A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial.

BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.

Platinum-based chemotherapy in triple-negative breast cancer.

BACKGROUND: Experimental data suggest that triple-negative (TN) breast cancer may have increased sensitivity to platinum-based chemotherapy but clinical data are limited. We present our long-term results with platinum-based chemotherapy for TN breast cancer. PATIENTS AND METHODS: In all, 94 (17 TN), 79 (11 TN) and 155 (34 TN) patients receiving platinum-based chemotherapy in neo-adjuvant/adjuvant and advanced setting were included. Response rates and outcome were compared for TN tumours versus others. RESULTS: Neo-adjuvant complete response rates were significantly higher for TN tumours (88%) than others (51%; P = 0.005). The 5-year overall survival (OS) for TN tumours following adjuvant/neo-adjuvant chemotherapy was 64% [95% confidence interval (CI) 44% to 79%] compared with 85% (95% CI 79% to 90%) for others. Five-year disease-free survival for TN tumours was 57% (95% CI 37% to 73%) compared with 72% (95% CI 64% to 78%) for others. For patients with advanced breast cancer, overall response rates were 41% for TN tumours and 31% for others (P = 0.3). Patients with TN tumours had a significantly prolonged progression-free survival of 6 months compared with 4 months for others (P = 0.05), though the OS was not significantly different between the two groups (11 versus 7 months). CONCLUSION: Platinum-based chemotherapy achieves increased response rates for TN tumours, with a trend towards worse survival in early breast cancer through an improved survival in advanced disease. Prospective randomised trials are warranted.

Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer--how low can you go?

Sixty-three patients received capecitabine at 1000 mg/m2 twice daily every 2 out of 3 weeks as first-line treatment for advanced disease at our institution. Forty-five patients (71%) had previously received adjuvant or neoadjuvant chemotherapy. The median number of capecitabine cycles administered was 5(1-40). Forty-eight patients had measurable disease with response rate (RR) of 29%. The median time to progression (TTP) was 18(2-122) weeks. Seven patients (11%) had TTP of >1 yr, four of whom received more than 10(24-40) cycles of capecitabine. Thirty-seven percent of patients still needed dose reductions. Our retrospective audit is consistent with a previously published study which used a higher starting dose of capecitabine as first-line chemotherapy. For a subgroup of patients, capecitabine can result in a long TTP with minimal toxicity. The benefit of continuing capecitabine beyond a fixed number of cycles should be investigated further. Schedules using even lower doses of capecitabine for longer periods may also be of interest.

Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer?

PURPOSE: This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. PATIENTS AND METHODS: One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P =.9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P =.09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. CONCLUSION: In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.

Low-dose oral fluorouracil with eniluracil as first-line chemotherapy against advanced breast cancer: a phase II study.

PURPOSE: Eniluracil (776C85) is an effective inactivator of dihydropyrimidine dehydrogenase that allows continuous low-dose oral fluorouracil (5-FU) to be given with predicable oral bioavailability. We have assessed this as first-line oral chemotherapy for patients with advanced/metastatic breast cancer. PATIENTS AND METHODS: Patients with histologically proven, locally advanced or metastatic breast cancer without previous chemotherapy for advanced disease were entered onto this open-label phase II study. Patients received oral 5-FU 1.0 mg/m(2) with eniluracil 10 mg/m(2), both given twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity. RESULTS: Thirty-three patients were entered, with a median age of 53 years. Sixteen partial responses were seen in twenty-nine assessable patients (55%; 95% confidence interval, 37% to 73%), including responses in four (40%) out of 10 patients who had received prior adjuvant 5-FU. Seven patients had stable disease for at least 3 months with symptom improvement. Median response duration was 14 months (range, 10 to 18+ months). Toxicity was low. There were only two episodes of drug-related grade 3 nonhematologic toxicity (diarrhea and infection), and only 6%, 3%, and 3% of patients developed granulocytopenia, thrombocytopenia, and neutropenic sepsis, respectively. Mild (grade 1/2) diarrhea occurred in 39% of patients, hand-foot syndrome in 15%, nausea in 27%, and mucositis in 18%. Toxicity-associated delay and dose reduction occurred in only 2% and 5% of courses, respectively. CONCLUSION: First-line treatment with the combination of oral 5-FU and eniluracil has high activity in patients with advanced breast cancer comparable with the most active conventional cytotoxic agents but with strikingly less toxicity.

Continuous infusional chemotherapy for early breast cancer: the Royal Marsden Hospital experience.

