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Biomedical subjects

G Bonadonna

Publications and source records attributed to G Bonadonna.

At least 127 records · Page 7Linked to original sources
PubMed1991

Testicular dysfunction in Hodgkin's disease before and after treatment.

Over a 7-year period, semen analysis was performed in 92 male patients with Hodgkin's disease prior to therapy. In 67% of patients semen revealed a decreased chance for fertility (i.e. oligozoospermia, asthenozoospermia and/or teratozoospermia). The mean basal levels of follicle-stimulating hormone (FSH), luteinising hormone, testosterone and prolactin were in the normal range. In 77 patients in complete remission after alternating MOPP/ABVD (mechlorethamine, vincristine, procarbazine, prednisone; doxorubicin, bleomycin, vinblastine, dacarbazine), testicular function was assessed. 87% of patients were azoospermic, 9% had semen abnormalities and only 4% were normospermic. Recovery of spermatogenesis was documented in only 17 of 42 (40%) reassessed patients after a median time of 27 months and was generally not affected by pretreatment sperm quality. After chemotherapy, the mean value of FSH [20.45 (S.E. 1.7) mUI/ml] was significantly superior compared with that of the mean pretreatment values. No difference was documented in the mean testosterone and prolactin values tested before and after treatment. Our findings indicate that, of patients with Hodgkin's disease, about half are affected by hypogonadism before starting chemotherapy. By utilising alternating MOPP/ABVD, persistent testicular dysfunction was documented in half of the patients.

Adolescent↗
PubMed1991

Tropisetron plus haloperidol to ameliorate nausea and vomiting associated with high-dose alkylating agent cancer chemotherapy.

Tropisetron is a novel antiserotoninergic drug with potent and specific activity against cancer chemotherapy-induced emesis. High-dose cyclophosphamide or high-dose melphalan are chemotherapeutic regimens associated with severe nausea and vomiting refractory to current antiemetic medications. We compared in a randomised open label study the antiemetic efficacy of tropisetron and alizapride in a first group of 32 consecutive patients treated with high-dose alkylating agent chemotherapy with or without autologous bone marrow transplantation. Tropisetron was more effective than alizapride in reducing vomiting episodes. In the first 24 h of treatment the median number of episodes in patients treated with tropisetron was 5 compared with 9 episodes in the alizapride group (P = 0.005). In the 72 h study period the median number of emetic episodes was 6 in the tropisetron group and 12 in the alizapride group (P = 0.004). In a second group of 26 consecutive patients, a combination of tropisetron plus haloperidol, a dopamine antagonist, was employed for prevention of emesis. This combination was more effective than tropisetron as single agent in preventing emetic episodes, as the median number of emetic episodes in the 72 h of observation was only 3, while they were 6 in the tropisetron group. The side-effects of tropisetron were mild and reversible upon discontinuation of the drug. We conclude that tropisetron is an effective antiemetic drug when employed in high-dose alkylating agent chemotherapy, and that its activity is potentiated by the association with haloperidol.

Adult↗
PubMed1991

Primary and salvage chemotherapy in advanced Hodgkin's disease: the Milan Cancer Institute experience.

This paper reviews the most relevant therapeutic results achieved by the Milan Cancer Institute through successive randomized studies in advanced Hodgkin's disease. The experience achieved confirms the therapeutic importance of an anthracycline-containing regimen such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) as salvage treatment and as primary chemotherapy, either when combined with irradiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Anthracycline-based combinations can be further refined to decrease toxicity. The biologic aspects of drug-sensitive v drug-resistant tumor cells and the accurate definition of prognostic categories at the time of first treatment failure are also discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Prolonged disease-free survival after high-dose sequential chemo-radiotherapy and haemopoietic autologous transplantation in poor prognosis Hodgkin's disease.

Although effective in achieving durable remission in selected tumors incurable by conventional-dose chemotherapy, high-dose regimens requiring bone marrow transplantation remain too toxic for widespread use. With the aim to improve the therapeutic index of high-dose therapy, we have developed a novel program whereby several non-cross-resistant agents (including total body irradiation at myeloablative dose) were delivered sequentially rather than concurrently. The regimen has been tested in 25 patients with Hodgkin's disease refractory to primary chemotherapy (MOPP and ABVD) or relapsed within 12 months after first complete remission. The efficacy of the sequential regimen (72% complete response rate, 49% event-free survival and freedom from progression at four years, with a median observation of 3.5 years for patients remaining alive) compares favorably with the activity so far reported for the most effective high-dose regimens. Toxicity was low; no toxic deaths occurred and only three life-threatening adverse events were documented after autografting. The excellent tolerability of the final myeloablative course most likely reflects the speed and completeness of haematologic recovery that followed the use of peripheral blood progenitors as the sole or additional source of myeloid stem cells. The reduction of haematologic toxicity was further emphasized when rhG-CSF was employed to both shorten post-chemotherapy neutropenic intervals and to collect large amounts of peripheral blood stem cells. We expect that the use of growth factors will have a major impact on the therapeutic index of high-dose regimens. This, in turn, will confirm their safety as primary treatment in selected high-risk subsets.

