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Aims and Background Methotrexate (MTX) and leucovorin (LV) can enhance the cytotoxicity of 5-fluorouracil (5FU) by modifying its metabolic pathway inside target cells. Some preclinical studies and clinical trials have suggested that the concurrent or sequential double modulation of 5FU by means of MTX and LV may give a higher activity than single biochemical modulations. The purpose of our phase II study was to assess the activity and toxicity of a biweekly regimen including MTX, levo-LV and 5FU in colorectal cancer patients. Methods From July 1994 to May 1997, 100 consecutive patients affected by advanced or metastatic colorectal carcinoma were given MTX, 750 mg/m2 iv (2-h infusion) on day 1, and levo-LV, 250 mg/m2 iv (2-h infusion) followed by 5FU, 800 mg/m2 iv bolus on day 2, every two weeks. Patients were treated until complete response or progressive disease was documented, or for a maximum of 16 courses. Results Among 97 eligible patients, 5 complete and 25 partial responses were obtained, giving an overall response rate of 31% (95% exact confidence limits, 22-41%). Response rate was significantly higher in patients with a good (ECOG scale 0) than with a poor (ECOG scale 1 or 2) performance status (40% versus 17%, P Conclusions The double biochemical modulation of 5FU by MTX and levo-LV is at least as effective as, and probably more effective than, the single modulation by MTX or by LV. It may therefore represent a therapeutic option for the palliative treatment of patients with advanced colorectal carcinoma.

Letrozole is a third-generation aromatase inhibitor for use in postmenopausal women with hormonal-sensitive breast cancer. This drug was found to reduce or effectively shrink tumors in a significant number of such patients. It exhibits antitumor activity at a relatively low daily dose, and is highly potent and selective and well tolerated. Results from recent phase III clinical studies have confirmed the efficacy and the key role of this drug in the therapy of advanced breast cancer in postmenopausal women. Moreover, letrozole demonstrated higher activity and lower toxicity compared to tamoxifen in the first-line therapy of postmenopausal women affected with advanced breast cancer. However, it also represents a valid option in second-line therapy after tamoxifen failure. New data on this agent in adjuvant or neoadjuvant treatment also suggest efficacy in the treatment of early breast cancer. This article reviews the clinical data on letrozole in all settings and its future potential in chemoprevention. (c) 2001 Prous Science. All rights reserved.

The paper reviews the current strategic approach of the Istituto Nazionale Tumori of Milan with adriamycin (ADM) in combination with other drugs as well as in combined treatment modalities for various neoplasias of adults and children. The preliminary results obtained during the past four years in malignant lymphomas, acute leukemias, carcinoma of the breast, and neuroblastoma are reported. With the exception of the group of malignant lymphomas treated with a quintuple drug regimen (MABOP), none of the patients admitted the different trials had received chemotherapy. Most studies were controlled with random allocation to two different combinations. Cross over was carried out on relapse. In advanced Hodgkin's disease, non-Hodgkin's lymphomas, mammary carcinoma, soft tissue sarcomas, embryonal carcinoma of testicle, ovarian carcinoma, and multiple myeloma the main purpose of the study was to develop two independent non cross resistant combinations to be used sequentially in subsequent trials. There is a preliminary evidence that this is being obtained in Hodgkin's disease (ABVD vs. MOPP), in non Hodgkin's lymphomas (ABP vs. CVP) and carcinoma of the breast (ADM + VCR vs. CMF). In the other groups the patients were too few to permit conclusions. In acute lymphoblastic leukemia, in the leukemic phase of non-Hodgkin's lymphomas as well as in the group of solid tumors of children, combination chemotherapy and combined treatment modalities were not designed in a controlled fashion. ADM was introduced in all treatments because of its definite activity when employed as a single agent in refractory disease. Few therapeutic results are as yet available since most studies were started in 1974. However, the remission rate observed in the limited group of acute leukemias treated with ADM + VCR + prednisone is worth noting. The wide spectrum of activity of ADM justifies its use in several protocols of combination chemotherapy and in combined treatment modalities. With both full and reduced regimens drug tolerance was good, and in practically all studies more than 80 % of the optimal dose of ADM could be administered. All trials were properly designed to avoid a total dose of ADM exceeding 550–600 mg/m2 since cardiomyopathy (reversible) was observed in 2 patients after 600 mg/m2.

