Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer.

The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.

Breast-conserving surgery with intra-operative radiotherapy: the right approach for the 21st century?

Wide local excision followed by external beam radiation therapy (EBRT) to the whole breast has become the standard of care for most patients with localised 'early' breast cancer in the UK, Europe, and the USA. Local relapse rates are low, and overall survival figures have improved during the past decade, with the advent of more effective systemic endocrine- and chemo-therapy. A policy of EBRT for every patient undergoing breast conserving surgery (BCS) is however associated with a number of practical difficulties, acute radiation side effects and longer term toxicity, all of which detract from the obvious benefits of EBRT. In addition, with a disease as common as early breast cancer and a treatment programme typically requiring sophisticated radiation planning and many fractions of treatment, the policy of BCS plus EBRT has enormous resource implications within departments of oncology, greatly contributing to lengthy pre-treatment delays. For all these reasons, we and others have developed an increasing interest in techniques of partial breast irradiation, with an emphasis in our own Department on the emerging technique of intra-operative radiotherapy (IORT), which we initially employed as a boost to the tumour bed for use in conjunction with EBRT to the whole breast. To test the possibility of replacing the whole of the EBRT 3-6 week programme by a single application of IORT at the time of surgery, we and others have commenced a large scale prospectively randomised clinical trail in selected patients. Nine international centres are currently participating, and 350 patients have now been randomised to receive either IORT as part of the initial surgical excision or conventional EBRT with a pragmatic dose policy according to the preference of the contributing centre. The majority of patients undergoing IORT receive this at the time of initial surgery but it is also permissible within the trial programme to randomise suitable patients after the excised specimen has been histologically examined, thus avoiding any unsuitable patients - for example, those with a lobular carcinoma. These patients will be stratified and assessed separately from the 'pre-pathology' group, whose surgery and IORT is completed within a single session; if the latter patients are found to have unfavourable histology we have the facility, within the trial, to add EBRT. The trial is ongoing and our early experience has been encouraging. We have also recently assessed the long term local failure rate in patients offered IORT as a tumour bed boost, in conjunction with conventional EBRT. This methodology will also be the subject of a future randomised clinical trial.

Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung.

An analysis of prognostic factors in small cell lung cancer has been carried out using data from 371 patients treated with identical chemotherapy in the context of a large prospectively randomized clinical trial. Prognosis was shown to be strongly correlated with initial performance status, disease extent, and routine biochemical tests at the time of diagnosis. Plasma albumin, plasma sodium, alkaline phosphatase, and gamma-glutamyl transpeptidase were all predictive of survival. An initial hemoglobin of less than 11 g/dl was also predictive, but age, sex, and initial WBC count were not. A multiple regression analysis identified performance status, plasma alkaline phosphatase, plasma sodium, disease extent, and plasma albumin as contributing independently to survival. Using these parameters, three prognostic groupings could be defined. The combination of performance status and the biochemical values more closely predicted survival than categorization on the basis of disease extent defined by clinical, radiological, and scanning criteria. Response to chemotherapy was strongly correlated with these prognostic groupings. A much higher response rate occurred in patients in the best prognostic category in whom the tumor mass is assumed to be smaller. These results provide a simple basis for predicting prognosis in small cell lung cancer and indicate that the better prognosis in chemotherapy responders is not solely due to the treatment.

A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer.

Between August 1984 and October 1987, 120 patients with stage IC to IV epithelial ovarian cancer were randomly assigned to receive carboplatin (400 mg/m2) or iproplatin (300 mg/m2) every 4 weeks as initial treatment. Stratification was made according to International Federation of Gynecology and Obstetrics (FIGO) stage and according to size of residual disease after surgery. Response was evaluated after six courses when patients were restaged, with laparoscopy or laparotomy in clinical complete responders or those with no assessable disease. Treatment was then stopped in surgically proven complete responders. Patients with partial (PR) or minor response (MR) received a further six courses of their original drug at a reduced dose (carboplatin 300 mg/m2, iproplatin 225 mg/m2). Patients with stable (SD), progressive (PD), or recurrent disease were treated with cyclophosphamide (1 g/m2). The response rates were 63% (95% confidence interval [CI], 50% to 74%) for carboplatin and 38% (95% CI, 26% to 51%) for iproplatin. Fifteen patients were not assessable for response. The median survival was 114 weeks (95% CI, 82 to 233 weeks) for carboplatin patients and 68 weeks (95% CI, 48 to 82 weeks) for iproplatin patients (P = .008). The amount of residual disease after initial laparotomy was a prognostic factor for survival. Myelosuppression was the main toxicity and was greater with iproplatin. This study shows carboplatin to be more active than iproplatin in the treatment of ovarian cancer and less toxic. Few responses to cyclophosphamide occurred following either drug, implying resistance to the alkylating agent.

