Re: Dormancy of mammary carcinoma after mastectomy.
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Breast Neoplasms↗
Biomedical subjects
P Valagussa
Publications and source records attributed to P Valagussa.
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↗
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↗
Impact of nodal status on indication for adjuvant treatment in clinically node negative breast cancer. Istituto Nazionale per lo Studio e las Cura dei Tumori.
We addressed the problem of the need for axillary dissection in clinically node-negative breast cancer by determining how the information provided by the dissection suggests a different treatment to that indicated by primary tumour characteristics and age alone. We examined retrospectively 260 cases of clinically node negative early breast cancer all of whom underwent breast surgery, radiotherapy and axillary dissection. We assigned adjuvant therapy according to accepted guidelines with and without consideration of pathological node status and compared the difference. Fifty-six patients had involved axillary nodes. There was no change in adjuvant chemotherapy indication for the 44 cases over 65 years. The change in indication for the remaining 216 cases was 18.5% to 6%, depending on whether none or all of the intermediate risk patients were originally assigned chemotherapy (all were originally assigned tamoxifen). Since the trend is for most intermediate risk patients is to be assigned adjuvant chemotherapy, and since tamoxifen is anyway considered effective therapy for low and intermediate risk patients, we conclude that the information provided by axillary dissection is probably not necessary if guidelines recommending wide application of systemic adjuvant chemotherapy are applied. Satisfactory prognostic information can be obtained by consideration of primary tumour characteristics, while new prognostic markers are likely to further refine prognostic precision in the near future.
Adult↗
The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial.
The lymph nodes of the internal mammary chain represent a primary station draining the lymph from the breast and their removal or their irradiation has been considered an important step in breast cancer treatment. From January 1964 to January 1968, 737 patients with breast cancer were randomised at the National Cancer Institute in Milan to undergo either Halsted mastectomy or extended mastectomy with internal mammary node dissection. Patients with non-disseminated carcinoma classified as T1, T2, T3, N0, N1 were eligible for the study. No patients received postoperative radiotherapy or systemic therapy. After 30 years of follow-up, the overall survival curves and the specific survival curves do not show any difference between the patients of the two groups. Among the 558 patients who died in the 30 year interval period, 395 (71%) died from breast carcinoma (201 in the Halsted group and 194 in the extended mastectomy group) and 163 from other causes. This study shows that the removal of internal mammary nodes does not improve the survival of patients treated for breast carcinoma. This finding supports the theory that treatment of regional nodes does not influence the survival of cancer patients. The prognostic value of internal mammary node status is, however, high and a biopsy on a selected lymph node should be considered for staging purposes.
Adult↗
Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of 'cures'.
PURPOSE: To comparatively analyse the risk of recurrence at given times after surgery for breast cancer patients receiving or not receiving adjuvant CMF. PATIENTS AND METHODS: A total of 1452 node positive patients, who entered controlled clinical trials carried out at the Milan Cancer Institute and underwent radical or modified radical mastectomy for operable breast cancer, were examined. In 575 cases no further treatment was performed, whereas 877 pts were given 6 or 12 courses of adjuvant Cyclophosphamide, Methotrexate, Fluorouracil (CMF). The recurrence risk was estimated by the event-specific hazard rate for first failure and distant metastases, and, following Efron, hazard rates were fitted by logistic regression models. RESULTS: The hazard rate for first failure and distant metastases showed a double peaked pattern for both treated patients and controls, with a first major peak at about 18-24 months from surgery (early metastases), a second minor peak at the 5th-6th year, and a tapered plateau-like tail extending over 10 years from surgery (late metastases). As expected, the recurrence risk of CMF treated patients was lower than the corresponding risk of patients undergoing surgery only. However, the difference was highly evident for early recurrences, while it declined and disappeared afterwards. CONCLUSION: Our findings confirm previous reports on patients not receiving adjuvant chemotherapy, suggesting that the recurrence risk for operable breast cancer has a multipeak pattern. As far as CMF treated patients are concerned, the unchanged peak timing together with the early recurrence risk reduction in comparison to controls are much more consistent with the real nonappearance of some early recurrences (putatively 'cured' patients) than with the delay in their manifestation. As late relapsing patients seem to have at most marginal benefits from adjuvant CMF, ways to recognize patients doomed to have late recurrence and new ways for treating micrometastases resulting in late recurrences are required.
Antineoplastic Combined Chemotherapy Protocols↗
Combined sequential approach in locally advanced breast cancer.