Combined treatment modality was applied in 110 consecutive women with primary inoperable (T3b-T4) Breast cancer. Treatment was started with four cycles of adriamycin plus vincristine (AV). This was followed in responders by high-energy radiotherapy (RT). At the end of combined therapy, patients in complete remission (CR) were randomized to either no further treatment or six more cycles of chemotherapy. AV induced objective response in 89% of patients (complete 15.5%, partial 54.5%, improvement 19%). At the end of RT, 81% of 98 (82.7%) patients responding to AV were classified in CR. The median duration of CR was 15 months. The median free interval was statistically prolonged by additional chemotherapy. The three-year survival was 52.8%. Altogether, present findings indicate that combined treatment modality has improved the three-year survival compared to the previous series treated with radiotherapy alone. However, to achieve a satisfactory control of T3b-T4 breast cancer a more aggressive and prolonged treatment is required.

From 1973 to 1980, we carried out a controlled study at the National Cancer Institute in Milan to consider the value of a conservative procedure in patients with breast cancer of small size. We randomized 701 patients with breast cancer measuring less than 2 cm in diameter and with no palpable axillary lymph nodes to Halsted radical mastectomy or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral residual breast tissue. We treated 349 patients with Halsted mastectomy and 352 with quadrantectomy. The two groups were comparable in age distribution, size and site of primary tumor, menopausal status, and frequency of axillary metastases. There were three local recurrences in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference between the two groups in disease-free or overall survival. From these results, mastectomy appears to involve unnecessary mutilation in patients with breast cancer of less than 2 cm and no palpable axillary nodes.

Methotrexate (MTX) was given by weekly rapid intravenous injections to 27 patients with inoperable oropharyngeal carcinoma. 9 cases were untreated while 18 had received radiotherapy or chemotherapy before administration of MTX. In 20 cases the dose was 40 mg/m2/week (patients over 50 years) and in 7 cases 60 mg/m2/week (table 1). In responsive patients, maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. 23 cases were adequately evaluable, i.e. they received treatment for a minimum of 3 weeks. Response to treatment was evaluated according to Karnofsky's scale. Considering only category 1 regressions, 11/16 (75%) patients adequately treated with 40 mg/m2 showed objective improvement and respectively 4/7 (57%) given 60 mg/m*. 8 out of 15 cases (41%) with category 1 response showed a regression greater than 50%. The mean duration of response for category 1 patients was 3.5 months, while the longest regression lasted 9 months (table 2). 18 patients had one or more side effects: 9 had oral lesions or gastroenteritis, 12 bone marrow depression, 3 hepatic and 1 renal toxicity. One patient died from hepatic and renal toxicity; in the remaining cases the side effects were quickly reversible (table 3). The percent regression rate for category 1 response and its average duration obtained with intravenous MTX seems comparable to intraarterial infusion (table 4). Systemic toxicity seems also comparable (table 5). Furthermore, intravenous administration obviates the typical local complications occurring with intra-arterial treatment and therapy can be given also at outpatients. For this reason, intravenous administration of MTX is preferred to intra-arterial infusion in the control of primary inoperable oropharyngeal carcinomas, provided no severe depression of liver, kidney and bone marrow is present.