High-dose cyclophosphamide in small-cell carcinoma of the lung.

Eighteen patients with untreated small-cell cancer of the lung have been treated with cyclophosphamide 200 mg/kg on two occasions at an interval of four weeks. An additional eight patients received etoposide in addition to cyclophosphamide. Measurements of tumor volume were made by thoracic computed tomographic (CT) scan before and after each cycle. When compared with our previous study in which only one cycle of cyclophosphamide was given, the double procedure did not increase response rate, decrease the incidence of local relapse, or prolong the relapse-free interval. Survival after relapse was shorter with two cycles of chemotherapy mainly due to greater difficulty in administering further chemotherapy. The CT scans showed a decrease in tumor volume from 99.2 cc to 21 cc after the first cycle, but a smaller decrease to 14.1 cc after the second. These results show that the rapid emergence of drug resistance imposes limitations on the use of very high-dose cytotoxic chemotherapy.

Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial.

PURPOSE: A randomized trial of chemotherapy, given on either a 1-week or a 3-week schedule, was performed in small-cell lung cancer (SCLC) patients. The aim was to determine if weekly scheduling produced survival superior to conventional treatment. PATIENTS AND METHODS: Four hundred thirty-eight patients with SCLC with either limited disease (LD; 276 patients) or good-prognosis extensive disease (ED; 162 patients) were randomized. Weekly chemotherapy was 12 alternating cycles of ifosfamide/doxorubicin and cis-platin/etoposide (PE), while 3-week treatment was six alternating cycles of cyclophosphamide/doxorubicin/vincristine (CAV) and PE. Thoracic irradiation was administered 3 weeks after completion of chemotherapy to LD patients who attained a complete response (CR) or partial response (PR). Patients were well matched for clinical characteristics and prognostic factors. RESULTS: Overall response was the same in both arms: 82.3% (39.4% CR) with weekly and 81.1% (36.9% CR) with 3-week treatment. The median survival (MS) durations were 10.8 and 10.6 months for weekly and 3-week chemotherapy, respectively. The 2-year survival rates were 11.8% and 11.7% in the weekly and 3-week arms, respectively. Received dose-intensity (DI) was 73.9% of projected for weekly treatment and 92.7% for 3-week treatment. Hematologic toxicity was the major dose-limiting toxicity for the weekly treatment. CONCLUSION: This trial excludes at 90% power a benefit of greater than 10% for 2-year survival for weekly treatment. The received DI was reduced to a greater extent with weekly treatment, mainly due to hematologic toxicity.

Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.

Defining the target in cancer of the oesophagus: direct radiotherapy planning with fluorodeoxyglucose positron emission tomography-computed tomography.

