All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an International Phase II Trial.

BACKGROUND: This multicentre, international phase II trial evaluated the efficacy and safety profile of a first-line combination of oral vinorelbine plus capecitabine for women with metastatic breast cancer (MBC). METHODS: Patients with measurable, HER2-negative disease received, as a first line in metastatic setting, 3-weekly cycles of oral vinorelbine 80 mg m(-2) (after a first cycle at 60) on day 1 and day 8, plus capecitabine 1000 mg m(-2) (750 if >or=65 years of age) twice daily, on days 1-14. Treatment was continued until progression or unacceptable toxicity. RESULTS: A total of 55 patients were enrolled and 54 were treated (median age: 58.5 years). Most (78%) had visceral involvement and 63% had received earlier (neo)adjuvant chemotherapy. The objective response rate (RECIST) in 49 evaluable patients was 51% (95% confidence interval (CI), 36-66), including complete response in 4%. The clinical benefit rate (response or stable disease for >or=6 months) was 63% (95% CI, 48-77). The median duration of response was 7.2 months (95% CI, 6.4-10.2). After a median follow-up of 41 months, median progression-free survival was 8.4 months (95% CI, 5.8-9.7) and median overall survival was 29.2 months (95% CI, 18.2-40.1). Treatment-related adverse events were manageable, the main grade 3-4 toxicity was neutropaenia (49%); two patients experienced febrile neutropaenia and three patients had a neutropaenic infection (including one septic death). A particularly low rate of alopaecia was observed. CONCLUSION: These results show that the all-oral combination of oral vinorelbine and capecitabine is an effective and well-tolerated first-line regimen for MBC.

Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability.

PURPOSE: The letrozole study 025 is a large (n = 907), international, double-blind, randomized, phase III trial in postmenopausal women with advanced breast cancer. This subanalysis compares the efficacies of letrozole and tamoxifen as first-line therapy in postmenopausual women with advanced breast cancer according to site of metastatic lesions and Karnofsky Performance Status (KPS). MATERIALS AND METHODS: Nine hundred seven patients with advanced breast cancer were randomly assigned to once-daily oral letrozole (2.5 mg; Femara; Novartis Pharma AG; Basel, Switzerland) or tamoxifen (20 mg; Tamofen; Leiras OY; Turku, Finland). Time to progression (TTP) was estimated using the Kaplan-Meier product-limit method. Treatments were compared by Cox proportional hazards regression models. RESULTS: Letrozole treatment significantly prolonged TTP in all subsets of patients: those with nonvisceral metastases, those with visceral metastases without liver involvement, and those with liver metastases. The reduction in risk of progression ranged from 25%, for patients with nonvisceral metastases, to 36%, for patients with liver metastases. The distributions of baseline KPS scores for both treatment groups were similar (57% had KPS scores >/=90). Time to worsening of 20 points or more in KPS score was significantly longer with letrozole than with tamoxifen, but modest numbers of patients experienced such deterioration (letrozole, 20%, tamoxifen, 22%, in patients without visceral metastases; 23%-24% in patients with liver metastases; and letrozole, 14%, tamoxifen, 30%, in patients with visceral metastases without liver involvement). CONCLUSION: These data demonstrate the consistent superiority of letrozole over tamoxifen and support the use of letrozole as a new standard of endocrine therapy in postmenopausal women with advanced breast cancer.

Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients. clinical outcomes and oncologists' preferences.

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Trocar implantation metastasis after laparoscopy in patients with advanced ovarian cancer: can the risk be reduced?

