Mitomycin C, vinblastine and cisplatin (MVP): an active and well-tolerated salvage regimen for advanced breast cancer.

This phase II study assessed the clinical efficacy and tolerability of a combination of mitomycin C, vinblastine and cisplatin in patients with metastatic breast cancer (MBC) previously treated with chemotherapy. A total of 87 patients with MBC, most of whom had been exposed to anthracyclines (92%) and/or taxanes (29%) in the adjuvant and/or metastatic setting, were treated with mitomycin C (8 mg m(-2) day 1 cycles 1, 2, 4 and 6), vinblastine (6 mg m(-2) day 1) and cisplatin (50 mg m(-2) day 1) repeated each 21 days for a maximum of six cycles. The overall response rate (ORR) was 32% (95% CI: 22-42%) with 31% partial response (PR) and one complete response (CR). Stable disease (SD) rate was 21% (95% CI: 12-29%). There was no statistically significant difference in the ORR when MVP was given as the first-line treatment for MBC vs second or subsequent line (38 vs 30%, P=0.6), or between patients with an early (<6 months) vs late (>6 months) relapse post-anthracyclines (30 vs 52%, P=0.3). Toxicity profile was mild. This platinum-based chemotherapy is an effective, well-tolerated and low-cost regimen for patients with MBC, including those pretreated with anthracyclines.

Studies of the potential utility of Ki67 as a predictive molecular marker of clinical response in primary breast cancer.

INTRODUCTION: Objectives were to characterise the relationship of the proliferation marker Ki67 with response to systemic treatment in early breast cancer and to assess its clinical utility, using fine needle aspirates. MATERIALS AND METHODS: Hundred and six women were treated with primary tamoxifen (n = 33), chemotherapy (n = 33) or chemotherapy and tamoxifen (n = 40). Treatment was not randomised and response was assessed clinically. Ki67 was evaluated prior to treatment and at Day 14 or 21 after commencing treatment. To assess reproducibility, Ki67 was evaluated in repeat FNAs taken from 37 untreated patients. RESULTS: The percentage change in Ki67 in first 21 days was different between responders and non-responders for patients treated with tamoxifen (p = 0.007) and chemotherapy (p = 0.005) but not for chemoendocrine treatment (p = 0.062). The reproducibility study indicated that a decrease to 36% or less of the pre-treatment Ki67 value in an individual patient was required for it to be regarded as a statistically significant change. A significant decrease in Ki67 was seen in responding patients treated with chemotherapy (p = 0.026) and chemoendocrine treatment (p = 0.041). Positive and negative predictive values for response were 85 and 59% for chemotherapy patients and 88 and 54% for chemoendocrine patients, respectively. CONCLUSION: Ki67 is unlikely to be useful as a predictive marker in individual patients. Further molecular markers that predict lack of response continue to be required.

Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy in patients with malignant mesothelioma.

The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m(-2), vinblastine: 6 mg m(-2), cisplatin 50 mg m(-2)) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 microg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing.

Mitomycin C, vinblastine and carboplatin: effective outpatient chemotherapy for advanced non-small cell carcinoma of the lung (NSCLC).

The majority of patients diagnosed with non-small cell lung carcinoma (NSCLC) present with advanced disease and, as such, are treated with palliative intent. Platinum-based combination chemotherapy plays an important role in the management of these patients, with response rates to most regimens being in the range of 30%-40%. with symptom relief in up to 60%. One of the most commonly utilized combinations is mitomycin C, vinblastine and cisplatin (MVP). Owing to the hydration regimen, and to the age and performance status of many of these patients, in reality this combination often necessitates an overnight stay in hospital. A combination of drugs that could be administered as an outpatient would be beneficial to patients and could result in substantial economic benefits. Forty-three patients with Stage IlIb and IV NSCLC were treated with the MVCarbo regimen, in which the cisplatin in the MVP regimen was replaced with carboplatin. All treatment was administered on an outpatient basis. The overall objective response rate was 30%; the symptomatic response rate was 60%, which was exactly equivalent to the response rate seen in a comparable group of patients treated with MVP in a trial on duration of chemotherapy at the Royal Marsden Hospital. There was no difference in progression-free or overall survival between patients treated with the two regimens. The MVCarbo regimen resulted in response rates and survival rates equivalent to those seen with standard MVP and, as such, provides an acceptable outpatient alternative to this treatment.