AIMS: Target definition in radiotherapy treatment planning (RTP) of oesophageal cancer is challenging and guided by a combination of diagnostic modalities. This planning study aimed to evaluate the contribution of single positron emission tomography-computed tomography (PET-CT) in the treatment position to RTP. MATERIALS AND METHODS: Nineteen patients referred for radiotherapy from April to December 2008 were retrospectively identified. Two sets of target volumes were delineated using the planning CT and the (18)F-fluoro-deoxy-D-glucose ((18)F-FDG) PET-CT data sets, respectively. Target volumes were compared in length, volume and geographic conformality. Radiotherapy plans were generated and compared for both data sets. RESULTS: PET-CT planning target volume (PET-CT(PTV)) was larger than the CT target (CT(PTV)) in 12 cases and smaller in seven. The median PTV conformality index was 0.82 (range 0.44-0.98). Radiotherapy plans conforming to normal tissue dose constraints were achieved for both sets of PTV in 16 patients (three patients could not be treated to the prescription dose with either technique due to very large target volumes and significant risk of normal tissue toxicity). Previously undetected locoregional nodal involvement seen on PET-CT in three cases was localised and included in the PTV. In nine cases, the CTPTV plan delivered less than 95% dose to 95% of the PET-CT(PTV), raising concern about potential for geographical miss. CONCLUSION: A single scan with diagnostic PET-CT in the treatment position for RTP allows greater confidence in anatomical localisation and interpretation of biological information. The use of PET-CT may result in larger PTV volumes in selected cases, but did not exclude patients from radical treatment within accepted normal tissue tolerance.

Variations in breast cancer management between a teaching and a non-teaching district.

We compared the management and outcome of 999 women with breast cancer presenting between 1982 and 1986 at two centres in a region, one in a teaching district. A comparison was also made with relevant research and The Kings Fund Consensus Statement. The centres frequently differed markedly in the investigations done, diagnostic procedures, histology reporting, axillary sampling, and in the treatment given, also differing from the Consensus with no trend towards it. Survival was better at the teaching centre, both disease-free (N.S.) and overall [odds ratio 1.46 (1.16-1.84) P = 0.0009 unadjusted]. This should be interpreted cautiously as the median follow-up time was relatively short and the study was non-randomised. We conclude that how women with breast cancer are managed is determined as much by where they are referred as by scientific evidence. This indicates the need to introduce standards and protocols into business plans, making audit and service specifications easier.

Quality of life during chemotherapy for small cell lung cancer: assessment and use of a daily diary card in a randomized trial.

Fifty-three patients who were taking part in a randomized trial of chemotherapy in small cell lung cancer (SCLC) were entered into a study of quality of life measurement using a daily diary card. Patients received either four or eight cycles of initial chemotherapy and daily records were scored, using a four point scale of nausea, sickness, appetite, sleep, mood, pain, activity and general well being. Two hundred and fifty-six of a possible 379 cards were returned (68% compliance). The first 31 patients took part in an assessment of the diary card where comparison was made with nurse ratings using the card, the EORTC questionnaire and the Spitzer quality of life index. These comparisons showed appropriate convergent and divergent validity and demonstrated the sensitivity of the diary card to short term changes compared with the other measures. In the randomized trial the diary card demonstrated a worsening of sickness and related variables as treatment continued. This spilled over into mood and general well being although physical variables of pain, sleep and activity were largely unaffected. Prophylactic cranial irradiation was associated with a transient increase in sickness and vomiting. The study shows that the diary card is an instrument sensitive to short term changes in quality of life and thus especially useful for comparing effects during the period of treatment.

Prospective randomised study of double hemi-body irradiation with and without subsequent maintenance recombinant alpha 2b interferon on survival in patients with relapsed multiple myeloma.

Immediately before first hemi-body irradiation, 59 patients with relapsed multiple myeloma were randomised to receive or not to receive subsequent alpha-2b interferon maintenance. 13 patients (22%) [8 of 31 (26%) controls, 5 of 28 (18%) in the interferon arm] received single hemi-body irradiation alone due to progressive disease and/or persistent cytopoenias following the initial procedure. Mean time between upper and lower hemi-body irradiation was 69 days (range 35-294). Of 23 patients randomised to receive interferon and completing double hemi-body irradiation, 15 (65%) achieved peripheral blood counts adequate to allow interferon administration as per study criteria commencing at a mean 116 days (61-241) from time of study entry. The mean period of interferon therapy, starting at a mean 65 days (26-160) post second hemi-body irradiation, is 16.4 months (2-33.5). There was no significant difference in median survival durations (10 months) from time of initial radiotherapy between control and interferon patients.

Current role of chemotherapy in head and neck cancer.

