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The advent of effective chemo-radiotherapy has made Hodgkin Disease (HD) a highly curable malignancy, but the great improvement in survival rates allowed the observation in long-term survivors of several treatment complications. Secondary malignancies are the most serious complications and breast cancer (BC) represents the most common solid tumor among female survivors. The aim of our analysis is to describe the clinico-pathological characteristics and management of BC occurred after HD treatment. Between 1960 and 2003, 2,039 patients were treated for HD at the Department of Radiotherapy-Oncology of the Florence University. In this study we considered 1,538 patients on whom a minimum follow up of 6 months had been obtained. Of these, 725 were women. The most represented histological subtype was nodular sclerosis (50.6%). Supradiaphragmatic alone or with subdiaphragmatic complementary extended field radiotherapy was delivered to 83.1% of patients while supradiaphragmatic involved field radiotherapy was delivered to 10.7% of patients. Concerning the characteristics and incidence of BC, we focused our analysis exclusively on the female group. We found that BC occurred in 39, with an overall incidence of 5.4%. The mean interval after Hodgkin treatment was 19.5 years (SD +/- 9.0). The median age of BC diagnosis was 50.8 years (SD +/- 13.3) while the median age of Hodgkin diagnosis was 31.2 years (SD +/- 14.5). Thirty-seven women received mediastinal irradiation. We observed a decreasing trend of the secondary BC incidence with increasing age of Hodgkin treatment with the maximum incidence registered in women treated at age 20 or younger. In Our Institute we perform a whole life follow up and recommend that annual mammography begins 10 years after HD treatment or, in any case, not later than age 40.

The Italian Society of Hematology (SIE), the Italian Society of Experimental Haematology (SIES) and the Italian Group for Bone Marrow Transplantation (GITMO) commissioned a project to develop practice guidelines for the initial work-up, therapy and follow-up of classical Hodgkin's lymphoma. Key questions to the clinical evaluation and treatment of this disease were formulated by an Advisory Committee, discussed and approved by an Expert Panel (EP) composed of senior hematologists and one radiotherapist. After a comprehensive and systematic literature review, the EP recommendations were graded according to their supporting evidence. An explicit approach to consensus methodologies was used for evidence interpretation and for producing recommendations in the absence of a strong evidence. The EP decided that the target domain of the guidelines should include only classical Hodgkin's lymphoma, as defined by the WHO classification, and exclude lymphocyte predominant histology. Distinct recommendations were produced for initial work-up, first-line therapy of early and advanced stage disease, monitoring procedures and salvage therapy, including hemopoietic stem cell transplant. Separate recommendations were formulated for elderly patients. Pre-treatment volumetric CT scan of the neck, thorax, abdomen, and pelvis is mandatory, while FDG-PET is recommended. As to the therapy of early stage disease, a combined modality approach is still recommended with ABVD followed by involved-field radiotherapy; the number of courses of ABVD will depend on the patient risk category (favorable or unfavorable). Full-term chemotherapy with ABVD is recommended in advanced stage disease; adjuvant radiotherapy in patients without initial bulk who achieved a complete remission is not recommended. In the elderly, chemotherapy regimens more intensive than ABVD are not recommended. Early evaluation of response with FDG-PET scan is suggested. Relapsed or refractory patients should receive high-dose chemotherapy and autologous hemopoietic stem cells transplant. Allogeneic transplant is recommended in patients relapsing after autologous transplant. All fertile patients should be informed of the possible effects of therapy on gonadal function and fertility preservation measures should be taken before the initiation of therapy.

Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial., Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method., Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25)., Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Purpose: To quantify the incidence of second malignant tumors (SMT) as a whole and that of second "solid" tumors (SST) and leukemia (L) in a large series of 1524 Hodgkin's disease (HD) patients (pts) treated at the Florence University Hospital (UFH); to define the clinical and therapeutic features possibly related with SMT occurrence; to evaluate the consequences of SMT for the overall survival of the series studied and for the choice of the treatment of HD at presentation., Methods and Materials: From 1960 to 1991, 1524 pts with HD, Clinical Stage (CS) I--IV have been treated at the UFH. Overall treatment consisted of radiation alone (RT, 36%), chemotherapy alone (CHT, 21%), or both (RT + CHT, 43%). The cumulative probability (CP) of SMT, SST, and L was calculated for the whole series and for the different clinical and therapeutic subgroups, and the results compared with uni- and multivariate analysis ("internal" comparison, IC). Standardized incidence ratios (SIR) for different SMT types (estimated on the basis of gender, age, period specific incidence rates of the general population) have been also calculated ("external" comparison, EC). The impact of the SMT-related mortality on the survival of the entire series has been estimated., Results: A 14.9% 20-year CP of SMT was registered, along with a SIR of 2.04 (95% confidence interval [CI]: 1.2--2.5). Both IC and EC showed a statistically significant relationship between L incidence and treatment with CHT, alone or in combination with RT. A significant excess of breast cancers has been observed in RT-treated patients with longer follow-up (SIR, 2.9); an excess of other common SST (lung, non-Hodgkin's lymphomas) is evident in pts treated with either RT, RT + CHT, or CHT. The actuarial long-term survival of the series would have been better of about 3%, in absence of the SMT mortality possibly due to HD treatment, which is almost equally divided between patients treated with RT alone, CHT alone, and RT + CHT., Conclusions: SMT represent an important late event in HD long-term survivors. The relationship between L and treatment with CHT seems to be the most clearly defined. The effect of SMT on the survival of the entire series, although not negligible, does not seem to justify by itself substantial alterations in the current standards for the treatment of HD at presentation.

Among 703 patients with supradiaphragmatic clinical stages I-II Hodgkin's disease consecutively treated 1960 through 1989 at the Florence Radiotherapy Department, we identified 98 cases presenting with cervical and supraclavicular nodes involvement only. The latter cases were retrospectively reviewed to assess: a) if they presented any peculiar clinicopathologic features and b) the possible prognostic and therapeutic implications (if any) of these features. The high incidence of lymphocytic predominance histology (33%) and Waldeyer's ring (WR) involvement (24%) and the very low risk of occult infradiaphragmatic involvement (observed in only 2 of 44 patients submitted to staging laparotomy with splenectomy, 4.5%) are among the distinctive features of the patients with supradiaphragmatic clinical stages I-II Hodgkin's disease. All the 98 patients were treated at presentation with irradiation alone. Actuarial cause-specific survival 20 years after the end of treatment was 87%; the corresponding value for relapse-free survival was 78%. The most frequent complications were irradiation pneumonia, most often asymptomatic, and xerostomia. Our data seem to suggest that, for the majority of these patients: a) staging laparotomy could be avoided and b) "mini mantle" irradiation is an adequate treatment. Moreover, WR irradiation could be avoided in the patients without clinical WR involvement.

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%; 20-40, 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.

Purpose: To compare the effectiveness of chemotherapy (CHT) with extended-field radiotherapy (RT) in the treatment of early-stage Hodgkin's disease (ESHD), we report an 8-year updated analysis of a study in which treatment with six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) CHT was randomly compared with extended-field RT., Patients and Methods: From August 1979 to December 1982, 89 adult patients with pathologic stage I-IIA Hodgkin's disease (HD) were randomly allocated to receive either RT with mantle field followed by periaortic irradiation (n = 45) or six monthly courses of MOPP CHT (n = 44)., Results: All patients in the RT arm and 40 of 44 in the CHT arm achieved complete remission. Twelve relapses occurred in each group. Eight patients treated with MOPP and two of the RT arm died of HD. Three other patients of the CHT group died because of a second cancer. With a median follow-up greater than 8 years, the overall survival rate is significantly higher in the RT than in the CHT group (93% v 56%; P less than .001), whereas the rates of freedom from progression and relapse-free survival (RFS) were similar in the two groups (76% v 64% and 70% v 71%, respectively). Of the 12 patients relapsing after RT, 11 (92%) achieved a second CR, compared with only six of the 12 (50%) in the MOPP group. Analysis of the response rate to salvage treatments showed that the type of relapse in the MOPP group was a prognostic indicator for the achievement of a second CR, whereas in the RT group, a second CR was obtained regardless of the characteristics of the relapses. At 80 months, the probability of survival of relapsing patients calculated from time of relapse was 85% and 15% in the RT and CHT groups, respectively (P = .02)., Conclusion: We conclude that RT alone is the treatment of choice for adult patients with ESHD with favorable prognostic factors.

