Tumor characteristics and prognosis in familial breast cancer.

BACKGROUND: Approximately 5-10% of breast cancers are hereditary and their biology and prognosis appear to differ from those of sporadic breast cancers. In this study we compared the biological features and clinical characteristics of non metastatic breast cancer in patients with BRCA mutations versus patients with a family history suggesting hereditary breast cancer but without BRCA mutations (BRCA wild type) versus patients with sporadic disease, and correlated these findings with clinical outcome. METHODS: We retrieved the clinical and biological data of 33 BRCA-positive, 66 BRCA-wild type and 1826 sporadic breast cancer patients contained in a single institution clinical database between 1980 and 2012. Specifically, we recorded age, tumor size, nodal status, treatment type, pattern of relapse, second primary incidence, outcome (disease-free survival and overall survival), and biological features (estrogen receptor [ER], progesterone receptor [PgR], tumor grade, proliferation and c-erbB2 status). Median follow-up was 70 months. RESULTS: BRCA-positive patients were significantly younger than sporadic breast cancer patients, and less likely to be ER-, PgR- or c-erbB2-positive than women with BRCA-wild type or sporadic breast cancer. Tumor size and grade, nodal status and proliferation did not differ among the three groups. Rates of radical mastectomy were 58, 42 and 37%, and those of conservative surgery were 42, 58 and 63% in women with BRCA-positive, BRCA-wild type and sporadic breast cancer (p = 0.03), respectively. The incidence of contralateral breast cancer was 12, 14 and 0% (p <0.0001) and the incidence of second primary tumors (non breast) was 9, 1 and 2% (p <0.0001) in BRCA-positive, BRCA-wild type and sporadic breast cancer, respectively. Median disease-free survival in years was 29 in BRCA-wild type, 19 in BRCA-positive and 14 in sporadic breast cancer patients (log-rank = 0.007). Median overall survival in years was not reached for BRCA-wild type, 19 for BRCA-positive and 13 for sporadic breast cancer patients (log-rank <0.0001). At multivariate analyses only BRCA-wild type status was related to a significant improvement in overall survival versus the sporadic breast cancer group (HR = 0,51; 95% CI (0,28-0,93) p = 0.028). CONCLUSIONS: The biology and outcome of breast cancer differ between patients with BRCA mutations, patients with a family history but no BRCA mutations and patients with sporadic breast cancer.

Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial.

BACKGROUND: Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. PATIENTS AND METHODS: We carried out a multicenter, randomized phase III study. Women aged 65-79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m(2) days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. RESULTS: From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83-1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80-2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. CONCLUSIONS: Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. CLINICALTRIALSGOV: NCT00331097.

Eribulin in combination with bevacizumab as second-line treatment for HER2-negative metastatic breast cancer progressing after first-line therapy with paclitaxel and bevacizumab: a multicenter, phase II, single arm trial (GIM11-BERGI).

BACKGROUND: We evaluated the efficacy and safety of the nontaxane microtubule dynamics inhibitor eribulin plus the humanized anti-VEGF monoclonal antibody bevacizumab in a novel second-line chemotherapy scheme in HER2-negative metastatic breast cancer (MBC) patients progressing after first-line paclitaxel and bevacizumab. PATIENTS AND METHODS: This is a multicenter, single-arm, Simon's two-stage, phase II study. The primary endpoint was the overall response rate, considered as the sum of partial and complete response based on the best overall response rate (BORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate. RESULTS: A total of 58 of the 61 patients enrolled in the study were evaluable for efficacy. The BORR was 24.6% (95% CI 14.5-37.3). The clinical benefit rate was 32.8% (95% CI 21.3-46.0). The median PFS was 6.2 months (95% CI 4.0-7.8), and median OS was 14.8 months (95% CI 12.6-22.8). Overall, adverse events (AEs) were clinically manageable and the most common AEs were fatigue, paresthesia, and neutropenia. Quality of life was well preserved in most patients. CONCLUSIONS: The results of this study suggest that second-line therapy with bevacizumab in combination with eribulin has a meaningful clinical activity and may represent a potential therapeutic option for patients with HER2-negative MBC.