Effusions are a frequent complication in the course of disseminated breast cancer. Intracavitary instillation of radioactive gold, particulate irritants such as talc, alkylating agents, quinacrine, fluorouracil, bleomycin have been used for symptomatic control. The usefulness of intracavitary administration of antineoplastic agents in the management of recurrent, intractable neoplastic effusions has been evaluated in 43 patients in which 67 instillations were made and 58 were evaluable (table 1). Many drugs were used, particularly alkylating agents an HN2 and as Thio-TEPA and antimetabolite as fluorouracil (table 2). In the present series 19 of the 58 patients (32.7 %) with metastatic carcinoma of the breast had objective control of the neoplastic effusion for periods ranging from 45 to 485 days (table 2). In comparison with other methods of treatment, cytostatic therapy of pleural effusion caused by metastatic carcinoma of the breast does not produce a higher percentage of therapeutic response. Particularly talc poudrage has been employed with better results.

Methotrexate (MTX) was given by weekly intravenous injections to 43 patients with inoperable or metastatic lung cancer (32 cases were untreated while 11 received radiotherapy or chemotherapy prior to administration of MTX). In 35 cases the dose was 40 mg/m2/week and in 8 cases 60 mg/m2/week. 36 patients were adequately evaluable. In most cases it was possible to continue the administration of MTX for 6–8 weeks (table 1). In responsive cases maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. Response to treatment was evaluated according to Karnofsky's scale. Considering only the category I responses 12/30 patients adequately treated with 40 mg/m2 showed objective improvement and 2/6 of those given 60 mg/m2. Regressions were short-lived and in no case did they last longer than 5 months (table 2). Regressions were seen in practically all histologic types (table 3). Of 43 patients receiving MTX 30 (70%) had one or more side-effects: 27 showed oral or gastrointestinal toxicity, 8 varying degrees of bone marrow depression, 6 hepatic and 4 renal toxicity. Four patients died because of toxicity, renal damage being present in all cases (table 4). The relatively small number of consistent objective regressions (about 40%), their short duration and the high incidence of severe toxicity, as observed in the present series, indicate that weekly high-dose intravenous MTX is of moderate therapeutic usefulness in lung cancer.