UFT/leucovorin plus bolus epirubicin and cyclophosphamide in advanced/metastatic breast cancer.

This article describes the design and early results of an open-label, nonrandomized phase I/II trial of oral UFT plus leucovorin therapy in combination with bolus injections of epirubicin and cyclophosphamide in patients with advanced or metastatic breast cancer. This study was designed as a cohort dose-escalation study with the principal aims being to determine dose-limiting toxicity, overall toxicity, maximum tolerated dose, tumor response, and time to disease progression. Currently there are 22 patients randomized in the study. Overall response rate to date is 56% (66% in the locally advanced group). Based on the preliminary data, the dose-limiting toxicity appears to be neutropenia and the optimum dose of UFT for use in a phase II study appears to be 300 mg/m2.

Investigating lymphadenopathy--report on the first 12 months of the lymph node diagnostic clinic at the Royal Marsden Hospital.

The lymph node diagnostic clinic was set up at the Royal Marsden Hospital to provide a direct access service for general practitioners. In the first year 82 patients were seen. The malignancy pick-up rate was 19.5% which compares very favourably to rates in breast and colorectal clinics. Patient and general practitioner satisfaction with the service was high.

Prognostic relevance of cerbB2 expression following neoadjuvant chemotherapy in patients in a randomised trial of neoadjuvant versus adjuvant chemoendocrine therapy.

Recent advances in the detection and treatment of breast cancer have led to an intensive search for new markers of both prognosis and chemoresponsiveness. The oncogene cerbB2 has proved to be one of the most promising markers currently under study, both as a predictor of chemoresponsiveness and as a marker of poor prognosis. In addition the increasing use of neoadjuvant chemotherapy has led to the loss of standard prognostic criteria. In order to study the potential role of cerbB2 expression as an indicator of chemoendocrine resistance and poor prognosis, both before and after chemotherapy, we obtained tumour sections from 283 women enrolled onto a neoadjuvant trial. In this trial patients were randomised to receive either primary surgery followed by adjuvant chemoendocrine treatment or neoadjuvant chemoendocrine therapy followed by surgery. CerbB2 status was determined immunohistochemically on all of these patients. Thirty-eight percent of the tumours were cerbB2 positive. There was no significant difference in expression between the adjuvant (41%) and neoadjuvant arms (35%). CerbB2 positive patients were much more likely to have shown non-response to chemoendocrine therapy (p < 0.001) and had a worse DES (p < 0.05). The best prognosis was seen in cerbB2 negative patients receiving neoadjuvant chemoendocrine therapy who showed a significantly better DFS (p < 0.05), than the cerbB2 negative patients receiving adjuvant therapy.

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy.

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.

Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients.

The aim of this study was to evaluate pretreatment clinical features and biological markers together with changes in these factors as predictors of response and relapse in patients receiving tamoxifen for primary breast cancer. Fine-needle aspiration cytology of the primary breast cancer was performed before tamoxifen treatment in 54 patients and repeated after therapy on day 14, day 60, or on both days in a subset of 35 patients. These samples were evaluated for estrogen receptor (ER), progesterone receptor (PgR), Ki67, S-phase fraction and ploidy. The overall response to tamoxifen was 57% (31 of 54 patients). Pretreatment ER and PgR significantly predicted for response by univariate analysis (P < 0.0001 and P < 0.003, respectively). By multivariate analysis, ER expression was the only independent predictor of response, and it was associated with 27 times the likelihood of response (95% confidence interval, 6-136). Increase in PgR and decrease in Ki67 on day 14 significantly predicted for response to tamoxifen (P < 0.03 and P < 0.04, respectively). Lack of ER, clinical node-positive disease, and failure to decrease Ki67 on day 14 were significantly associated with increased risk of relapse (P < 0.05). By multivariate analysis, ER expression was the only independent predictor of relapse (P < 0.005). Pretreatment and early changes in molecular marker expression may assist in the prediction of response and clinical outcome in primary breast cancer patients receiving tamoxifen.

Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer.

PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P =.05), lack of ER (P <.05) and PgR (P <.05), and failure to attain GCR (P =.008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P =.02), lack of ER expression (P =.04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P =.05). ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival.

Systemic candidiasis with candida vasculitis due to Candida kruzei in a patient with acute myeloid leukaemia.

Candida kruzei-related systemic infections are increasing in frequency, particularly in patients receiving prophylaxis with antifungal triazoles. A Caucasian male with newly diagnosed acute myeloid leukaemia (AML M1) developed severe and persistent fever associated with a micropustular eruption scattered over the trunk and limbs during induction chemotherapy. Blood cultures grew Candida kruzei, and biopsies of the skin lesions revealed a candida vasculitis. He responded to high doses of liposomal amphotericin B and was discharged well from hospital.

Clinical studies of apoptosis and proliferation in breast cancer.

The interaction between cell death and cell proliferation determines the growth dynamics of all tissues. Studies are described here which relate the changes in proliferation and apoptosis that occur in human breast cancer during medical therapeutic manoeuvres. Xenograft studies strongly support the involvement of increased apoptosis as well as decreased proliferation after oestrogen withdrawal, and limited studies in clinical samples confirm the involvement of both processes. Cytotoxic chemotherapy induces increases in apoptosis within 24 h of starting treatment. However, after 3 months therapy the residual cell population shows apoptotic and proliferation indices much below pretreatment levels. Further molecular studies of this "dormant" population are important to characterise the mechanism of their resistance to drug therapy. The early changes in proliferation and apoptosis may provide useful intermediate response indices.

Variation in endometrial thickening in women with amenorrhea on tamoxifen.

Tamoxifen is reported to increase the risk of endometrial cancers mostly in postmenopausal women. In the Royal Marsden chemoprevention programme, we noted that premenopausal women at the start of tamoxifen/placebo who developed amenorrhea may be at special risk of endometrial cancer. The aim of this report was to investigate recently amenorrheic women by measuring plasma estradiol (E2), follicular stimulating hormone (FSH), and endometrial thickness (ET) by transvaginal ultrasound (TVUS). ET readings and E2 levels were available in the same proportion of women on tamoxifen or placebo. Women on placebo developed amenorrhea with upper limit of E2 readings of 450 pmol/L. In both postmenopausal women and recently amenorrheic women with low E2 (< or = 450 pmol/L), tamoxifen significantly increased endometrial thickening (p < 0.0001 and < 0.005 respectively). Conversely, tamoxifen did not result in endometrial thickening in women with high E2 (> 450 pmol/L), with a trend to lower ET readings (p = 0.07). Finally, all five women who developed endometrial cancer were premenopausal at the start of tamoxifen/placebo. Two of these five women were asymptomatic with increased ET readings (17 mm and 17 mm) and low E2 levels (32 and 51 pmol/L). These results indicate that women who develop amenorrhea on tamoxifen may be at special risk of endometrial cancer. Tamoxifen causes endometrial thickening in amenorrheic women with low E2 but has an opposite antiestrogenic effect in women with high E2. We recommend that women who develop amenorrhea on tamoxifen especially in the presence of endometrial thickening, low E2 levels, and/or gynaecological symptoms warrant further investigations.

Prediction of response to neoadjuvant chemoendocrine therapy in primary breast carcinomas.