Ovarian metastasis following gallbladder carcinoma: a case report.

BACKGROUND: Mucinous ovarian cancer raises problems of differential diagnoses because it is often difficult to distinguish the primary from the metastatic form. Most metastatic ovarian tumors originate from the gastrointestinal tract, mainly colorectal, gastric, pancreatic; the gallbladder is a very rare source of ovarian metastases. CASE: We report a case of ovarian metastases from a gallbladder cancer, incidentally diagnosed more than 2.5 years earlier during a laparoscopic intervention for biliary lithiasis. CONCLUSION: The interest of this case lies in the long progression-free survival, the venous thromboembolism syndrome that preceded by a few months the diagnosis of the ovarian mass and the discrepancy between the radiologic and the laparoscopic stage assessment.

Laparoscopic surgery in the treatment of stage I adult granulosa cells tumors of the ovary: Results from the MITO-9 study.

OBJECTIVE: Surgery represents the mainstay of treatment of stage I adult type granulosa cell tumors of the ovary (AGCTs). Because of the rarity and indolent course of the disease, no prospective trials are available. Open surgery has long been considered the traditional approach; oncological safety of laparoscopy is only supported by small series or case reports. The aim of this study was to compare the oncological outcomes between laparoscopic and open surgery in stage I AGCTs treated within the MITO (Multicenter Italian Trials in Ovarian cancer) Group. METHODS: Data from patients with stage I AGCTs were retrospectively collected. Clinicopathological features were evaluated for association with relapse and death. Survival curves were calculated using the Kaplan-Meier method and compared with the log-rank test. The role of clinicopathological variables as prognostic factors for survival was evaluated using Cox's regression model. RESULTS: 223 patients were identified. Stage 1A, 1B and 1C were 61.5%, 1.3% and 29.6% respectively. 7.6% were apparently stage I. Surgical approach was laparoscopic for 93 patients (41.7%) and open for 130 (58.3%). 5-years DFS was 84% and 82%, 10-years DFS was 68% and 64% for the laparoscopic and open-group (p = 0.6).5-years OS was 100% and 99%, 10 years OS was 98% and 97% for the laparoscopic and open-surgery group (p = 0.8). At multivariate analyses stage IC, incomplete staging, site of primary surgery retained significant prognostic value. CONCLUSION: The present study suggests that surgical route does not affect the oncological safety of patients with stage I AGCTs, with comparable outcomes between laparoscopic and open approach.

c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases.

PURPOSE: We studied retrospectively the interaction between c-erbB2 overexpression and adjuvant tomoxifen in node-negative breast cancer patients enrolled in the Gruppo Universitario Napoletano 1 (GUN-1) trial. PATIENTS AND METHODS: c-erbB2, evaluated by immunohistochemistry in 145 of 173 patients randomly assigned to 2-year adjuvant tamoxifen or no further therapy, was considered overexpressed if greater than 10% of the cells showed specific membrane staining. The role of each prognostic variable and their independent effect were studied using the Cox model. Disease-free (DFS) and overall (OAS) survival curves were estimated by the Kaplan-Meier method. RESULTS: As of November 30, 1994, the median follow-up period was 12 years. c-erbB2 was overexpressed in 43 of 145 patients (29.7%), which directly correlated with tumor size and inversely with estrogen receptor (ER) level. At univariate analysis, overexpression of c-erbB2 did not affect either DFS or OAS; tamoxifen had a greater effect on reducing the risk of recurrence than of death. Addition of c-erbB2 to a multivariate Cox model that contained menopausal status, tumor size, nuclear grade, and treatment as covariates did not affect the significance of the model for DSF or OAS, whereas addition of the first-order interaction between c-erbB2 and tamoxifen was statistically significant both for DFS and OAS. The same result was obtained when the model contained ER status and ER-tamoxifen interaction. Indeed, adjuvant tamoxifen significantly prolonged DFS and OAS in c-erbB2-negative cases, whereas it had no effect on DFS and OAS in c-erbB2-positive patients. CONCLUSION: In early-stage breast cancer patients, overexpression of c-erbB2 is a marker of lack of efficacy of adjuvant tamoxifen.

