The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size. METHODS: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). INTERPRETATION: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Can computerised tomography replace bone scintigraphy in detecting bone metastases from breast cancer? A prospective study.

BACKGROUND: The aim of this study was to determine whether bone scans (BS) can be avoided if pelvis was included in CT thorax and abdomen to detect bony metastases from breast cancer. MATERIALS AND METHODS: Results of 77 pairs of CT (thorax, abdomen, and pelvis) and BS in newly diagnosed patients with metastatic breast cancer (MBC) were compared prospectively for 12 months. Both scans were blindly assessed by experienced radiologists and discussed at multidisciplinary team meetings regarding the diagnosis of bone metastases. RESULTS: CT detected metastatic bone lesions in 43 (98%) of 44 patients with bone metastases. The remaining patient had a solitary, asymptomatic bony metastasis in shaft of femur. BS was positive in all patients with bone metastases. There were 11 cases of false positive findings on BS. CONCLUSION: Our findings suggest routine BS of patients presenting with MBC is not required if CT (thorax, abdomen, and pelvis) is performed.

Weight gain during adjuvant and neoadjuvant chemotherapy for breast cancer: an audit of 100 women receiving FEC or CMF chemotherapy.

Weight gain is reported as a common finding in patients treated for breast cancer but its aetiology appears to be complex. The aim of this study was to investigate the incidence and degree of weight gain during chemotherapy and to examine possible contributory factors. Data were collected on 100 women treated with CMF or FEC chemotherapy. The mean change in weight was +3.68 kg (P<0.001). 64% of patients gained more than 2 kg in weight, 31% maintained a stable weight (within + or - 2 kg) and 5 patients lost more than 2 kg. Approximately 1/3 of patients (33) gained more than 5 kg and 6 patients gained more than 10 kg in weight. The majority of patients (85%) received steroids as antiemetics but no effect of steroid dose was seen on the level of weight change. No significant differences in weight gain were seen in patients receiving tamoxifen (37%) compared with those not taking it. Similarly, menopausal status did not appear to be a significant factor influencing weight gain. In summary, a high incidence of weight gain was found. The literature on weight gain in breast cancer and possible interventions to avoid weight gain are discussed.

Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity.

DNA repair defects might contribute both to cancer progression and to the extreme reactions to radiotherapy observed in approximately 5% of patients. Polymorphic microsatellites in three DNA repair genes, XRCC1, XRCC3 and XRCC5, were analyzed for possible linkage to cancer status or clinical radiosensitivity. XRCC1, 3 and 5 proteins are involved in single-strand DNA break rejoining, recombinational repair, and double-strand DNA break rejoining respectively. Mendelianly inherited microsatellite polymorphisms in these genes were analyzed in three groups: volunteers with no cancer history; radiosensitive cancer patients; cancer patients with acceptable reactions to radiotherapy. Rare heterozygous alterations in all three gene regions were found solely in the cancer subpopulation. Association testing between these rare polymorphisms and cancer status revealed a significant association for XRCC1 (P = 0.005), and XRCC3 (P = 0.004). There was also an association between these polymorphisms and clinical radiosensitivity for XRCC1 (P = 0.03), and XRCC3 (P = 0.005).

Growth of fibroblasts as a potential confounding factor in soft agar clonogenic assays for tumour cell radiosensitivity.

Soft agar clonogenic assays are considered to be a standard method for measuring tumour cell radiosensitivity and it has been widely reported that fibroblast contamination does not occur. We report here that human fibroblasts can proliferate to form colonies in a modified form of the Courtenay-Mills soft agar clonogenic assay. It was observed that early passage skin fibroblasts could form colonies in soft agar, although the plating efficiencies were reduced compared with growth on plastic. It was demonstrated that normal lung could proliferate in agar with similar plating efficiencies to fresh tumours and that fibroblastic cells were present in these cultures. Characterisation of primary lung tumour cultures also showed that fibroblastic cells were present in these cultures. Characterisation of primary lung tumour cultures also showed that fibroblastic cells were present which lacked epithelial features and which resembled closely the cells found in cultures of normal lung. This is an important finding for workers using soft agar assays to culture human tumour cells and is of interest in understanding the processes of normal growth control of human fibroblasts.

A comparison of doxorubicin, epirubicin and mitozantrone as single agents in advanced breast carcinoma.