Adult↗
PubMed1991

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes.

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.

Adenocarcinoma↗
PubMed1991

Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes.

In the attempt to improve current adjuvant results in patients with one to three positive axillary lymph nodes, in November 1981 we activated a prospective randomized study to assess the effectiveness of intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) for 12 courses versus CMF for eight courses followed by Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) for four courses. The 5-year results were evaluated in a total of 486 patients entered into the study up to December 1987. CMF chemotherapy was delivered IV for a total of 12 courses when given alone and for eight courses when followed by four courses of Adriamycin. All drugs were recycled every 3 weeks. Rather than temporarily reducing doses, drug administration was delayed for 1 to 2 weeks in the face of myelosuppression on the planned day of treatment. After a median follow-up of 61 months, no significant differences were evident between the treatment groups in terms of relapse-free (CMF 74% v CMF followed by Adriamycin 72%) and total survival (CMF 89% v CMF followed by Adriamycin 86%). Drug treatments were fairly well tolerated and devoid of life-threatening toxicity. Present results, which were not influenced by menopausal status, indicate that Adriamycin given after CMF failed to improve treatment outcome over CMF alone. However, the role of Adriamycin in an adjuvant setting remains to be further clarified. Considering the good 5-year results achieved in this study at the expense of minimal toxicity, full-dose CMF remains, at present, the adjuvant chemotherapy of choice for patients with one to three positive nodes.

Adenocarcinoma↗
PubMed1990

Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more.

In 165 women with breast cancer who were candidates for mastectomy because the largest diameter of the tumor was 3 cm or more, we administered primary chemotherapy in the attempt to substitute conservative for mutilating surgery. We then systematically quantitated tumor reduction by clinical, radiologic, and histopathologic evaluations. Five consecutive groups of 33 patients received cyclophosphamide, methotrexate, and fluorouracil (CMF); fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC); or fluorouracil, epirubicin, and cyclophosphamide (FEC). The regimens for the five groups were as follows: group 1, three cycles of CMF; group 2, four cycles of CMF; group 3, three cycles of FAC; group 4, four cycles of FAC; and group 5, three cycles of FEC. In response to primary chemotherapy, 157 of the 161 assessable patients showed measurable tumor shrinkage; progressive disease was documented in four. Tumor shrinkage to less than 3 cm was documented in 127 (81%) of the 157 women subjected to surgery, thus allowing a breast-saving procedure, rather than modified radical mastectomy, in these 127 women. Histopathologic complete remission was documented in seven patients. Tumor response was unrelated to age, menopausal status, DNA content (ploidy), [3H]thymidine-labeling index, drug combination used, or number of treatment cycles in excess of three. The degree of response was inversely proportional to the initial tumor size, and the frequency of response was greater in receptor-negative tumors. Severe vomiting and hair loss were less frequent with CMF than with anthracycline-containing regimens, and the frequency of severe leukopenia and thrombocytopenia was minimal. Our results challenge the classical indication for primary mastectomy by showing that use of full-dose primary chemotherapy, sequentially combined with conservative surgery and radiation, can offer an effective and safe alternative to women concerned about the preservation of body integrity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Pharmacology and clinical toxicity of 4'-iodo-4'-deoxydoxorubicin: an example of successful application of pharmacokinetics to dose escalation in phase I trials.

In a prospective phase I trial involving 35 patients with metastatic carcinoma, we tested a pharmacokinetic strategy for guiding dose escalation of the anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX), a new analogue reported to be more potent and less toxic than doxorubicin. This strategy is potentially a safe and more rapid way of determining the maximum tolerated dose (MTD) of anticancer agents. Retrospective studies have shown that the total plasma drug exposure after a dose lethal to 10% of mice (LD10) is approximately equivalent to the total exposure produced in humans by the MTD. Thus, we intended to aim dose escalation in humans to achieve the area under the curve for I-DOX plasma concentration x time (AUC) equivalent to that produced in mice by an LD10. However, differences in I-DOX pharmacokinetics and metabolism in BDF1 mice and humans at the initial dose prevented immediate application of this strategy. Therefore, we escalated the dose by the modified Fibonacci scheme while investigating the pharmacology of I-DOX and its major plasma metabolite 4'-iodo-4'-deoxy-13-dihydrodoxorubicin (I-DOXOL). Plasma pharmacokinetics was characterized by rapid elimination and extensive metabolism of I-DOX to I-DOXOL. The ratio of I-DOXOL to I-DOX plasma AUC was 12.8 +/- 7.3 SD. The plasma pharmacokinetics of I-DOX and I-DOXOL were linear in the range of tested doses (2-90 mg/m2). The LD10 in mice was 6.8 mg/kg for I-DOXOL and 6 mg/kg for I-DOX, and the concentration of drug that inhibited by 50% (IC50) the growth of human granulocyte-macrophage colony-forming units (CFU-GM) was 80 nM for I-DOXOL and 50 nM for I-DOX. From these findings, we concluded that the toxic effects of I-DOX and I-DOXOL are equivalent and reset the pharmacokinetic target of escalation to the sum of I-DOX and I-DOXOL AUCs at I-DOX LD10. Then we safely applied pharmacokinetically guided escalation to determine the MTD (80 mg/m2). The plasma AUC of I-DOX and I-DOXOL at the human MTD is 71% of the AUC at mouse LD10. The only dose-limiting toxic effect was severe granulocytopenia.