Partial deficiency of adrenal 11-hydroxylase. A possible cause of primary hypertension.

Results of supraphysiological adrenocorticotropic hormone (ACTH) stimulation of biosynthetic pathways of adrenal zona fasciculata indicate that a deficiency of 11-hydroxylase exists in patients with essential hypertension. The deficiency is suggested by the much greater stimulus of synthesis of deoxycorticosterone (DOC) and deoxycortisol in hypertensive subjects than in controls (p less than 0.001). No significant difference in the synthesis of cortisol, corticosterone, progesterone, 17-hydroxyprogesterone (17-OHP), and delta-4-androstenedione (D4) was observed between the two groups. The ratios for synthesis of DOC and corticosterone and for deoxycortisol and cortisol found in hypertensive patients were significantly higher than those found in controls (p less than 0.001); no significant difference was observed in the synthesis of 17-OHP and progesterone. The synthesis of DOC and deoxycortisol was not significantly correlated with either blood pressure or plasma renin activity. Plasma renin activity was significantly lower in hypertensive subjects than in normotensive subjects (p less than 0.0001), while no difference was found in aldosterone secretion between the two groups. The 11-hydroxylase deficiency in the adrenal zona fasciculata may be one of the genetic factors causing hypertension together with environmental factors (particularly salt intake and work-related stress). The investigation performed in our study may be useful for the evaluation of adrenal zona fasciculata enzymatic activities during the study of hypertensive patients.

Selecting high-risk early breast cancer patients: what to add to the number of metastatic nodes?

High-risk early breast cancer patients are usually identified by the number of metastatic axillary nodes. To study whether other easily and inexpensively detectable morphological factors are able to detect high-risk patients, we performed a retrospective analysis of tumor size, and skin/fascia and nipple invasion. The data consisted of 941 node-positive cases registered between 1978 and 1991. Tumour size, and skin/fascia and nipple invasion were closely associated with the number of metastatic nodes (chi 2 test). The number of metastatic nodes, tumour size, skin/fascia and nipple invasion significantly affected disease free survival (DFS) and overall survival (OS) at univariate analysis. These results were confirmed by multivariate analysis with a model containing the number of metastatic nodes, tumour diameter categories, skin/fascia invasion, nipple invasion and adjuvant therapy as covariates: all variables significantly and independently affected risk of relapse and of death. All the variables studied were prognostic, within individual nodal categories, for both DFS and OS. In conclusion, the number of metastatic nodes is not the only prognostic tool with which to select high-risk patients for new intensive adjuvant programmes. Tumour size, and skin/fascia invasion or nipple invasion, taken singly or combined, are valuable prognostic factors that can identify patients with few metastatic nodes and poor outcome. On the basis of our data, we believe that a reconsideration of the pT4 category within the pTNM classification is in order, that is, chest wall invasion should be substituted by fascia invasion, and combined skin/fascia invasion could be a subcategory of each class defined by tumour size.

Low-dose dopamine induces early recovery of recombinant interleukin-2--impaired renal function.

Recombinant interleukin-2 (rIL-2) can produce impairment of renal function with hypotension, fluid retention, elevated blood urea nitrogen, oliguria and low fractional sodium excretion; these side-effects are a common cause of reduction or interruption of rIL-2 infusion. The aim of this study was to investigate the control and treatment of renal toxicity induced by rIL-2 therapy. Here we show that dopamine, at a low dose of 2 micrograms/kg/min, completely prevented renal toxicity induced by rIL-2. While continuing rIL-2 therapy, 24-h continuous infusion of low-dose dopamine produced a rapid normalisation of urine output and a significant decrease in serum creatinine levels and body weight (P < 0.01), with an early and complete recovery of the rIL-2--impaired renal function: mean recovery time of renal function in patients treated with dopamine was significantly lower (P < 0.05) than in nontreated patients (4.8 days vs. 10 days, respectively).

