Delayed adjuvant tamoxifen: ten-year results of a collaborative randomized controlled trial in early breast cancer (TAM-02 trial)

AIM: Immediate adjuvant tamoxifen reduces disease recurrence and improves survival in patients with early breast cancer. However, is it too late to administer tamoxifen to patients who have already undergone treatment, but were unable to benefit from this adjuvant therapy? The French National Cancer Centers (FNCLCC) have investigated the efficacy of delayed tamoxifen administration in a randomized controlled trial. PATIENTS AND METHODS: From September 1986 to October 1989, women with primary breast cancer, who had undergone surgery, radiotherapy, and/or received adjuvant chemotherapy but not hormone therapy more than two years earlier, were randomized to receive either 30 mg/day tamoxifen or no treatment. The 10-year disease-free and overall survival rates of the two groups of patients and of various subgroups were determined according to the Kaplan-Meyer method and compared by the log-rank test. RESULTS: This intention-to-treat analysis comprised 250 Introduction women in the tamoxifen group and 244 in the control group. Patient characteristics (age, T stage, number of positive nodes, receptor status, and interval since tumor treatment) were comparable in both groups. Delayed adjuvant tamoxifen significantly improved overall survival only in node-positive patients and in patients with estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+) tumors. Disease-free survival, however, was significantly improved in the global population and in several patient subgroups (node-positive, ER+, PR+). Patients in whom the interval between primary treatment and delayed adjuvant tamoxifen was greater than five years also had significantly improved disease-free survival. CONCLUSIONS: Overall and disease-free survival results indicate that delayed adjuvant tamoxifen administration (30 mg/day) is justified in women with early breast cancer, even if this treatment is initiated two or more years after primary treatment.

Clinical relevance of gallium-67 scintigraphy in lymphoma before and after therapy.

The clinical impact of gallium-67 scintigraphy before and after therapy for lymphoma remains controversial. The aims of this study were: (1) to compare the staging of lymphoma by 67Ga scintigraphy only with staging by clinical examination and conventional imaging (CI), and (2) to analyse the clinical relevance of both 67Ga imaging and CI after treatment. From March 1995 to November 1998, 86 67Ga scintigraphy studies were performed in 62 patients with Hodgkin's disease (n=52) or non-Hodgkin's lymphoma (n=10). 67Ga scintigraphy was performed at diagnosis (n=44) or after therapy (n=42) using 185-220 MBq 67Ga citrate and planar and single-photon emission tomography (SPET) studies. Treatment comprised radiotherapy, chemotherapy or combined modalities. CI included plain chest radiography, computed tomography (CT) of the chest and abdomen/pelvis, ultrasound of the abdomen, lymphography, bone marrow biopsy and, when necessary, magnetic resonance imaging (MRI) and bone scintigraphy. For individual suspected sites of disease before treatment, complete agreement between clinical examination and CI on the one hand and 67Ga scintigraphy on the other hand was observed in 25/44 patients (57%; 95% confidence interval 41%-72%). Clinical examination and CI showed more sites than did 67Ga scintigraphy in 12/44 patients (27%) and 67Ga imaging demonstrated more sites than CI in 6/44 patients (11%). The clinical stage of the disease as assessed using 67Ga scintigraphy only was in agreement with that using all diagnostic procedures in 34/44 patients (77%; 95% confidence interval 62%-89%). Compared with CI staging, 67Ga scintigraphy downstaged seven patients (16%) and upstaged three (7%). 67Ga scintigraphy downstaged mainly because of the limited value of the technique below the diaphragm and upstaged owing to the good sensitivity in the lung. After therapy, both CI and 67Ga scintigraphy were normal in 11 patients. All but one of these patients were in complete remission after a median follow-up of 31 months. In contrast, radiological residual mass was observed in 31/42 patients. 67Ga imaging was normal in 22/31 (71%); 17 of these 22 patients, including nine with a large residual mass (> or =2 cm), were in complete remission after a median follow-up of 32 months, while four suffered relapses 8-45 months later. The cause of death remained unknown in one patient. 67Ga scintigraphy showed abnormal uptake in 9 of the 31 patients with a large residual mass. Active disease was demonstrated in eight patients and one patient was in complete remission 30 months thereafter. Our data show that 67Ga imaging cannot replace CI in initial staging but can demonstrate additional individual sites of disease in more than 10% of patients and can lead to clinical upstaging with potential prognostic and therapeutic consequences. After therapy, 67Ga scintigraphy has a clinical impact when radiological abnormalities persist because it can either avoid unnecessary complementary treatment or confirm the need to change treatment modalities.

Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group.

PURPOSE: This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy. PATIENTS AND METHODS: Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles. RESULTS: In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups. CONCLUSION: Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy.

[Tamoxifen adjuvant delays early breast cancer. Results of a cooperative randomized trial]. / Tamoxifène adjuvant retardé dans le cancer du sein curable. Résultats d'un essai coopératif randomisé.

Adjuvant tamoxifen (TAM) has been proved to reduce recurrence and mortality in early breast cancer, nevertheless many patients did not receive TAM as adjuvant therapy after local treatment. In order to study the efficacy of delayed TAM therapy in patients who were not given immediate adjuvant hormonal treatment, a multicenter randomized trial has been conducted by the French National Cancer Centers (FNCLCC). According to eligibility criterias all women with breast cancer who received curative local treatment at least 2 years before (surgery +/- radiotherapy) with or without adjuvant chemotherapy but no hormonal treatment could have been included. Between September 1986 and October 1989, 494 women were randomized to receive either TAM 30 mg/day for 5 years or no treatment. Patients' characteristics such as age, tumoral stage, number of positive nodes, receptors status and time from local treatment were equally distributed in the 2 groups. An improvement in the disease free survival in the TAM treated patients can be observed with a significative difference (p = 0.05), nevertheless the overall survival is not improved in the TAM group. In the same way, in nodes positive patients although no significative improvement in the overall survival can be observed, a significative improvement in the disease free survival (p = 0.05) can be noted. In estradiol receptors positive patients tamoxifen gives a significative reduction in the odds of death (p = 0.04) and recurrence (p = 0.03). The disease free improvement seems to be limited to 50 and more years old patients. The first results of this trial lead to prescribe tamoxifen to all postmenopausal women previously treated for an early breast cancer without adjuvant tamoxifen treatment.

Late psychosocial sequelae in Hodgkin's disease survivors: a French population-based case-control study.

PURPOSE: To evaluate late psychosocial sequelae in long-term survivors of Hodgkin's disease (HD) in the population of Calvados, France. PATIENTS AND METHODS: Ninety-three patients issued from the Calvados General Tumor Registry, treated from 1978 to 1990, free of relapse and second malignancy since January 1991, were enrolled onto cross-sectional case-control study. One hundred eighty-six healthy controls, matched for sex, age, and residency, were selected at random from electoral rolls. Two self-administered questionnaires were mailed in the spring of 1995. RESULTS: Compared with controls, HD patients reported (1) more physical (P < .001), role (P < .001), and cognitive (P = .015) functioning impairments, as well as dyspnea (P < .001) and chronic fatigue (P = .025), while no statistical difference was found in global health status; (2) to be more often childless (P = .04), fewer divorces or separations (P = .013), fewer changes in relationships with friends (P = .012), similar proportions at work but less ambitious professional plans (P < .001), and greater difficulties in borrowing from banks (P < .001); (3) a slight increase in the number of visits to a general practitioner (P = .05) and greater consumption of medical resources (mainly thyroid extracts, P = .05). CONCLUSION: The study demonstrated that French long-term HD survivors have good global health status and good psychologic, familial, and professional status, although difficulties in borrowing from banks remain a major limitation in daily life. Although physical, role, and cognitive functioning impairments persist that might limit their activities, HD survivors seem to have learned to cope with problems related to their disease and its treatment.

Lenograstim prevents morbidity from intensive induction chemotherapy in the treatment of inflammatory breast cancer.

PURPOSE: To compare the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) versus its inert vehicle in patients with unilateral nonmetastatic inflammatory breast cancer treated with fluorouracil, epirubicin, and cyclophosphamide high-dose (FEC-HD) neoadjuvant chemotherapy. PATIENTS AND METHODS: One hundred twenty patients have been enrolled by nine French centers in this double-blind, parallel-group, vehicle-controlled study to compare at each cycle subcutaneous lenograstim (5 micrograms/kg/d) with placebo given from day 6 to day 15 after the induction chemotherapy (day 1 to day 4, fluorouracil 750 mg/m2 continuous intravenous [IV] infusion; day 2 to day 4, epirubicin 35 mg/m2 and cyclophosphamide 400 mg/m2 both IV push). Four cycles were planned every 3 weeks before locoregional treatment. Patients with febrile neutropenia remained blinded for the subsequent cycles. RESULTS: Lenograstim significantly reduced the duration of neutropenia at less than 0.5 x 10(9)/L and less than 1 x 10(9)/L to a median duration of 2 and 3 days, respectively, as compared with 5 and 7 days in the placebo group. This translated into a statistically significant reduced incidence of microbiologically documented infections, and a decreased need for rehospitalizations for infectious events and antibiotic use. Clinical objective tumor response rate observed after four cycles was 89.6% and 93%, respectively, in the placebo and treated groups. Mild transient bone and injection-site pain, myelemia, and hyperleukocytosis were the most frequently reported adverse events associated with lenograstim. CONCLUSION: Lenograstim is safe and effective to reduce morbidity associated with FEC-HD neoadjuvant chemotherapy in inflammatory breast cancer. Response rate is not affected.

