Fear of cancer recurrence in young women with a history of early-stage breast cancer: a cross-sectional study of prevalence and association with health behaviours.

PURPOSE: Fear of cancer recurrence (FCR) is common and associated with younger age. This study aimed to explore the prevalence and correlates of FCR amongst younger survivors of early breast cancer. SUBJECTS: A total of 218 women aged 18-45 were diagnosed with stage 0-2 breast cancer at least 1 year earlier. METHODS: The participants completed a web-based survey including a validated measure of FCR and items exploring medical surveillance practices and health care use. RESULTS: A total of 70% of participants reported clinical levels of FCR. Higher FCR was associated with higher frequency of unscheduled visits to the GP, higher frequency of breast self-examination and other forms of self-examination for cancer, not having mammograms or ultrasounds or other forms of cancer screening in the past year, more complementary therapy use and the use of counselling and support groups. CONCLUSIONS: Young women with breast cancer are particularly vulnerable to FCR. The present study provides preliminary evidence that FCR is associated with higher health costs and lower surveillance rates which may compromise health outcomes. Routine screening for FCR in follow-up care is recommended.

Clinical characteristics and outcomes of bilateral breast cancer in an Australian cohort.

PURPOSE: Uncertainty remains about the impact of bilateral breast cancer. Characteristics and outcomes of unilateral and bilateral breast cancer were compared within an Australian multi-institutional cohort. METHODS: Demographic, tumour and treatment characteristics were compared among unilateral (n = 2336) and bilateral cases (52 synchronous, 35 metachronous) using descriptive analyses. Disease-specific outcomes were investigated using Cox regression modelling to adjust for prognostic and treatment factors. RESULTS: Factors associated with increased risk of bilateral breast cancer included lobular histology (p = 0.046), family history (p = 0.025) and metropolitan residence (p = 0.006). Mastectomy was more common for bilateral cases (p = 0.001) while radiotherapy was less common (p = 0.015). Index metachronous cases were less likely to receive hormonal therapy (p = 0.001). Five-year survivals for metachronous, synchronous and unilateral cases were 79%, 88% and 94%, respectively. Poorer outcomes remained after adjusting for prognostic factors [HR = 2.26, 1.21-4.21]. CONCLUSION: Our results confirm international findings indicating worse outcomes from bilateral compared with unilateral breast cancer.

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.

Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients.

We have performed a systematic review and meta-analysis of proliferation markers (Ki-67, mitotic index (MI), proliferating cell nuclear antigen (PCNA) and thymidine or bromodeoxyuridine labelling index (LI)) with respect to survival in early breast cancer. Eighty-five studies involving 32,825 patients were analysed. Ki-67 (43 studies, 15,790 patients), MI (20 studies, 7021 patients), and LI (11 studies, 7337 patients) were associated with significantly shorter overall and disease free survival, using results from univariate and multivariate analyses from the individual studies. PCNA (11 studies, 2677 patients) was associated with shorter overall survival by multivariate analysis only, because of lack of data. There was some evidence for publication bias, but all markers remained significant after allowing for this. Ki-67, MI, PCNA and LI are associated with worse survival outcomes in early breast cancer. However, whether these proliferation markers provide additional prognostic information to commonly used prognostic indices remains unclear.

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/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) 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.

Phase II trial of weekly docetaxel for patients with relapsed ovarian cancer who have previously received paclitaxel--ANZGOG 02-01.

OBJECTIVE: To determine the response rate of weekly docetaxel in women with relapsed epithelial ovarian cancer previously treated with paclitaxel and at least one line of platinum-based chemotherapy. METHODS: In this multi-center phase II trial, 37 patients with relapsed disease were enrolled and treated with weekly docetaxel at 35 mg/m for 5 out of 6 consecutive weeks. Two patient cohorts were considered, those who progressed or relapsed within 4 months (N=7) or at greater than 4 months (N=30) from the time of completing their last course of paclitaxel. RESULTS: Patients in both cohorts received a median of 2 cycles of treatment (range; 1-4). In evaluable patients, the combined overall response rate, using both CA125 and RECIST response criteria was 18.9% (7/37; 95% CI; 10-34%). The combined overall progression-free survival was 3.1 months (95% CI; 2.5-3.8), and the combined overall survival was 12.3 months (95% CI; 8.2-16.4). Treatment was generally well tolerated with the only grade 4 toxicity being skin toxicity (3%). The most common grade 3 toxicities were fatigue (14%) and watery eyes (8%) with grade 3 neutropenia observed in only 5% of patients. CONCLUSION: Weekly docetaxel is well tolerated and has activity in patients with relapsed ovarian cancer previously treated with platinum and paclitaxel.