OBJECTIVE: The purpose of this study was to determine risk factors for trocar implantation metastasis after diagnostic laparoscopy in patients with primary or recurrent advanced ovarian cancer. STUDY DESIGN: Eighty-three women with primary advanced ovarian cancer and 21 women with recurrent ovarian cancer undergoing a laparoscopy for a tissue diagnosis and for assessment of operability were included in the study. The occurrence of implantation metastasis at the trocar incision scars was analyzed according to clinicopathologic characteristics. RESULTS: A recurrence developed at the trocar site in 7 (58%) of 12 patients undergoing a laparoscopy in which only the skin was closed at the end of the procedure and in 2 (2%) of 92 patients undergoing a laparoscopy with closure of all layers (odds ratio, 63; 95% confidence interval, 10.3-385; P <.001). The International Federation of Gynecology and Obstetrics stage at initial presentation, tumor histologic type, tumor differentiation, maximal tumor diameter at the time of diagnosis, estimated weight of the metastatic tumor, residual tumor after cytoreductive surgery, surgical characteristics, and type of chemotherapy were well balanced among both groups. Patients with implantation metastasis had significantly more ascites (median, 700 mL vs 300 mL; P =.032) and a longer interval between the start of platinum-based chemotherapy or cytoreductive surgery (median, 6 days vs 17 days; P <.01) compared with patients without abdominal wall recurrence. A palpable abdominal wall metastasis developed in none of the patients undergoing a laparoscopy with closure of all layers of the abdomen followed by cytoreductive surgery or chemotherapy within 1 week after the laparoscopy. Kaplan-Meier survival analysis showed that patients with abdominal wall implantation metastasis had a survival rate similar to that of the other patients. CONCLUSIONS: Laparoscopy with careful closure of the peritoneum, rectus sheath, and skin followed by chemotherapy or cytoreductive surgery with excision of the trocar trajectories within 1 week is safe in patients with disseminated ovarian cancer.

Late relapse of a non-seminomatous germ cell tumour from residual mature teratoma.

A patient with a late relapse of non-seminomatous germ cell tumour in a localisation of residual mature teratoma in the lung is reported. The mechanisms for late relapse and the therapeutic options, as reported in the literature, are discussed.

Tumor lysis syndrome in a patient with metastatic Merkel cell carcinoma.

A first course of combination chemotherapy for large volume metastatic disease in a patient with Merkel cell carcinoma resulted in a tumor lysis syndrome. After this course a nearly complete response was documented. This case report extends further the chemosensitivity of Merkel cell carcinoma and demonstrates the need for tumor lysis syndrome prophylaxis in patients with bulky disease or fast-growing tumors.

Phase II study of an intensive combination chemotherapy with cisplatin, adriamycin, etoposide and cyclophosphamide (CAVE) in small cell lung cancer.

One hundred and twelve patients with small cell lung cancer (SCLC) were treated with a combination (CAVE) of cisplatin (60 mg/m2 day 1), adriamycin (45 mg/m2 day 1), etoposide (80 mg/m2 days 1-2-3) and cyclophosphamide (1 g/m2 day 1) given every 4 weeks. A total of 10 courses were given. Response evaluation was initially evaluated after the first two courses of CAVE and repeated at least after treatment completion. This regimen was associated with severe hematological toxicity, mainly leucopenia; five toxic deaths related to sepsis were observed. One hundred and one patients were evaluable for response: 63 with limited disease and 49 with extensive disease. Overall complete and partial response rates after the first two courses of chemotherapy were 16% and 63% respectively but 14 late complete responses were documented, leading to a 30% total complete response rate; 38% in patients with limited disease and 19% in those with disseminated disease. Median overall survival was 46 weeks with a 17% 2 year survival. The only significant prognostic factor for survival was the type of response. There was no survival difference between 'early' and 'late' complete responders. Complete responders had a 75 week median survival time with a 34% 2 year survival. CAVE is thus an effective regimen for SCLC, but with a considerable toxicity.

Oral versus intramuscular high-dose medroxyprogesterone acetate (HD-MPA) in advanced breast cancer. A randomized study of the Belgian Society of Medical Oncology.

Ninety postmenopausal women with advanced breast cancer were randomly assigned to be treated with HD-MPA administered either by oral route (daily dose 900 mg) or by intramuscular injections (1 g IM daily X 5 q w during 4 consecutive weeks followed by maintenance with 1 g twice weekly). Among 78 evaluable cases, most heavily pretreated, remissions, lasting for a median duration of 11 months, were more frequent on oral (8/37 = 22%) than on IM therapy (5/41 = 12%). In both arms, high estrogen receptor levels and various clinical factors were associated with higher response rates i.e., age greater than 60, Karnofsky greater than 70, light prior systemic treatment. Side-effects, consisting mainly of weight gain, hypertension and tremor occurred with equal frequency on oral or IM treatment. Five patients complained of pain at the sites of IM injections. Thus, we recommended that, whenever possible, the oral route should be preferred. During the same study, in 20 patients (11 on oral and 9 on IM therapy), blood was drawn at 0, 30, and 60 days of treatment for the assessment of MPA and hormone levels. In both arms, at 60 days, comparable levels of circulating MPA were obtained, with a very significant drop of cortisol, androstenedione, and estrone. These endocrine results, together with our clinical data, indicate that HD-MPA therapy is active on estrogen-dependent tumors with the same specificity as that of other modalities aiming to suppress the adrenal function. Its antineoplastic action in humans could be ascribed at least in part to its suppressive action on the adrenals, resulting in a severe estrogenic deprivation in postmenopausal women.

