Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial.

BACKGROUND: The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. PATIENTS AND METHODS: Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. RESULTS: A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2-4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89-1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90-1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23-0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24-0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. CONCLUSIONS: The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. CLINICALTRIALS.GOV NUMBER: NCT01093235.

Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

Comparing cancer mortality and GDP health expenditure in England and Wales with other major developed countries from 1979 to 2006.

BACKGROUND: Cancer and gross-domestic-product on health expenditure (GDPHE) are critical issues for major developed countries (MDC). Each country's economic input, GDPHE 1980-2005 is contrasted with clinical outputs, cancer mortality rates (CMRs), to compare their efficiency and effectiveness in reducing CMR. METHODS: World Health Organization's CMR data for baseline years (1979-1981) are compared with 2004-2006 by sex and age. The χ(2)-tests are used to determine differences between MDC. Efficiency is analysed by calculating a ratio of average GDPHE to reduced CMR over the period. RESULTS: Inputs: All the countries GDPHE grew substantially. For the United Kingdom this reached 9.3%, which is below the MDC average (10%). Outputs: CMR fell substantially (>20%) in six of the ten countries. The male average (15-74 years) CMR in England and Wales had been third highest but by 2004-2006 was sixth, a 31% reduction, which was significantly greater than seven other countries. Initially England and Wales female average CMR was the highest of all countries and is now the second highest. There were significantly greater reductions for the 55-64 and 65-74 years old than in seven and four countries, respectively. GDPHE reduced CMR ratios--the average GDPHE:reduced CMR ratio of England and Wales was 1:120, greater than all MDC and double that in four countries. CONCLUSION: Comparing GDPHE input with CMR output showed that relatively the NHS achieved more with proportionately less than other MDC.

A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.

BACKGROUND: Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection. PATIENTS AND METHODS: Poor-risk CLM was defined as follows: more than four metastases, diameter >5 cm, R0 resection unlikely, inadequate viable liver function if undergoing upfront resection, inability to retain liver vascular supply, or synchronous colorectal primary presentation. Patients underwent baseline computed tomography, magnetic resonance imaging, and/or positron emission tomography (PET) for staging and received neoadjuvant CAPOX plus bevacizumab, with resectability assessed every four cycles. Primary end point was radiological objective response rate (ORR). RESULTS: Forty-six patients were recruited, of which 91% underwent PET to ensure metastases confined to liver. Following neoadjuvant CAPOX plus bevacizumab, the ORR was 78% (95% confidence interval 63% to 89%). This allowed 12 of 30 (40%) patients with initial nonsynchronous unresectable CLM to be converted to resectability. In addition, 10 of 15 (67%) patients with synchronous resectable CLM underwent liver resection, with four additional patients being observed alone due to excellent response to neoadjuvant therapy. No grade 3-4 perioperative complications were seen. CONCLUSION: Neoadjuvant CAPOX plus bevacizumab resulted in a high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability.

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.

The impact of primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric adenocarcinoma--individual patient data from 1775 patients in four randomised controlled trials.

BACKGROUND: It is unclear if differential chemotherapy effects exist on overall survival (OS), response rate (RR) and toxicity depending on primary tumour origin [oesophageal versus oesophago-gastric junction (OGJ) versus gastric adenocarcinoma]. PATIENTS AND METHODS: A total of 2110 patients were enrolled in four randomised controlled trials (RCTs) assessing fluoropyrimidine +/- platinum-based chemotherapy. This analysis used individual patient data and restricted to patients with adenocarcinoma who received one or more dose of chemotherapy. Gastric origin was the control in comparisons of tumour origin. RESULTS: Of the 2110 patients randomised, 1775 (84%) patients had adenocarcinoma with oesophageal (n = 485), OGJ (n = 457) and gastric (n = 833) origins. The median OS was 9.5 months in oesophageal, 9.3 months in OGJ and 8.7 months in gastric cancer (P = 0.68). RR was 44.1% in oesophageal, 41.1% in OGJ and 35.6% in gastric cancers (P = 0.11 and 0.27, respectively, compared with gastric cancer on multivariate analysis). Toxicity composite end point occurred in 46%, 47% and 45% in oesophageal, OGJ and gastric cancers, respectively (P = 0.85 and 0.62 compared with gastric). CONCLUSIONS: In our large multicentre RCT dataset, no significant differences were demonstrated on multivariate analyses in OS, RR and toxic effects among patients with advanced oesophageal, OGJ and gastric adenocarcinoma. Future RCTs should not exclude oesophageal adenocarcinoma.

