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G Bonadonna

Publications and source records attributed to G Bonadonna.

At least 19 recordsLinked to original sources
PubMed2006

Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials.

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.

Combined Modality Therapy↗
PubMed2005

Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process.

PURPOSE: The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy. PATIENTS AND METHODS: Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy. RESULTS: (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent. CONCLUSIONS: At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer.

BACKGROUND: To study prospectively the activity of primary chemotherapy with cisplatin, fluorouracil and leucovorin (PFL) in patients with paranasal cancer receiving surgery and postoperative radiotherapy. PATIENTS AND METHODS: Forty-nine patients, previously untreated, with resectable paranasal carcinoma were enrolled. PFL (leucovorin 250 mg/m2/day for 5 days as a 120 h continuous infusion (c.i.), 5-fluorouracil 800 mg/m2/day from day 2 as a 96 h c.i. and cisplatin 100 mg/m2 day 2 q 3 weeks) was planned for five courses. RESULTS: Thirty-two patients (65%) completed three or more chemotherapy courses. Two deaths from thrombotic events were observed after the first cycle. Eight cardiac toxicities were recorded during chemotherapy causing treatment discontinuation. Objective response to PFL was observed in 21 patients [43%; 95% confidence interval (CI) 29% to 58%], including four complete responses (CRs) (8%; 95% CI 2% to 20%) and 17 partial responses (PRs) (35%). Pathological complete remission (pCR) was achieved in eight of 49 patients (16%). At 3 years, overall survival was 69% and event-free survival 57%. Overall and event-free survival in patients achieving pCR is 100%. CONCLUSIONS: PFL is active in paranasal cancer. Patients who attain a pathological complete remission have a favorable prognosis. Cardiovascular complications represent the limiting toxicity. Primary chemotherapy combined with surgery-sparing treatment approaches deserves further investigation.

Adult↗
PubMed2002

Double-peaked time distribution of mortality for breast cancer patients undergoing mastectomy.

PURPOSE: To gather information on the natural history of breast cancer from the time-distribution of deaths of patients undergoing mastectomy alone. PATIENTS AND METHODS: A total of 1173 patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy without any adjuvant therapy for operable breast cancer, were examined. The risk of death at a given time after surgery was studied utilizing the death-specific hazard rate. The risk distribution was assessed relative to tumor size, axillary lymph node involvement, and menopausal status. RESULTS: The hazard rate for death presented an early peak at about the 3rd-4th year after surgery and a second late peak near the 8th year. The double-peaked pattern was almost completely generated by N+ patients, while N- patients did not show relevant structures. Pre-menopausal patients showed an initial mortality wave covering about 6 years, with maximum height at the 4th year, followed by a peak 8 years after surgery, while post-menopausal patients showed an early high mortality surge peaking at the 3rd year, followed by a modest increase at the 8th year. Detailed analysis revealed that post-menopausal patients with early mortality had significantly larger tumors and higher nodal involvement, while no special trait characterized the corresponding pre-menopausal patients. Moreover, patients of the late mortality peak were more likely to have suffered early local-regional or contra-lateral recurrence or to be pre-menopausal patients recurring anywhere at the second recurrence peak. CONCLUSION: The double-peaked hazard curve confirmed the occurrence of discontinuous features in the natural history of breast cancer for patients undergoing mastectomy. Indeed, the mortality pattern maintained definite signs of the previous double-peaked structure of recurrences. However, death events did not parallel the corresponding recurrence events and, moreover, pre and post-menopausal patients revealed dissimilar survival after recurrence, at least for early deaths. These findings, showing disconnection of mortality pattern from recurrence pattern for subsets of patients, suggest that parameters other than those influencing the recurrence risk may determine the survival of recurred patients.

Adult↗
PubMed2002

Multimodal treatment with primary single-agent epirubicin in operable breast cancer: 5-year experience of the Michelangelo Cooperative Group.

BACKGROUND: To assess the efficacy of primary single-agent epirubicin (120 mg/m(2) every 3 weeks for three cycles) in reducing tumor burden in operable breast cancer >or=2.5 cm in largest diameter at diagnosis and its effect on the rate of conservative surgery. PATIENTS AND METHODS: A total of 319 eligible patients, who were all candidates for mastectomy, were enrolled on to a multicenter prospective non-randomized study. Tumor response was assessed clinically and pathologically. Relapse-free and overall survival were assessed on major prognostic variables. RESULTS: After primary epirubicin, complete disappearance of invasive neoplastic cells accounted for only 2.6% of patients, but 40% of patients had their primary tumor downstaged to <or=2 cm in diameter. Conservative surgery was performed in 67% of patients. At a median follow-up of 5 years, both primary tumor size at diagnosis (P <0.01) and pathological nodal involvement (P <0.01) significantly influenced treatment outcome. After conserving surgery and breast irradiation, local recurrences accounted for approximately 4% of patients. CONCLUSIONS: This multicenter study confirms that three cycles of full-dose epirubicin can avoid mutilating surgery in a high proportion of patients with tumors not amenable to primary conservative surgery. This multimodal treatment can be safely administered outside of clinical trials in patients presenting with large tumors and with a desire to preserve their body integrity.