Adjuvant chemoendocrine therapy for early breast-cancer - is it worthwhile - (review).

The overview published in 1999 by the Early Breast Cancer Trialist' Cooperative Group demonstrated that systemic therapy after surgical removal of primary breast tumors prolongs both disease-free and overall survival of patients when compared with no systemic therapy, Specifically, both chemotherapy and ovarian ablation in patients aged less than 50 and tamoxifen in those aged 50 or more achieve a reduction of one-fifth to one-fourth in the annual odds of recurrence or death from any cause. The relative effect of different therapies is independent of the stage of the disease, while the absolute benefit depends not only upon the relative effect of treatment but also upon the baseline prognosis of patients. The overview did not report a direct estimation of the effect of combined chemoendocrine adjuvant therapy. Among the effects that may confound the evaluation of chemoendocrine adjuvant therapy are: (a) the possibility of biological interactions between drugs; (b) the presence on tumor cells of steroid hormone receptors; (c) the suppression of ovarian activity induced by chemotherapy in most premenopausal patients; (d) the scheduling of chemotherapy and endocrine therapy. Based on data of the overview, relevant questions are: (i) does the addition of endocrine therapy (tamoxifen dr ovarian ablation) to chemotherapy improve the outcome of premenopausal patients? (ii) does the addition of chemotherapy to tamoxifen improve the outcome of postmenopausal patients? We have reviewed single randomised trials in an attempt to answer these questions. In premenopausal patients, the addition of tamoxifen to chemotherapy probably induces only small advantages. The addition of ovarian ablation to chemotherapy could improve survival. The relationship between oophorectomy and receptor status has not been extensively studied; however, the addition of oophorectomy, like the addition of tamoxifen, to chemotherapy could be cost effective in cases of estrogen receptor-positive tumors. The effect of tamoxifen in association with ovarian ablation, after chemotherapy, has not yet been studied. In postmenopausal patients the addition of chemotherapy to tamoxifen is debated. The role of receptor status seems to be important in these patients. Most studies found that chemotherapy does not significantly increase the effect of tamoxifen in the subgroup of patients with receptor-positive tumors, while it does increase toxicity. On the contrary, the addition of chemotherapy to tamoxifen, in patients with receptor-negative tumors could significantly improve results.

Tailored therapy for aggressive non-Hodgkin's lymphoma: results of a phase II study with a long-term follow-up.

Aim of the study was to improve cure rate and survival of aggressive non-Hodgkin's lymphoma (NHL) with a tailored program of therapy based on histologic type, prognostic characteristics of patients and response to therapy, and with the use of differentiating or cytostatic agents such as Ara-C at low doses and alphaIFN. Fifty-four consecutive patients with aggressive NHL were treated in the induction phase with 4 sequential courses of a third generation regimen (modified CODBLAM IV), followed in responsive patients by 1 cycle of doxorubicin and cyclophosphamide and 1 cycle of high dose methotrexate with folinic acid rescue (AC-MTX). Patients who achieved partial response (PR) were treated with the combination of CCNU + vinblastine if affected by high grade NHL, or with low dose Ara-C plus alphaIFN if affected by intermediate grade NHL. Patients who obtained complete response (CR) with basal adverse prognostic factors were treated with alphaIFN as maintenance therapy for two years. Radiotherapy and surgery were effected in selected cases. Thirty-four patients (62.9%) achieved CR and 12 patients (22.2%) showed PR after induction therapy. Among the 12 patients who achieved PR, 6 prolonged CRs were obtained in 7 patients treated with Ara-C at low doses plus alphaIFN and 4 CRs were obtained in 5 patients treated with CCNU + vinblastine. After completion of treatment, 44 patients (81.5%) obtained CR, 2 patients (3.7%) showed PR and 8 patients (14.8%) presented progression of disease (PD). Fifteen patients received alphaIFN as maintenance therapy. The overall survival and failure-free survival rates are 53.7% and 50% respectively, with a median follow-up of 82 months: 27 patients remain alive, disease-free without relapses, and can be considered cured. This tailored program of therapy resulted effective and moderately toxic and may improve the outcome in aggressive NHL.