Bleomycin (BLM), a new antitumor antibiotic isolated in Japan from cultures of Streptomyces Verticillus, was administered by single intravenous injections to patients with different types of lymphomas and miscellaneous solid tumors for phase I evaluation. 85 out of the 110 patients included in the study were suitable for the evaluation of acute and delayed toxicity, while 93 patients were evaluable to detect the therapeutic effects of the drug. The average age of the patients was 54 years (range 7–83). 16 patients were untreated and 77 had received one or more courses of radiotherapy and/or chemotherapy. During this trial different doses and schedules were employed (table 2): A) 30 mg/m2 × 2/week × 4 weeks; B) 30 mg/m2/day × 8 days; C) 15 mg/m2/day × 8 days. After a month interval all 3 courses were repeated; D) 15 mg/m2/day × 5 days to be repeated twice after 3 weeks interval. Maintenance therapy consisted of 15–30 mg/m2/week. To diminish the febrile reaction, a suppository of indometacin (100 mg) was given 30–60 minutes prior to drug administration. The incidence of toxic manifestations, irrespective of dose and schedule, was as follows (fig. 4): sclerotic changes of the skin of hands (80%), fever (67%), alopecia (61 %), skin hyperpigmentation (60 %), stomatitis (48 %), gastrointestinal disturbances (20%) and pulmonary symptoms (19%). No definite signs of marrow toxicity nor significant changes in the blood chemistry attributable to the drug were observed. Symptoms and signs of pulmonary toxicity, appearing 1–4 weeks after the last dose were: rhonchi, rales and pleural friction rubs, in some cases associated with fever and dyspnea. The chest X-ray showed evidence of interstitial lesions (in early phases most marked at the costophrenic angle) which may become widespread with a bronchopneumonia-like appearance (fig. 5 and 6). No clearcut radiological signs of pulmonary fibrosis were observed (patients were not followed for a period longer than 5 months). If BLM is stopped in time and carticosteroids are given in association to antibiotics, both clinical and radiological findings may disappear completely (fig. 7). Of the 7 patients studied post mortem, 6 revealed lesions attributable to drug toxicity (alveolar collapse with edema, histiocytic proliferation, hyaline membranes, alveolar and interstitial fibrosis (fig. 8–11). In 7 patients pulmonary toxicity was suspected only on clinical grounds, in 2 cases the radiological aspect of the lungs was suggestive of interstitial lesions without concomitant physical findings, in 9 cases a good correlation between clinical and radiological diagnosis was observed and, finally, in 6 patients the pulmonary fibrosis was detected on histological examination (table 3). In the 17 patients in whom the diagnosis of pulmonary toxicity was documented either radiologically or histologically, the average age was 56,5 years (7–78 years) and the mean total dose, producing toxicity was 230 mg/m2 (range 60–480). Practically, all these patients prior to the treatment had different grades of chronic pulmonary lesions (emphysema, fibrosis post RT or tuberculosis, silicosis in 1 case). It is difficult to estimate in what proportion BLM could have contributed to the cause of death, since most patients dying during treatment had also lung metastases. However, at least in 1 case in whom postmortem examination did not disclose lymphosarcoma cells (complete remission), the cause of death could be related to drug administration (total 225 mg/m2) since extensive pulmonary fibrosis was seen on histological examination (table 4). Table 5 shows the incidence of side-effects after the first course of BLM. No significant differences were observed among cases treated with 4 different schedules, and the first sign of toxicity appeared in all groups after the 4th–6th dose irrespective of the dose and schedule. Regressions in different types of tumors were observed during this phase I study (table 6). The overall regression rate was 69 % (24 % greater than 50 % and 5% complete). The therapeutic response was prompt but usually short-lived (average 4–6 weeks). No cross-resistance with radiotherapy nor with some of the conventional agents was observed. The most responsive tumors were carcinomas of head and neck, carcinomas of esophagus (fig. 17) and malignant lymphomas (fig. 16). One 7-year-old boy with acute lymphosarcoma cell leukemia had a complete remission and autopsy revealed no signs of neoplastic disease. In 2/3 patients with CLL a moderate decrease in the volume of hepato-splenomegaly was observed without significant fall in the WBC. The minimal toxic dose was 45–60 mg/m2 in malignant lymphomas and 60–120 mg/m2 in the other solid tumors. BLM appears to be a potent new growth-inhibiting compound specific for epidermoid carcinomas and devoid of bone marrow toxicity. The optimal dose schedule as well as the real incidence and course of pulmonary toxicity should be more clearly defined in future studies.

The case of a 65-year old man with chronic lymphocytic leukemia associated with reticulum cell sarcoma (histiocytic diffuse lymphoma) is reported. The patient was not pretreated with radiotherapy and/or chemotherapy. The simultaneous diagnosis was made when the patient was first hospitalized and not post-mortem. The coexistence of the two types of association (CLL+RSA and CLL+Hodgkin's disease, known as Richter's syndrome) is discussed.

The toxic and therapeutic results obtained during phase I and phase II evaluation of adriamycin (ADM) and bleomycin (BLM) in 92 adequately treated cases with malignant lymphomas are reviewed. The number of pretreated patients as well as the different histologic expression of lymphoma are given together with the incidence of toxic manifestations (table 3, text-fig. 1). Stomatitis and alopecia are caused by both drugs and show about the same incidence as first sign of toxicity. Interstitial pulmonary lesions produced by BLM were observed in a fairly large percentage of cases and represent at the dosage used a limiting factor to prolonged administration. The therapeutic response has been evaluated on the Karnofsky's scale. With ADM category I response occurred in 72.2% of cases and with BLM in 50% (table 5, 6). Complete remissions for more than 1 year occurred in 3 patients treated with ADM and 1 with BLM. With both drugs all types of lesions responded, including bone marrow invasion. In responsive patients remissions occurred promptly (average 13.7 days with ADM and 10.3 days with BLM) (table 4). Because of their toxic and therapeutic properties, both drugs appear suitable for therapeutic trials in combination with conventional agents.