[What can be now expected of the determination of estrogen and progesterone receptors in the treatment of breast cancers]. / Que peut-on attendre aujourd'hui du dosage des récepteurs d'oestrogènes et de progestérone dans la thérapie des cancers du sein?

Since the first published correlations around the years 1975 between estrogen and progesterone receptors and response to hormone therapy, numerous data have modified our insight on hormone dependency. For instance, it is now well established that tumors are not "receptor positive" or "receptor negative" but contain variable receptor quantities synthesized by a more or less important fraction of tumor cells. This allows to better understand events leading to partial response or to relapse. Receptor detection by classical assays gives no indications on receptor functionality, and data from molecular biology have shown that mutated receptors exist that have lost their property to induce genes, or that present new acquired properties. Nevertheless, these functional modifications are rare, and must not mask a reality: 75 to 80% of tumors with high receptor levels respond to hormone therapy, and the clinician must take this fact into account in three situations: for adjuvant therapy, for metastasis therapy, and for some special cases of difficult diagnosis.

[Abnormality of chromosome number 1 in 3 cases of acute transformation of chronic myeloid leukemia]. / Anomalies du chromosome no 1 dans trois cas de transformation aiguë de leucémie myéloïde chronique.

The authors report three cases of Ph1-positive chronic myelogenous leukemia (CML) with chromosome no 1 abnormalities. Such abnormalities have seldom been reported: three cases out of 42 in blast crisis and none of the 70 patients in the chronic phase in our series. In case no 1 a translocation: (t(1q;14q) was noted. In case no 2 the rearrangement was more complex: partial duplication of the long arm of chromosome no 1 and presence of a 21q+ corresponding to chromosome no 21 on which a part of the long arm of chromosome no 1 was transferred. In case no 3 a double translocation was noted between chromosomes no 1 and no 11, involving either the p or q arm. A review of the literature shows that abnormalities of chromosome no 1 are more frequent during the blast crisis that in the chronic phase of CML. Chromosome no 1 abnormalities are found in a number of myeloproliferative syndromes but even more frequently in solid tumors. The rearrangement sites are reviewed by the authors. Such rearrangements of chromosome no 1 may indicate an increased potential of malignancy.

Two cases of acute leukemia following treatment of malignant glioma.

Two female patients, 42 and 30 years old, respectively, died of acute nonlymphocytic leukemia 43 and 38 months, respectively, after a subsequent treatment: chemotherapy for one and irradiation and chemotherapy for the other, following excision of a malignant glioma. At the time of death, both seemed to be in complete remission of their brain tumor. Both had been treated with procarbazine and nitrosoureas. The latter were responsible for severe myelosuppressive episodes and seem to have played an essential role in the induction of the leukemia. In one case, a myelodysplasia was observed before the onset of the AL and the diagnosis of refractory anemia with excess of blasts seemed warranted. Secondary acute leukemias are rare in the evolution of malignant gliomas and the usefulness of subsequent radiochemotherapy cannot be questioned at the present time. The risks involved in this therapy are minor when compared to the short-term fatal prognosis of this type of tumor.

Hematologic and cytogenetic study of two cases of acute leukemia associated with breast cancer.