The impact of schedule on acute toxicity and dose-intensity of high-dose chemotherapy with epirubicin and cyclophosphamide plus colony stimulating factors in advanced breast cancer.

To increase the dose-intensity of two drugs in metastatic breast cancer, we tested the feasibility, in phase I studies, of two schedules of epirubicin (E) and cyclophosphamide (C) - sequential (E--> C) and alternating (E/C) - with respect to the standard combination (EC). Drugs were given at three planned-dose levels, plus either G-CSF or GM-CSF. Patients with metastatic (30), inoperable stage IIIb (2) or inflammatory (7) breast cancer were treated. The doses of EC, given every 21 days (4 cycles), were 75/1500, 82.5/2250, 90/3000 mg/m2. In the E/C schedule, epirubicin was given at cycles 1, 3 and 5, and cyclophosphamide at cycles 2, 4 and 6. In the E--> C schedule, three cycles of epirubicin then three cycles of cyclophosphamide were administered. In both experimental schedules, drugs were given every 14 days for 6 cycles at doses of 100, 110, 120 mg/m2 (E) and 2000, 3000, 4000 mg/m2 (C). The average relative dose-intensity was 1.2-fold and 2-fold greater with E/C and E--> C, respectively, than with EC. The third level dose was feasible with all schedules. Grade 4 leucopenia occurred in 77% of patients. Thrombocytopenia was absent in 6 cases and grade 4 in 12 (30.8%). Eighty-one percent of patients on experimental schedules required red blood cell support versus 44.4% of patients on EC. At the third level, platelet transfusions were more frequent among patients treated with EC (27. 8%). Non-haematological toxicity was mild: about 20% of patients experienced grade 3 vomiting, irrespective of schedule. Only 2 patients had grade 3 mucositis; no patient developed heart failure. Fever (61% of patients) and bone pain (55.5% of patients) were relevant in the GM-CSF treated groups and 12 patients shifted to G-CSF. The overall response rate was 84.6%: 5/39 (12.8%) complete response and 28/39 (71.8%) partial response. At 30/9/98, median survival was 29.5 months, with no difference between patients with metastatic and stage IIIb/inflammatory breast cancer. Median follow-up of surviving patients was 62 months (range 17-83). The 5-year estimated survival was 19% (95% confidence intervals = 7-31%). Rapidly alternating or sequential cycles of epirubicin and cyclophosphamide with CSF support is a feasible strategy that allows a higher increase of dose-intensity of the single drugs. Hospitalization and anemia were more frequent with the experimental schedules, and thrombocytopenia with the standard schedule. Overall, this intensified therapy was very active.

Phase I study of carboplatin, cisplatin, and cyclophosphamide without and with lenograstim for the treatment of ovarian cancer.

Cisplatin and carboplatin are both active in ovarian cancer with different toxicity profiles; thus, dose intensification may be possible by combining them. The aim of the present study was to determine the maximum tolerated dose of carboplatin combined with fixed doses of cisplatin and cyclophosphamide without and with support of lenograstim. Cisplatin (60 mg/m(2)), cyclophosphamide (600 mg/m(2)) and carboplatin (starting dose 200 mg/m(2)) were given on day 1 every 3 weeks for 4 cycles. Escalated dose levels for carboplatin were planned by increments of 50 mg/m(2) per level. Lenograstim (L) (150 mu g/m(2)/day subcutaneously) was given in case of grade 4 leukopenia (levels without support) or from day 5 up to leukocyte >10,000/mm(3) after nadir (levels with support). Four levels were studied (200, 250, 250 + lenograstim, 300 + lenograstim) with 7, 7, 8, and 7 patients enrolled, respectively. Unacceptable toxicity was induced in 1 patient at the level I (grade 4 thrombocytopenia), in 4 patients at the level 2 (2 prolonged grade 2 leukopenia, 1 grade 4 leukopenia with concomitant grade 4 thrombocytopenia and 1 grade 4 thrombocytopenia), in 1 patient at the level 2 + L (grade 4 thrombocytopenia) and in 3 patients at the level 3 + L (3 grade 4 thrombocytopenia). Thus, 200 mg/m(2) and 250 mg/m(2) were defined as carboplatin MTDs without and with lenograstim support, respectively. Median total platinum (cisplatin + 1/4 carboplatin) delivered dose-intensities were 33, 32, 38 and 44 mg/m(2)/week at the four levels, respectively. Hematological toxicity was overall mild. In no case was febrile neutropenia recorded. Grade 4 thrombocytopenia was always transient and never symptomatic. Grade 3 vomiting was the only severe non-hematological toxicity reported in 5 patients. Out of 16 patients with measurable disease, 11 objective responses were obtained (5 complete and 6 partial) for an overall response rate of 69% (95% exact CL 41-89%). Recommended dose of carboplatin is 200 mg/m(2) without and 250 mg/m(2) with support of lenograstim when combined with cisplatin 60 mg/m(2) and cyclophosphamide 600 mg/m(2). Dose limiting toxicity is persistent leukopenia without and grade 4 thrombocytopenia with support of lenograstim.

