Cardiopulmonary response to exercise in patients with different degrees of lung toxicity after radio-chemotherapy for Hodgkin's disease.

The combination of mediastinal radiotherapy (RT) and polychemotherapy (CT) regimens can produce late toxic pulmonary and cardiac effects which often remain at the subclinical level. The aim of the present study was to investigate the cardiopulmonary response to exercise in this kind of patient. Therefore, 126 patients suffering from Hodgkin's disease were investigated after a follow-up of at least 5 years from the completion of the combined treatment. Sixty-two patients had been submitted to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-RT, 40 to ABVD-MOPP (mechloretamine, vincristine, procarbazine, prednisone)-RT and 24 to VEBEP (vincristine, epidoxorubicin, bleomycin, cyclophosphamide, etoposide, prednisone)-RT. The patients were divided into three groups on the basis of respiratory function: group 1 (67 patients), normal spirometry and lung transfer function for carbon monoxide (DLCO); group 2 (52 patients), normal spirometry and DLCO less than 80% of predicted; and group 3 (7 patients), total lung capacity and DLCO less than 80% of predicted. The patients were submitted to respiratory function evaluation and 2D-echocardiography before exercise, and to the determination of cardiac output by the acetylene rebreathing method before and during symptom-limited exercise on a cycloergometer using an incremental protocol. The patients of group 3 and to a lesser extent the patients of group 2 showed, in comparison to patients of group 1, a lower tolerance to exercise, a lower oxygen consumption, a higher respiratory rate, a lower O2 pulse and a lower cardiac output per oxygen uptake. These data indicated an abnormal exercise physiology in the patients with persistent pulmonary impairment, especially when the reduction of DLCO was associated with a decrease of total lung capacity. The lower exercise capacity seems to be due to a combination of decreased cardiac performance and an impairment of gas diffusion capacity.

A cell-based approach for the early assessment of the phospholipidogenic potential in pharmaceutical research and drug development.

Phospholipidosis is a term commonly used to indicate a phospholipid storage disorder; in affected cells, phospholipids accumulate in lysosomes that acquire a multilamellar morphological appearance. Cationic amphiphilic drugs (CADs) are suggested to induce phospholipidosis by direct interaction of xenobiotics with intracellular phospholipids or by the action of xenobiotics on the synthesis and metabolism of phospholipids. To date, electron microscopy (EM) represents the most reliable and the preferred method for the demonstration of phospholipidotic cell damage. Nevertheless, EM has a low throughput, it is expensive, and it is not suitable for screening purposes. We discuss here the assessment of the the phospholipidogenic potential of drugs using a cell culture-based model. In this test, intracellular phospholipids of treated U-937 cells (a human monocyte-derived cell line) were measured using the fluorescent probe Nile red. Eleven CADs reported to induce phospholipidosis in vivo and eight nonphospholipidogenic drugs were tested. Results obtained with the U-937 model confirmed the phospholipidogenic potential of drugs tested as described in the literature. Results have also been correlated with data obtained with a physical-chemical model (chromatographic hydrophobicity index measurement). Good correlation was obtained, confirming that the physical-chemical properties of CADs play a crucial role in the development of phospholipidosis. This work demonstrates that the U-937 model is a rapid and sensitive method for the determination of phospholipidosis-mediated cell damage. The specificity and the predictive potency observed make this method suitable for screening purposes in pharmaceutical development.

Effect of an intensive chemotherapy followed by mediastinal irradiation on pulmonary and cardiac function in advanced Hodgkin's disease.

Mediastinal irradiation combined with chemotherapy in patients with Hodgkin's disease have been associated with cardiopulmonary toxic effects that can last over the years. In this study we monitored pulmonary and cardiac function in 39 patients affected by advanced Hodgkin's disease (stage II B-III and IV) with mediastinal involvement and submitted to an intensive chemotherapy regimen (epirubicin, vincristine, ciclophosphamide, and etoposide) followed by involved field irradiation. Pulmonary function was verified with chest x-ray, spirometric parameters, arterial blood gas analysis, single breath CO transfer factor (DLCO), and its components Dm and Vc. Cardiac function was verified with electrocardiogram (EKG) and left ventricular ejection fraction (LVEF) by means of radionuclide angiocardiography. The median follow-up was 40 months. Spirometric parameters did no show modifications at the end of treatment, on the contrary they improved during the follow-up. Chest x-ray showed radiographic parenchimal damage in 51% of patients. DLCO remained constantly decreased. sEKG did not show significant modification, whereas LVEF significantly decreased at the end of treatment and remained persistently decreased during follow-up. None of the patients with reduction of DLCO or LVEF showed clinical symptoms of heart and pulmonary dysfunctions. One patient, 49 years old, suffered from myocardial infarction 25 months after the completion of radio-chemotherapy. These data indicate that this combined regimen can induce persistent pulmonary and cardiac damages at subclinical level.