Adult↗
PubMed2001

Does surgery modify growth kinetics of breast cancer micrometastases?

Surgery should be considered as a major perturbing factor for metastasis development in laboratory animals. The different time distribution of mortality for 1173 patients undergoing mastectomy in comparison with 250 untreated patients suggests that primary tumour removal could result in changes of the metastatic process even for breast cancer.

Adult↗
PubMed2001

Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.

PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS). RESULTS: Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively. CONCLUSION: CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.

Aged↗
PubMed2001

Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation.

PURPOSE: To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer. PATIENTS AND METHODS: All 1,000 patients from three prospective trials of adjuvant chemotherapy containing doxorubicin (n = 637, median total dose of 294 mg/m(2)) or not containing the anthracycline (cyclophosphamide, methotrexate, and fluorouracil [CMF] regimen alone, n = 363) were analyzed for the relative incidence of congestive heart failure (CHF) and myocardial infarction (MI) during 14 years of follow-up. The 462 women continuously free of disease as of February 1996 were recalled, and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction (LVEF) to assess the relative incidence of abnormalities in long-term survivors. RESULTS: Among the 1,000 patients, there were six cases of CHF and three cases of MI. Cumulative cardiac mortality accounted for 0.4% (doxorubicin-treated = 0.6%; CMF-treated = 0). Eighteen (5%) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic (< 50%, n = 8) or borderline (50% to 55%, n = 10) LVEF. Systolic dysfunction was higher in doxorubicin-treated (15 of 192; 8%) than in CMF-treated patients (three of 150; 2%). Breast irradiation had a significant impact on the occurrence of early CHF (four of 116; 3%), but not on systolic dysfunctions. CONCLUSION: At longer than 10 years of follow-up, the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease.

Adult↗
PubMed2001

Adjuvant and neoadjuvant treatment of breast cancer.

Treatment of early breast cancer has been revolutionized during the past 30 years and new data continue to refine our knowledge of systemic treatments for this stage of disease. The updated worldwide overview has confirmed that, in terms of recurrence and survival, the balance of the known long-term benefits and risk favors some months of adjuvant polychemotherapy and/or a few years of tamoxifen for a wide range of patients. Both the overview and individual trials have shown that anthracycline-containing regimens can achieve additional reduction of the risk of disease relapse and death over cyclophosphamide, methotrexate, and fluorouracil (CMF)-like regimens. Paclitaxel-containing regimens appear promising, but require additional confirmation with longer follow-up. By contrast, controversy still exists on the role of high-dose chemotherapy in high-risk patients. Primary (neoadjuvant) chemotherapy is a new modality to treat large operable breast cancers and offers the possibility of breast conservation with treatment results at least similar to those achieved with classical adjuvant regimens. In the near future, newer agents and information gained on the role of prognostic and predictive factors will probably increase the effectiveness of adjuvant and neoadjuvant treatments.

Antibiotics, Antineoplastic↗
PubMed2001

Phase I/II study of gemcitabine in association with vinorelbine for metastatic breast cancer.

BACKGROUND: Gemcitabine (G) and vinorelbine (V) have favorable safety profile and antitumor activity in metastatic breast cancer. To exploit their different mechanism of action and lack of overlapping toxicity, we performed a phase I and II study of G and V in combination. PATIENTS AND METHODS: Fifty-three patients with metastatic breast cancer were treated. In the dose-finding phase, seven cohorts of patients (22 women) received increasing doses to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination. Patients recruited in the phase II portion of the study (31 women) received the dose level immediately below the one defined as MTD (i.e., G 1200 mg/m2, V 30 mg/m2, on day 1 and day 8, every 3 weeks). RESULTS: Dose escalation was discontinued at G 1400mg/m2 and V 30 mg/m2 because of toxic death due to thrombocytopenia and CNS hemorrage. No other limiting toxicities were observed, and tolerability was similar at all dose levels studied in the escalation portion of the study. The main toxicity was granulocytopenia of grade 3/4 in 36 and 48% of the patients on phase I and II respectively, without episodes of neutropenic fever. Thrombocytopenia was uncommon. Other side effects were usually mild to moderate. In 46 evaluable patients, the response rate was 24% (complete response 7%, partial response 17%). Disease stabilization was observed in further 17%. The median duration of response was 12 months (range 5-14) and the median survival was 20 months (range 1 to 45+). CONCLUSIONS: G and V, on day 1 and 8 of 3-weekly cycles, can safely be administered to patients with metastatic breast cancer at the dose of 1200 and 30 mg/m2, respectively. The antitumor activity of G and V in combination was similar to that reported when using either drug as single agent.