Colorectal tubulovillous adenomas identified on fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography scans.

OBJECTIVE: The aim of this retrospective study was to assess the significance of incidental focal colonic lesions on fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) scans in patients undergoing staging for noncolorectal cancer. METHOD: Of the 110 patients in our PET/CT database, 10 were found to have abnormally high uptake of tracer in their large bowel. RESULTS: Seven patients who underwent further endoscopic evaluation of these abnormalities had intermediate to high-risk adenomatous polyps. CONCLUSION: Benign colonic polyps produce high-intensity focal FDG uptake in large bowel. Endoscopic evaluation is recommended before curative resectional surgery of the presenting cancer where appropriate.

Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: A pooled analysis of three clinical trials.

The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (> or =70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged > or =70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients > or =70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities.

Ultrastructural localization of BHRF1: an Epstein-Barr virus gene product which has homology with bcl-2.

BHRF1 is an Epstein-Barr virus encoded protein which has a 38% sequence similarity with bcl-2 over the carboxyl portion. Like bcl-2, BHRF1 has been shown to suppress programmed cell death from apoptosis. Previously BHRF1 has been detected in mitochondrial, microsomal, and nuclear compartments by cell fractionation analysis. In this study we have used the technique of immunoelectron microscopy to define the ultrastructural distribution of the BHRF1 product in the EBV converted cell lines B95.8 and P3HR-1. The BHRF1 product was localized at the periphery of the mitochondria in a pattern similar to that of bcl-2 and by analogy with bcl-2 this is likely to be the functional destination. Sequence analysis of the BHRF1 protein disclosed similarity with the recently described bcl-2 homologues bcl-x (32%) and bax (34%) over the carboxyl portion, with several domains of complete identity. BHRF1 appears to be a member of a gene family involved in the regulation of programmed cell death. The identity between BHRF1 and bcl-2, an apparent shared ability to abrogate apoptosis, and the common ultrastructural localization is compelling and suggests that bcl-2 and BHRF1 are both functionally and mechanistically similar.

Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women.

PURPOSE: Tamoxifen is an effective treatment for metastatic and primary breast cancer and is now being evaluated as a chemoprevention agent in healthy women. Any long-term effects on estrogen-sensitive tissues such as bone may have important therapeutic implications. METHODS: We measured bone mineral density (BMD) in the lumbar spine and hip using dual-energy x-ray absorptiometry (DXA) in premenopausal and postmenopausal healthy women who participated in our placebo-controlled tamoxifen chemoprevention of breast cancer trial. RESULTS: BMD data are now available from 179 women for this analysis. In premenopausal women, BMD decreased progressively in the lumbar spine (P < .001) and in the hip (P < .05) for women on tamoxifen, but not those on placebo. The mean annual loss in lumbar BMD per year over the 3-year study period in tamoxifen-treated compliant women who remained premenopausal throughout the study period was 1.44% (1.88% calculated on an intent-to-treat basis) compared with a small gain of 0.24% per annum for women on placebo (P < .001). Tamoxifen had the opposite effect in postmenopausal women. The mean annual increase in BMD for women on tamoxifen was 1.17% in the spine (P < .005) and 1.71% in the hip (P < .001) compared with a noninsignificant loss for women on placebo. CONCLUSION: These results indicate that tamoxifen treatment is associated with a significant loss of BMD in premenopausal women, whereas it prevents bone loss in postmenopausal women. These adverse and beneficial effects of tamoxifen should be considered in the assessment of the therapeutic benefits for both the adjuvant treatment and the chemoprevention of breast cancer.

