Robin Stuart-Harris

Prediction of life-expectancy in hospice patients: identification of novel prognostic factors.

The prediction of life-expectancy in terminally ill patients is important both for medical and social reasons but is widely recognized as being inaccurate. In this study we prospectively collected data items which we proposed might influence survival on 148 consecutive patients at first admission to one of two hospices. Of the 19 parameters collected, four were associated with a significantly shortened survival. These were low performance status (PS), requirement for admission at first referral to the palliative care service, elevated serum bilirubin, and hypotension. Factors previously identified as predictive of shortened survival such as hyponatraemia, weight loss, confusion and tumour type were not confirmed as statistically significant independent variables. We plan to collect these data items on future patients in order to test the validity of these results.

What survival benefits do premenopausal patients with early breast cancer need to make endocrine therapy worthwhile

BACKGROUND Adjuvant endocrine therapies such as tamoxifen, goserelin, and oophorectomy improve survival for premenopausal women diagnosed with early-stage breast cancer. However, these treatments often result in menopausal symptoms, sexual dysfunction, permanent infertility, or the need to delay pregnancy. We aimed to quantify the survival gains that premenopausal patients with early-stage breast cancer require to justify the side-effects and inconvenience of adjuvant endocrine treatments. METHODS Participants consisted of 102 women who had been diagnosed with early-stage (stage I-II) breast cancer 6-60 months previously, who were aged 40 years or younger at diagnosis, and who had been treated for a minimum of 3 months with endocrine therapy (67 with tamoxifen alone, seven with goserelin alone, and 28 with tamoxifen and goserelin or oophorectomy). 76 patients also received chemotherapy, and 75 received radiotherapy. Participants attended a face-to-face patient-preference interview, in which they were presented with four hypothetical clinical scenarios that were used to quantify the gains in survival rate and life expectancy that women judged necessary to make their endocrine therapy worthwhile. They also completed a questionnaire on standard psychological measures. FINDINGS About half of participants thought that adjuvant endocrine therapy was worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85%, and for a gain in life expectancy of 3 months from a baseline of 5 years and of 6 months for a baseline of 15 years. Women who had had more severe endocrine side-effects required larger gains to make endocrine therapy worthwhile (univariate p=0.02, multivariate p=0.04). INTERPRETATION Modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer. Knowing and incorporating what women think should enhance shared decision-making.

Etoposide, carboplatin, cyclophosphamide and vincristine in previously untreated patients with small-cell lung cancer

SummaryThe efficacy and toxicity of 120 mg/m2 etoposide and 100 mg/m2 carboplatin given i.v. daily x 3 together with 750 mg/m2 cyclophosphamide and 14 mg/m2 vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limitedstage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring <1.0×109 WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of <50×109 platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, welltolerated program for previously untreated patients with small-cell lung cancer.

Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37–78), were enrolled. A median of six cycles (range, 1–8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6–9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9–21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.

Isolated central nervous system relapse of non-seminomatous germ cell tumour of the testis : A case report and review of the literature

Isolated central nervous system (CNS) relapse of non-seminomatous germ cell tumour (NSGCT) of the testis has been reported in only 12 patients previously. We report a patient with an isolated CNS relapse of NSGCT, following a prior systemic relapse. From a review of previous cases, isolated CNS relapse appears to be more common in patients with embryonal cell histology (alone or mixed with other elements) and occurred after a median of 8.5 months following initial presentation. Long-term survival appears possible using multi-modal treatment with whole-brain radiotherapy, surgery and/or chemotherapy. However, the optimal treatment of isolated CNS relapse remains undefined.

Rational use of trastuzumab in metastatic and locally advanced breast cancer: Implications of recent research

The management of HER2-positive metastatic breast cancer, a disease renowned for its aggressive natural history, has been revolutionized by the introduction of trastuzumab. Indeed, outcomes for patients with HER2-positive advanced breast cancer are now equivalent to, if not better than, those of their HER2-negative counterparts. Since the pivotal registration trial, a wealth of new clinical data has emerged regarding the use of trastuzumab in a variety of clinical contexts - adding to the evidence but also highlighting areas of uncertainly and debate. These include the optimal partner chemotherapy(ies) to trastuzumab; the effectiveness of combining trastuzumab with endocrine therapy; the benefits of continuing trastuzumab after progression on a trastuzumab-containing regimen; and the role of trastuzumab in locally advanced and inflammatory breast cancer. In this paper we review major clinical trials addressing these questions, clinical recommendations that can be made as a result, and the strength of evidence that supports them. Finally, we identify areas of ongoing uncertainty, and propose recommendations for future research in this field.

The prognostic significance of single hormone receptor positive metastatic breast cancer: an analysis of three randomised phase III trials of aromatase inhibitors.

We analysed the outcomes of women with metastatic breast cancer (MBC) from three randomised phase III trials of aromatase inhibitors according to oestrogen receptor (ER) and progesterone receptor (PgR) status. Both receptors were analysed in 1010 of the 1870 women (54%), including 31 that were ER-/PgR-, which were excluded. Of the remaining 979, 726 (74%) were ER+/PgR+ but 253 were single hormone receptor positive (213 ER+/PgR-, 40 ER-/PgR+). Although there were no differences in clinical benefit or time to progression, the median overall survival of women with ER+/PgR+ tumours was significantly longer than those with single HR positive tumours (800 versus 600 days, p=0.01). In women with ER+ tumours, the median overall survival of those with tumours that were also PgR+ was significantly longer than those that were PgR- (800 versus 625 days, p=0.02). The PgR status is an important prognostic factor for survival in MBC.

Prospective evaluation of cognitive function in patients with early breast cancer receiving adjuvant chemotherapy

Aim:  To assess cognitive function prospectively in women with early breast cancer before, during and after the administration of adjuvant chemotherapy.

Adjuvant chemotherapy for early breast cancer: Is cyclophosphamide, methotrexate and 5-fluorouracil still the standard?

Background:  Oral cyclophosphamide, methotrexate and 5‐fluorouracil (CMF) was one of the first combination chemotherapy regimens used as adjuvant chemotherapy for early breast cancer. The value of CMF in reducing both recurrence and mortality from early breast cancer has been firmly established by the overviews of randomized trials of polychemotherapy, which have used CMF as their standard. The purpose of this review is to review the usage of oral CMF and the variants of CMF and to compare both the activity and side‐effects of CMF with more modern adjuvant chemotherapy regimens.