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.

The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine.

AIMS: To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c. i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. METHODS: Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. RESULTS: After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l- 1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P = 0. 09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P = 0.03 and P< 0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log-transformed AUC ratio 0.78, 90% CI 0.66-0.93), M6G (0.72, 90% CI 0.63-0.82), or M3G (0.65, 90% CI 0.54-0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. CONCLUSIONS: Although bioequivalence was demonstrated between the s. c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.

Continuous infusion of vincristine, ifosfamide and epirubicin over 6 weeks in treatment-resistant advanced breast cancer.

28 patients with recurrent advanced breast cancer were treated with a salvage regimen consisting of vincristine, epirubicin and ifosfamide/mesna (VIE). All patients had poor prognostic characteristics defined as relapse within 12 months of chemotherapy or as relapse within a radiotherapy field. Chemotherapy was infused continuously through a central venous catheter using a portable pump. Ifosfamide (3 g/m2) mixed with mesna (3 g/m2) was infused for 7 days followed by epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2) over a further seven days and alternated for a total of 6 weeks. 9 of the 28 patients (32%) responded to VIE (six partial and three complete responses). This included 6 of the 18 patients (33%) who had previously received doxorubicin or mitoxantrone, 6 of the 17 patients (35%) who had an inoperable in-field relapse after radiotherapy for locally advanced cancer, and 5 of the 21 patients (24%) relapsing within 6 months of previous chemotherapy. Median duration of response and overall survival were 3.7 and 6.9 months, respectively. Myelotoxicity was mild. One patient had neutropenic sepsis, 3 patients ahd grade 3 nausea and vomiting and one patient developed paralytic ileus attributed to vincristine. Central venous catheter complications occurred in 12 of 33 catheters requiring removal in 6. Continuous infusional chemotherapy using vincristine, epirubicin and ifosfamide achieves a 32% overall response rate in treatment-resistant advanced breast cancer, and is associated with minimal toxicity and a short treatment period. VIE may be a suitable alternative to conventional chemotherapy.

The Sacred Heart Hospice: an Australian centre for palliative medicine.

The Sacred Heart Hospice, Sydney, was founded in 1890 and is the largest inpatient palliative-care facility in Australia. Patients with advanced cancer form the predominant patient group, although patients with HIV/AIDS account for approximately 20% of admissions. A community-outreach service, established in 1983, cares for more patients at home than in the Hospice. Recently the Hospice has participated in a number of clinical trials and intends to become a regional centre for palliative-care research, education and training.

The clinical use of ondansetron. New South Wales Therapeutic Assessment Group.

OBJECTIVE: To establish guidelines for use of ondansetron. DATA SOURCES: MEDLINE computer search (to July 1993) and information from the manufacturer. DATA EXTRACTION: We circulated a position paper based on our literature review for comment by clinicians and directors of pharmacy in major teaching hospitals in New South Wales who had an interest in ondansetron. DATA SYNTHESIS: Ondansetron is effective in the control of nausea and vomiting occurring 24-48 hours after highly emetogenic chemotherapy and after radiotherapy. There are no data to support its use in delayed emesis. Combination with dexamethasone may improve emetic control. The most commonly reported adverse effects are headache and constipation. Optimal dose, frequency of dosing and route of administration have not been established. The cost for each inpatient treated successfully is about 3% more than conventional antiemetic therapy. CONCLUSIONS: Ondansetron shows clinical benefit in the management of acute nausea and vomiting in patients receiving highly emetogenic chemotherapy, those who have responded poorly to other antiemetics after moderately emetogenic chemotherapy, those who have intolerable side effects with conventional antiemetic agents and those receiving radiotherapy to the upper abdomen. It is also marketed for the prevention and treatment of postoperative nausea and vomiting.

Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hematology and oncology wards of four teaching hospitals. PATIENTS: 218 patients with cancer who had fever (temperature > 38.2 degrees C) and neutropenia (neutrophil count < 1.0 x 10(9)/L) after chemotherapy. INTERVENTION: Patients were randomly assigned to receive filgrastim (12 micrograms/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 x 10(9)/L and until 4 days without fever (temperature < 37.5 degrees C) had elapsed. MEASUREMENTS: Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics. RESULTS: Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of < 0.5 x 10(9)/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (> 11 days, 4th quartile) by half (relative risk, 2.1 [95% CI, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x 10(9)/L. CONCLUSIONS: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.