Although cytotoxic chemotherapy is not fully established as an accepted part of the primary management of head and neck cancer, numerous studies over the past 10 years have been undertaken, notably in the USA and Europe. Several classes of antineoplastic chemotherapy have activity and can induce tumour regression in patients with squamous or anaplastic cancers, the most common cell types. While response rates with newer combinations, such as cisplatin and fluorouracil, are reportedly as high as 90%, response duration is generally short-lived. The most promising use of chemotherapy appears to be synchronous or adjuvant therapy with radiotherapy and/or surgery. Combined modality therapy of this type is able to improve the local control rates; 2 prospectively randomised studies from the United Kingdom each with several hundred patients have suggested a possible improvement in overall survival as well. The most active agents are methotrexate, cisplatin, bleomycin and fluorouracil. Further studies are urgently needed to assess the true role of and the indications for chemotherapy, and because of the world-wide importance of these tumours, the identification of even a modest improvement would have profound benefit. The use of chemotherapy outside studies should still be discouraged.

Concurrent daily cisplatin and radiotherapy in locally advanced squamous carcinoma of the head-and-neck and bronchus.

In order to exploit the cytotoxic and radiosensitising actions of cis-platinum, we have treated 35 patients with locally advanced squamous cell carcinoma of the bronchus or head-and-neck. Each patient underwent radical irradiation (60 Gy/30 fractions over 6 weeks) with daily low-dose intravenous cisplatin (10 mg absolute dose per day) administered within 30 min of each daily radiation fraction. Total dose of cisplatin was 300 mg over 6 weeks. Although treatment was complicated by nausea in almost all patients and transient renal dysfunction in the majority, 27 patients completed treatment and renal function returned to normal or near normal in almost all cases. There was no obvious enhancement of pulmonary or skin toxicity, beyond what would have been expected from treatment with radical radiotherapy alone. There were two treatment-related deaths from renal failure. The response rate was high: all patients achieved at least a partial response, and in head-and-neck sites, there were nine complete responders and seven partial responders. Of the initial 35 patients, of whom all but two had advanced inoperable disease, 11 have died and 21 remain in continuous remission, 8-120 weeks from the start of treatment (median 55 weeks).

Social consequences of brain or liver relapse in small cell carcinoma of the bronchus.

The time spent in hospital when cerebral metastases occur as the first site of relapse in patients with small cell carcinoma of the lung (SCCL) has been analysed and compared to the consequences of relapse in the liver. In the course of a clinical trial with 370 patients, 50 patients relapsed initially in the brain and 20 in the liver. The 2 groups were comparable with respect to performance status at diagnosis and the amount of home support available. Patients who relapsed in the brain suffered a greater deterioration in performance status, and spent a greater proportion of their remaining life in hospital than did patients whose initial relapse was in the liver. This difference was most marked in patients who died soon after relapse. Radiotherapy (20 Gy in 5 fractions over one week or 30 Gy in 10 fractions over 2 weeks) and dexamethasone were not very effective treatments for brain relapse though subjective responses were common. The substantial morbidity and lengthy hospitalisation resulting from brain relapse compared with relapse at another site is a important factor to be considered in assessing whether prophylactic cranial irradiation should routinely be offered to patients with SCCL.

Hemibody irradiation in multiple myeloma.

Eighteen patients with multiple myeloma were treated by hemibody irradiation using large single fractions, usually to a dose of 10 Gy (lower half) and 7.5 Gy (upper half). All except one patient had previously been treated by multiple courses of conventional chemotherapy with melphalan and prednisone, and were considered to be resistant to further chemotherapy. In most cases, local field irradiation had also been given for symptomatic bone pain. Of the 13 patients who had symptoms at the start of hemibody irradiation, 11 improved sufficiently for their analgesia requirement to be reduced. In eight patients, there was a significant fall in circulating immunoglobulin but no patient with Bence-Jones proteinuria had complete resolution of this biochemical abnormality. Although thrombocytopenia and neutropenia were common, only two patients required platelet transfusion and the treatment was in general extremely well tolerated. Survival following hemibody irradiation was similar to the survival reported from the use of "second-line" chemotherapy and we feel that hemibody irradiation is a more acceptable alternative for most patients.