Between July 1985 and December 1987, 87 patients with advanced breast carcinoma were randomized to receive single agent doxorubicin (70 mg/m2), epirubicin (70 mg/m2) or mitozantrone (14 mg/m2) at 3-weekly intervals. The patients had received no previous chemotherapy for their advanced disease but 91% had received prior hormonal therapy. The response rates were 36% with doxorubicin, 32% with epirubicin and 26% with mitozantrone, but these differences did not reach statistical significance. The median survival of all patients was 8.3 months. There was no significant difference in response rates or survival according to menopausal status. The toxicities of the three agents are compared. Nausea, vomiting and alopecia were more severe in patients treated with doxorubicin or epirubicin than those treated with mitozantrone. Myelosuppression and infective episodes occurred more frequently with mitozantrone. Two cardiac complications were reported. This study shows that the toxicity and low efficacy of all three agents limit their use as single agents in advanced breast carcinoma. The role of single agent chemotherapy and the relative toxicities of these drugs are discussed.

Treatment strategies in advanced and metastatic cancer: differences in attitude between the USA, Canada and Europe.

Six-hundred and forty four radiation therapists from 21 European countries, Canada, and the USA responded to a questionnaire regarding the management of three cases of advanced cancer. The cases were a 64-year-old man with brain metastases from small cell carcinoma of the lung; a 64-year-old woman with bone metastases from carcinoma of the breast and a 59-year-old man with squamous cell carcinoma of the bronchus and mediastinal nodes. There was variation as to the perceived prognosis and appropriate aims of therapy, particularly for the case of squamous cell carcinoma of the bronchus. The total dose and number of fractions could be related to the perceived aims and expectations of treatment, for example, those aiming to extend life gave higher doses of radiotherapy and those aiming only to relieve symptoms gave lower. Similarly, those describing treatment as radical and estimating longer survival gave higher doses and more fractions than those treating palliatively. Variations in the role of the radiation oncologist in the management of advanced and metastatic cancer in the USA, Canada and Europe are discussed.

Treatment strategies for advanced and metastatic cancer in Europe.

ESTRO members were surveyed by questionnaires regarding the management of three cases of advanced cancer and the organisation of cancer care in their centre. There were 278 replies from within Europe from a total of 21 countries and 231 centres. The cases were a 64-year-old man with brain metastases from a small cell carcinoma of the lung, a 64-year-old woman with bone metastases from carcinoma of the breast on tamoxifen and a 59-year-old man with a squamous cell carcinoma (NSCLC) of the bronchus and positive mediastinal lymph nodes. Over 90% of respondents replied that they would give radiotherapy in each of these cases. The median total doses were 30 Gy for the brain metastases, 30 Gy for the bony metastases and 56 Gy for the case of NSCLC. There was variation as to the perceived prognosis and appropriate aims of therapy, particularly for the case of NSCLC. The total dose and number of fractions of radiotherapy could be related to the perceived aims and expectations of treatment, e.g. those aiming to extend life gave significantly higher total doses of radiotherapy (p = 0.0001) and those aiming to relieve symptoms gave significantly lower total doses (p = 0.0001). Treatment for this case was described as "radical" by 53% of respondents and as "palliative" by 47% and the prognosis was estimated to be less than 12 months by 41% and 1-2 years by 44%. Those describing treatment as radical and estimating longer survival gave higher doses and more fractions than those treating palliatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug abusers' perceptions of their parents.

Many clinicians in the area of drug addiction believe that emotional problems arise from particular styles of parenting. To investigate this link, 63 young male and female addicts who had sought treatment completed the Parental Bonding Instrument which tapped their perceptions of their relationship with each parent. Addicts reported early parental experiences differing from those of a control group. Drug abusers judged their parents as cold, indifferent, controlling and intrusive. In addition, these perceptions were shared by male and female addicts. These results, together with previous research suggest that these perceptions might well point to a general risk factor for the development of a broad range of psychological and psychiatric disorders. In addition, the issue of family factors in the design and implementation of drug treatment programs needs to be addressed.

Coronary ostial stenosis after radiotherapy: angioplasty or coronary artery surgery?

A thirty year old man underwent coronary angioplasty for an isolated ostial stenosis of the ostium of the right coronary artery after mediastinal radiotherapy given ten years previously. Despite an angiographically acceptable angioplasty result, he had a myocardial infarction two months later and coronary artery surgery was performed. The most effective form of myocardial revascularisation for radiotherapy related coronary artery lesions remains to be established.