A phase II study of carboplatin and cisplatin in advanced ovarian cancer.

In view of the single agent activity of both cisplatin and carboplatin in epithelial ovarian cancer, and their different toxicity profiles, we carried out a phase II study of low dose cisplatin (50 mg/m2) in combination with moderate dose carboplatin (300 mg/m2) in patients with advanced ovarian cancer. Fourteen patients, all of whom had bulky disease and over half of whom had Stage IV disease, were eligible for assessment of response and toxicity. An overall response rate of 71% was demonstrated (57% complete response, 14% partial response), which is at least equivalent to other regimens used in first line treatment of ovarian cancer. Toxicities encountered were nausea/vomiting and myelosuppression, however no serious renal neuro or ototoxicity was observed and the regimen does not cause significant alopecia. This combination may be a practical alternative to regimens which use high dose cisplatin to achieve similar efficacy.

The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group.

PURPOSE: In an effort to maintain the excellent long-term results achieved with combination chemotherapy for good-prognosis germ cell carcinoma, but to reduce the toxicities encountered, a randomized trial was conducted comparing cisplatin and vinblastine with or without bleomycin. PATIENTS AND METHODS: Two hundred eighteen assessable patients with a good prognosis were randomized to receive induction chemotherapy with cisplatin 100 mg/m2 intravenously (IV) day 1 and vinblastine 6 mg/m2 IV days 1 and 2 every 3 weeks (PV) with or without bleomycin 30 mg intramuscularly (IM) weekly (PVB) for a maximum of 12 weeks. Once maximum response was achieved, patients with a complete remission (CR) received two courses of consolidation chemotherapy, while those with residual abnormalities and normal tumor markers underwent surgical resection whenever possible. RESULTS: Toxicities encountered in this study were clearly greater for those patients who received bleomycin, with significantly more leukopenia, thrombocytopenia, anemia, alopecia, and renal and pulmonary toxicities. The proportion of patients who achieved CR and had no evidence of disease (resection of all viable malignancy) was 89% for PV and 94% for PVB (P = .29). After a minimum of 4 years of follow-up, relapses have occurred in 7% of patients who received PV and 5% who received PVB. A total of five patients on each therapy arm were successfully treated with further salvage chemotherapy and surgery. Thus, deaths from progressive malignancy have occurred in 15% of patients on PV and 5% on PVB (P = .02), a rate that was partly offset by the higher proportion of toxic deaths with PVB (P = .06). CONCLUSION: Despite the toxicities encountered with bleomycin in cisplatin-based combination chemotherapy for these patients, complete deletion of this drug compromises therapeutic efficacy.

Ifosfamide combination regimens for soft-tissue sarcoma.

Two trials using ifosfamide-based combination chemotherapy for advanced soft-tissue sarcoma have been completed. In the first study, 50 evaluable patients received ifosfamide (5 g/m2) with mesna (5 g/m2) and doxorubicin (40 or 60 mg/m2) intravenously (i.v.) every 3 weeks. In all, 11 patients (22%) achieved an objective response [3 complete responses (CRs) and 8 partial responses (PRs)]. Toxicities included leukopenia, febrile neutropenia, nausea and vomiting, and alopecia. The overall median survival was 12 months. In the second study, 51 evaluable patients received ifosfamide (3 g/m2) with mesna (3 g/m2), both being given i.v. on day 1, together with etoposide (100 mg/m2) infused i.v. daily for 3 days. Six patients (12%) achieved objective responses (1 CR, 5 PRs). Toxicities included leukopenia, nausea and vomiting, and alopecia. The overall median survival was 7.4 months. Neither of these combination regimens appears to be more effective in advanced soft-tissue sarcoma than single-agent therapy with either ifosfamide or doxorubicin. If the results of chemotherapy in the management of these tumors are to be improved a new approach to therapy is clearly required.

Hypercalcaemia in small cell lung cancer: report of a case associated with parathyroid hormone-related protein (PTHrP).

Although hypercalcaemia is frequently associated with malignancy, it is very rare in small cell lung cancer despite the high incidence of lytic bone metastases. We report a patient with extensive small cell cancer who presented with hypercalcaemia. Investigations suggested parathyroid hormone (PTH) receptor stimulation, although the serum PTH level was not elevated. PTH related protein (PTHrP) was localised in a biopsy specimen from the tumour. Although hypercalcaemia is rare in small cell lung cancer, when hypercalcaemia does occur, PTHrP may be a causal factor.

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.