Anaplastic lymphoma kinase (ALK) is not expressed in Hodgkin's disease: results with ALK-11 antibody in 327 untreated patients.

The t(2;5)(p23;q35) or other rare chromosomal abnormalities involving 2p23 upregulate the ALK gene, which is not expressed in normal lymphocytes. Thus, detection of ALK protein is presumptive evidence of these 2p23 abnormalities. The t(2;5) and ALK immunoreactivity are common in anaplastic large cell lymphoma of T/null-cell lineage. However, a small subset of cases of Hodgkin's disease (HD) have been reported to either carry the t(2;5) or express ALK. In this study, we have immunohistochemically evaluated 327 cases of HD with the ALK-11 antibody. ALK-11 is a well characterized polyclonal antibody raised against an intracellular portion of the ALK protein. We detected ALK-11 immunoreactivity in 8 (2.4%) cases of HD. We further studied these positive cases with ALK-1 monoclonal antibody, which reacts with an intracellular portion of ALK, similar to ALK-11. All 8 ALK-11 positive cases were negative for ALK-1. These results indicate that rare cases of HD may react with ALK-11 antibody, similar to previous reports by others using different polyclonal anti-ALK antibodies. However, the absence of ALK-1 expression in these HD cases suggests that ALK protein is not truly present and that polyclonal anti-ALK antibodies may rarely yield non-specific cross reactivity. These results further support the use of anti-ALK antibodies in the differential diagnosis of HD from ALCL.

Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms.

Following intraperitoneal or oral administrations, CHF 3381 ([n-(2-indanyl)-glycinamide hydrochloride]) protected rats against maximal electroshock (MES) test seizures. As glutamatergic pathways play a pivotal role in epilepsy, to better characterize the molecular mechanisms of action of CHF 3381, the drug effects on the binding of the excitatory amino acid antagonist [3H]-MK-801 in the presence of n-methyl-D-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [3H]-MK-801 specific binding in a noncompetitive fashion in respect to NMDA and polyamines recognition sites. CHF 3381 failed to change the kinetic characteristic of glycine B receptors labeled with [3H]-glycine; in contrast, it significantly increased K(d) values when the receptors were labeled with the more specific compound [3H]-MDL 105,519. CHF 3381 antagonized dopamine (DA)-induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [3H]-DA release from rat striatal slices, but it failed to change either the kinetic characteristics of D1, D2, or D3 receptors in synaptic plasma membranes (SPM) or the [3H]-DA uptake from striatal synaptosomes. Moreover, in primary cell cultures of cortical neurons, this drug exhibited glycine-independent neuroprotective effects against glutamate-induced excitotoxicity. It is concluded that this compound could have a potential use in several disease states where a pathological high level of NMDA receptor activation is thought to occur.

High-dose ifosfamide and vinorelbine as salvage therapy for relapsed or refractory Hodgkin's disease.

In an effort to improve results in patients with relapsed or refractory Hodgkin's disease (HD), an intensive regimen combining vinorelbine (25 mg/m2 i.v. days 1 and 5) and high-doses of ifosfamide (3000 mg/m2/d, days 1-4 by continuous infusion) with mesna uroprotection and G-CSF support was designed. Forty-seven patients were treated; 14 had failure to initial induction therapy and 33 had disease relapsed from an initial response. The response rate was 83%, with 21 complete (45%, CR) and 18 partial remissions (38%, PR). Partial response was achieved after a median of two cycles (range 1-3) and CR after a median of six cycles (range 2-10). At the end of ifosfamide and vinorelbine, 10 patients in CR, one in PR, and one with stable disease also received radiotherapy to nodal sites of relapse. Eleven patients who had undergone peripheral blood stem cell (PBSC) harvesting following ifosfamide-vinorelbine proceeded to receive high-dose chemotherapy (HDCT) and PBSC transplantation. The main toxic effect was grade III-IV neutropenia, documented in 65% of cycles with a median duration of 4 days, and non-haematological toxicity was mild. The combination of high-doses of ifosfamide and vinorelbine was well tolerated and an active regimen in treatment of patients with relapsed and refractory HD. It was not only useful as salvage therapy with or without consolidative radiotherapy but it also was a valuable induction regimen before high-dose intensification therapy followed by PBSC reinfusion in patients eligible for this approach.

Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study.

PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin's disease. PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m(2), was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1, 250 mg/m(2) to 1,500 mg/m(2). RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients' main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study. CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin's disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.

Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in Hodgkin's disease, the milan cancer institute experience.

Alterated cytokine secretion may play a role in determining Hodgkin's disease-related immunosuppression. The aim of this study was to analyze the clinical significance of interleukin-10 (IL-10) serum levels in 73 chemotherapy-naive patients with Hodgkin's disease. We evaluated the relationship between pretreatment circulating values of IL-10 and both the clinical characteristics of the disease as well as the prognosis in terms of freedom from progression and overall survival. Abnormally high pre-treatment serum levels (mean+/-standard error: 26.79+/-13.24 pg/ml) were detected in 33/73 (45%) patients. The percentage of patients with enhanced IL-10 secretion was significantly higher in the presence of advanced disease (56% vs 32%, P<0.03), systemic symptoms (57% vs 34%, P<0.04) and more than 3 involved sites (61% vs 36%, P<0.03). The high basal levels of IL-10 negatively influenced long-term results: at 8-years freedom from progression (FFP) and overall survival (OS) for patients with IL-10>6 pg/ml vs

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.

Long-term results of an intensive regimen: VEBEP plus involved-field radiotherapy in advanced Hodgkin's disease.

PURPOSE: This pilot study was conducted to evaluate the efficacy and toxicity of a new intensive drug regimen, combined with involved-nodal-field radiotherapy, in advanced Hodgkin's disease not treated by chemotherapy. PATIENTS AND METHODS: From September 1990 to March 1993, 73 evaluable patients with newly diagnosed stage IIB, III (A and B), and IV (A and B) Hodgkin's disease or who were relapsing after primary subtotal or total nodal irradiation were treated with eight cycles of etoposide, epirubicin, bleomycin, cyclophosphamide, and prednisolone (VEBEP) followed by radiotherapy (30-36 Gy) to the nodal site or sites of pretreatment disease. The median duration of follow-up was 68 months. RESULTS: The complete remission rate was 94% (95% CI: 86-98). At 6 years, freedom from progression and overall survival rates were 78% (95% CI: 68-88) and 82% (95% CI: 73-91), respectively. There was one episode of fatal sepsis after bone marrow aplasia that occurred after VEBEP and extended-field irradiation. Hematologic toxicity during chemotherapy was acceptable; without the support of growth factors, grade IV leukopenia and grade IV neutropenia, as determined within cycles, occurred in 38% and 85% of patients, respectively, but was reversible in the vast majority of patients by the day of treatment recycle. No episodes of epidoxorubicin-related cardiomyopathy or symptomatic pulmonary toxicity were documented. Overt and/or subclinical hypothyroidism occurred in 38% of cases. Gonadal damage was evident in the large majority of male patients but reversible in half of them, whereas permanent sterility was observed in females at least 35 years of age. No secondary leukemia has been so far detected. DISCUSSION: VEBEP followed by involved-nodal-field radiotherapy is an effective treatment for chemotherapy-naive Hodgkin's disease and is associated to acceptable rates of acute and intermediate-term toxicity. This intensive regimen, which does not routinely require the support of hematopoietic growth factors and can be delivered in an outpatient setting, warrants a prospective comparison in a randomized trial versus one of the more effective standard-combination regimens.

The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function.

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.

Lung function and serum concentration of tumor necrosis factor-alpha, interleukin-6 and fibronectin in patients treated with ABVD chemotherapy followed by radiotherapy for mediastinal Hodgkin's disease.

UNLABELLED: Mediastinal radiotherapy and polychemotherapy regimens can produce late toxicity leading to pulmonary fibrosis. There is evidence for the involvement of various cytokines in this process. We evaluated lung function in 20 patients with stage I-IIA Hodgkin's disease and submitted to chemotherapy including bleomycin (ABVD) and radiotherapy. Lung function tests were performed before, at the end of treatment and after a median of 12 months from the end of therapy. Tumor necrosis factor-alpha (TNF-alpha), fibronectin and interleukin-6 (IL-6) were determined on serum samples collected at the same time intervals. A modification of tests indicative of a restrictive lung disease was observed at end of treatment, whereas a persistent decline of transfer lung factor for carbon monoxide (DLCO) was documented. TNF-alpha constantly decreased, fibronectin increased and IL-6 showed a decline after treatment and a rise during the follow-up but the differences were not statistically significant. No significant correlations were observed between changes of lung function tests and serum cytokine concentration. CONCLUSIONS: This lack of correlation could be due to: a) incorrect selection of serum collection time, or b) to the fact that cytokine plasma concentration does not reflect events occurring in the alveolar phase.

Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease.

Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m2/d, days 1-4 through continuous intravenous infusion) and vinorelbine (25 mg/m2, i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals. Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.

Serum level of the soluble form of the CD30 molecule identifies patients with Hodgkin's disease at high risk of unfavorable outcome.

Preliminary reports suggested a prognostic significance for serum levels of soluble CD30 (sCD30) in patients with Hodgkin's disease (HD). In this study, we investigated the prognostic impact of sCD30 concentration at diagnosis in relation to the other recognized prognostic parameters in 303 patients with HD observed in three different institutions between 1984 and 1996. sCD30 levels were correlated with stage, presence of B symptoms, and tumor burden. High sCD30 levels entailed a higher risk of poor outcome, and the event-free survival (EFS) probability at 5 years for patients with sCD30 levels >/=100 and less than 100 U/mL was 59.9% (95% confidence interval [CI], 40.6% to 65.9%) and 87.5% (95% CI, 81.5% to 91.6%), respectively (P < .001). On the basis of the results of univariate analysis of 14 pretreatment characteristics, we included five prognostic factors (high sCD30 serum level, stage III-IV, B symptoms, low hemoglobin level, and age >/=50 years) into a multivariate model. High sCD30 and advanced stage were independently associated with an unfavorable prognosis. Their combined evaluation identified patients at high risk (stages III and IV and sCD30 >/=100 U/mL: EFS, 46.9%) and low risk (stages I and II with sCD30 <100 U/mL: EFS, 88. 7%) of treatment failure (P < .001). We conclude that the combined evaluation of sCD30 serum level and stage at presentation identifies patients with HD at high risk of an unfavorable outcome.

Soluble interleukin-2 receptors (sIL-2R) in Hodgkin's disease: outcome and clinical implications.

The aim of this study was to assess the prognostic role of soluble interleukin-2 receptors (sIL-2R) in Hodgkin's disease (HD) both in the achievement of complete remission (CR) and in predicting disease relapse. Between August 1988 and June 1993 sIL-2R serum levels were measured in 174 untreated patients; in 137 of them evaluation was repeated at the end of treatment and in 132 also during the follow-up. Baseline sIL-2R levels (mean+/-standard error) were significantly higher in patients than in 65 healthy control subjects (1842+/-129 U ml(-1) vs 420+/-10 U ml(-10, P< 0.0001). At the end of treatment 135 out of 137 evaluated patients achieved complete response (CR) and their mean sIL-2R serum levels were significantly lower than those at diagnosis (635+/-19 U ml(-1) vs 1795+/-122 U ml(-1), P=0.0001). After a median follow-up of 5 years, sIL-2R remained low in 114 patients in continuous CR, while they increased in 9 out of 12 patients (75%) who relapsed. However, a temporary increase was also observed in six patients (5%) still in CR. Treatment outcome in terms of freedom from progression was linearly related to sIL-2R levels. Our study confirms that patients with untreated HD have increased baseline levels of sIL-2R compared with healthy subjects and that their pretreatment values may be an indication of disease outcome similar to other conventional prognostic factors, such as number of involved sites, presence of B symptoms and extranodal extent.

Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD.

PURPOSE: This study analyzed long-term results in patients with Hodgkin's disease who were resistant to or relapsed after first-line treatment with MOPP and ABVD. Response to salvage treatments and prognostic factors were also evaluated. PATIENTS AND METHODS: The study population included 115 refractory or relapsed patients among a total of 415 patients treated with alternating or hybrid MOPP-ABVD followed by radiotherapy (25 to 30 Gy) to initial bulky sites. The median follow-up duration of the present series was 91 months. Thirty-nine of 115 patients (34%) showed disease progression while on primary treatment (induction failures); 48 relapsed after complete remissions that lasted < or = 12 months and 28 after complete remission that lasted more than 12 months from the end of all treatments. RESULTS: At 8 years, the overall survival rate was 27%, being 54% and 28% in patients whose initial complete remission was longer or shorter than 12 months, respectively, and 8% in induction failures (P < .001). Response to first-line chemotherapy and disease extent at first progression significantly influenced long-term results, as well as the incidence and duration of complete remission. CONCLUSION: The present data confirm previous observations that showed the main prognostic factors to influence outcome after salvage treatment are response duration to first-line therapy and disease extent at relapse. The results indicate that patients who relapse after the alternating MOPP/ABVD regimen have a prognosis similar to that of patients who relapse after a four-drug regimen (MOPP or ABVD alone). Re-treatment with initial chemotherapy seems the treatment of choice for patients who relapse after an initial complete remission that lasts greater than 12 months, while the real impact of high-dose chemotherapy or new regimens should be assessed in resistant patients.