A retrospective analysis of 118 patients with non-Hodgkin's lymphomas who received one or more drugs of single agent chemotherapy was conducted to determine the relationship between the histopathologic category of lymphoma, based on the classification proposed by Rappaport et al., and the results (type of regression and survival) of sequential chemotherapy. In 96/118 cases, slides were available for histopathologic reclassification. Patients were selected according to the following criteria: chemotherapy with single agents administered in sequence (e.g. alkylating agents, vincristine, adriamycin, bleomycin); change in drug administration only after an adequate course and either no response or clinical resistance after prior regression; measurable disease; performance status greater than 40. Prior to chemotherapy 66 patients had diffuse (extranodal) disease, 39 adenopathies above and below the diaphragm, and 13 adenopathies only above or below the diaphragm. 49/118 patients were pretreated with radiotherapy. The data were most complete for alkylating agents which were administered as a single agent in 93 patients. Complete remission (CR) plus partial remission (PR) greater than 50% occurred in 39% of patients with lymphocytic lymphoma, in 39% with histiocytic and in 50% with mixed type lymphoma (table 4). This type of response was observed with all drugs in 70% of nodular lymphomas and in 36% of diffuse lymphomas (table 7). The overall response rate to adriamycin was 75% in nodular lymphomas, and 55% in diffuse lymphomas. These data were 40% and respectively 14% after treatment with bleomycin. Median survival of all non-Hodgkin's lymphomas was 16.2 months (fig. 1); median survival was 23.4 months for nodular lymphomas and 17.4 months for diffuse lymphomas (fig. 2). Among nodular lymphomas, no significant differences were observed between nodular histiocytic and nodular lymphocytic well differentiated (fig. 3). Diffuse lymphocytic well differentiated lymphomas showed better survival in comparison to diffuse lymphocytic poorly differentiated, diffuse histiocytic and diffuse undifferentiated types (fig. 4). Patients responding to 2 drugs or more showed a better median survival (66 months) than those responding only to one drug (22.4 months) and unresponsive patients (10.2 months) (fig. 5). This study confirms most of the data reported by the Stanford group and emphasizes the need to employ a more deteailed histopathologic classification such as that proposed by Rappaport et al. Although this retrospective analysis has a number of drawbacks, it does provide, in terms of survival, a measurable indication that the responsiveness to at least two drugs is associated with better survival in non-Hodgkin's lymphomas than little or no responsiveness.

The clinical records and histologic material of 18 consecutive patients with malignant histiocytosis were reviewed. The age of the patients ranged from 20 months to 72 years (median 35 years). There were 14 males and 4 females (3.5:1). Lymph node and liver enlargement, fever, and skin nodules were the most common physical findings; and leukocytosis was frequently the most abnormal laboratory test. Seven of 18 patients died, and their survival ranged from 1 to 15 months (median 8 months) after histopathologic diagnosis. The histologic findings on lymph nodes, spleen, liver, bone marrow, and skin were investigated with special reference to both the cellular composition and the pattern of lymph node involvement. Vascular invasion of small perinodal vessels was observed in 4 fatal cases. The absence of capsular invasion and the lack of cohesiveness among atypical proliferating histiocytes of malignant histiocytosis appeared to be inconstant. Sequential lymph node biopsies revealed in later stages the extension of the histiocytic proliferation from the sinuses into the cords and the complete obliteration of the nodal structures. The radiologic investigations yielded numerous pathologic findings that were consistent with the dissemination of the disease. Complete response to initial treatment was achieved in patients that were treated with radiotherapy and/or chemotherapy. Complete response with chemotherapy was achieved only when the treatment included adriamycin. The histologic and clinical features of the present series provide further evidence for the recognition of malignant histiocytosis as a distinct clinical and pathologic entity.

