Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients.

PURPOSE: The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer. METHODS: The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety. RESULTS: A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity. CONCLUSIONS: Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses.

[Survival results after 10 years of 39 patients with inflammatory breast cancer treated by two different neoadjuvant chemotherapy protocols]. / Survie à 10 ans de 39 patientes porteuses d'un cancer du sein à cinétique rapide traitées selon deux protocoles de chimiothérapie néoadjuvants différents.

The aim of this study was to compare the survival results at ten years of two groups of respectively 19 and 20 females who had an inflammatory breast cancer, treated with two different neoadjuvant chemotherapy protocols of six days for the first one, and of one day for the second one. Among these 39 patients, 16 are alive, 15 without any symptoms of disease since the end of the treatment. There is no statistically significant difference between the two groups for the disease free survival interval and for the survival population.

Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: This study investigated the therapeutic effects of single-agent intravenous (IV) weekly Navelbine (vinorelbine or 5'-nor-anhydro-vinblastine; Pierre Fabre Médicament, Boulogne, France), a semisynthetic vinca alkaloid, in women who had received no prior chemotherapy for locally advanced or metastatic breast cancer. PATIENTS AND METHODS: One hundred fifty-seven patients with assessable advanced or metastatic breast cancer who had received no prior chemotherapy were entered onto the study. They were stratified into five groups according to the main assessable tumor target: lung, liver, lymph nodes, skin, and others. One hundred forty-five patients were assessable for toxicity and response using World Health Organization (WHO) criteria; the 12 patients who were not evaluated were excluded because they were found not to meet the eligibility criteria. Navelbine was administered as a weekly 30-mg/m2 short IV infusion, and treatment was continued until disease progression. RESULTS: The overall response rate (WHO criteria) was 41% (complete response [CR], 7%; partial response [PR], 34%; 95% confidence interval [CI], 33% to 49%). In addition, 30% of the patients had stable disease. The response rate according to target was lymph nodes (28 of 42), 67%; liver (nine of 39), 23%; lung (10 of 30), 33%; skin (21 of 30), 70%; primary tumor (10 of 16), 56%; and bone (three of 10), 30%. The median time to treatment failure was 6 months and the median survival was 18 months. A total of 1,673 cycles were given to 145 eligible patients. At least one episode of WHO grade 3 or 4 granulocytopenia was seen in 72% of the patients. Nausea and/or vomiting, anemia, and/or thrombocytopenia were seen in less than 1% of cycles. Other side effects were rare, and additional toxicities were documented in the following proportions of patients: grade 2 to 3 alopecia, 8%; infectious episodes, 6%; and peripheral neuropathy, 3%. CONCLUSION: Our data confirm that Navelbine has major single-agent antitumor activity as front-line therapy in advanced breast cancer. Given its excellent tolerance profile and low toxicity, it should be considered for inclusion in first-line combination chemotherapy regimens.

Phase II trials of tetrahydropyranyl-adriamycin (Pirarubicin) on renal and colon carcinoma, melanoma, and soft tissue sarcoma.

Eighty patients with measurable metastatic colon or renal cancer, melanoma, or sarcoma entered these Phase II studies. A dose of 25 mg/m2/day of Pirarubicin (THP) for 3 consecutive days every 4 weeks for the first patients, and then 20 mg/m2/day for 3 days every 3 weeks was given by i.v. push. These patients received 225 cycles for a median cumulative dose of 165 mg/m2 (range: 55-630). The mean number of cycles given was 2.8 (range: 1-8). Only 3 partial responses and 18 stable disease (22%) were observed. Hematologic toxicity was the main problem; it was responsible for one death and a 19% and 44% incidence of grade 3 and 4 WHO neutropenia, respectively. Alopecia was rare (4%). Chemotherapy was discontinued in three cases because of suspicion of cardiac toxicity, but only one patient had a significant drop in left ventricular ejection fraction at a cumulative THP dosage of 120 mg/m2. A lack of efficacy in renal and colon cancer and melanoma was presupposed and confirmed by these trials. Due to pretreatment with anthracycline in most patients, definite evaluation of THP in soft tissue sarcoma could not be given.