A survey of the ethical considerations in randomised trials for lung cancer.

BACKGROUND: In order to promote a more productive debate on the ethics of randomised clinical trials (RCTs), we present a survey on the ethical aspects of published RCTs for lung cancer. METHODS: Data from 92 published reports of RCTs for lung cancer, as identified from the Cancerlit 1993-1995 database were supplemented by a questionnaire mailed to the authors of those publications. The analysis focused on respect of autonomy, non-maleficence, beneficence, and justice as the ethical principles applicable to society, patients in trials, patients not included in RCTs and physicians. ETHICAL ANALYSIS: The benefits to society include an objective evaluation of new treatments. The principle of autonomy was often violated for patients who were inadequately informed about the disease or about RCT. In some trials with prolonged recruitment, the principle of non-maleficence was not fully respected since patients continued to be randomised in spite of an obvious advantage of one of the treatments. When compared to those not included in a trial, patients in RCTs were reported to benefit from more precise standards, superior quality assurance of diagnostic and therapeutic procedures, more attention from the physician, easier appointments and easier access to hospitalisation. However, these benefits diminish patients' autonomy and lead to injustice towards patients not included in the trials. While benefits to physicians were usually modest and in proportion to their contribution, an influence upon their autonomy cannot be excluded. CONCLUSION: More attention to the aforementioned ethical caveats of RCTs should alleviate the ethical costs and might also bring more patients into future trials.

High-dose cyclophosphamide with autologous marrow transplantation for small cell carcinoma of the bronchus.

Twenty-five patients with previously untreated small cell carcinoma of the bronchus have been treated with cyclophosphamide 160-200 mg/kg and subsequent radiotherapy to the primary site. Eighty-four percent of patients responded to the single cycle of chemotherapy, with 56% attaining a complete response. Median duration of remission was 43 weeks and median survival 69 weeks. 2-Mercaptoethane sulphonate was given to prevent urothelial toxicity. Autologous bone marrow transplantation was used to mitigate bone marrow depression but sequential delay in reinfusing cryopreserved bone marrow did not alter the period of cytopenia. Other toxicities were mild. The procedure proved safe and manageable. High-dose chemotherapy may prove to be useful in the initial management of this tumour.

Sequential chemotherapy in good-prognosis patients with small-cell lung cancer.

A sequential combination chemotherapy regimen was evaluated in 23 patients with small-cell lung cancer (16, limited disease; 7, extensive disease). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal serum sodium and albumin levels and alkaline phosphatase values of less than 1.5 times the upper limit of normal. Treatment comprised ifosfamide and either vindesine or vincristine given on weeks 0, 2 and 4; cisplatin and etoposide given on weeks 6, 9 and 12; and doxorubicin and methotrexate given on weeks 15 and 17. The overall response rate at the end of chemotherapy was 91% and the complete response rate was 43%. Treatment was generally well tolerated and the delivered dose intensity was 83% of that projected. Median survival was 54 weeks, with 4 patients (17%) being alive 2 years after the completion of therapy.

A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix.

Forty-one patients with advanced progressing carcinoma of the cervix were treated with ifosfamide 1.5 g/m2 daily in a 30-min infusion for 5 days every 3 weeks. The overall response rate (complete + partial) was 12/39 (31%), or 12/30 (40%) in those who had not received previous chemotherapy. Six patients achieved a complete remission of disease and four of these remain disease-free 24-39 months later. Durable response were seen in patients with disease progressing after radical radiotherapy. Bone marrow suppression was the dose-limiting toxicity and led to dosage modification in 24 patients. Nausea and vomiting was experienced by all patients at some time during therapy and all patients developed alopecia. Mild neurological toxicity occurred in seven patients but severe life-threatening neurotoxicity was not seen with this schedule of administration. Further studies are needed to identify the optimum dose and schedule of ifosfamide and to ascertain its place in combination therapy.

Intensive chemotherapy with autologous bone marrow transplantation for small-cell lung cancer.

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.