Six cycles of mechloretamine, vincristine, procarbazine and prednisone (MOPP) chemotherapy were randomly compared with extended field radiotherapy (RT) in 89 adult patients with pathological stage I-II A Hodgkin's disease (HD). 45 patients received RT and 44 were treated with MOPP. Complete remission (CR) was obtained in all patients in the RT group and in 40 of 44 in the MOPP group. 12 patients relapsed in both groups. 10 out of 44 patients treated with MOPP died of HD, compared with only 2 in the RT group. 3 more patients died in the MOPP group following the occurrence of second cancers. 11 out of the 12 (96%) patients relapsing after RT achieved a second CR, compared with 6 out of the 12 (50%) patients relapsing after MOPP. Analysis of the response rate with salvage treatment, shows that, of the 12 patients who relapsed after MOPP, the pattern of relapse might predict the likelihood of achieving a second CR, whereas in the RT group a second CR was achieved regardless of the characteristics of relapse. Survival probability for relapsing patients at 80 months calculated from relapse was 85% in the RT group and 15% in the MOPP group (P = 0.02). With a median follow-up of more than 8 years, the overall survival of patients was significantly better for RT compared with MOPP; 93 and 56%, respectively (P < 0.001). On the basis of these results we conclude that, to date, RT alone remains the treatment of choice for adult patients with early-stage HD with favourable prognostic factors.

The immunoglobulin-synthesizing activities of peripheral blood mononuclear cells from 57 untreated patients with Hodgkin's disease and 47 normal subjects were compared. Cumulative amounts of IgM and IgG synthesized and secreted by unstimulated and pokeweed mitogen-stimulated cells over a 7-d period were determined in a solid-phase radioimmunoassay. Synthesis of IgM in unstimulated cultures and of both IgM and IgG in cultures stimulated with pokeweed mitogen was markedly reduced in patients with Hodgkin's disease, whereas the mean level of the spontaneous IgG synthesis was enhanced. The degree and frequency of in vitro abnormalities were not influenced by disease stage or histology. Depression of pokeweed mitogen-induced immunoglobulin synthesis did not correlate with excessive number of monocytes and it was unaffected by removal of phagocytic cells or addition to the cultures of monocytes from normal individuals. On the other hand, monocytes isolated from blood of patients with Hodgkin's disease were even more effective than normal monocytes in supporting pokeweed mitogen-induced immunoglobulin synthesis by normal phagocyte-depleted mononuclear cells. Synthesis of both IgM and IgG induced by pokeweed mitogen remained subnormal after addition to patient B cell cultures of autologous irradiated T cells or allogeneic normal T lymphocytes. T cells from patients with Hodgkin's disease appeared at least as effective as normal T cells in helping pokeweed mitogen-induced immunoglobulin production by normal B cells. However, when normal T cells were co-cultured with B cells from patients with Hodgkin's disease, spontaneous IgG synthesis declined, whereas the addition of patient T cells to normal B cells resulted in an increase of spontaneous IgG synthesis. In patients showing depression of pokeweed mitogen-induced immunoglobulin synthesis the lymphoproliferative response and immunoglobulin synthesis stimulated by Staphylococcus aureus bacteria of the Cowan first strain, a T cell independent B cell mitogen, were also markedly reduced. These studies demonstrate impairment of immunoglobulin synthesis by cultured lymphocytes from untreated patients with Hodgkin's disease after stimulation with polyclonal B cell activators and suggest that the in vitro abnormalities may be, at least in part, the result of a preexisting in vivo activation of lymphocytes in Hodgkin's disease patients.

In order to assess whether mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (CT), which is less expensive and more easily available than radiotherapy (RT), is at least as effective as RT in terms of cure rate and has less iatrogenic damage, 89 consecutive patients with Hodgkin's disease (HD) (pathological stage I-IIA) were randomly allocated to receive mantle plus lumbar bar RT (36-45 Gy) or CT (six courses of MOPP). Forty-five patients were entered in the RT group and 44 in the CT group. The median follow-up was 60 months. Complete remission (CR) was obtained in all patients in the RT group and in 40 of 44 patients in the CT group. Overall survival (OS) and disease-free survival (DFS) were, respectively, 87.2% and 72.7% in the CT group and 93.5% and 74% in the RT group. Survival probability of relapsing patients was 76% for the patients in the RT group and 45% in the CT group. Treatment-related complications were more severe in the CT group as compared with the RT group.