Randomized trial of chemoendocrine therapy started before or after surgery for treatment of primary breast cancer.

PURPOSE: To evaluate in a randomized clinical trial systemic chemoendocrine therapy used as primary (neo-adjuvant) treatment before surgery in women with primary operable breast cancer. PATIENTS AND METHODS: Patients aged less than 70 years with clinically palpable, primary operable breast cancer diagnostically confirmed by fine-needle aspiration cytology (FNAC) and suitable for treatment with surgery, radiotherapy, cytotoxic chemotherapy, and tamoxifen were considered eligible. Patients randomized to neoadjuvant treatment received four cycles of chemo-therapy for 3 months before surgery followed by another four cycles after surgery, and were compared with patients randomized to adjuvant therapy who received eight cycles of chemotherapy over 6 months after surgery. RESULTS: Of 212 patients who were randomized to receive either adjuvant (n = 107) or neoadjuvant (n = 105) chemoendocrine therapy, 200 are now assessable for response. The two groups are comparable for age, menopausal status, disease stage, and surgical requirements. The overall clinical response rate was 85%, with a complete histologic response rate of 10%. There was a significant reduction in the requirement for mastectomy in patients who received neoadjuvant treatment (13%) as compared with those who received adjuvant therapy (28%) (P < .005). Symptomatic and hematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy. The median follow-up period for patients in this trial is 28 months, during which time four patients have relapsed locally and 20, including one of the local relapses, have developed metastatic disease, 19 of whom have died. The follow-up period is too brief to evaluate relapse rate or survival duration. CONCLUSION: This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.

Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil.

PURPOSE: To investigate and measure the metabolism of colorectal cancer liver metastases using 18F-fluorodeoxyglucose positron emission tomography (FDG PET), before and during the first month of chemotherapy. The findings were compared with tumor outcome conventionally assessed using changes in tumor size. PATIENTS AND METHODS: Patients with colorectal cancer liver metastases were treated with fluorouracil (5FU) as a protracted venous infusion (300 mg/m2/d), with or without interferon-alpha 2b for two 10-week blocks separated by a 2-week break. Before and at 1 to 2 and 4 to 5 weeks on treatment, FDG PET scans were performed. Patients fasted, were injected intravenously with FDG (50 to 100 MBq), and scanned using a large-area positron camera; the image data was processed such that regions of interest could be identified. The results were expressed as a ratio of FDG uptake in the tumor and normal liver (T:L) or as a semiquantitative standardized uptake value (SUV). These measures were compared with the tumor dimensions measured on a computed tomographic (CT) scan performed at 12 weeks from commencement of chemotherapy. RESULTS: Twenty patients were studied; however, two did not have assessable liver metastases. Objective partial responses were observed in 11 of 18 patients. A total of 27 metastatic lesions were assessable. Pretreatment T:L ratios and SUVs did not correlate with tumor response, although response was associated with lower 1- to 2-week (1.84 v 2.17; t=2.667; P < .02) and 4- to 5-week (1.36 v 2.28; t=5.02; P < .001) T:L ratios, and 4- to 5-week (3.57 v 4.95; t=2.492; P < .05) SUVs. Expressed as a percent of the baseline values of the T:L ratio, responding lesions had a greater reduction in metabolism (67% v 99%; t=7.53; P < .001). The 4- to 5-week T:L ratio was able to discriminate response from nonresponse both in a lesion-by-lesion and overall patient response assessment (sensitivity 100%; specificity 90% and 75%, respectively). CONCLUSION: Positron emission tomography used to evaluate the uptake of FDG in tumors yields data that correlate with the antitumor effect of chemotherapy in patients with liver metastases from colorectal cancer.