The authors present two cases of patients with breast cancer with lymph node extension and who both had surgery. As a pancytopenia with hypercellular bone marrow was discovered at the same time in the first patient, she received no complementary treatment; 4 months later, she presented with an acute lymphocytic leukemia (ALL) for which a remission was easily induced, but she died of a pulmonary infection. The second patient received local radiotherapy (50 grays) and adjuvant chemotherapy (Alkeran for 26 months). Forty-seven months after the diagnosis of breast cancer and 16 months after the end of the treatment, an acute nonlymphoblastic leukemia (ANLL; M6) was diagnosed after 8 months of a preleukemic state. Treatment did not produce any results and death occurred on the 17th day. Cytogenetic studies on the bone marrow cells of both patients were performed. In the first patient in the ALL phase normal cells coexisted with a 47 chromosome clone, the extra chromosome being a D (+ 13?). In the second patient, several karyotype abnormalities were already present in the preleukemic state and also during the acute leukemic phase. No normal mitoses were found; hypodiploidy was present as well as major abnormalities such as markers, rings, and, among others, the systematic loss of a #5 and a #7. The first patient seems to have presented with a de novo ALL, associated with the malignant tumor; whereas, the second patient showed all the characteristics of an induced ANLL. The clinical, hematologic, and cytogenetic characteristics of these two patients are analyzed and compared to those of other cases in the literature.

[Anti-smooth-muscle antibody activity of monoclonal IgM in Waldenström's disease]. / Activité anticorps anti-muscle lisse de l'IgM monoclonale au cours d'une maladie de Waldenström.

The authors report a case of Waldenstrom disease in which the IgM kappa immunoglobulin had an anti-smooth-muscle activity at a very high titre (1/100 000). This activity was found in the purified IgM but not in the Fab fragment; nevertheless, the immunofluorescence inhibition by this fragment is evidence in support of the anti-smooth-muscle activity of the IgM. The IgM specificity in this patient is different from the anti-smooth-muscle antibodies already described.

[Acute leukemia associated with breast cancer (author's transl)]. / Leucémie aiguë et cancer du sein.

Two cases of acute leukemia in patients with breast cancer are reported. In the first patient, erythroleukemia occurred three years after breast cancer was treated by mastectomy, followed by local radiotherapy ; complementary chemotherapy (melphalan) has been given for twenty-six months. The second patient had onset of acute lymphoblastic leukemia four months after breast cancer was treated by surgery only. This patient subsequently has complete remission. Both patients died shortly after onset of leukemia. In the first patient, bone marrow cytogenetic studies evidenced major abnormalities at an early stage of the disease, with abnormal mitoses in all the cells, whereas, in the second patient, only minor abnormalities were found. A review of previously published cases of breast cancer with acute leukemia was done. Our findings suggest that the association of leukemia with breast cancer may result from therapy is some cases (secondary induced acute leukemias) while in others it may occur spontaneously.

[Psoriatic arthritis with renal amyloïdosis. A case-report. Review of the literature (author's transl)]. / Rhumatisme psoriasique et amylose rénale. A propos d'un cas. Revue de la littérature.

A case of severe psoriatic arthritis with both spinal and peripheral joint involvement is reported. The patient, an HLA B27-positive man, was thirty-one years old at onset. Both antiinflammatory drugs and immunosuppressive agents (chlorambucil followed by azathioprine) were ineffective and the patient became bed-ridden. Thirty-three months after onset a severe nephrotic syndrome developed. Renal biopsy let to diagnosis of secondary renal amyloïdosis. The patient died five months later in spite of chemotherapy with melphalan and prednisone. Autopsy could not be performed. A review of the literature showed twelve other cases of psoriatic arthritis with secondary amyloïdosis. Men are affected more often than women. Twelve years was the average interval between onset of joint involvement and diagnosis of amyloïdosis. In three instances, however, this interval was less than thirtyeight months. Arthritis often included both spinal and peripheral joint involvement. Amyloïdosis was evidenced by a nephrotic syndrome in eight out of twelve cases. Prognosis is poor with a fourteen months average interval between onset of clinical amyloidosis and death.

Myelodysplasia and leukaemia related to chemotherapy and/or radiotherapy--a haematological study of 13 cases. Value of macrocytosis as an early sign of bone marrow injury.

Clinical and haematological features of 13 patients with secondary myelodysplastic syndromes (MDS) were studied, MDS developed subsequent to chemotherapy and/or radiotherapy for various haematological or non-haematological diseases. In six cases, the first sign was a persistently increased mean cell volume (MCV) and a macrocytosis preceding from 6 to 18 months the appearance of severe anaemia or acute leukaemia. In five cases, the initial finding was a macrocytic anaemia. Dysmyelopoiesis was a constant and prominent feature of the bone marrow smears at some time during the course of the disease. Two cases without macrocytosis at any time directly developed overt acute leukaemia.