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.

Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: ten-year results.

PURPOSE: To compare, in a prospective randomized trial, the efficacy of two different sequences of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in untreated advanced Hodgkin's disease. PATIENTS AND METHODS: From June 1982 to September 1990, 427 consecutive previously untreated patients with pathologic stage IB, IIA bulky, IIB, III (A and B), and IV (A and B) disease were prospectively randomized to receive two different sequences of MOPP and ABVD for a minimum of six cycles followed by radiotherapy (median dose, 30 Gy) to the nodal site(s) of pretreatment bulky disease. Of 415 assessable patients, 211 received one cycle of MOPP monthly, alternated with one cycle of ABVD (alternating regimen), and 204 patients received one-half cycle of MOPP alternated with one-half cycle of ABVD within a 1-month period (hybrid regimen). RESULTS: The complete remission (CR) rate was 91% with the alternating regimen and 89% with the hybrid regimen. At 10 years, the freedom-from-progression (FFP) rate was 67% versus 69% and the overall survival (OS) rate was 74% versus 72%, respectively. After attainment of CR, 85 patients relapsed in nodal (n = 60) versus extranodal with or without nodal (n = 25) sites. In patients given consolidative radiation because of bulky lymphoma, the true recurrence rate was 13%. A total of 23 second malignancies (6%) were documented, including 11 cases of acute nonlymphocytic leukemia. No cases of congestive heart failure attributable to doxorubicin or pulmonary toxicity related to bleomycin were documented. CONCLUSION: By delivering MOPP and ABVD, it is possible to cure approximately 70% of patients with advanced Hodgkin's disease. The two different drug sequences yielded superimposable results.

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.

Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy.

In an attempt to reduce some of the delayed sequelae associated with combined modality therapy in Hodgkin's disease, we randomly tested stages IIB, IIIA, and IIIB MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) v ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine). In 232 previously untreated patients, three cycles of either combination preceded and followed extensive irradiation. The complete remission rate was 80.7% following MOPP and 92.4% following ABVD (P less than .02). The 7-year results indicated that ABVD was superior to MOPP in terms of freedom from progression (80.8% v 62.8%; P less than .002), relapse-free survival (87.7% v 77.2%; P = .06), and overall survival (77.4% v 67.9%; P = .03). Moreover, the comparative iatrogenic morbidity showed that irreversible gonadal dysfunction as well as acute leukemia occurred only in patients subjected to MOPP, while cardiopulmonary studies failed to document significant laboratory differences between the two treatment groups. Present findings indicate that ABVD followed by extensive irradiation represents a valid therapeutic alternative to the widely used alkylating agent-containing regimens plus radiotherapy.

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.

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 decarbazine) or VBM (vinblastine, bleomycin and methotrexate) to reduce the incidence of MOPP-associated gonadal dysfunction and leukaemogenesis.

ABVD in the treatment of Hodgkin's disease.

This paper summarizes the clinical results achieved at the Milan Cancer Institute in advanced Hodgkin's disease through successive randomized studies performed during the last two decades. Long-term results confirm the therapeutic activity of a regimen containing bleomycin and doxorubicin, such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), as salvage treatment and as primary chemotherapy, either when combined with radiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Delayed iatrogenic morbidity (namely, sterility and leukemogenesis) was less frequently documented in ABVD-treated patients compared with MOPP-treated patients. Nevertheless, bleomycin- and anthracycline-containing regimens can be refined in the attempt to further decrease iatrogenic toxicity.

Third-line salvage chemotherapy in Hodgkin's disease.

CEP (CCNU, etoposide, and prednimustine) was tested as third-line chemotherapy in 40 patients resistant to both MOPP and ABVD. The observed response rate (complete remission, 35%, and partial remission, 25%) is encouraging. Treatment was generally well tolerated and all acute side effects were reversible.

CCNU, etoposide, and prednimustine (CEP) in refractory Hodgkin's disease.

Starting in February 1980, 58 patients with Hodgkin's disease refractory to both MOPP and ABVD received as third-line chemotherapy a combination of CCNU or lomustine, etoposide, and prednimustine (CEP). Complete response (CR) was achieved in 40% of cases and partial response (PR) in 14%. The median duration of CR was greater than 15 months, and the median survival of complete responders was longer than 24 months. In addition, CEP alternating with ABVD was given to 21 patients refractory to MOPP chemotherapy. In this series, CR was documented in 67% of patients with a median duration of 24+ months and a median survival of 36+ months. Treatment was generally well tolerated, and all acute side effects were reversible. Present findings indicate that CEP is an effective regimen in patients refractory to MOPP and ABVD.