Chlorambucil, vincristine and cytarabine (COA) treatment of low grade lymphomas.

Forty-five patients with stage III-IV low grade non-Hodgkin's lymphoma (NHL) were treated with a non-intensive polychemotherapy regimen including chlorambucil-vincristine and cytarabine (Ara-C), termed COA, for a total of 366 courses, beginning in June 1986. Grade 4 myelotoxicity occurred in only 4/45 patients. No treatment related death was observed. All patients were evaluable for response. Overall, 38 (84%) objective responses, including 31 (69%) complete responses (CR), were observed. At a median follow-up of 57 (21-84+) months, only 8 deaths occurred. Twenty-seven (60%) patients are still disease-free. All disease-free patients were in their first CR. The seven-year estimated survival is 71% and the estimated 7-year progression-free survival (PFS) was 48%. The estimated probability of complete responders to be disease-free at 6 years is 78%. Pretreatment laboratory parameters (serum levels of thymidine kinase, LDH and TNF-alpha showed a good prognostic relevance at using univariate analysis. At multivariate analysis, only the pretreatment serum levels of TNF-alpha were significantly associated with a higher CR achievement probability (p = 0.02) and a longer PFS (p = 0.02). We established a risk model for clinical outcome based on these 3 parameters. Patients having all parameters within the normal range at diagnosis, showed a very good prognosis (100% 7-year PFS and survival), while patients with all parameters increased had a very poor prognosis (0% 7-year PFS and 22% 7-year survival). In conclusion, COA treatment appears to be a non-toxic and very effective treatment for low-grade non-Hodgkin's lymphomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance therapy with recombinant interferon alpha-2B (alpha IFN) in prognostically unfavourable aggressive non-Hodgkin's lymphomas (NHL).

Fifteen patients from a series of 37 consecutive patients with aggressive NHL who achieved a complete remission (CR) with first line chemotherapy were defined at high or high-intermediate risk of relapse according to International Prognostic Risk Index and were treated with alpha IFN as maintenance therapy for two years. After a median follow-up of 62 months only 3/15 patients (20%) relapsed and 2/15 (13.3%) died in the alpha IFN treated group, favourably comparing with the expected relapse and death rate in that setting; on the other hand 40.9% of 'low risk' patients from the same series, who did not receive alpha IFN, had relapsed. alpha IFN maintenance therapy appears to result in prolonged response duration and survival in patients with aggressive and prognostically unfavourable NHL.

Prognostic-significance of multifocality in primary breast-cancer.

The impact of multicentricity in primary breast cancer on relapse or death after radical or modified radical mastectomy was evaluated in 1336 consecutive patients. Multiple tumor foci were found in 11.7% of breast cancers: in 8.4% multicentricity was infiltrating, while in 3.3% of cases an in situ growth pattern was observed. There was a statistically significant association between multicentric primaries and lobular infiltrating carcinoma, age less than or equal to 50 years, large tumors and metastatic axillary nodes, while no relationship was observed with histological grade. Both 5-year disease-free survival and overall survival were shorter in patients with infiltrating multicentric primary tumors. Multivariate analysis confirmed the prognostic role of infiltrating multicentric tumors after adjusting for nodal status, tumor size, age and adjuvant therapy.