Role of magnetic resonance imaging in predicting relapse in residual masses after treatment of lymphoma.

PURPOSE: This prospective study of patients treated at the Royal Marsden Hospital Lymphoma Unit was designed to evaluate the role of magnetic resonance imaging (MRI) in the assessment of residual masses evident on computed tomographic (CT) scanning following treatment of lymphoma. PATIENTS AND METHODS: All patients had MRI, gallium-67 single-photon emission CT (67Ga SPECT), and erythrocyte sedimentation rate (ESR) performed within 3 months of completing therapy. Patients were monitored for 1 year posttreatment and observed for signs of relapse. Investigation results were correlated with disease status, and the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) calculated. Time-to-relapse curves were derived and the log-rank test used to determine whether patients with a positive result were more likely to have a relapse within the mass than those with a negative result. RESULTS: Thirty-four patients were studied, 14 of whom relapsed, 11 within the area of residual mass. Overall, MRI had a high specificity (90%), PPV (71%), and NPV (75%), but poor sensitivity (45%). The results for 67Ga SPECT were similar, apart from lower sensitivity (33%). ESR had inferior performance in predicting relapse compared with the other tests. MRI was the only investigation to show statistical significance (P = .14) in predicting relapse, and this was particularly evident in Hodgkin's lymphoma (P = .003). Combining results of 67Ga SPECT and MRI did not improve predictive power. CONCLUSION: These data demonstrate that MRI is a valuable tool in the setting of a residual mass after treatment, giving clinically useful prognostic information. 67Ga SPECT also has a role, but is less effective in predicting relapse than MRI.

Impact of protracted venous infusion fluorouracil with or without interferon alfa-2b on tumor response, survival, and quality of life in advanced colorectal cancer.

PURPOSE: The aim of this study was to investigate the effects of adding interferon alfa-2b (IFN) to protracted venous infusion fluorouracil (PVI 5-FU) from the start of treatment in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients who attended our unit with histologically confirmed advanced colorectal cancer were randomized to receive either PVI 5-FU 300 mg/m2/d via Hickman line, and IFN 5 MU subcutaneously three times weekly, or PVI 5-FU alone. Treatment was given for a maximum of two 10-week blocks, with a 2-week gap for reassessment of all parameters. Quality of life (QL) was measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) pretreatment and every 6 weeks thereafter. RESULTS: A total of 160 patients were randomized, with 155 eligible for assessment. Radiologic response was observed in 43 patients (28%): 17 of 77 (22%) in the 5-FU-plus-IFN arm (all partial responses [PRs]) and 26 of 78 (33%) in the 5-FU-alone group (complete responses [CRs] and 22 PRs) (difference not significant). Symptomatic improvement occurred in the majority of patients, and equally in both arms: 61% to 80% depending on the symptom. There was no significant difference between the two groups in failure-free survival (median, 161 v 193 days) or overall survival (median, 328 v 357 days). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .001), neutropenia (P = .04), mucositis (P = .008), and alopecia (P = .0002). There were no toxic deaths and few notable differences in QL between the two arms. CONCLUSION: This study confirms that PVI 5-FU is effective in treating the symptoms associated with metastatic colorectal carcinoma, with only mild to moderate toxicity and maintenance of QL. IFN 5 MU three times weekly does not enhance these palliative benefits.

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.

Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin.