Mitomycin C was administered to 22 patients with metastatic breast cancer, refractory to hormonal therapy and conventional chemotherapy. Treatment was given by intravenous bolus injection at 20 mg/m2 of the drug and repeated at 6-week intervals. The overall response rate was 23 %. Two complete remissions were seen in soft tissue lesions. Leukopenia occurred in 68 % of the patients, thrombocytopenia in 36 %, and anemia in 14 %. One case of cardiotoxicity after previous treatment with adriamycin was observed. We conclude that mitomycin C is an active agent in disseminated breast cancer resistant to hormone therapy and chemotherapy. Combination of mitomycin C with other chemotherapeutic drugs will be tested.

Sixty-two women with advanced breast cancer were admitted to a pilot study in which a modified CMF regimen was administered. Cyclophosphamide was administered i.v. at a dosage of 600 mg/m2 on the same day as fluorouracil (600 mg/m2/i.v.) and methotrexate (40 mg/m2/i.v.). The therapy was recycled on the 21st day and in the presence of myelosuppression, the administration of the drugs was delayed for 1-2 weeks recovery of the hematologic values. CR + PR were obtained in 42% of patients and no change in 32% (U.I.C.C. criteria). Metastases to soft tissues showed CR + PR in 55% of the cases, bone in 33% and viscera in 35%. The menopausal status, the disease-free interval and the number of involved sites did not influence statistically the percentage of responses; however, the response rate was influenced statistically by previous treatment. The median duration of response was 7.5 months; the median overall survival of the 60 evaluable patients was 18 months. Due to myelosuppression, CMF i.v. administration was delayed 90/620 times (14%). Toxicity was acceptable and had a lower incidence than that reported in the literature in different series of CMF administered p.o. Nausea and vomiting, in particular, were limited to 24-48 h after administration of the drugs, and alopecia was seldom observed.

Adriamycin is a new antitumor antibiotic of the anthracycline group. Its chemical structure is very close to that of daunorubicin. Pharmacological studies demonstrated that adriamycin has a higher therapeutic index (1.21) than daunorubicin (0.67). Adriamycin was given intravenously to 53 patients with different types of leukemia and cancer (13 children and 40 adults). Three doses were used: 0.4 mg/kg (pretreated patients), 0.65 mg/kg (untreated adults), 0.8 mg/kg (children). Three different schedules were also employed regardless of the single dose/kg (table 1): A) Loading-dose schedule: treatment for 4 consecutive days followed by a 3 day interval: the drug was then restarted 1–2 times a week; B) Alternate day-dose schedule: treatment every other day for 4–6 doses followed by a 3 day interval; the drug was then restarted 1–2 times a week; C) Intermittent-dose schedule: two treatments for 3 consecutive days separated by two intervals of 4 days; the drug was then restarted 1–2 times a week. The chief evidence of toxicity was a triad of symptoms: stomatitis, bone marrow depression and alopecia (table 2). The oral ulcerations where the first sign of toxicity in more than 50 % of cases. The first sign of toxicity usually precedes the other side effects by 1–3 days. Fever, gastroenteritis and phlebitis at the site of injection were toxic signs of minor importance. However, to avoid phlebitis the drug should be injected through a tube of a free-running intravenous infusion. Adriamycin seems from the present series to be devoid of significant cardiac toxicity. As expected, children tolerated higher doses than adults and all pretreated patients became rapidly intoxicated with small doses. The less toxic schedule appears to be the intermittent one (C). Prompt and consistent responses were observed in many cases (table 4), but they were usually short lived. The drug appears therefore to be a potent growth-inhibiting compound more useful for inducing the first remission than for mantaining it. Acute lymphoblastic and chronic myelogenous leukemias as well as malignant lymphomas, neuroblastomas and soft tissue sarcomas were the diseases most sensitive to adriamycin.

