dramatically following TNI. A slow restitution was seen, but pretreatment levels were not reached even four years following therapy. The responses to ConA and PPD but not PWM were significantly reduced shortly after TNI. The mitogen response did not increase with time as did the PPD response. Lymphocyte counts and lymphocyte stimulation, which were severely depressed before treatment of patients in the chemotherapy group, remained unchanged 2-36 months after termination of therapy. A significant reduction of IgM levels was observed regardless of the mode of treatment. Splenectomy prevented the profound reduction of blood lymphocyte and T-cell counts following therapy but did not influence the other immunologic variables under study.

Dynamic dose-shaping by gravity-oriented absorbers for total lymph node irradiation

Rotational therapy with gravity-oriented absorbers is proposed for better total lymph node irradiation (TLI). Two metal semicylinders are joined coaxially (face to face) to form a radiation absorber that is centrally suspended in the beam. During rotation this absorber is kept parallel to itself by gravity, like the riders of a Ferris wheel. The vertebrae remain continuously protected under the absorber's “shadow”. The circular full-dose region, achieved by ordinary rotation, is now transformed into a “horse-shoe” region embracing the spine anteriorly. The abdominal lymph nodes are thus irradiated while the spine and most of the normal tissue around the spine are protected. A similar technique is applied for the selective irradiation of the pelvic lymph nodes, which are confined in the two legs of an inverted V region.

Radiotherapy versus Radiotherapy plus Chemotherapy in Stages I and II Hodgkin's Disease.

In a multi-centre study in which data from all Danish Hodgkin patients have been registered since 1971, all patients in supradiaphragmatic stages I or II, as confirmed by staging laparotomy, were randomized to either radiotherapy (RT) to supra- and infradiaphragmatic lymph node regions (total nodal irradiation, TNI), or RT to a mantle field followed by 6 cycles of MOPP combination chemotherapy (RT+CT). Interim results up to July 1979, when 237 patients had entered the study, showed a treatment failure rate of 19/117 in the TNI group and 4/120 in the RT+CT group (P less than 0.05). 19 of the 23 relapsing patients were under the age of 40, and 14 in the TNI group and 3 in the RT+CT group belonged to stage II. 13 patients had nodular sclerosis, 9 had mixed cellularity and 1 had lymphocytic predominance histology. 12 of 19 relapsing patients in the TNI group had hilar or mediastinal involvement as against 51 of the 117 patients in the entire group. Most of the TNI failures could be retreated, and as yet there is no difference in the overall survival.

The place of radiotherapy in the management of localised Hodgkin's disease (report no 11)

This report reviews the experience of the BNLI in managing localised Hodgkin's disease, since the BNLI began in February 1970. The original problem investigated by this study was the evaluation of 'prophylactic' irradiation treating adjacent apparently unaffected regions, as opposed to radiation directed to only the affected regions of the body. Because lower half Hodgkin's disease is uncommon, the study was confined to patients presenting with upper half disease, without 'B' symptoms. Diagnostic laparotomy and splenectomy was not considered to be a mandatory investigation and at the commencement of the study was recommended by only two collaborators. By the completion of the study the majority of collaborators were recommending this procedure routinely. This study therefore includes two additional subgroups of patients with Stages I, IIA (upper half) Hodgkin's disease. In the laparotomised group of patients a 10-year survival rate of almost 95% with either 'local' or 'prophylactic' irradiation suggests that wide field irradiation (including total nodal irradiation) is not essential in the cure of apparently localised Stages I, IIA (upper half) Hodgkin's disease, provided the extent of the disease has been accurately determined by previous investigation. In those patients treated with strictly 'localised' (as opposed to 'prophylactic') irradiation, relapses in adjacent unirradiated regions have been completely controlled by additional treatment, usually irradiation, and none have died of Hodgkin's disease.

Second malignant neoplasms in patients treated for hodgkin's disease with radiotherapy or radiotherapy and chemotherapy

The incidence of second malignant neoplasms (SMN) was assessed in 248 patient with Hodgkin's disease (HD) treated by radiotherapy alone (XRT) or in combination with chemotherapy (XRT + C) between January/1960 and June/1977. Radiation therapy was categorized as less than extended field (less than EF), extended field (EF) or total nodal irradiation (TNI). Chemotherapy was scored as single agent (SAC) or multiagent (MAC). MAC consisted primarily of either nitrogen mustard, vincristine, prednisone and procarbazine (MOPP) or cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP). Ten metachronous malignancies occurred 1-21 years (median 10 years) after the diagnosis of HD. With a median follow-up of 6 years the observed-to-expected ratio (O/E) was 4.2 for XRT alone and 7.6 for XRT + MAC. For 46 patients with greater than or equal to 10 years follow-up (median 13 years) the O/E ratio was 16.1 for XRT and 26.5 for XRT + MAC. All SMN occurred in patients who had not had a splenectomy at or prior to the time of HD diagnosis. Only four of nine solid SMN were within treatment portals or near portal margins. The diagnosis of another malignant neoplasm was made prior to or simultaneous with the diagnosis of HD in four additional patients. This observation, and the occurrence of five of six SMN outside of the treatment field in the XRT alone group, suggest that there may be factor(s) associated with the incidence of SMN in HD in addition to treatment itself.