PURPOSE: So far there are no published data on optimal duration of chemotherapy for advanced non-small-cell lung cancer (NSCLC); six or more courses are usually recommended. We have carried out a multicenter randomized trial comparing three versus six courses of chemotherapy. PATIENTS AND METHODS: Patients with stage IIIb or IV NSCLC were randomized at start of treatment to receive either three or six courses of mitomycin 8 mg/m(2) (courses 1, 2, 4, and 6), vinblastine 6 mg/m(2), and cisplatin 50 mg/m(2) (MVP) every 21 days. Treatment was stopped early in both arms for progressive disease or unacceptable toxicity. Key end points were overall survival, duration of symptom relief, and quality-of-life assessment using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 with lung cancer-specific module QLQ-LC13. RESULTS: Three hundred eight patients were randomized. Seventy-two percent of the 155 patients randomized to three courses completed treatment. In the 153 patients randomized to six courses, 73% completed three courses and 31% six courses. Median survival was 6 versus 7 months, respectively, and 1-year survival 22% versus 25% (P =.2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief (P =.4). Quality-of-life parameters were the same or improved for patients randomized to only three courses, including significantly decreased fatigue (P =.03) and a trend toward decreased nausea and vomiting (P =.06). CONCLUSION: Our findings show no evidence for additional clinical benefit by continuing MVP chemotherapy beyond three courses. This challenges current orthodoxy of six courses or more. Further trials addressing duration of chemotherapy are now warranted, particularly with newer chemotherapy schedules.

High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma.

PURPOSE: We report the results of intensive chemotherapy with high-dose melphalan (HDM) following conventional-dose cytoreductive chemotherapy in previously untreated patients with myeloma. PATIENTS AND METHODS: From 1986 to 1991, 53 previously untreated patients with myeloma received HDM 200 mg/m2 plus methylprednisolone 1.5 g daily (MP) for 5 days with autologous bone marrow transplantation (ABMT) after cytoreductive chemotherapy. RESULTS: At the time of HDM administration, responses to induction therapy were complete remission (CR) in nine patients, partial remission (PR) in 38, and no response (NR) in six. Following HDM, all but one patient responded, with 40 patients achieving a CR (75%). There was one treatment-related death following HDM. The median time to reach a WBC count more than 1,000/microL and platelet count more than 25,000/microL was 19 days (range, 13 to 30) and 24 days (range, 15 to 55), respectively. The median duration of response has not been reached at 20 months, and it is significantly longer for patients in CR than for those in PR (P < .025). Currently, with a median follow-up duration of 31 months (range, 6 to 58), 12 patients are dead and 40 are alive, and the estimated probability of survival at 54 months is 63%. Multivariate analysis found hemoglobin (Hb) more than 10 g/dL (P = .012), and stage A disease (P = .001) at diagnosis to be favorable indicators for survival. CONCLUSION: Myeloma patients who are able to receive HDM plus ABMT following conventional chemotherapy achieve a high proportion of CRs, which may be associated with prolonged survival.

High-dose melphalan for multiple myeloma: long-term follow-up data.

PURPOSE: To present long-term follow-up data of patients with myeloma treated with high-dose melphalan HDM, including an assessment of prognostic factors. PATIENTS AND METHODS: Between November 1981 and April 1986, 63 previously untreated patients with multiple myeloma received HDM 140 mg/m2 without autologous bone marrow transplantation. RESULTS: The overall response rate was 82% (51 of 62), with 32% (20 of 62) patients entering complete remission (CR). The median duration of response was 18 months, and six patients remain alive and free from disease progression at 60+ to 84+ months. Improvements in quality of life associated with remission were immediate in terms of pain grade (89% of patients) and performance status (92%), and later in terms of bone healing (29%). Currently, at a median follow-up duration of 74 months (range, 63 to 100) since HDM, 23 patients are alive with a median survival duration of 47 months, and 35% of patients are expected to be alive at 9 years. Apart from early-stage disease, no factors were found to predict long-term survival. No second malignancies or other late side effects have been recorded. CONCLUSION: Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is associated with a high objective response rate, relatively long remission durations, and good symptom control.

Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m(2) every 3 weeks, cisplatin 60 mg/m(2) every 3 weeks and PVI 5-FU 200 mg/m(2)/d) or MCF (mitomycin 7 mg/m(2) every 6 weeks, cisplatin 60 mg/m(2) every 3 weeks, and PVI 5-FU 300 mg/m(2)/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P =.692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P =.315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.