Soft tissue and bone sarcomas.
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Antineoplastic Agents↗
Biomedical subjects
G Bonadonna
Publications and source records attributed to G Bonadonna.
Primary chemotherapy in operable breast cancer.
The origins of primary chemotherapy lie in the experience gained more than 20 years ago in the multimodal treatment for locally advanced breast cancer. Today, primary chemotherapy followed by surgery and radiation is emerging almost all over the world as a common approach for large but resectable breast cancers. The mounting interest for this approach has resulted in increasing number of available reports on this subject. Unfortunately, there is remarkable heterogeneity among most studies as far as patient selection, locoregional treatment, drug therapy, as well as criteria of tumor response and length of follow-up are concerned. At present, the most recognized benefit of primary chemotherapy is prompt tumor shrinkage, enabling surgeons to increase the use of breast-conserving procedures. However, as clinical experience grows, it is becoming clear that the most important scope of the early use of full-dose chemotherapy is a more effective eradication of systemic micrometastases. This review summarizes the current state of knowledge about this multidisciplinary approach and outlines future prospects. In conventionally resectable breast cancer, innovative prospective controlled studies, well designed and properly conducted, are warranted to definitely assess whether the administration of primary chemotherapy can further improve the continuous relapse-free survival over classical adjuvant systemic treatments.
Animals↗
VIII. Women's health perception and breast cancer: issues of fertility, hormone substitution, and cancer prevention.
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Adult↗
Primary chemotherapy in surgically resectable breast cancer: the experience of the Milan Cancer Institute.
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Antineoplastic Combined Chemotherapy Protocols↗
Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up.
BACKGROUND: Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil was administered after radical mastectomy for primary breast cancer with histologically positive axillary lymph nodes to assess whether it would improve treatment outcome as compared with surgery alone. Here we report a 20-year follow-up of this investigation. METHODS: In 1973 we began a trial involving 386 women who were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant combination chemotherapy (207 women). All patients were admitted to the Istituto Nazionale Tumori in Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. RESULTS: After a median follow-up of 19.4 years, the patients given adjuvant combination chemotherapy had significantly better rates of relapse-free survival (unadjusted relative risk of relapse, 0.71; 95 percent confidence interval, 0.56 to 0.90; P = 0.004; adjusted relative risk, 0.65, 95 percent confidence interval, 0.51 to 0.83; P < 0.001) and total survival (unadjusted relative risk of death, 0.78; 95 percent confidence interval, 0.62 to 0.99; P = 0.04; adjusted relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97; P = 0.03). With the exception of postmenopausal women, a benefit from adjuvant chemotherapy was evident in all subgroups of patients. CONCLUSIONS: The long-term results of this trial of adjuvant combination chemotherapy confirm our preliminary observations of the effectiveness of the treatment in women with node-positive breast cancer.
Adult↗
Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results.
OBJECTIVE: To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. DESIGN: A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years. SETTING: The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. PATIENTS: A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P = .08). MAIN OUTCOME MEASURE: Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method. RESULTS: Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P = .002) and total survival was 58% vs 44% (P = .002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients. CONCLUSIONS: Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF.
Adult↗
Conservation surgery after primary chemotherapy in large carcinomas of the breast.
OBJECTIVE: The authors evaluated the utility of preoperative chemotherapy in patients with large size breast carcinoma, with a view to rendering a conservative surgical approach possible or easier. SUMMARY BACKGROUND DATA: Two hundred twenty-six of 227 patients with breast cancer involving a tumor larger than 3 cm at greatest dimension were candidates for mastectomy. They were treated with various primary preoperative chemotherapies and evaluated for surgery. METHODS: After administering various chemotherapeutic regimens, the authors reevaluated the patients' conditions clinically and radiologically to plan definitive surgical treatment. If the tumor diameter was sufficiently reduced, quadrantectomy was planned; otherwise, mastectomy was performed. Complete axillary lymph node dissection was done in all cases. RESULTS: In 90% of the cases, the size reduction was sufficient to justify breast conservation; in 10%, tumor size did not decrease enough or increased, thus mastectomy was performed. In 11.8% of the cases, the tumor was no longer identifiable at surgical inspection, and in 3.5% no tumor was found on microscopic examination. Axillary lymph nodes were free of metastases in 39% of cases. Twelve local recurrences occurred among the 203 patients treated with breast conservation (5.9%) and five among the 23 patients treated with mastectomy (21.7%). CONCLUSIONS: Primary chemotherapy can expand the indication for breast conservation to large tumors; careful attention, however, must be paid to surgical technique. The position of the tumor should be marked with tattoo points on the skin before chemotherapy. The macroscopic extent of the tumor regression must be evaluated carefully, and multiple frozen section biopsies may be needed. The margins of the resected breast should be evaluated microscopically. All microcalcifications present before treatment must be resected. The skin incision and mammary resection must fulfill criteria of radicality as well as good cosmetic outcome.