Background In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Methods Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (10%, 25 000 women). Findings About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44·6% versus 49·5% (absolute reduction 5·0%, SE 0·8, 2p These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30·5% versus 35·9% (reduction 5·4%, SE 1·7, 2p=0·0002; overall mortality reduction 5·3%, SE 1·8, 2p=0·005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54·7% versus 60·1% (reduction 5·4%, SE 1·3, 2p=0·0002; overall mortality reduction 4·4%, SE 1·2, 2p=0·0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1·18, SE 0·06, 2p=0·002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1·12, SE 0·04, 2p=0·001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1·27, SE 0·07, 2p=0·0001) and lung cancer (rate ratio 1·78, SE 0·22, 2p=0·0004). Interpretation In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

International audience; Adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have proven highly effective in rapidly proliferating breast cancer (RPBC). It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant epirubicin (E) followed by CMF is superior to the inverse sequence in RPBC. Patients with node-negative or 1-3 node-positive RPBC (Thymidine Labeling Index > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%) were randomized to receive E (100 mg/m i.v. d1, q21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m i.v. d1 and 8, q28 days for 4 cycles) (E → CMF) or CMF followed by E (CMF → E) or CMF for 6 cycles. From November 1997 to December 2004, 1066 patients were enrolled: E → CMF 440, CMF → E 438, and CMF 188. At a median follow-up of 69 months, 5-year OS was 91% (95% CI 88-94) for E → CMF and 93% (95% CI 90-95) for CMF → E, with adjusted hazard ratio of 0.88 (95% CI 0.58-1.35), and DFS was 80% in both arms, with adjusted hazard ratio of 0.99 (95% CI 0.73-1.33, Cox model). Adverse events were similar, apart from a higher rate of neutropenia in the CMF → E arm. No important differences in clinical outcome were observed between the two different sequences, making both a valid option in early breast cancer. Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence.

The sequential doxorubicin → CMF (CMF = cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF × 6 cycles (CMF); (b) doxorubicin × 4 cycles followed by CMF × 6 cycles (A → CMF); (c) CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (CMF → GT); and (d) doxorubicin × 4 cycles followed by CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (A → CMF → GT). The study used a 2 × 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A × CMF or arms a + c vs b + d) and (2) the effect of adding GT after chemotherapy (arms a + b vs c + d). At a median follow-up of 72 months, A → CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR) = 0.740 (95% confidence interval (CI): 0.556-0.986; P = 0.040) and produced a nonsignificant improvement of overall survival (OS) (HR = 0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR = 0.74; 95% CI: 0.555-0.987; P = 0.040), with a nonsignificant improvement of OS (HR = 0.84; 95% CI: 0.54-1.32). A → CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients. © 2005 Cancer Research UK.

OBJECTIVE: This phase III study was aimed at evaluating whether the addition of gemcitabine (G) to vinorelbine (V) could improve the survival and quality of life (QoL) of elderly patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC, aged >or=70 years, were randomly allocated to receive V 30 mg/m(2) on days 1 and 8 every 3 weeks or G 1200 mg/m(2) plus V 30 mg/m(2) on days 1 and 8 every 3 weeks. Survival was the main end point of the study. The estimated sample size was 120 patients per arm, but an interim analysis of survival was planned on the first 60 patients per arm. RESULTS: In May 1999, an interim analysis was performed with the survival data of the first 120 eligible patients (V(arm)=60, G+V(arm)=60). Forty-nine patients had stage IIIB disease and 71 patients stage IV disease, median potential follow-up of 14 months (range; 3-22), 93 patients had died (G+V(arm)=41, V(arm)=52). Median survival time (MST) was 29 weeks and projected 1-year survival was 30% in the G+V(arm); these values were 18 weeks and 13% in the V(arm). At multivariate Cox analysis, the risk of death in the G+V(arm) compared with V(arm) was 0.48 (95% C1=0.29-0.79; P

