Detailed Sub-study Analysis of the SECRAB Trial: Quality of Life, Cosmesis and Chemotherapy Dose Intensity.

AIMS: SECRAB was a prospective, open-label, multicentre, randomised phase III trial comparing synchronous to sequential chemoradiotherapy (CRT). Conducted in 48 UK centres, it recruited 2297 patients (1150 synchronous and 1146 sequential) between 2 July 1998 and 25 March 2004. SECRAB reported a positive therapeutic benefit of using adjuvant synchronous CRT in the management of breast cancer; 10-year local recurrence rates reduced from 7.1% to 4.6% (P = 0.012). The greatest benefit was seen in patients treated with anthracycline-cyclophosphamide, methotrexate, 5-fluorouracil (CMF) rather than CMF. The aim of its sub-studies reported here was to assess whether quality of life (QoL), cosmesis or chemotherapy dose intensity differed between the two CRT regimens. MATERIALS AND METHODS: The QoL sub-study used EORTC QLQ-C30, EORTC QLQ-BR23 and the Women's Health Questionnaire. Cosmesis was assessed: (i) by the treating clinician, (ii) by a validated independent consensus scoring method and (iii) from the patients' perspective by analysing four cosmesis-related QoL questions within the QLQ-BR23. Chemotherapy doses were captured from pharmacy records. The sub-studies were not formally powered; rather, the aim was that at least 300 patients (150 in each arm) were recruited and differences in QoL, cosmesis and dose intensity of chemotherapy assessed. The analysis, therefore, is exploratory in nature. RESULTS: No differences were observed in the change from baseline in QoL between the two arms assessed up to 2 years post-surgery (Global Health Status: -0.05; 95% confidence interval -2.16, 2.06; P = 0.963). No differences in cosmesis were observed (via independent and patient assessment) up to 5 years post-surgery. The percentage of patients receiving the optimal course-delivered dose intensity (≥85%) was not significantly different between the arms (synchronous 88% versus sequential 90%; P = 0.503). CONCLUSIONS: Synchronous CRT is tolerable, deliverable and significantly more effective than sequential, with no serious disadvantages identified when assessing 2-year QoL or 5-year cosmetic differences.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

From 25 Fractions to Five: How Hypofractionation has Revolutionised Adjuvant Breast Radiotherapy.

There is a sound empirical basis for hypofractionation in radiotherapy for breast cancer. This article reviews the radiobiological implications of hypofractionation in breast cancer derived from a series of clinical trials that began when 50 Gy in 25 fractions over 5 weeks was commonplace. These trials led first to 40 Gy in 15 fractions over 3 weeks and, subsequently, to 26 Gy in five fractions over 1 week being adopted as standards of care for many patients prescribed whole- or partial-breast radiotherapy after primary surgery.

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation.

INTRODUCTION: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. IPSILATERAL BREAST TUMOUR RELAPSE (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4-3.1), 1.7% (1.2-1.6) after 27 Gy and 1.4% (0.2-2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. NORMAL TISSUE EFFECTS: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. RADIOBIOLOGICAL CONSIDERATIONS: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/ß estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. CONCLUSION: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

NEAT: National Epirubicin Adjuvant Trial--toxicity, delivered dose intensity and quality of life.

The NEAT trial reported considerable benefit for ECMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil) of 28% for relapse-free survival (RFS) and 30% for overall survival (OS), when compared with classical CMF in early breast cancer. To assess tolerability, toxicity, dose intensity and quality of life (QoL) analyses were undertaken. All 2021 eligible patients had common toxicity criteria (CTC), delivered chemotherapy and supportive treatments details and long-term morbidities recorded. The QoL substudy used multiple validated measures. ECMF produced low CTC scores, although higher than CMF for nausea, vomiting, alopecia, constipation, stomatitis (P<0.001), infection (P=0.001) and fatigue (P=0.03). Supportive treatments required, however, were similar across randomised treatments. On-treatment deaths were more common with CMF (13) than ECMF(5). Optimal course-delivered dose intensity (CDDI > or =85%) was received more often by ECMF patients (83 vs 76%: P=0.0002), and was associated with better RFS (P=0.0006). QoL over 2 years was equivalent across treatments, despite minimally worse side effects for ECMF during treatment. ECMF benefit spanned all levels of toxicity, CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions. ECMF is tolerable, deliverable, and significantly more effective than CMF, with no serious long-term toxicity or QoL detriment.

Trastuzumab infusion reactions in breast cancer. Should we routinely observe after the first dose?