Pulmonary function tests were performed in 43 patients with Hodgkin's disease before mantle irradiation and at 3, 6, 9, 12 and 15 or more months thereafter. Treatment was given with a telecobalt unit to a total dose of 36 to 42 Gy, the higher dose being reserved for cases with considerable mediastinal involvement. The functional parameters explored included static and dynamic lung volumes, gas exchanges, ventilatory efficiency, and airway resistance. Measured parameters were expressed as a percentage of the pre-treatment value (PTV) in the individual patient. In the whole group, only small variations in the functional indices were observed at 3 to 6 months after mantle irradiation. In patients with normal PTVs a greater variation in static and dynamic volumes was observed at 3 to 6 months after mantle irradiation, with complete recovery thereafter. The gas exchange parameters also showed a similar variation at 3 to 6 months but no recovery was demonstrated in the subsequent examinations. No changes in ventilatory efficiency and airway resistance were observed. In patients with abnormal PTVs, usually presenting large mediastinal adenopathy, all parameters improved after mantle irradiation, and the favourable effect of tumour regression was probably more important than the radiation damage on the pulmonary parenchyma.

Sixty-seven patients with nodular sclerosis (Hodgkin's disease stages I and II) have been subclassified according to the cellular composition and the amount of fibrosis. Predominance of mature lymphocytes and rarity of Reed Sternberg cells were associated with less extensive disease at presentation and more favourable outcome. A less definite correlation to the amount of fibrosis was found.

In vitro lymphocyte response to phytohemagglutinins (PHA), concavalin A (Con A), and pokeweed mitogen (PW) was evaluated in untreated and treated patients with Hodgkin's disease (HD). The responding capacity to PHA was depressed, though not constantly, in the untreated patients compared with the response to lymphocytes from normal individuals. The depression was more evident, at group level, when the cells were stimulated with suboptimal concentrations of PHA. Radiotherapy constantly induced a strong decrease or a complete loss of the responding capacity of the cells which persisted at low levels for many months. Some years after the initial course of treatment, the response was clearly depressed, but it was better in patients in remission than during relapse. Splenectomy did not affect the responding capacity of the cells. The depressive effect induced by chemotherapy was apparently less marked and persistent than that of radiation. Con A- and PW-induced lymphocyte transformation usually paralleled the PHA-induced response. The depressed response to PHA was not due to an inhibitory activity of HD serum. Washed HD lymphocytes in fetal calf serum were not stimulated better than in autologous plasma, nor were HD sera able to depress the response of normal lymphocytes to PHA, Con A, PW, and PPD. Supernatants from HD lymphocytes cultured for 24 h without any stimulant, and extracts of these cells were also unable to affect the response of normal lymphocytes to PHA.

Serum IgE levels were evaluated in 119 untreated and 112 treated patients with Hodgkin's disease (HD). 38 of the nonatopic untreated patients showed significantly increased (> 300 IU/ml) IgE concentrations. No relationship could be found between increased IgE levels and depressed lymphocyte response to phytohemagglutinin (PHA) or the imbalance of TM and TG lymphocyte subsets. On the other hand, the mean level of suppressor activity elicitable from cells of untreated HD patients by concanavalin A preincubation did not differ significantly from that of healthy control subjects. In contrast, in treated patients, where there was a significant reduction in the number of circulating T lymphocytes, a further depression of the lymphocyte response to PHA, a more marked disproportion of TM and TG cell subsets and a noticeable fall in IgE concentration was found. These data suggest that increased IgE concentrations seen in untreated patients with HD are unrelated to the T-cell defects. They also suggest that hyperproduction of IgE is probably not invariably a consequence of a suppressor cell deficiency.