Our aim was to determine whether biological molecular markers can predict response to neoadjuvant chemoendocrine therapy in patients with early breast cancer. Ninety patients (median age 56 years; range, 28-69 years) with primary operable breast carcinoma were studied. They were treated with four 3-weekly cycles of chemotherapy with mitozantrone, methotrexate (+/- mitomycin C), and tamoxifen prior to surgery. Fine-needle aspiration was used to obtain samples from patients prior to therapy, and the following parameters were assessed: estrogen receptor (ER), progesterone receptor (PgR), p53, Ki67, Bcl-2, and c-erbB-2 measured by immunocytochemistry, and ploidy and S-phase fraction (SPF) by flow cytometry. The tumors of 78% of the subjects responded (complete response, 9%; partial response, 69%) and 22% did not (no change, 20%; progressive disease, 2%). Response rates according to disease stage and patient age were as follows: T1, 74%; T2, 79%; T3/T4, 78%; age 50, 79% (P = not significant). Response rates for other parameters were as follows: ER-positive, 82%, and -negative, 70%; PgR-positive, 86%, and -negative, 71%; p53-positive, 74%, and -negative, 81%; Bcl-2-positive, 85%, and -negative 61%; c-erbB-2-positive, 57%, and -negative, 93%; Ki67 high, 77%, and low, 81%; SPF high, 77%, and low, 77%; aneuploid, 71%; and diploid, 85%. Only the difference for c-erbB-2 was statistically significant (P = 0.007). A trend for higher response rates to neoadjuvant chemoendocrine therapy for tumors that were positive for ER, PgR, and Bcl-2 was observed but did not reach statistical significance. Tumors negative for c-erbB-2 had a higher response rate, which was statistically significant. In contrast, Ki67, ploidy, SPF, and p53 failed to predict for response.

A randomised trial of six versus twelve courses of chemotherapy in metastatic carcinoma of the breast.

Chemotherapy given to patients with metastatic carcinoma of the breast is palliative in intent. Longer regimens would be justified if there was a proven prolongation of symptom response or survival. We conducted a randomised trial to assess the survival of patients receiving up to six extra courses of chemotherapy compared with our conventional regimen of six courses. The patients received either VAC, VEC (vincristine, doxorubicin or epirubicin and cyclophosphamide) or MMM (mitozantrone, methotrexate and mitomycin C) therapy. Patients who had stable disease or were responding after six courses of chemotherapy were randomised to either stop or continue treatment for another six courses. Those patients receiving maintenance therapy had a significantly longer duration of response (P < 0.02) and a significantly longer progression-free survival (P < 0.01). However, there was no survival difference between the two groups. Furthermore, treatment toxicity, which was similar in the two groups, persisted for longer in the maintenance group. These results indicate no clinical advantage for giving maintenance chemotherapy in order to prolong survival of patients with metastatic breast cancer.

The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study.

BACKGROUND: The role of hormone replacement therapy (HRT) in women who have been treated for breast cancer remains controversial. The addition of tamoxifen may protect these women from any proliferative effect of exogenous oestrogen on the breast. The aim of this analysis was to determine if tamoxifen and HRT may be safely administered together. METHODS: We studied the interaction between HRT and tamoxifen on serum cholesterol, fibrinogen, antithrombin III (AT III) and bone mineral density (BMD) in postmenopausal healthy women enrolled in a randomised tamoxifen chemoprevention trial. RESULTS: Tamoxifen decreased serum cholesterol by a mean of 13% from pretreatment values (n = 153). The addition of HRT to tamoxifen did not result in further reduction in serum cholesterol (n = 20). HRT alone led to a reduction of serum cholesterol by a mean of 5% in 14 women on placebo. The addition of tamoxifen to HRT resulted in further reduction in serum cholesterol by a mean of 7% (n = 44). Significant reductions of plasma fibrinogen by 14% and AT III by 8% were seen in women who received tamoxifen. There were no further significant changes in these coagulation factors in women on tamoxifen/HRT combinations. Tamoxifen resulted in an annual increase in BMD of the femur and spine by 2% and 1.5%, respectively, when compared to placebo (n = 38). The addition of HRT to tamoxifen resulted in further 2% annual increase in BMD of the femur. CONCLUSIONS: We conclude that there were no significant adverse intereactions with tamoxifen and HRT in this small series of patients. The combination results in a reduction of serum cholesterol, increase in BMD especially in the femur and appears not to have any adverse effect on coagulation factors. Multicentre studies should be conducted to evaluate the effect of this combination on relieving menopausal symptoms, disease relapse and overall survival in women who have received treatment for breast cancer.