5-FU is a cycle-specific S-phase-dependent drug with a short half life of 10-20 min. There is therefore a rationale for its use in long-term continuous infusional therapy, with doses of up to 300 mg/m2 per day proving feasible for prolonged periods. The schedule is active in patients with heavily pre-treated breast cancer, with responses in up to 53% (overall 29%). At the Royal Marsden Hospital we have evaluated infusional 5-FU 200 mg/m2 per day for up to 6 months in combination with 3-weekly bolus epirubicin (E) 60 mg/m2 and cisplatin (C) 60 mg/m2 (infusional ECF) as pre-operative/neo-adjuvant treatment in 123 patients with operable breast cancer greater than 3 cm (median 6 cm), initially in a phase II study of 50 patients and subsequently as part of a randomised phase III trial. One hundred and eighteen (96%) have achieved objective tumour responses, with 67 (57%) achieving CR. The 5-year actuarial survival rate is 78% and the local recurrence rate without associated metastatic disease 12%. The pathological complete remission (CR) rate was 16%, with a further 5% having residual DCIS only. Pathological CR but not clinical CR is an independent predictor for disease-fee survival. The Royal Marsden is now conducting two multicentre randomised trials of infusional ECF: (i) versus conventional AC (adriamycin cyclophosphamide) as pre-operative/neo-adjuvant chemotherapy, with 376 patients so far randomised towards a target of 400; and (ii), more recently, a similar adjuvant trial versus conventional FEC (5-FU, epirubicin, cyclophosphamide), with 168 patients so far randomised. These trials will determine whether encouraging phase II activity with continuous infusional chemotherapy translates eventually into real survival benefit for patients with early breast cancer.

High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer.

PURPOSE: To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS: Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS: Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION: Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.

MMM (mitomycin/mitoxantrone/methotrexate): an effective new regimen in the treatment of metastatic breast cancer.

MMM (mitomycin 7-8 mg/m2 i.v.) every 6 weeks; mitoxantrone 7-8 mg/m2 i.v. every 3 weeks; methotrexate 35 mg/m2 i.v. every 3 weeks) is a new combination chemotherapy regimen for advanced breast cancer. It has been compared in two complementary randomized trials with CMF (cyclophosphamide 100 mg orally, days 1-14; methotrexate 35 mg/m2 i.v. days 1 and 8; 5-fluorouracil 1 g i.v. days 1 and 8; courses repeated at 28-day intervals) and VAC (vincristine 1.4 mg/m2 every 3 weeks, anthracycline 30 mg/m2 every 3 weeks, cyclophosphamide 400 mg/m2 every 3 weeks) in patients with advanced metastatic breast cancer. In the first trial, which involved 227 patients, 53% of patients receiving MMM and 49% receiving VAC responded to treatment. There was no significant difference between treatment groups in median response duration or survival. Incidence of neuropathy, alopecia, and nausea and vomiting was significantly higher in patients receiving VAC. Hematologic toxicity was greater in the MMM group. In the second trial, which involved 120 patients, 51% of patients receiving MMM and 60% receiving CMF responded to treatment. Again, there was no significant difference between treatment groups in median response duration or survival. Both regimens were well tolerated with a low incidence of alopecia and serious nausea and vomiting, and there were no significant differences in toxicity. Significant reductions in serial left ventricular ejection fractions occurred in 4 patients given CMF and in 2 given MMM. MMM is an effective, well-tolerated regimen for advanced breast cancer, with toxicity similar to that of CMF and less than that of an anthracycline-containing regimen.

Primary medical (neo-adjuvant) chemotherapy for operable breast cancer.

84 patients with large operable breast cancer have been treated with primary medical chemotherapy rather than mastectomy in three sequential studies. 86% had tumours greater than 4 cm in diameter; median diameter was 6 cm (range 1-12). Median age was 46 years (range 23-66). In the first two studies 64 patients were treated with either CMF [cyclophosphamide 100 mg orally days 1-14, methotrexate 50 mg intravenously (i.v.) days 1 and 8, and 5-fluorouracil 1 g i.v. days 1 and 8, repeating at 28-day intervals for six courses] or MMM (mitozantrone 8 mg/m2 i.v. once every 3 weeks, methotrexate 50 mg i.v. once every 3 weeks, mitomycin C 8 mg/m2 once every 6 weeks, for 8 courses). 69% achieved an overall response including 17% complete remissions. 27% have had local relapse but only 3% uncontrolled local relapse. Only 14% have required mastectomy. In the third study which is ongoing, 19 patients have been treated with infusional FEC (5-fluorouracil 200 mg/m2 i.v. 24 hourly by continuous infusion via a Hickman line for 6 months, epirubicin 50 mg/m2 i.v. bolus once every 3 weeks for 6 months, cisplatin 60 mg/m2 i.v. once every 3 weeks for 6 months with appropriate intravenous hydration). Overall response rate so far is 84% with 58% complete remissions. There have been no local relapses and no patient has required mastectomy. This study demonstrates that primary medical chemotherapy can be used to avoid mastectomy in the great majority of patients presenting with large operable primary breast cancer. Infusional FEC may be more active than conventional chemotherapy in terms of overall response and complete remission rate, and infusional FEC chemotherapy now needs to be compared with conventional chemotherapy. The concept of primary medical therapy should also be compared with conventional mastectomy followed by adjuvant chemotherapy.