Comparison of gallium scan, computed tomography, and magnetic resonance in patients with mediastinal Hodgkin's disease.

BACKGROUND: In patients with Hodgkin's disease, the use of gallium-67 scintigraphy (Ga-67) compared to conventional staging and restaging techniques is still controversial. In particular, in a combined modality treatment with chemotherapy and radiotherapy given in sequence, its role in detecting active disease after chemotherapy may be useful in planning the subsequent radiotherapeutic strategy. PATIENTS AND METHODS: From March 1990 to September 1994, 125 patients with previously untreated histologically proven Hodgkin's disease were enrolled in two different prospective trials according to clinical stage. Staging procedures included Ga-67, chest-abdominal computed tomography (CT), and/or magnetic resonance (MR). All three tests were performed in 53 patients at staging and in 47 at restaging. Results of Ga-67 at staging were compared to conventional procedures or pathological findings. Results of Ga-67, CT scan, and MR at restaging were compared to disease outcome during the follow-up. Finally a cost/benefit ratio for each test was determined. RESULTS: At staging, Ga-67 showed lower sensitivity than CT and MR (90 vs. 96 and 100%, respectively) because of the number of false-negative images. Nevertheless, by using both CT and Ga-67 scan, the sensitivity is equal to that observed with MR (100%). At restaging, Ga-67 is superior to CT scan and equivalent to MR in detecting true negative patients (specificity: 98% vs. 45% vs. 92%). CONCLUSIONS: As a single technique, Ga-67 scan cannot substitute for CT scan or MR in staging patients with Hodgkin's disease. Nevertheless, Ga-67 scan has an important role in defining complete remission after treatment and therefore in planning subsequent treatment. Considering the lower costs of CT scan plus Ga-67 ($320) versus MR alone ($810), the two tests may be considered procedures of choice in staging as well as in restaging patients with Hodgkin's disease.

Late pulmonary toxicity after treatment for Hodgkin's disease.

The combination of mediastinal radiotherapy (RT) with chemotherapy (CT) including bleomycin is associated with an increased risk of pulmonary toxicity. The aim of the present investigation was to evaluate late pulmonary effects of RT plus CT consisting of the ABVD regimen in patients suffering from early stage Hodgkin's disease. For this purpose pulmonary function was serially evaluated before, at the end and at least 1 year after therapy in 32 patients (median age 28 years) with Hodgkin's disease stages IA,B-IIA. Treatment consisted of four cycles of ABVD chemotherapy followed by mediastinal irradiation at the median dose of 36 Gy (range 30.6-43.2). At the end of treatment, resting mean pulmonary function tests showed a significant decline of forced expiratory volume in 1 second (FEV1), forced expiratory flow at 25-75%, (FEF25-75%), total lung capacity (TLC), vital capacity (VC) and carbon monoxide diffusing capacity (DLCO). The decline of TLC, VC and DLCO, indicative of a pulmonary defect of restrictive type, persisted 1 year from the end of therapy. Only seven patients developed symptoms of cough and mild shortness of breath with effort. These data confirm that RT combined with short term ABVD result in pulmonary dysfunction that does not seem to have clinical significance.

Vinorelbine: a new promising drug in Hodgkin's disease.

Vinorelbine is a new semisynthetic vinca alkaloid that differs chemically from vinblastine by a substitution of the catharanthine moiety. The powerful cytostatic activity of vinorelbine against murine tumors, human malignant cell lines and human tumor xenografts in nude mice has been demonstrated. Phase I-II studies of intravenous vinorelbine, administered weekly as single agent or in combination chemotherapy have been conducted since 1986. Results suggest that vinorelbine has high activity in non-small cell lung cancer, breast cancer and cisplatin-resistant ovarian cancer with mild toxicity, being neutropenia the major treatment related complication. In this paper we critically review the activity of vinorelbine in pretreated Hodgkin's patients. Available results strongly suggest the inclusion of this drug in first or second line chemotherapy regimens in Hodgkin's disease.