Carcinoma of the cervical stump: a review of 213 cases.

From 1970 to 1987, 213 cases of carcinoma of the cervical stump were accrued in a multi-institutional prospective cooperative study. This group accounted for 5.5% of cervical carcinoma diagnosed during the same period. 13 had in situ carcinoma and 200 had invasive carcinoma (96% squamous cell carcinoma, 4% adenocarcinoma). Radiotherapy alone (external and brachytherapy) was given to 77%, brachytherapy and surgery to 15% and surgery alone to 8%). FIGO stage distribution was: I (31%), IIa (15%), IIb (27%), IIIa (5%), IIIb (17%) and IV (5%). Five-year locoregional control per stage was 100% in Ia, 85% in Ib, 82% in IIa, 71% in IIb, 45% in IIIa, 54% in IIIb and 30% in IV. Corrected 5-year survival per stage was 82% in Ib, 78% in IIa, 73% in IIb, 69% in IIIa, 38% in IIIb and 0% in IV. The diameter of disease in stage II strongly influenced the 5-year locoregional control (81% for tumours of less than 3 cm vs. 68% for tumours more than 3 cm). Lymphangiogram was associated with a 44.5% 5-year locoregional control when positive vs. 74% when non-positive. Brachytherapy was advantageous in obtaining locoregional control in patients receiving external irradiation and brachytherapy: 81.5% vs. 38.5% in patients treated with external radiotherapy alone. Surgery was performed only for in situ carcinoma and for part of stages Ia, Ib and IIa. There is no significant difference in locoregional control at equal stage between radiotherapy alone and treatment schemes including surgery. However, lethal complications were observed in 6% of the patients of the surgical group as compared to 0.6% of the patients treated with radiotherapy alone. Radical radiotherapy seems to provide similar results of locoregional control and survival at equal stages in carcinoma of the cervical stump compared to carcinoma developed on an intact uterus. The rate of severe complications reported with the French-Italian glossary is 13% for G3 and 3% for G4, which is close to the observed rate during the same period in our series of radical radiotherapy to the intact uterus.

Cervical and vaginal cancer associated with pessary use.

From 1967 to 1990, 96 previously untreated patients with cervicovaginal cancer associated with a history of vaginal pessary use to control uterovaginal prolapse were referred to eight radiation therapy departments in France. Sixty-eight patients had cervical cancer, and 28 had vaginal cancer. The mean interval between pessary insertion and cancer diagnosis was 18 years, with a range of 1 to 41 years. Most patients received radiation therapy and brachytherapy. Few (5%) had Grade 3 treatment side effects. The overall 5-year relative survival rate was 54%; nonsurvival was related to locoregional recurrence. Because almost all tumors occurred at the site of pessary insertion, foreign body chronic inflammation in association with viral infection may be the cause of the tumors.

Phase II trial of idarubicin (4-demethoxydaunorubicin) in advanced breast cancer. The Clinical Screening Group of the European Organization for Research and Treatment of Cancer.

A phase II trial of idarubicin (IDR-4 demethoxydaunorubicin) was carried out in patients with advanced breast cancer. A dose of 45 mg/m2 was given orally once every 3 weeks. A total of 66 eligible patients were entered into the trial, 56 of whom were evaluable for response (65 were evaluable for toxicity at least). Therapeutic activity was demonstrated with an overall objective response rate of 21% (95% CI: 11-32%). When used as a first-line treatment, the response rate was 33% (95% CI: 9-57%) but this dropped to 17% when the treatment was administered after chemotherapy. Nausea-vomiting was the most frequent and severe non-hematological toxicity observed (WHO grade 3-4: 29%). Loss of hair was noticed in 48% of the patients but only 4% suffered from complete alopecia. Moderate myelotoxicity was reported but no cardiac dysfunction was noticed. IDR could be very advantageous as compared to other anthracyclines, due to its simplicity of administration associated with the lack of risk of extravasation or chemical phlebitis and also the possibility of it being able to reduce cardiotoxicity. Even if the equiefficacy of IDR and DXR has not, as yet, been clearly demonstrated, IDR should be chosen with preference to DXR when administration is not suitable.