Adult↗
PubMed1990

Prognostic factors for patients with diffuse large cell or immunoblastic non-Hodgkin's lymphomas: experience of the non-Hodgkin's Lymphoma Pathologic Classification Project.

Prognostic factors for long-term survival of 312 patients with diffuse large cell or immunoblastic non-Hodgkin's lymphoma are presented based on analysis of the multiinstitution clinicopathologic study sponsored by the National Cancer Institute. At the time of analysis, 75% of the patients had died and the median follow-up for patients still alive was 11 years. The distribution of Ann Arbor stages was 21% stage I, 32% stage II, 17% stage III, and 30% stage IV. Factors of prognostic significance for survival included age, stage, histologic subtype, presence of B symptoms, size of the largest lesion, number of extra-lymphoid organs involved, and extent of lymphatic involvement. Recursive partitioning analysis suggested a prognostic classification system based on stage, age, size of the largest lesion, and presence of mediastinal involvement. Stage I patient less than 50 years of age had a 10 year survival rate of 65% compared to 36% for older stage I patients. Stage II patients less than 65 years old without bulky lesions or mediastinal involvement had a 10 year survival rate of 45% compared to 10% for the poorer risk stage II patients. Although statistically significant prognostic factors were identified for the stage III/IV patients, they were not strong discriminants of 5-10 year survival rate. Because of the correlation among potential prognostic factors, there is no uniquely best classification system. Reasons for discrepancies among reported prognostic factor analyses are discussed, and a prognostic grouping that synthesizes our results with those of others is proposed.

Adult↗
PubMed1990

Prognostic factors in locally advanced noninflammatory breast cancer. Long-term results following primary chemotherapy.

Since 1973 we have treated T3b-T4 (stage III) breast cancer with various forms of multidisciplinary approaches through prospective trials. The present report analyses the 10-year results of 277 patients. Primary chemotherapy consisted of adriamycin plus vincristine given for three or four cycles prior to high-energy irradiation or surgery. In 205 of 277 (74%) additional chemotherapy was planned following the local-regional modality. Primary chemotherapy yielded complete plus partial remission in 62% (CR 7%). Long-term freedom from progression and overall survival were significantly improved by the addition of chemotherapy following local-regional treatment (radiotherapy or surgery). Further chemotherapy was able to significantly affect treatment outcome when it was analyzed both singly and in the presence of other prognostic variables. Thus, in our experience, the variables significantly affecting the 10-year results were represented by duration of treatment and tumor cell burden expressed by size of primary malignancy and clinical nodal status. Locally advanced breast cancer appears a pleomorphic disease difficult to control over a long period of time because of its frequent presentation with bulky tumor and the very high risk of disseminated micrometastases. Thus, the management of this stage of disease almost invariably requires a multidisciplinary approach.

Adult↗
PubMed1990

Total body irradiation and high-dose melphalan with bone marrow transplantation at Istituto Nazionale Tumori, Milan, Italy.

The technique of total body irradiation (TBI) developed at Istituto Nazionale Tumori, Milan, Italy, is described. This technique consists of i) administration of 12.5 Gy and 14.85 Gy TBI for autologous and allogeneic bone marrow transplantation respectively; ii) in all cases in vivo dosimetry of absorbed TBI dose; and iii) radiation doses to lungs higher than previously described. As of June 1988, seventeen patients with Hodgkin's disease and four with lymphoblastic lymphoma received TBI and 120-180 mg/m2 melphalan. Respiratory function was prospectively evaluated demonstrating moderate and transient reduction of pulmonary function.

Adolescent↗
PubMed1990

Current issues in the management of advanced Hodgkin's disease.

During the past two decades, the standard drug regimen has been the MOPP program and its variants MVPP or ChlVPP. The search for less toxic chemotherapy in terms of decreased sterility and myelodysplasia-acute non-lymphocytic leukemia prompted the design of ABVD. Recent data from different countries indicate that adriamycin-based combinations as ABVD or MOPP alternating with ABVD appear very useful to improve treatment outcome compared to MOPP alone. The combination of chemotherapy and radiation has been utilized by many institutions in practically all stages of Hodgkin's disease. The intent is to optimize the cure rate and with the theory that less intensive therapy of both modalities may carry a lower risk of iatrogenic complications without compromising treatment outcome. In patients relapsing from curative radiotherapy, combination chemotherapy such as ABVD or MOPP/ABVD is recommended as the most effective salvage regimen, associated to further irradiation if technically feasible. In patients relapsing from primary chemotherapy, clinicians have first to take into consideration whether the duration of first complete remission is longer than 12 months. In this case, retreatment with the same drug regimen remains the treatment of choice. In patients with progressive lymphoma while on primary chemotherapy or showing remission duration lesser than 12 months, non-cross resistant chemotherapy or high dose therapy plus autologous bone marrow transplantation are indicated.

Antineoplastic Combined Chemotherapy Protocols↗