Adult↗
PubMed2001

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.

Adult↗
PubMed2001

Breast cancer.

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Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Cell proliferation and outcome following doxorubicin plus CMF regimens in node-positive breast cancer.

At the Istituto Nazionale Tumori of Milan, a randomised adjuvant chemotherapy trial was carried out from 1982 to 1990 to compare alternating with sequential regimens of doxorubicin and CMF in 403 patients with more than 3 positive axillary nodes. Tumour proliferative activity was determined in 71% (285 cases) of women entering the clinical study. We investigated the relation between proliferative rate, determined as the [(3)H]thymidine labelling index (TLI) on tumour specimens obtained at diagnostic surgery, and clinical outcome following the 2 regimens, in which the same drugs were administered at the same dose intensity but with a different schedule. A high TLI was significantly associated with 12-year overall relapse (P = 0.009), distant metastasis (P = 0.001), and death (P = 0.002), even in the presence of information provided by tumour size, lymph node involvement, oestrogen receptors, and treatment regimen. The highest relapse-free survival (RFS) probability (45%, 95% CI 34-55%) was observed for patients with tumour TLI <5% and subjected to the sequential treatment. The lowest RFS probability (11%, 95% CI 0-26%) was observed for patients with tumour TLI >9% following the alternating regimen. Intermediate RFS probabilities, ranging from 23% to 34%, were observed for the other kinetic subgroups following the 2 treatment regimens. The benefit of sequential administration of doxorubicin and CMF was evident mainly in patients with tumours at low to intermediate proliferation.

Adult↗
PubMed2000

Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion.

Elimination of tumor cells ("purging") from hematopoietic stem cell products is a major goal of bone marrow-supported high-dose cancer chemotherapy. We developed an in vivo purging method capable of providing tumor-free stem cell products from most patients with mantle cell or follicular lymphoma and bone marrow involvement. In a prospective study, 15 patients with CD20(+) mantle cell or follicular lymphoma, bone marrow involvement, and polymerase chain reaction (PCR)-detectable molecular rearrangement received 2 cycles of intensive chemotherapy, each of which was followed by infusion of a growth factor and 2 doses of the anti-CD20 monoclonal antibody rituximab. The role of rituximab was established by comparison with 10 control patients prospectively treated with an identical chemotherapy regimen but no rituximab. The CD34(+) cells harvested from the patients who received both chemotherapy and rituximab were PCR-negative in 93% of cases (versus 40% of controls; P =.007). Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical and molecular remission in all 14 evaluable patients, including all 6 with mantle cell lymphoma (versus 70% of controls). In vivo purging of hematopoietic progenitor cells can be successfully accomplished in most patients with CD20(+) lymphoma, including mantle cell lymphoma. The results depended on the activity of both chemotherapy and rituximab infusion and provide the proof of principle that in vivo purging is feasible and possibly superior to currently available ex vivo techniques. The high short-term complete-response rate observed suggests the presence of a more-than-additive antilymphoma effect of the chemoimmunotherapy combination used.

Adult↗
PubMed2000

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</=6 pg/ml were 69% and 76% vs 97. 5% and 95%, respectively. The multivariate analysis confirmed the prognostic value of IL-10 basal serum levels (FFP, P=0.0001; OS, P=0. 06). Our study suggests that high pre-treatment circulating levels of IL-10 are associated with a poor prognosis, irrespective of other common prognostic variables.

Adolescent↗
PubMed2000

Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin's lymphoma: a phase II randomized study.

BACKGROUND: It is unclear whether the purine analogs fludarabine (Flu) and cladribine (CdA) are non-resistant. PATIENTS AND METHODS: Sixty patients with relapsed or refractory low-grade NHL were randomly allocated to initial treatment with either Flu 25 mg/m2, or CdA 0.14 mg/kg, each for five consecutive days every four weeks. Upon treatment failure, eligible patients were crossed over to the other study drug. RESULTS: Overall response and CR were 68% and 48% with Flu, and 72% and 38% with CdA, respectively. For responders, actuarial three-year progression-free survival was 58% with Flu and 52% with CdA. Treatment with both drugs was well tolerated, with toxic effects primarily hematological. Two patients (8%) in the Flu group and 15 patients (47%, P = 0.001) in the CdA group were taken off study because of persistent hematological toxicity. After cross over, none of seven refractory patients responded, while eight of nine previously responsive patients achieved second responses. CONCLUSIONS: Our study confirms that Flu and CdA have similar response rates and durations. However, further studies are required to optimize the CdA schedule and dosage in order to ameliorate its toxic profile while maintaining antitumor activity. The two drugs appear to be cross-resistant.

Adult↗