Further follow-up of results of treatment in 90 laparotomy-negative stage I and II Hodgkin's disease patients: Significance of mediastinal and non-mediastinal presentations

A preliminary report described the results of radiotherapy treatment in 90 patients with laparotomy-negative stage I and II Hodgkin's disease. 15 This group has now been followed a minimum of five years. The maximum follow-up is just over ten years. The findings in the preliminary report are now confirmed. The projected ten year survival is approximately 93%; the projected ten year disease free survival is about 60%. None of the patients received total nodal radiotherapy. More than half of the patients received no elective irradiation below the diaphragm and some of them received less than full mantle treatment. Present philosophy in the management of Hodgkin's disease is tentatively based on combining the results of the treatment of patients variously staged, either with or without laparotomy or with or without lymphangiography. Analysis of patterns of failure in patients who have had a laparotomy strongly suggest that a more conservative radiotherapy approach than is currently the norm in most institutions can be equally effective. Indications for a combined chemotherapy/ radiotherapy program for mediastinal presentations is discussed.

The decision to perform staging laparotomy in symptomatic Hodgin's disease.

This study defines patients with symptomatic Hodgkin's disease for whom risks of staging laparotomy (LAP) outweigh benefits conferred by accurate knowledge of stage. From a database of more than 900 pathologically-staged patients, probabilities of pathological stage are calculated for combinations of basic findings and lymphangiogram results. Decision-making thresholds are defined at which results of treatment after LAP, taking operative mortality into account, are equivalent to immediate treatment appropriate to clinical stage. These thresholds are substantially altered by varying LAP mortality estimates, by assigning a false negative rate to LAP, and by considering uncertainty in treatment results. Fifty-four combinations of findings are described for which immediate therapy with MOPP is justified; total nodal irradiation (TNI) is never indicated in B patients without prior LAP staging. Analysing 94 B patients who had LAP showed an appreciable number might have been spared this, particularly when uncertainty in treatment results is considered. With 0.03 (=3%) uncertainty in treatment, and 1% LAP mortality, LAP was not indicated in one in seven patients; nearly one third of patients should have immediate treatment with 3% LAP mortality. Threshold analysis can define those patients for whom risks of LAP outweigh benefits.

Long‐Term Influence of Splenectomy on Immune Functions in Patients with Hodgkin's Disease

Immunological functions of 9 non-splenectomized and 8 splenectomized patients with Hodgkin's disease were studied before and after treatment. The two groups compared well with regard to age, clinical and immunological findings at diagnosis and observation time. When retested, all patients had enjoyed an unmaintained complete remission for 2 to 5 years following total nodal radiotherapy. After therapy, total lymphocyte and T-lymphocyte counts decreased in non-splenectomized patients but remained unchanged in splenectomized patients. The blood lymphocyte DNA synthesis after activation by concanavalin A or pokeweed mitogen persisted at the same low level after treatment. The delayed skin hypersensitivity and the lymphocyte activation by PPD antigen were restored in several patients in both groups. The IgM concentration decreased after therapy independent of splenectomy. The IgA level was low in non-splenectomized patients. Splenectomy seems to protect from the therapy-induced lymphocytopenia. No alterations of immunoglobulins and blood lymphocyte functions could be ascribed to splenectomy.

The management of stage 111a hodgkin's disease

Forty patients with pathological Stage IIIA Hodgkin's disease were allocated to receive either total nodal irradiation (TNI) or 6 cycles of chemotherapy with Nitrogen Mustard (Mustine), Vinblastine, Procarbazine and Prednisolone (MVPP) as initial treatment. The complete remission rate for both groups was 100%, with 5-year actuarial disease-free survival figures of 74 and 87% for TNI and MVPP respectively (median duration of follow-up = 48 months). Eighty-eight per cent of TNI treated patients were alive at 5 years compared with 100% in the MVPP group. Three patients died, two who were treated with TNI and one who received MVPP. Treatment related morbidity included one patient with osteonecrosis and one with a second malignancy. Given the length of follow-up available, these results demonstrate no significant difference between TNI and MVPP for patients with Stage IIIA disease; it is unlikely that further patient entry into this particular study will allow any conclusion to be reached regarding the optimal form of management. We would recommend that individual disease characteristics within Stage IIIA be used as a basis for future treatment decisions with the understanding that further information regarding morbidity may become available with prolonged follow-up.