Extended-field radiotherapy in favorable stage IA-IIA Hodgkin's disease (prognostic role of stage).

PURPOSE: The study was undertaken to evaluate the long-term results in a favorable subset of patients with pathological Stage IA-IIA treated with irradiation alone. METHODS AND MATERIALS: One hundred and forty-seven adults with laparotomy- Staged IA-IIA "favorable" Hodgkin's disease were treated with primary subtotal nodal irradiation. Patients with infradiaphragmatic presentation were irradiated through paraortic and inguino-iliac node chains (inverted Y field) followed by prophylactic mediastinal and supraclavicular fields. RESULTS: Actuarial overall survival (OS) at 7 years (median follow-up 77 months) was: 93% for the whole series, 94% for Stage I, and 92% for Stage II. The freedom from first progression (FFP) (80% for the whole series) showed a statistically significant difference (p = 0.008) between Stage I (88%) and Stage II (71%). By univariate analysis, stage alone had an independent prognostic significance for OS and FFP. Of the 29 relapsed patients, 8 were previously classified as Stage I and 21 as Stage II; 16 of 29 (55%) of the relapses occurred in the pelvis and 9 in extranodal sites. After salvage treatment with chemotherapy all patients achieved a second complete remission. Seven second malignancies (two acute nonlymphocytic leukemias, one preleukemic syndrome, and four solid tumors) have been detected so far. Hypothyroidism was observed in 16% of patients and a reversible pulmonary restrictive syndrome in 14% of cases, respectively. CONCLUSIONS: Within 7 years from radiation therapy, about one-quarter of the patients with Stage II disease will experience a relapse and need intensive salvage chemotherapy. This is not invariably successful and safe, for it may be complicated by either acute or potentially fatal long-term adverse effects, such as second malignancies and cardiac or pulmonary sequelae, in about 5% of patients. The high frequency of relapse in Stage IIA patients suggests a combined modality approach with relatively short-term chemotherapy not including alkylating agents.

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.

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.

Preliminary clinical experience with 4-epidoxorubicin in advanced human neoplasia.

4'-Epidoxorubicin (epi-DXR) was tested in 56 patients with various types of advanced malignancies. The pattern of acute toxicity was similar to that of doxorubicin (DXR), but epi-DXR produced a lower incidence of vomiting, stomatitis, alopecia, and myelosuppression. The study of cardiac toxicity, utilizing only noninvasive methods, indicated that epi-DXR also is cardiotoxic. The increase in the systolic time intervals after the first dose as well as after cumulative doses was slightly lower compared with that observed after DXR. Antitumor activity occurred in a variety of tumors including malignant melanoma, renal cancer, and rectal cancer, which are refractory to DXR. Present results suggest that further studies with epi-DXR are indicated.

Hodgkin's disease: the Milan Cancer Institute experience with MOPP and ABVD.

The report includes the essential therapeutic and toxic results following MOPP vs. MOPP/ABVD and MOPP vs. ABVD within a combined modality setting. The findings indicate that in stage IV the alternating regimen is superior to MOPP while in stage IIB-III ABVD plus radiotherapy yielded superior results associated with no treatment-induced sterility and leukemia compared with MOPP plus radiotherapy.

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.

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.

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.

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.

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

Toxic and therapeutic activity of 4'-epi-doxorubicin.

A Phase I-II study with 4'-epi-doxorubicin (epi-DX) was performed in 108 patients with various types of advanced malignancy. The pattern of acute toxicity was similar to that of doxorubicin (DX). However, epi-DX was better tolerated than DX because of comparative lower incidence of vomiting, stomatitis, complete alopecia and severe myelosuppression. Cardiac toxicity was studied by utilizing noninvasive methods, and the electrocardiographic results suggested a slightly lower cardiac damage after epi-DX compared to DX. Antitumor activity was documented in a variety of neoplasms, and objective response was also observed in those considered refractory to DX such as malignant melanoma and renal cancer. X