Breast Neoplasms↗
Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.
PURPOSE: To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. PATIENTS AND METHODS: Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. RESULTS: Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model. CONCLUSION: The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.
Aged↗
A summary of the Milan experience with multimodality therapies in patients with small cell lung cancer: attempts to improve long-term outcome.
From February 1985 to June 1993, 173 consecutive, previously untreated patients with small cell lung cancer received individualized treatment tailored to disease extent. Almost all patients (14 of 16) with stage I and II disease and 30 patients with operable stage III disease were submitted to surgery preceded or followed by chemotherapy. Chest irradiation and prophylactic brain radiotherapy (in complete responders) were administered at the end of treatment in 42 of 44 cases. Patients with inoperable limited disease received chemotherapy followed by radiotherapy in 67 of 71 cases, while chemotherapy alone or followed by radiotherapy in sites of either initially bulky or residual disease was administered to 58 patients with extensive disease. The overall response rate was 77% (complete response, 45%; partial response, 32%). Complete responses were documented more frequently in limited disease than in extensive disease (57% v 22%; P < .001). The 2- and 5-year freedom from progression rates (24% and 16%, respectively), as well as overall survival rates (31% and 16%, respectively) were significantly affected by disease extent. No patient with extensive disease was progression free and alive at 2 years, while more than half of stage I and II patients were disease free and alive at 5 years. This retrospective analysis performed on a large number of consecutive, nonrandomized patients suggests that, at least in patients with limited disease, it is possible to achieve favorable long-term results using treatment tailored to disease extent. Nonetheless, the disappointing results commonly achieved in the treatment of small cell lung cancer strongly support the need for either prospective, randomized studies to confirm recently reported improved results or new pilot studies with investigation of entirely innovative approaches.
Adult↗
Combined modality approach for high-risk breast cancer. The Milan Cancer Institute experience.
After 20 years of successive clinical trials, the results achieved at the Milan Cancer Institute have helped to establish the effectiveness of adjuvant combination chemotherapy in high-risk women with resectable breast cancer. The most significant findings can be summarized as follows: (1) the clinical benefit in terms of relapse-free and total survival can be prolonged up to 20 years from surgery; (2) the use of anthracyclines (doxorubicin) can contribute to improved treatment outcome; (3) dose intensity and dose size are the leading prognostic variables; and (4) adjuvant treatments are not associated with important iatrogenic morbidity. New modalities that could profoundly change current treatment strategies will involve high-dose sequential chemotherapy and primary chemotherapy. In fact, the use of rhG-CSF-elicited hematopoietic progenitors will grant a substantial reduction in granulocytopenia and related toxicities; this, in turn, will permit the administration of regimens based on high dose size and dose intensity. As far as primary chemotherapy is concerned, the shift from mutilating to breast-conserving operations has led to important advantages in a society concerned for body integrity. In the few studies with sufficient follow-up, objective tumor response to primary chemotherapy has been translated into superior relapse-free survival compared with that of nonresponders. In particular, from the first Milan study the knowledge is clearly emerging that the response rate is inversely related to the initial tumor volume and that the degree of tumor regression (complete pathologic remission versus moderate versus minimal response) appears to represent a marker of outcome. Should this crucial observation be confirmed in other ongoing trials, then the amount of tumor shrinkage could rank among the most important prognostic variables because it is reproducible and inexpensive. As a consequence, the achievement of complete (or near complete) pathologic remission will become the major goal of properly intensified drug regimens to ensure a durable relapse-free survival rate. To make legitimate the wide adoption of the strategy involving primary chemotherapy, most breast cancer specialists correctly advocate that the initial promising results be validated through classic randomized trials. The question to answer appears simple: Will preoperative chemotherapy be superior to postoperative chemotherapy in terms of relapse-free and total survival? In our opinion, the simple attempt to shift from postoperative (adjuvant) to preoperative (primary) chemotherapy may not be enough, although formally correct, to maximize treatment outcome, and thus become the new strategy of choice.(ABSTRACT TRUNCATED AT 250 WORDS)
Bone Marrow Transplantation↗
Parametric survival analysis of adjuvant therapy for stage II breast cancer.