Carboplatin, cisplatin and paclitaxel in the treatment of patients with epithelial ovarian cancer.

BACKGROUND: Prognosis of advanced ovarian cancer is unsatisfactory. Chemotherapy can be intensified combining active drugs at their highest possible doses. PATIENTS AND METHODS: In this phase I/II trial, 77 untreated patients received escalating doses of paclitaxel (135, 155, 175, 195 and 215 mg/m2, infused over 3 hours) with carboplatin (AUC 3.6) and cisplatin (60 mg/m2). Nine, 16, 13, 8 and 3 patients were treated at the five levels, respectively. A further 28 patients were treated at the maximum tolerable dose (MTD). RESULTS: Dose-limiting toxicities (one WHO grade 3 constipation, one grade 2 prolonged peripheral neurotoxicity and one grade 3 cardiac toxicity) occurred at 215 mg/m2 in 3 out of 3 patients. MTD was reached at level 4 paclitaxel dose (195 mg/m2). Response was evaluated in 62 patients. A complete response was achieved in 23 patients (37.1%-95% CI 25.2-50.3), including 16 (25.8%) pathological and partial response in 28 (45.2%), for an overall response rate of 82.3% (95% exact CL: 70.5%-90.8%). The probability of response was affected by the degree of initial debulking (p = 0.002) and not by the paclitaxel dose. In patients with stage III-IV disease, median progression-free survival was 17 months (95% CI 14-25). After a median follow-up of 28 months, median survival had not been reached; 2-year estimated survival was 67%. CONCLUSION: Paclitaxel can be safely given at the dose of 195 mg/m2 in combination with carboplatin (AUC 3.6) and cisplatin (60 mg/m2). This combination is active and safe and could be considered in clinical settings requiring intensive short treatment.

Intensive alternating combination chemotherapy and high dose chest radiotherapy in small cell lung cancer.

Sixty-nine patients, 32 with limited and 37 with extensive small cell lung cancer (SCLC), were admitted to the present study. Patients with limited disease underwent alternating combination chemotherapy consisting of CAV (cyclophosphamide, adriamycin, vincristine) and PE (cisplatin and etoposide) regimens and concurrent high dose thoracic radiotherapy (6,000 cGy); prophylactic brain irradiation (3,000 cGy) was administered to complete responders. Patients with extensive disease received the same alternating chemotherapy but not radiotherapy. In the 25 evaluable patients with limited disease we obtained an objective response (OR) in 80% with a complete response (CR) in 54% and partial response (PR) in 24%, stable disease (SD) in 4% and progressive disease (PD) in 16%. Median duration of response was 9.5 months for CR and 8.5 months for PR. Median survival was 14 months for all patients with 12% long-term survivors. Toxicity was acceptable. In the 32 evaluable patients with extensive disease we observed 65.6% OR with 18.7% CR and 46.8% PR, 9.3% minimal response and 25% PD. Median duration of response was 7 months for CR and 8 months for PR. Median survival was 10 months for all patients. The treatment was well tolerated. Our study did not show a therapeutic advantage for alternating combination chemotherapy in SCLC and failed to show the use of high dose chest radiotherapy in combined modality for limited disease.

Salvage chemotherapy with CCNU and methotrexate for small cell lung cancer resistant to CAV/PE alternating chemotherapy.

CCNU and methotrexate were employed as salvage treatment in 34 small cell lung cancer patients resistant to CAV/PE alternating induction chemotherapy. In the 33 evaluable patients we observed an objective response rate of 21.2% and 3% complete response; median survival was 4 months with 2 patients alive 18 months from starting salvages chemotherapy. The treatment was well tolerated. CCNU and methotrexate has shown to be a moderately active and tolerable salvage treatment for small cell lung cancer after CAV/PE alternating first-line chemotherapy.