Purpose: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex®) (TOM + LFA 5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU). Patients and methods: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 850 mg/m 2 s i.v. bolus (arm A); TOM, 3 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 1050 mg/m 2 i.v. bolus (arm B); or MTX, 750 mg/m 2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m 2 i.v. infusion and 5-FU, 800 mg/m 2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more. Results. The RRs were: 34% (95% confidence interval (95% CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs. in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA-5-FU. Median relative dose intensity over eight cycles (DI 8 ) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA 5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI 8 was 93% for TOM, and 82% for 5-FU. Conclusions: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA-5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

We determined the activity and toxicity of gemcitabine plus cisplatin in patients with inoperable or metastatic transitional cell carcinoma of the urinary tract.A total of 54 patients with transitional cell carcinoma, measurable disease and Eastern Cooperative Oncology Group performance status 2 or greater were enrolled in this multicenter phase II trial. Previous adjuvant or neoadjuvant therapy for locally advanced disease was acceptable if it had been completed more than 1 year before study entry. Every 4 weeks patients received 1,000 mg./m.2 gemcitabine intravenously on days 1, 8 and 15, and 70 mg./m.2 cisplatin intravenously on day 2.All patients were evaluable for response and toxicity. Notably only 7 of the 54 patients (13%) previously received chemotherapy in an adjuvant or neoadjuvant setting. Overall we observed 26 objective responses (48%), of which 15% were complete. Median time to progression was 23 weeks and median survival was 54 weeks. Treatment was well tolerated. The main toxicities were leukopenia (grade 3 in 28% and grade 4 in 11% of patients), anemia (grade 3 in 34% and grade 4 in 6%) and thrombocytopenia (grade 3 in 14% and grade 4 in 6%). Other relevant side effects were nausea and vomiting in 20% of cases, fever in 24%, alopecia in 22%, renal failure in 7.4% and mucositis in 2%.Combined cisplatin plus gemcitabine is highly active in advanced transitional cell carcinoma of the urinary tract with manageable toxicity. The response rate, time to treatment failure and overall survival appeared to be comparable to those achieved with combined methotrexate, vinblastine, doxorubicin and cisplatin. Conversely toxicity appeared lower. Evaluation of this regimen in randomized studies with methotrexate, vinblastine, doxorubicin and cisplatin is strongly suggested.

From January 1992 to December 1995, 129 patients with previously untreated non-Hodgkin's lymphoma were randomised in a phase III multicenter trial to receive CEOP-B/VIMB or ProMACE-CytaBOM. Eligibility criteria included intermediate or high grade lymphoma (follicular large cell, diffuse small cleaved-cell, diffuse mixed, diffuse large-cell and immunoblastic) with an Ann Arbor stage II bulky, III or IV. All patients entered into the study were considered evaluable according to intent to treat analysis. At a median follow-up of 60 months there were no significant differences between the treatment response rates [82% (60%CR) for CEOP-B/VIMB vs. 81% (69% CR) for ProMACE-CytaBOM]. Conversely, with regard to disease-free survival, a significant difference was observed between the two treatment arms (42% for CEOP-B/VIMB vs. 24% for ProMACE-CytaBOM at 5 years; p=0.046). However, this difference did not translate in a significant difference in overall survival (45% vs. 39% at 5 years). Moreover, when response rates and outcome were analysed for different prognostic subgroups according to International Prognostic Index, no significant differences were observed between the treatment groups. It is important to note that neither regimen was able to improve outcome of poor risk patients who fared badly with both treatments (median survival 9 and 8 months respectively). Toxicity was also similar in both treatments with grade 3-4 leukopenia observed in 39% and 47% of cases and grade 3-4 thrombocytopenia in 24% and 27% of cases respectively. In conclusion, in this study CEOP-B/VIMB was not superior to ProMACE-CytaBOM in aggressive lymphomas and the alternating strategy failed to improve outcome of poor risk patients in which newer more aggressive treatments are needed.