BACKGROUND: Standard, nonparametric statistical methods estimate only the impact of therapy on survival rate up to a selected follow-up interval. In contrast, parametric methods can estimate the impact of treatment on the two cardinal parameters of malignancy: likelihood of cure and recurrence free survival time among uncured patients. METHODS: The authors screened a total of six parametric survival models. Three of these, including the log normal model, were applied to survival data from five clinical trials of adjuvant therapy for Stage II breast cancer. For comparison, the log rank test, a standard nonparametric method, was also applied to the same data. RESULTS: Both parametric and nonparametric methods identified a significant therapeutic in three of the five trials. In only one of these three trials, however, did parametric analysis identify a significant difference in the likelihood of cure between treatment groups. In the remaining two trials, a significant difference was found in recurrence free survival time among uncured patients. The three parametric survival models gave similar results. CONCLUSION: These findings suggest that parametric analysis may warrant further study as a method for measuring the long term clinical impact of adjuvant therapy on Stage II breast cancer.
Breast Neoplasms↗
Local recurrences following mastectomy: support for the concept of tumor dormancy.
BACKGROUND: Local or regional recurrence of breast cancer occurs in 5%-30% of patients treated by Halsted radical or modified radical mastectomy. Lag time between treatment and recurrence varies widely, and it is not known whether the recurring tumor grows at a constant growth rate or at a more rapid rate after a period of tumor dormancy. PURPOSE: This study was undertaken to discriminate between the above-mentioned hypotheses, i.e., determine whether a tumor that recurs after mastectomy grows at a constant rate or whether it grows rapidly following a period of tumor dormancy. METHODS: A series of 122 patients with local recurrence as a first event after mastectomy for resectable breast cancer was evaluated. We measured the diameter of the recurring tumor (Dr) in each patient and calculated the diameter that the recurring tumor could have reached at the immediately preceding physical examination (Dpe), when no local relapse had yet been detected, by assuming an exponential growth during the treatment-free interval. For patients who had a calculated diameter Dpe that was large enough to have been detected at the previous examination, we assumed that a tumor 5 mm in diameter had been mistakenly missed, and the expected corresponding tumor diameter at the time of detection (Drc) was calculated. Finally, the minimum growth rate (mGR) consistent with the sequence "no detection-->recurrence of diameter Dr" was obtained by assuming an exponential growth from the tumor volume corresponding to a diameter 1 mm less than the diameter detection threshold. RESULTS: A wide overlap between Dr and Dpe values was observed. Seventy-two (59%) of 122 Dpe values were larger than the minimum Dr; 18 (15%) were even larger than the median Dr value. The difference between expected and observed detection rates was highly significant (P < .0001). Furthermore, when treatment-free intervals were longer than 4 years, the difference between median Dr and median Dpe values failed to reach statistical significance. The Drc values were significantly lower than the related Dr values, while the mGR values were significantly higher than the corresponding growth rates (paired sample t test: P < .001). CONCLUSION: This study provides evidence that the hypothesis of uninterrupted constant growth of locally recurring breast tumors should be rejected, as it implies a statistically significant departure from observed data. Our results suggest that a period of tumor dormancy followed by more rapid growth could provide an alternative and more reasonable description of tumor recurrence.
Adult↗
Clinical utilisation of human haematopoietic progenitors elicited in peripheral blood by recombinant human granulocyte colony-stimulating factor (rHuG-CSF).
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Antineoplastic Agents↗
Modern treatment of malignant lymphomas: a multidisciplinary approach? The Kaplan Memorial Lecture.
The aim of this review is to examine critically, in Hodgkin's disease and in non-Hodgkin's lymphomas, (a) whether combined modality treatment is superior to optimal radiotherapy or chemotherapy alone in most stages of the disease; (b) whether its indications could be further expanded by the use of new drug regimens and newer radiation techniques that can now substantially reduce the risk of long-term iatrogenic morbidity; and (c) whether it may become a necessary approach in the future because staging laparotomy and even lymphangiography are progressively falling into disuse. In conclusion, for the next decade or so, I do not foresee a departure from complex treatment programs. Although fewer patients are being referred to major research centers, the treatment of malignant lymphomas is not ready as yet to be relegated to the care of the single physician in a private office or local hospital.
Actuarial Analysis↗
Durability of hematopoiesis following autografting with peripheral blood hematopoietic progenitors.