BACKGROUND: The interaction between primary and adjuvant chemotherapy is a crucial point in the treatment of locally advanced breast cancer. OBJECTIVE: To evaluate the therapeutic efficacy of a sequential treatment with primary anthracyclines and adjuvant CMF in this patient subset. DESIGN: Prospective cohort study. PATIENTS: Eighty-eight breast cancer patients, stage T3b-T4 abc, N0-2, M0. RESULTS: From February 1991 to July 1994, 88 consecutive patients with locally advanced breast cancer were treated at the Istituto Nazionale Tumori, Milano, with full-dose doxorubicin (75 mg/m2) or epirubicin (120 mg/m2) for three cycles followed by surgery, adjuvant chemotherapy with i.v. CMF for six cycles and local radiotherapy +/- Tamoxifen. A high rate of objective responses (70%), but a low incidence of pathologic complete remission (2%), were observed following primary treatment with single-agent anthracyclines. Frequency of responses was not associated with tumor estrogen or progesterone receptors status, Mib-1 or grading. In 28 patients (32%) conservative surgery could be performed. At a median follow-up of 52 months, relapse free survival and overall survival are 52% and 62%, respectively. A multivariate analysis demonstrated a significant favorable prognosis in patients with limited nodal involvement at surgery and negative Mib-1 values. This drug sequence failed to significantly ameliorate the long term results in this unfavorable patient subset and more effective drug regimens and innovative therapeutic strategies are needed.
Adult↗
Diffuse large-cell lymphoma of the testis.
PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.
Adult↗
Putting taxanes to work in operable breast cancer: a search for selective indications from empirical studies.
The taxanes paclitaxel and docetaxel are the prototype drugs of a new class of anticancer drugs that exploits a completely new mechanism of action. Their testing in metastatic breast cancer has been extensive. The results indicating very high response rate with either taxane have given rise to an unprecedented effort in the scientific community to define their optimal application in all stages of the disease. In metastatic breast cancer, initial data suggest that paclitaxel may increase the survival obtained with standard combinations such as CMFP, and similarly promising studies of docetaxel are almost complete. Significant therapeutic benefit has also been observed by the addition of sequential paclitaxel after adjuvant doxorubicin plus cyclophosphamide in operable breast cancer. Overall, more than 20 randomized studies with paclitaxel or docetaxel, either as single agents or in combination, are ongoing or planned in women with high-risk operable breast cancer. This massive effort is mainly based on empirical study designs. However, some preclinical characteristics of the taxanes, such as their increased antitumor effect in tumors overexpressing HER2/neu, the preclinical and clinical evidence of potential synergism with monoclonal antibodies directed against the HER2 receptor, and preclinical evidence of antiangiogenic properties should be pursued to test whether the use of taxanes in breast cancer could be tailored to individual tumor characteristics rather than following the usual pattern of indiscriminate application.
Breast Neoplasms↗
Soluble interleukin-2 receptors (sIL-2R) in Hodgkin's disease: outcome and clinical implications.
The aim of this study was to assess the prognostic role of soluble interleukin-2 receptors (sIL-2R) in Hodgkin's disease (HD) both in the achievement of complete remission (CR) and in predicting disease relapse. Between August 1988 and June 1993 sIL-2R serum levels were measured in 174 untreated patients; in 137 of them evaluation was repeated at the end of treatment and in 132 also during the follow-up. Baseline sIL-2R levels (mean+/-standard error) were significantly higher in patients than in 65 healthy control subjects (1842+/-129 U ml(-1) vs 420+/-10 U ml(-10, P< 0.0001). At the end of treatment 135 out of 137 evaluated patients achieved complete response (CR) and their mean sIL-2R serum levels were significantly lower than those at diagnosis (635+/-19 U ml(-1) vs 1795+/-122 U ml(-1), P=0.0001). After a median follow-up of 5 years, sIL-2R remained low in 114 patients in continuous CR, while they increased in 9 out of 12 patients (75%) who relapsed. However, a temporary increase was also observed in six patients (5%) still in CR. Treatment outcome in terms of freedom from progression was linearly related to sIL-2R levels. Our study confirms that patients with untreated HD have increased baseline levels of sIL-2R compared with healthy subjects and that their pretreatment values may be an indication of disease outcome similar to other conventional prognostic factors, such as number of involved sites, presence of B symptoms and extranodal extent.
Adolescent↗
Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease.
Twenty-six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m2/d, days 1-4 through continuous intravenous infusion) and vinorelbine (25 mg/m2, i.v. days 1 and 5) with mesna uroprotection and G-CSF support. Courses were given at 3-week intervals. Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.
Adult↗
Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute.
PURPOSE: Primary chemotherapy was administered to patients with tumors that measured > or = 2.5 cm in largest diameter to decrease the size of the primary tumor and allow for effective local and distant control while avoiding mastectomy. PATIENTS AND METHODS: Two prospective nonrandomized studies were performed that used different regimens of primary chemotherapy followed by breast-sparing surgery in the presence of objective tumor remission. Additional postoperative chemotherapy was given to women at high risk of disease relapse. The median follow-up duration was 65 months. RESULTS: A total of 536 assessable patients were enrolled, and the main characteristics were fairly comparable between the two trials. Following primary chemotherapy, 85% of patients could be subjected to breast-sparing surgery; in 14 patients (3%), surgical specimens failed to show any residual neoplastic cell. In the final multivariate analysis, the histologically assessed extent of axillary node involvement (P < .001), as well as degree of response to primary chemotherapy (P = .034), represented the significant variables able to influence 8-year relapse-free survival. In women subjected to a breast-conserving approach, the cumulative risk of local relapse as first event alone was 6.8% (95% confidence interval, 3.9% to 8.8%). CONCLUSION: Current findings indicate that primary chemotherapy can be safely administered in women with large tumors (>5.0 cm) and can allow breast-sparing surgery in a high fraction of patients (62%). However, to assess effectively the worthiness of this approach on long-term results, properlyconceived large randomized studies with newer and more effective drug regimens are warranted.