The effects of low and high dose medroxyprogesterone acetate on sex steroids and sex hormone binding globulin in postmenopausal breast cancer patients.

The possibility that medroxyprogesterone acetate (MPA) is clinically effective at least in part by its suppression of adrenal steroidogenesis and a resultant reduction of circulating oestrogen levels was investigated in 49 postmenopausal patients with advanced breast cancer. Thirty-one patients were treated with low dose MPA (100 mg three times daily) and 16 patients with high dose MPA (250 mg four times daily). Plasma levels of androstenedione, testosterone, oestrone and oestradiol were all significantly reduced during treatment, with the suppression being most marked for the 17 beta hydroxysteroids, testosterone and oestradiol. The fall in oestradiol levels was to about 50% of pretreatment levels, but a concomitant fall in SHBG levels to less than 25% of baseline probably resulted in the fall in free, biologically active oestradiol being only to about 70-80% of pretreatment. It is unlikely that this is a major determinant of the activity of MPA in breast cancer.

Hydrocortisone alone vs hydrocortisone plus aminoglutethimide: a comparison of the endocrine effects in postmenopausal breast cancer.

The endocrine effects of replacement doses of hydrocortisone in postmenopausal women with advanced breast cancer were compared with the same doses of hydrocortisone plus aminoglutethimide. Fifteen patients received aminoglutethimide (AG) 250 mg three times a day plus hydrocortisone (HC) 20 mg twice a day for 2 weeks, then AG was increased to 250 mg four times a day. Another 13 patients received HC alone for 2 weeks, then AG was added. HC alone significantly suppressed oestrone (75% of baseline) and oestradiol (50% of baseline). Addition of AG to these patients produced further oestrone suppression (50% of baseline) significantly greater than HC alone. HC alone suppressed dehydroepiandrosterone sulphate as much as AG + HC. delta 4-androstenedione (delta 4A) and dehydroepiandrosterone (DHA) were suppressed by HC alone. Addition of AG produced a rise of delta 4A to basal levels. These results show that 3-beta-ol de hydrogenase is not induced by AG. AG plus HC together from day 1 produced significantly greater oestrone suppression (50% of baseline) than HC alone. Because high-dose steroids may induce aromatase and replacement doses produced marked peripheral endocrine effects, the use of replacement hydrocortisone should be reassessed in advanced breast cancer.

Adjuvant aminoglutethimide therapy for postmenopausal patients with primary breast cancer: progress report.

A group of 122 postmenopausal patients with histologically proven node-positive primary breast cancer have been randomized to receive aminoglutethimide-hydrocortisone or placebo aminoglutethimide-placebo hydrocortisone for 2 years. Median follow-up is 17 months. In general, treatment was well tolerated, but 15 patients required a reduction in the dose of aminoglutethimide, and of these four patients were unable to continue therapy due to side effects. Primary staging, incidence of extensive node involvement, and estrogen receptor were similar in the treatment and control arms. Dehydroepiandrosterone sulfate (DHA-S) and estrone were measured in a subgroup of patients, and significant suppression of DHA-S levels throughout the duration of the treatment period as seen in patients receiving the active drug. No significant suppression of either DHA-S or estrone levels was seen in the controls. Patients were monitored for metastases by serial liver function tests, carcinoembryonic antigen, and chest X-rays, and of 26 relapsing patients only three patients were not detected by this screen. We conclude that adjuvant aminoglutethimide is moderately well tolerated. It is capable of suppressing DHA-S throughout 2 years of treatment. A further 280 patients will be entered into the study to assess the survival benefit for those taking aminoglutethimide-hydrocortisone.

Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II.

cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m2. Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m2. The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m2, with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m2 but seldom persisted beyond 24 h. Serial measurements of 51Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and beta 2-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving greater than 120 mg/m2. A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400-500 mg/m2. JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.