Feasibility of Different Combinations of Chemotherapy (6 MOPP) plus Radiotherapy in Hodgkin's Disease

During a preliminary clinical experience (1973-1977) we experimented three different sequences in associating 6 MOPP cycles (CT) with radiotherapy (RT) for the treatment of stage II and III Hodgkin's disease. A total of 55 consecutive previously untreated patients can be estimated to contribute in defining feasibility, immediate results and toxicity of the combined treatment. In this group of patients RT preceded CT in 20 cases (RT-6 MOPP), the opposite sequence (6 MOPP-RT) was preferred in 16 cases, whilst a split-course CT fitting in the RT (3 MOPP-RT-3 MOPP) was employed in 19 cases. Except for the sequence used with respect to irradiation, the CT was carried out in all the cases according to the classical scheme proposed by De Vita et al. (11). RT was effected with 60Co-teletherapy and a wide field or segmental sequential fields, having variable extension depending on the stage ("extended nodal irradiation" for stage II and III cases with lymph node involvement not below L3; "total nodal irradiation" for the remaining cases in stage III). The programmed doses were 45.0 Gy to the involved areas and 40.0 Gy to the clinically uninvolved regions for the RT-6 MOPP and 6 MOPP-RT groups. Doses of 35.0/30.0 Gy were planned for the 3 MOPP-RT-3 MOPP group. The three different groups are not homogeneous with regard to certain important clinical and pathological characteristics; in fact, a higher quota of stage III patients, with systemic symptoms and spleen positivity is present in the 6 MOPP-RT and 3 MOPP-RT-3 MOPP groups. The combined treatment has achieved a complete clinical remission in 18/20 patients in the RT-6 MOPP group (90.0%), in 12/16 patients of the 6 MOPP-RT group (75.0%), and in 17/19 cases in the 3 MOPP-RT-3 MOPP "sandwich" combination (89.5%). The average overall duration of the treatment was 48 weeks for the sandwich combination, 50 weeks for the RT-6 MOPP group, and 56 weeks for the 6 MOPP-RT association. As regards the sandwich combination, both CT and RT took a reasonable length of time to complete. On the contrary, both the medical treatment and irradiation required an excessively long time and were not well tolerated when preceded by either RT or CT in full doses. In particular, myelosuppression was less acute and prolonged in the 3 MOPP-RT-3 MOPP group, whereas the actual doses of CT and RT were higher than those which can be reached with respect to other groups. Three preliminary cycles of CT considerably reduce the target volumes and complications arising from RT. The first CT time gave an objective response greater than 50% in 9/9 cases of the 3 MOPP-RT-3-MOPP group with mediastinal involvement. In this group, rather considerable pulmonary complications were observed in 3/9 patients (33.3%) with respect to the 40% found for the 6 MOPP-RT group (2/5 cases) and the 67.7% for the RT-6 MOPP group (6/9 cases).

Non-Hodgkin's lymphoma and acute myeloblastic leukemia.A report of 12 cases and review of the literature

Twelve cases of non-Hodgkin's lymphoma and acute myeloblastic leukemia or one of its variants are reported. An additional 33 cases from the literature are reviewed. The mean interval between the diagnosis of lymphoma and acute leukemia is 5.2 years. In 5 patients the two diseases occurred simultaneously or within 6 months of each other. All but 10 of the 45 patients received radiation therapy for their lymphoma. Nine patients had either total nodal or total body irradiation or both. Eight patients received chemotherapy alone. No patient was untreated. Survival after the diagnosis of acute leukemia ranged from 3 days to 14 months, with a median of 3 months. Four patients achieved complete hematological remission following antileukemic therapy. Acute leukemia is estimated to occur in patients with non-Hodgkin's lymphoma in New York State with a 37-fold increased frequency over the expected number. Although acute leukemia may occur in a higher than expected frequency in patients with non-Hodgkin's lymphoma because of an increased risk of a second neoplasm in patients with a primary tumor, it seems more likely that the acute leukemia may be related to the radiotherapy and/or chemotherapy administered to treat the lymphoma. Late death from leukemia after chemotherapeutic or radiotherapeutic remission of advanced non-Hodgkin's lymphoma is preferable to morbidity and/or early death from untreated or inadequately treated lymphoma.