Adult↗
End points in the analysis of breast cancer survival: relapse versus death from tumor.
BACKGROUND: To determine whether relapse and death from tumor are comparable as survival end points for assessing therapeutic efficacy, five prospective, randomized clinical trials of adjuvant therapy for stage II breast cancer were analyzed. One thousand eight hundred ninety patients were combined from five clinical groups into a single group for analysis. METHODS: Actuarial and parametric survival methods were used to generate three estimates for the likelihood of cure (LOC): (1) for all patients, with relapse as the end point to survival (LOCR); (2) for all patients, with death from tumor as the end point (LOCD); and (3) for patients with relapse only with death from tumor as the end point (LOCRD). Linear regression analysis was used to compare time to relapse for each patient with time from relapse to death. RESULTS: Estimates of LOCR ranged from 33.5% to 38.4%, estimates of LOCD ranged from 36.3% to 44.2%, and estimates of LOCRD ranged from 0% to 6%. Thus LOCR and LOCD are approximately equal for these patients. On the other hand, time to relapse correlated poorly with time from relapse to death (r2 = 0.005). CONCLUSIONS: If therapy affects LOC, relapse and death should ultimately lead to the same conclusion with respect to therapeutic efficacy, because both end points lead to essentially the same LOC. If therapy affects time to relapse, however, these two end points may ultimately lead to different conclusions, because time to relapse correlates poorly with time from relapse to death.
Actuarial Analysis↗
Hodgkin's disease and the risk of acute leukemia in successfully treated patients.
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Antineoplastic Combined Chemotherapy Protocols↗
High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma.
BACKGROUND: We compared a regimen of six chemotherapeutic agents administered sequentially at high doses, followed by myeloablative treatment and bone marrow transplantation, with a regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as initial or salvage treatment for adults with diffuse large-cell lymphoma. METHODS: Ninety-eight eligible patients with diffuse large-cell lymphoma of the B-cell type were randomly assigned to receive either MACOP-B (50 patients) or high-dose sequential therapy (48 patients). The study design allowed for patients in whom the assigned treatment failed to cross over to the other treatment group. RESULTS: After a median follow-up of 55 months, the patients given high-dose sequential therapy, as compared with those treated with MACOP-B, had significantly higher rates of complete response (96 percent vs. 70 percent, P=0.001), freedom from disease progression (84 percent vs. 49 percent, P<0.001), freedom from relapse (88 percent vs. 70 percent, P=0.055), and event-free survival (76 percent vs. 49 percent, P=0.004). The difference in overall survival at seven years, which also favored the group assigned to high-dose sequential therapy, was marginally significant (81 percent vs. 55 percent, P=0.09). CONCLUSIONS: High-dose sequential therapy is superior to standard-dose MACOP-B for patients with diffuse large-cell lymphoma of the B-cell type.
Adolescent↗
The trials of Dr. Bernard Fisher: a European perspective on an American episode.
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Bias↗
Computer simulation of a breast cancer metastasis model.
Recent analysis of relapse data from 1173 untreated early stage breast cancer patients with 16-20 year follow-up shows that frequency of relapse has a double peaked distribution. There is a sharp peak at 18 months, a nadir at 50 months and a broad peak at 60 months. Patients with larger tumors more frequently relapse in the first peak while those with smaller tumors relapse equally in both peaks. No existing theory of tumor growth predicts this effect. To help understand this phenomenon, a model of metastatic growth has been proposed consisting of three distinct phases: a single cell, an avascular growth, and a vascularized lesion. Computer simulation of this model shows that the second relapse peak can be explained by a steady stochastic progression from one phase to the next phase. However, to account for the first relapse peak, a sudden perturbation of the development at the time of surgery is necessary. Model simulations predict that patients who relapse in the second peak would have micrometastases in states of relatively low chemosensitivity when adjuvant therapy is normally administered. The simulation predicts that 15% of T1, 39% of T2, and 51% of T3 staged patients benefit from adjuvant chemotherapy, partially offsetting the advantage of early detection. This suggests that early detection and adjuvant chemotherapy may not be symbiotic strategies. New therapies are needed to benefit patients who would relapse in the second peak.
Breast Neoplasms↗
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.
Adult↗