The present study was undertaken to determine the effect of radiotherapy on subpopulations of peripheral blood T cells from patients with Hodgkin's disease. T cell were purified from each specimen, and proportions and absolute numbers of T lymphocytes bearing receptors for the Fc portion of IgG (TG) and for Fc portion of IgM (TM) were enumerated by rosetting T cells with ox red blood cells (ORBC), which had been coated with anti-ORBC rabbit IgG or IgM, respectively. In untreated patients, the percentage of TG cells was significantly increased, and the percentage of TM cells was significantly decreased when compared with control values. In patients examined after radiotherapy, there was a severe depletion of total T lymphocytes. The percent and absolute values of TM cells were also markedly decreased in comparison with those found in either normal controls or untreated patients. In contrast, relative proportions of TG cells were significantly increased in the same treated patients, but the absolute numbers of these cells were essentially unchanged in comparison with those found before radiation therapy. There was a partial and progressive restoration of the number of TM lymphocytes some years after the treatment, but reduced percentages of TM lymphocytes and increased percentages of TG lymphocytes were still found in patients in continuous complete remission for at least five years or more. Similar alterations of the two T-cell subsets were also found in the peripheral blood of a small group of patients treated with radiation for testicular seminoma. These data clearly demonstrate that radiation therapy has a differential effect on identifiable and distinct subsets of cells in the human T-cell class.

Twenty patients with Hodgkin's disease limited to infradiaphragmatic (ID) nodes have been treated at the University and Hospital Radiotherapy Departments in Florence between 1960 and 1978. Clinicopathologic features and treatment modalities of these patients were reviewed and results compared with those of 2 similar series previously published by other authors. With respect to the patients with disease above the diaphragm, the ID presentation occurred more often in males in all the 3 reviewed series; a relative prevalence of the lymphocytic predominance histotype and of an older age was observed in 2 only of the 3 series; laparatomy seems unnecessary in lymphographic-negative patients. The analysis of therapeutic results suggests that inverted Y irradiation is a sufficient treatment when inguinal or lower iliac nodes only are affected; paraortic region and spleen involvement warrant a more radical program including the supradiaphragmatic irradiation or systemic chemotherapy.

The files and the roentgenographic documentation of 624 patients affected by Hodgkin's disease have been reviewed. The presence and location of involved nodes in the different lymph node chains of the mediastinum have been determined and correlated with the distribution of the main anatomoclinic prognostic parameters of the disease. Feminine sex, histology of nodular sclerosis, presence of constitutional symptoms and age younger than 36 were found to be significantly more frequent in patients with mediastinal adenopathies than in patients with a normal mediastinum. Patients with mediastinal adenopathy at presentation were also more likely develop pulmonary involvement as first evidence of new manifestation of disease after the primary treatment. A different probability to be affected by disease was evident among the different lymph node groups in the mediastinum. The involvement of hilar nodes appeared to accompany a more advanced stage of disease and to favour the adjacent lung extension.

The present study was undertaken to investigate the clinico pathologic features of Hodgkin's disease in a series of 114 elderly patients (age greater than 60 yrs), with particular reference to prognosis and treatment. Mixed cellularity (63.2%) was the most frequent histologic subtype. Clinical presentation was characterized by superficial lymphadenopathy (92%) and the presence of general symptoms (40.4%); mediastinal involvement was observed in 16.6% of cases; 17.5% of patients had a primitive infradiaphragmatic presentation. Thirty-eight patients were treated with radiotherapy alone (33.4%), 69 with chemotherapy alone (60.5%), while 7 received combined treatment. Complete remission was obtained in 85 patients (74.6%), 25 of whom relapsed. Elderly patients had an overall 5-year survival rate of 61.8% (considering only disease progression as a cause of death). Proportional-hazard multi variate statistics showed that survival was strongly influenced by the achievement of complete remission (P less than 0.001) and stage (P = 0.011). The achievement of complete remission was also significantly linked to the presence of constitutional symptoms, advanced stage and age greater than 70 yrs, as demonstrated by discriminant statistical analysis. The actuarial incidence of second cancer (28.7% at 15 yrs) was slightly higher than that previously reported in younger patients. Overall, our data indicate that the treatment of elderly patients with Hodgkin's disease should be aimed at achieving a cure, using the same therapeutic modalities commonly employed in younger subjects.

Of 750 patients with stage I, II or III Hodgkin's disease, admitted to the University and Hospital Radiotherapy Divisions, Florence, between 1960 and 1981, 28 (3.7%) had involvement of Waldeyer's ring (WR). In 25 patients there was associated involvement of upper cervical nodes. Other factors associated with WR involvement were age over 55 years, lymphocyte predominant histological sub-type, uninvolved mediastinum, and size of involved upper cervical nodes greater than that of involved lower cervical nodes. These factors help to define indications for prophylactic irradiation of WR.