Trastuzumab (Herceptin) is used in neoadjuvant, adjuvant and metastatic breast cancer. Infusion reactions are a common side effect most of which are mild and easily managed, anaphylaxis occurs rarely. The summary of product characteristics recommends observation for 6 hours after the commencement of the first administration; we wanted to evaluate this practice. We assessed first administrations of trastuzumab infusions retrospectively to determine both rate and timing of reactions. Medical and nursing notes of 94 patients who had been prescribed intravenous trastuzumab in 2012 were reviewed; 2 additional patients did not have records available. Fourteen patients received palliative, 73 adjuvant and 7 neoadjuvant trastuzumab.r. Two (2%) had a reaction to trastuzumab occurring at 70 and 80 min from infusion commencement. We did not observe a reaction in the 4.5 hours after the 90 min infusion was complete. We recommend discharge with verbal and written advice immediately after uncomplicated first administration.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

The safety of intravenous chemotherapy and zidovudine when treating epidemic Kaposi's sarcoma.

Patients with epidemic Kaposi's sarcoma, who are often taking zidovudine, may be treated with cytotoxic chemotherapeutic agents. Both cytotoxic chemotherapy and zidovudine are myelotoxic and we have treated 16 patients with this combination. We report an acceptable rate of anaemia, leucopaenia, thrombocytopaenia and non-haematological side effects. This combination can be safely administered to this group of patients, although much of our experience is with the relatively non-myelotoxic chemotherapeutic agents, bleomycin and vincristine.

Methods of ovarian suppression used in the UK.

Ovarian suppression in the management of breast cancer has had a resurgence in the 1990s. In view of the development of luteinizing hormone-releasing hormone (LHRH) analogues and advances in laparoscopic surgery, we wished to determine whether more consultants are considering these methods for achieving ovarian suppression than radiotherapy. A questionnaire was designed to determine the current practice of consultants in the UK and to discover who is involved in making this decision. It was distributed via the Adjuvant Breast Cancer (ABC) trials office to consultants who enter patients into the ABC premenopausal trial. Seventy-four (72%) questionnaires were analysed. The preferred method of treatment was radiotherapy in 60%, surgery in 30% and LHRH analogues in 9%. Seventy-three per cent of consultants were using more than one technique but did not always involve the patient in the decision-making process to determine which treatment modality to use. Radiotherapy techniques used included using bony landmarks for field borders (46%), using a standard field size (20%) or using ultrasound localization (15%).

Strontium-90 for conjunctival AIDS-related Kaposi's sarcoma: the first case report.

AIDS-related Kaposi's sarcoma is often treated by local therapy for physically or cosmetically disabling symptoms. We present the first case of a bulbar conjunctival Kaposi's sarcoma lesion to be treated with a strontium-90 ophthalmic applicator. The treatment is simple, effective and well tolerated and we recommend that it should be considered for the management of superficial Kaposi's sarcoma lesions of the conjunctiva.

Para-aortic nodal irradiation for early stage testicular seminoma.

Early stage seminoma of the testis has an excellent prognosis when post-orchidectomy para-aortic and ipsilateral pelvic radiotherapy is given. However, studies on testicular lymphangiograms and the rarity of isolated pelvic nodal disease suggest that pelvic radiotherapy is not necessary, except in cases where there is the possibility of altered lymphatic drainage. We report on 27 patients with stage I and IIA seminoma treated between 1983 and 1989. Seventeen patients received radiotherapy to the para-aortic region only. There have been no pelvic recurrences. No long term complications have been encountered. We discuss the reported data which suggest that a reduced complication rate should result from the proposed field reduction. We conclude that irradiating only the para-aortic region in early stage seminoma is logical, should not increase the relapse rate and should reduce the complication rate.

Management of malignant phaeochromocytoma: a retrospective review of the use of MIBG and chemotherapy in the West Midlands.

Metastatic malignant phaeochromocytoma is a rare disorder, with no randomized and few prospective data to facilitate choice between the two main treatment modalities, chemotherapy and radiolabelled metaiodobenzylguanidine (MIBG). In the last decade the latter modality has been preferred and radiological response rates of 30% have been reported. There are fewer patients described in the literature who have received chemotherapy but one prospective trial of chemotherapy reported radiological response rates of 57%. A recent prospective trial combining the two modalities has been disappointing with only one patient completing the treatment schedule. We present six patients with malignant phaeochromocytoma or paraganglioma who received MIBG therapy. Four patients also received chemotherapy. A retrospective review of the case notes was performed. Radiological and hormonal responses were determined and the time to progression after each modality was calculated. One partial hormonal response was seen with MIBG treatment. One complete and one partial hormonal response and one partial radiological response were seen with chemotherapy. The median time to disease progression from commencement of MIBG was 12 months (range 3-44) and from commencement of chemotherapy used as first or second line treatment was 22.5 months (range 7-25). Chemotherapy may be a more active modality in this disease than previously considered. MIBG uptake may increase after a partial radiological response to chemotherapy, enabling subsequent MIBG therapy. Researchers carrying out future trials on combined therapy should consider administering chemotherapy prior to MIBG for the reasons that we outline in this article.

Alpha-interferons: impact on survival of patients with renal cell carcinoma.