[Locoregional recurrence of breast cancer. Long-term course of 49 cases treated by excision and omentoplasty]. / Récidives loco-régionales de cancer du sein. Evolution à distance de 49 cas traités par exérèse avec épiplooplastie.

Extensive local recurrence of breast cancer may require wide parietal resection, demanding the use of other tissues to compensate for the loss of substance. We preferably resort to omentoplasty when the defect is larger than 300 cm2. A group of 49 patients with recurrence of the tumor in the breasts (treated with omentoplasty) has been studied, with special emphasis on long-term results. In our series, 86% of the patients were followed up for more than 4 years, with an actuarial survival rate of 46% after 7 years. It thus appears that this procedure can be advocated for slow-developing cancers, the local recurrence of which is extensive and usually isolate for various reasons (most often a deficient initial local treatment).

Two partial remissions induced by an LHRH analogue in two postmenopausal women with metastatic breast cancer.

We report two cases of metastatic breast cancer occurring in two postmenopausal women. Treatment with a luteinizing hormone-releasing hormone (LHRH) analogue, D-TRP6-LHRH, induced partial remission. The blood levels of the follicle stimulating hormone (FSH) and luteinizing hormone (LH) fell sharply under treatment, but the levels of estradiol, estriol, and estrone did not change significantly. We also described the putative mechanisms of action of the LHRH analog.

Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: a French cooperative study of 1383 cases.

A French Cooperative study of 1383 cases with invasive carcinoma of the intact uterine cervix treated with radiation therapy alone, using the guidelines provided by G. H. Fletcher led to the following conclusions: The techniques of treatment were easily reproducible in 9 French centers, working in a prospective cooperative study; Results similar to those of the original study were achieved in Stages I and IIA (MDAH substaging) with a locoregional failure rate of 7%; In Stage IIB, the locoregional failure rate of 16% is also comparable in both studies; Locoregional failures in Stage III are slightly lower than those reported in Houston, probably reflecting differences in patient's prognostic factors in France and Texas; The 5-year survival rate obtained in advanced Stages (UICC FIGO staging) are among the highest in the literature (76% in Stage IIb, 62% in Stage IIIa and 50% in Stage IIIb); The rate of severe complications remains acceptable and decreased throughout the study thanks to a better use of computer dosimetry.

Role of chemotherapy in acute breast cancer. Analysis of 41 cases.

Clinical and therapeutic results in a series of 41 patients treated for inflammatory cancer of the breast lend emphasis to the selection criteria to be included in a short (approximately two months) clinical history to complement Haagensen's criteria. Chemotherapy improved the previous very poor results obtained in this condition. Survival after surgery and radiotherapy were less than 5% at five years, and this is compared with the prognosis in the series study. However, these results are still only fair in absolute terms and there is still no currently available alternative solution to attempt to achieve a marked improvement in the course of the lesion.

Variations in the percentages of lymphocyte subtypes during the menstrual cycle in women.

In view of the well-known circadian variations in lymphocytes and their subtypes, we decided to study the possible variations in the proportions of these cells during the menstrual cycle in women. In order to do this, lymphocyte populations were determined during 3 successive cycles on D1, D13, D14, D15 and D25 in 6 women with 28-day cycles who were not on oral contraceptives. In each of these women, we then compared the percentages of lymphocyte subtypes during the different periods of the cycle; this amounted to over 400 comparisons. A statistically significant variation, at the 1% level was found in only one case, when comparing the percentages of T4 lymphocytes on D1 and D13. In the light of this experience, we can therefore assume that there are no statistically significant variations in the proportions of lymphocyte subtypes during the menstrual cycle in women, which does not exclude the possibility of variations in their total numbers.