Long term follow-up of combination chemotherapy-radiotherapy of stage III Hodgkin's disease. A cancer and acute leukemia group B study

The Cancer and Acute Leukemia Group B studied the effect of combination chemotherapy-radiotherapy on Stage III Hodgkin's disease. Chemotherapy consisting of 4 weekly doses of vinblastine and one dose of mechlorethamine hydrochloride was followed by no therapy (CT), radiation to involved fields (CTIF) or total nodal radiation (CTTN). Two other treatment arms included total nodal radiation alone (TN) or total nodal radiation followed by chemotherapy (TNCT). Maximum follow-up is ten years. Complete remission percentages were 36 (8/22) for CT, 71 (17/24) for CTIF, 100 (21/21) for CTTN, 86 (19/22) for TNCT and 89 (16/18) for TN. Disease-free survival in patients receiving radiation +/- chemotherapy is 23% (19/73) at 5 years, but even after 9 years relapses were observed in two patients. Forty-one percent of all patients are alive and 32% have survived for five years. Ability to administer adequate therapy was the main determined for response duration and survival. Factors influencing the outcome of the disease include histology, age, splenectomy, initial white blood cell count and performance status, whereas symptomatology, initial absolute lymphocyte count and sex played no role on survival.

An evaluation of total nodal irradiation as treatment for stage III a Hodgkin's disease

Between April 1969 and December 1974, 37 patients with surgically staged III A Hodgkin's disease were treated with total nodal irradiation (TNI). Their probability of relapse-free survival at 7 years is 51% and overall survival 82% with the majority of patients remaining disease free after retreatment with MOPP (10 of 16). In contrast, 21 stage III B patients treated with TNI and MOPP chemotherapy over the same time period have a relapse-free survival of 74% and overall survival of 91%. Because of superior results in treating stage III B patients with combined modality treatment, we fell that a relapse-free survival of 51% may not justify continuation of TNI as the only modality of treatment for patients with stage III A disease, and we have initiated a trial of combined radiation therapy and MOPP chemotherapy in these patients. The most effective treatment of stage III A Hodgkin's disease, however, remains uncertain and depends both on the ultimate risk of combined modality treatment and the success of retreatment following relapse after radiation.

Clinical course of early extranodal non-Hodgkin's lymphomas

The subsequent sites of relapse following local X-ray therapy treatment of early stage non-Hodgkin's lymphoma were analyzed. The short interval to recurrence, the involvement of noncontiguous sites, and the rapid progression to death all suggest that seemingly early extranodal non-Hodgkin's lymphoma often is disseminated at diagnosis and that local treatment alone is ineffective. The analysis of sites of first relapse suggests that extended field treatment such as total nodal irradiation would benefit only a minority of these patients but would be superior to a radiation technique covering only the adjacent lymph node regions. While immediate contiguity of lymph node involvement was often seen with extranodal presentations, the more common pattern of relapse in bone marrow, liver, lung, stomach, and extranodal sites, indicates the need for an effective systemic therapy.

The incidence of post‐splenectomy sepsis and herpes zoster in children and adolescents with Hodgkin disease

The occurrence of sepsis due to Streptococcus pneumoniae and Hemophilus influenza and of herpes zoster (HZ) was reviewed in a series of 72 consecutive, previously untreated children and adolescents with Hodgkin disease. There was not a statistically significant difference in the risk of developing sepsis within five years of diagnosis between patients who had (16.6%) or had not (6.2%) undergone splenectomy. Sepsis occurred most frequently among patients treated initially with total nodal irradiation and combination chemotherapy. The estimated risk of HZ during the first five years after diagnosis was 34%. Patients treated initially with irradiation and combination chemotherapy had a significantly greater risk of developing HZ than patients treated initially with only irradiation (P less than 0.05). Although trends were present which suggested that splenectomy and the extent of disease at diagnosis may influence the occurrence of HZ, these did not achieve statistical significance. Survival was not influenced by the occurrence of HZ.

Comprehensive radiotherapy for advanced Hodgkin's disease refractory to chemotherapy.

Seven patients with advanced nodular sclerosing Hodgkin's disease who relapsed after initial intensive combination chemotherapy were selected for individualized pathologic restaging and comprehensive radiotherapy. One patient failed to respond completely to mantle-field irradiation and no further staging or radiotherapy was undertaken. Six other patients underwent staging laparotomy and received total nodal irradiation including prophylactic lung irradiation (5 cases) and hepatic irradiation (3 cases). Irradiation was well tolerated. Complete remission was achieved by 5 patients and 2 continue in remission 29+ and 32+ months after beginning of irradiation. Five of the 7 patients remain alive. This study indicates that comprehensive irradiation is a relatively well tolerated and effective treatment for carefully selected patients with advanced Hodgkin's disease who have relapsed after combination chemotherapy. For selected patients, pathologic restaging and comprehensive radiotherapy can be considered as an alternative to further chemotherapy.