BACKGROUND: It is still not known whether hematopoiesis reconstituted by autografting with the peripheral blood hematopoietic progenitors (CPCs) after myeloablative high dose radiotherapy and/or chemotherapy is durable and capable of coping with the increased demand imposed by boost radiotherapy, surgery, or infection. PATIENTS AND METHODS: The durability of hematopoiesis was evaluated in 34 consecutive cancer patients treated with myeloablative total body irradiation (n = 17, median follow-up 3 years, range 3-49 months) and/or alkylating-agent chemotherapy (n = 17, median follow-up 8 months, range 6-41 months) and autografted with CPCs because bone marrow autografting was contraindicated. CPCs (> or = 8 x 10(6) CD34 + cells/kg) had been collected during mobilization into the circulation in response to previous anticancer therapy and hematopoietic growth factor(s). RESULTS: Following brief temporary pancytopenia, all patients achieved normal and durable hematopoiesis. The newly reconstituted hematopoietic system was capable of reacting favorably to stressful and debilitating events such as surgery, radiotherapy, or varicella-zoster infection. No secondary irreversible failure of blood cell production occurred. CONCLUSIONS: The documentation of the durability of normal hematopoiesis following myeloablative cancer therapy and autografting with mobilized CPCs implies that the latter procedure, rather than being solely an alternative to bone marrow autografting, represents an advantageous tool of choice permitting substantial amelioration of the therapeutic index of high-dose cancer therapy.
Adult↗
Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer.
AIM: To assess the frequency and type of cardiac effects in women treated with adjuvant chemotherapy with or without breast irradiation for operable breast cancer. PATIENTS AND METHODS: Retrospective analysis of a series of 825 women taking part in prospectively randomized trials on adjuvant chemotherapy with or without adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) for operable breast cancer at high risk of new disease manifestations. A total of 360 patients (44%) also received breast irradiation because of conservative surgery. Median follow-up in first clinical complete remission from end of all adjuvant treatments was 80 months. According to the protocol requirements, electrocardiograms were obtained before breast cancer surgery, before starting therapy with adriamycin and at the end of all adjuvant treatments. During the follow-up observation, electrocardiograms were systematically obtained at least once a year. In the presence of suspicious findings as well as of clinical symptoms and signs of cardiovascular disease, additional cardiac investigations were undertaken. However, percutaneous endomyocardial biopsies were never performed. RESULTS: Congestive heart failure occurred in a total of 4 women (0.5% of all patients; 0.8% following adriamycin-containing chemotherapy; 2.6% after both adriamycin and irradiation to the left breast), in two of whom it was fatal. ST-segment and T-wave abnormalities in the absence of other symptoms and signs were detected in 3.4% of the case series. Other cardiac events were documented in 6.8% of all patients Overall, cardiac effects were more frequently detected in women who received irradiation to the left breast. In addition, age greater than 55 years at surgery and history of risk factors were important risk modifiers in the occurrence of cardiac events. CONCLUSIONS: The addition of full-dose adriamycin to alkylating-containing adjuvant chemotherapy, as given in our studies, failed per se to increase the frequency of cardiac effects. Thus anthracyclines, which have the potential to improve current treatment results, deserve a proper place in the design of future adjuvant studies.
Adult↗
Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer.
BACKGROUND: Only a few studies have evaluated the long-term effects of adjuvant chemotherapy for breast cancer. Furthermore, neither the relation between the risk of second malignancies and type of adjuvant regimen utilized nor the interaction between chemotherapy and breast irradiation or age of the patients have been described in detail. METHODS: A total of 2,465 patients entered into prospective studies of CMF-based adjuvant chemotherapy carried out at the Milan Cancer Institute between June 1973 and July 1990 were evaluated. The median follow-up was 12.0 years and detailed information about therapy was available for all patients. RESULTS: At 15 years, the cumulative actuarial risk of second malignancies (excluding contralateral breast cancer and basal skin cancer) was 6.7% +/- 0.8% for the total series. The figures were 8.4% +/- 2.9% after local-regional treatment alone, 6.4% +/- 0.9% following CMF, and 5.1% +/- 1.0% following CMF plus Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy). Compared to the general female population, the relative risk following CMF-based adjuvant chemotherapy was 1.29. Three patients, all of whom had received CMF-based chemotherapy, developed acute non-lymphocytic leukemia (cumulative risk 0.23% +/- 0.15%; relative risk 2.3). No differences were evident when breast irradiation was considered, but the cumulative risk of second tumors was slightly higher in women aged > or = 50 years at surgery (7.7% +/- 1.3%) than in younger patients (6.0% +/- 1.0%). CONCLUSIONS: At present, there is no evidence of a significantly increased risk of second malignancies following adjuvant CMF-based chemotherapy such as the one given in this case series. A low risk of acute leukemia was associated with the cumulative total dose of cyclophosphamide administered, and breast irradiation did not enhance this risk. IMPLICATIONS: Our findings suggest that there is no reason to omit alkylating agents from short-term effective adjuvant chemotherapy.
Actuarial Analysis↗