[Determination of sub-populations of circulating T lymphocytes in alcoholic cirrhosis using monoclonal antibodies OKT3, 4, 5, Leu 2 and Leu 15. Effect of hepatitis B virus infection]. / Détermination des sous-populations lymphocytaires T circulantes au cours de la cirrhose alcoolique par les anticorps monoclonaux OKT3, 4, 8, Leu 2 et Leu 15. Influence de l'infection par le virus de l'hépatite B.

Peripheral T lymphocyte subpopulations were quantified in 24 alcoholic cirrhotic patients, 11 of them having anti-HBs and/or anti-HBc antibodies, and were compared with 35 healthy control subjects, 10 of them having anti-HBs and/or anti-HBc antibodies. The monoclonal antibodies utilized (OKT3, OKT4, OKT8 in simple staining, Leu 2 and Leu 15 in double staining) are considered as markers of mature (CD3), helper (CD4), cytotoxic/suppressor (CD8, Leu 2), suppressor (Leu [2+ 15+), and cytotoxic (Leu 2+ 15-) T cells. In cirrhotics, when compared to controls, the number of CD3 cells was reduced (p less than 0.01); the proportion of CD4 cells was within normal range, and that of CD8 cells diminished (p less than 0.001), contrasting with an increased proportion of Leu 2+ cells (p less than 0.01), related to an increased proportion of Leu 2+ 15+ cells. Leu 2+ 15- lymphocytes were within normal range. In control subjects, a decreased proportion of Leu 2+ 15+ cells was found (p less than 0.05) when Ac HBs and/or Ac HBc were present. In cirrhotics having at least one serologic marker of hepatitis B virus infection, when compared with negative ones, increased proportions of Leu 2+ (p less than 0.05) and Leu 2+ 15+ (p less than 0.05) cells were found. These results show that data concerning T lymphocyte subpopulations are conflicting when various types of antibodies are used. However, they suggest abnormalities of immune regulation, possibly a defect of T suppressor cell function. Hepatitis B virus infection probably modifies immune regulation in alcoholic cirrhosis, and perhaps in normal subjects.

Mitoxantrone combined with vincristine, cyclophosphamide and fluorouracil for advanced breast cancer. A study of short-term response rate.

50 patients with advanced breast cancer were treated with the combination of Mitoxantrone 10mg/m2 IV day 2, 5-Fluorouracil 400mg/m2 IV and Cyclophosphamide 300mg/m2 IV day 3, 4, 5, 6 of each monthly cycle. 49 patients are evaluable for toxicity and 47 for efficacy after three months of treatment. Hematologic toxicity was substantial and dose-limiting, with one toxic death early in the trial. Other toxicities were moderate and manageable in this short-term study. The response rate after three cycles was 53% +/- 14% with 4 complete remissions, 21 partial remissions, 16 stable disease and 6 progressions. Using the fixed response rate hypothesis of Gehan generalised by Lee and Wesley, with an expected response rate of 60% consistent with the reported response rate of advanced breast cancer to Adriamycin containing regimens, we conclude that the combination studied is not less efficient for the induction of remissions in advanced breast cancer than comparable combinations with Adriamycin. As there is now substantial experimental and clinical evidence of reduced toxicity, mainly on the cardiac muscle, of Mitoxantrone as compared to Adriamycin, we feel that the routine substitution of the latter by the former in chemotherapy for advanced breast cancer is justifiable.

A quantified approach to the analysis and prevention of urinary complications in radiotherapeutic treatment of cancer of the cervix.

This paper is the report of a dosimetric study of 79 urinary complications after radical radiation treatment (1975-1979) of 624 cervical uterine tumors. Treatment consisted of external irradiation (25 MeV linear accelerator) and intracavitary irradiation (Fletcher-Suit-Delclos applicator). Dosimetric-computerized studies were expressed as the maximum bladder dose on the trigone, as proposed by the I.C.R.U. Bladder doses were actually studied as a function of intracavitary irradiation and intracavitary + external irradiation. The results show a significant difference in patients with and without complications based on the dose reaching the bladder. The relative contribution of external therapy and intracavitary irradiation and their value can serve as one of the primary indicators for predicting complications. These values should be determined before placement of intracavitary sources. We found that the dose to the critical organs cannot be defined as a single number. These results argue in favor of adapting individual patient therapy based on rectal and bladder dosimetry and may be adjustable to all treatment modalities.