Combination chemotherapy with mitomycin and vindesine in advanced non-small cell lung cancer: a pilot study by the Lung Cancer Working Party (Belgium).

The combination of mitomycin plus vindesine in advanced non-small cell lung cancer induced an objective response rate of 23% in 43 evaluable patients: 33% in nonpretreated patients (nine responses among 27 patients) and 6% in pretreated patients (one response among 16 patients). Toxicity was tolerable. We conclude that the regimen was a moderately active and easy to administer treatment for advanced non-small cell lung cancer.

[Polychemotherapy of undifferentiated small cell bronchial cancer. Long-term results]. / Polychimiothérapie du cancer bronchique indifférencié à petites cellules. Résultats à long terme.

Long-term results of 2 studies combining etoposide and adriamycin with cisplatin (CAV) or cyclophosphamide (AVE) in small cell lung cancer indicate a 2-year survival rate of 22% and 18% respectively. The complete response rate 2 years after the onset of chemotherapy was 8% (8/98) : 11% (4/36) with CAV and 5% (4/62) with AVE. Among these 8 patients, 2 had a late relapse and one died of an unrelated cause. The actual long-term survival rate was 6% with CAV and 5% with AVE.

Prostacyclin, thromboxane and prostaglandin F2 alpha; plasma levels in breast cancer.

In this study, 6-keto-prostaglandin F1 alpha, TXB2, and 15-keto-13,14-dihydro-prostaglandin F2 alpha plasma levels (i.e., theprostacyclin, thromboxane, and PGF2 alpha-metabolites, respectively) were determined, using a radioimmunoassay, in 32 breast cancer patients (21 without evidence of disease and 11 with metastases), and in a control group of 16 patients. Neither group of breast cancer patients showed an increased plasma level of any of these products compared with the control group. This study suggests that the increased 6-keto-prostaglandin F1 alpha, TXB2 and prostaglandin F2 alpha levels which have been observed in breast cancer tissues are not detectable in the plasma.

Binding of serum ferritin to concanavalin A in patients with malignancy.

The percentage non-glycosylated, tissue type ferritin was measured in the serum of 30 cancer patients and 11 normal subjects, as well as in 10 tumour cytosols. As expected, in normal subjects the larger part of serum ferritin corresponded to glycosylated ferritin, and in tumour cytosols the larger part corresponded to non-glycosylated ferritin (tissue ferritin). In all but one cancer patients a significant part of the protein did not bind to Con A, thus behaving as tissue ferritin. The findings obtained suggest release of tissue type, non-glycosylated, ferritin by damaged cells or through abnormal secretion. This relative increase of the non-glycosylated ferritin fraction appears to be very frequently present in cancer, although not specific for it. Assaying for Con A binding may prove to be valuable in the study of malignant disease, and therefore deserves further investigation.

Combination chemotherapy with adriamycin, etoposide, and cyclophosphamide for small cell carcinoma of the lung. A study by the EORTC Lung Cancer Working Party (Belgium).

The current study reports the results of Adriamycin (doxorubicin), etoposide, and cyclophosphamide (AVE) in small cell bronchogenic carcinoma. The overall rate of response was 82% in patients with limited disease and 66% in patients with extensive disease; complete remissions have been achieved in 20% of the patients with limited disease and in 7% of those with extensive disease. The median duration of survival was 14 months in patients with limited disease and 8.3 months in those with extensive disease. The results, and the analysis of literature, suggest that survival rather than response should be used to compare studies of chemotherapy in small cell bronchogenic carcinoma.

Dysgerminoma of the ovary in association with XY gonadal dysgenesis.

A case is reported of an adolescent presenting with primary amenorrhea. On pelvic examination a large unilateral ovarian tumor was palpated. Microscopic examination of the tumor removed at laparotomy revealed a pure dysgerminoma. Further gynecological-endocrinological investigations and chromosome analysis showed an XY gonadal dysgenesis. A review of current approaches to diagnosis, prognosis and especially to the controversial therapeutic modalities is presented.