We studied the effect of treatment on tumour response and survival of 76 evaluable patients with renal cell carcinoma, treated in this unit over a 12-year period. For the purpose of this study patients were classified into three groups according to the treatment they received: (a) 22-patients were evaluable for treatment with alpha-interferons; (b) 20 for treatment with immune modulation, other than interferon; (c) 34 patients received hormone treatment, chemotherapy or had no systemic treatment. Objective tumour regressions were observed only among patients who received interferon. No difference in overall survival from first diagnosis or from diagnosis of Stage IV disease could be demonstrated in these three groups. Alpha-Interferons are the first agents to induce clinically meaningful and reproducible regression of metastases in renal cell carcinoma. This treatment, however, has not been shown to have a major impact on survival.

Ultrasound localization of the ovaries for radiation-induced ovarian ablation.

The case notes and simulator films were reviewed from 70 sequential patients who received pelvic irradiation to induce an early menopause as part of their treatment for breast cancer at the Staffordshire Oncology Centre. These patients underwent ultrasound localization of the ovaries immediately prior to simulation. Altogether, 128 ovaries were plotted on a diagrammatic representation of a gynaecoid pelvis to represent their position in both craniocaudal and lateral dimensions in relation to the true bony pelvis. The craniocaudal ovarian position varied from 2.5 cm above the lower aspect of the sacroiliac joint to 2.0 cm above the symphysis pubis. Three (4.6%) right sided ovaries were within 1 cm medial to the right lateral side wall, with none lying lateral to the wall. Seventeen (26%) left sided ovaries were lying within 1 cm of the left pelvic side wall, with four of these lying outside. The limits of the pelvic fields used were from the top of the sacroiliac joint to the bottom of the symphysis pubis. Sixty-one (88%) upper borders were on or above the lower sacroiliac joint. Twenty-six (38%) and 49 (71%) fields were outside the right and left pelvic side walls respectively. This would suggest that field sizes were larger than standard; however, 87% were smaller than 150 cm(2) (assuming a 10x15-cm field as standard). Only one patient failed to respond to treatment. This was thought to be due to underdosing rather than a geographical miss. This patient was successfully retreated. The authors advocate the use of ultrasound localization prior to planning an irradiation menopause, to ensure that the ovaries are encompassed in the pelvic field, thus preventing a geographical miss and reducing field sizes.

Hyperfractionated accelerated radiotherapy for carcinoma of the oesophagus.

We report on 48 patients with carcinoma of the oesophagus treated by hyperfractionated accelerated radiotherapy. The patients, aged 46 to 93 years, were considered suitable for radiotherapy on their performance status irrespective of the presence of metastases. The radiotherapy was given three times a day over 2 weeks with a minimum of 3 h between treatments. The treatment was well tolerated acutely and to date there have been no unacceptable long-term side-effects. Dysphagia was improved in 39 (81.2%) patients. Product-limit survival was 35.7%, 18.5% and 12.3% at 1, 2 and 3 years. We conclude that this regime is feasible within the normal working day, well tolerated, effective and the shorter overall treatment duration desirable.

Salvage mastectomy after failed breast-conserving therapy for carcinoma of the breast.

The indications, technique and complications of salvage mastectomy in 25 patients with local recurrence after breast-conserving therapy for carcinoma of the breast have been reviewed. Two patients required myocutaneous flaps to repair the defect, and six patients (24%) suffered wound infection or breakdown. Subsequent local relapse occurred in a total of five patients, two of whom died with uncontrolled chest wall skin nodules.

The primary management of breast cancer: is breast conservation feasible for all patients?

A consecutive series of 411 patients with primary breast cancer treated by a consistent policy of breast conservation, regardless of tumour size, location, clinical stage or histological subtype, is reported. Actuarial 5-year survival was 84% for UICC Stage I, 73% for Stage II and 47% for Stage III/IV. The incidence of local recurrence at 5 years was 13% for Stage I, 12% for Stage II, and 26% for Stage III/IV. The probability of salvage mastectomy at 5 years was 5% for Stage I, 8% for Stage II, and 15% for Stage III/IV. Of local recurrences, 40% were managed with further breast conservation. Primary treatment with breast conservation results in satisfactory local control rates, 5-year survival and cosmesis, but the prevention, diagnosis and treatment of local recurrence within the conserved breast requires further evaluation.

Breast radiotherapy: less is more?

A 3 week schedule of whole breast radiotherapy is firmly established in the UK and is becoming more accepted internationally, especially as accelerated partial breast radiotherapy regimens become more common. It seems that a 3 week schedule is unlikely to be the lower limit of whole breast hypofractionation and the partial breast may even be adequately treated with just a single treatment. It is, however, essential that these hypotheses are rigorously tested within well-designed trials to ensure the highest quality of radiotherapy. This overview will address the rationale for hypofractionation in breast cancer, discuss past trials and outline the design of current studies.