[Resection-reconstruction of the femur shaft by a massive allograft fixed by an interlocking nail]. / Résection-reconstruction diaphysaire fémorale par allogreffe massive fixée par clou médullaire verrouillé.

Case report of a central midshaft osteosarcoma of the femur, treated conservatively under Rosen procedure. Bone resection was followed by reconstruction with a deep frozen (-196 degrees) conserved massive homograft, fixed by an interlocked Kuntscher's nail. The purpose of this paper is to expose the advantages of this type of fixation, V.S. conventional nails, or plates. X-Ray showed a bridging bone spindle between host and graft cortical bone, induced by initial stability of the nail, and a rapid fusion after secondary dynamisation of the nail, by removing one screw. We obtained an early functional recovery and a complete and rapid autonomy necessary to allow social and school reinsertion, whatever should the medium or long term presumed survival be.

[French FAC vs FEC study in advanced breast cancer]. / Die französische FAC-vs-FEC-Studie bei fortgeschrittenen Mammakarzinomen.

239 patients were evaluable: 116 in the FAC arm, 123 in the FEC arm. There is no significant difference in the therapeutic responses between 2 regimens: 52 +/- 9% vs 49 +/- 9%. Duration of responses (273 vs 303 d) and overall survival were also similar. FEC appears less myelotoxic, less toxic also in terms nausea, vomiting and grade 3 alopecia than the adriamycin combination. 9 patients required treatment cessation due to grade 2 cardiac dysfunction with 3 CHF, against no case in the epirubicin regimen.

Phase II clinical evaluation of doxifluridine.

Disease-oriented phase II trials of doxifluridine were performed in advanced colorectal, breast, renal, endometrial, stomach, and ovarian carcinomas. The dose schedule recommended by the phase I trial (12.5 g/m2 by continuous iv infusion over 6 hours once a week for 3 weeks followed by a 1-week rest) was chosen first: the initial dose was later decreased to 10 g/m2 due to the fact that several neurotoxic effects were reported. A total of 207 patients were entered: 137 patients who received at least two courses of treatment were evaluable for response. Therapeutic activity was demonstrated in breast cancer [two complete responses (CR) and 13 partial responses (PR) among 42 patients], colon cancer (seven PRs among 35 patients), and rectal cancer (six PRs among 23 patients). Some therapeutic activity was detected in ovarian cancer (one CR among nine patients), endometrial cancer (one PR among five patients), and stomach cancer (one PR among five patients). No significant activity was noticed in renal cancer (one PR among 18 patients). Nonhematological toxicity was evaluated according to World Health Organization criteria. Nausea and vomiting were recorded in 50% of the patients (Grade 3-4 in 5%), diarrhea was recorded in 20% (Grade 3-4 in 5%), and cutaneous and allergic reactions were recorded in 10% (Grade 3-4 in 2%). Myelotoxicity during the first treatment course was mild; median wbc and platelet count nadirs (x 10(9) cells/L) were 4.1 (range, 0.1-11) and 194 (range, 20-482), respectively. Nevertheless, some cases of acute leukopenia and thrombopenia were reported. Consciousness alterations and neurologic symptoms were the major side effects (72 of 173 evaluable patients), since treatment had to be interrupted in 34 patients and four lethal neurotoxic effects occurred. At the same total dose of doxifluridine, the risk of neurotoxicity significantly increases with age and with the weekly dose and to the contrary it decreases with increasing bilirubin level. Although activity was demonstrated, this treatment cannot be recommended because of major neurotoxicity. Further pharmacological studies seem warranted to define the optimal dosage schedule and to obtain a better therapeutic index.