Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

The impact and indications for Oncotype DX on adjuvant treatment recommendations when third-party funding is unavailable.

OBJECTIVES: Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. METHODS: Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. RESULTS: Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. CONCLUSION: Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

Use of palliative chemotherapy in patients aged 80 years and over with incurable cancer: experience at three Sydney cancer centres.

BACKGROUND: Octogenarians represent a growing population reviewed in medical oncology clinics, yet there is a paucity of data on how chemotherapy is tolerated in this age group. AIM: To describe the use of palliative first-line chemotherapy in patients 80 years and over and factors associated with its use. METHODS: We identified all new patients aged 80 years or older diagnosed with incurable advanced solid organ cancer and seen in one of three Sydney medical oncology outpatient clinics between January 2009 and December 2013. Patient, disease and treatment details were summarised and factors associated with chemotherapy use explored. RESULTS: Of 420 eligible patients, 100 (24%) started first-line chemotherapy. Younger age at diagnosis was the only factor associated with receiving chemotherapy (median 82.9 vs 84.1 years, P = 0.002). A total of 78% of patients had single-agent chemotherapy, and 41% received a full dose for the first cycle. During treatment, 54% experienced toxicity, necessitating dose reduction, delay or omission, and 32% were hospitalised. These events were associated with receipt of combination chemotherapy (OR 5.1; P = 0.04) and full-dose chemotherapy for cycle 1 (OR 3.5; P = 0.02). Radiological disease control was achieved in 60%. Chemotherapy was stopped because of progressive disease (48%), toxicity (37%) or completion of planned course (17%). CONCLUSION: A quarter of patients 80 years and older received first-line palliative chemotherapy. Despite most receiving a modified dose, one third were hospitalised during treatment. These findings highlight the need for careful clinical assessment and selection of older cancer patients for chemotherapy.

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

BACKGROUND: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. PATIENTS AND METHODS: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. RESULTS: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. CONCLUSION: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.

Doctor-to-doctor communication of prognosis in metastatic cancer: a review of letters from medical oncologists to referring doctors.

BACKGROUND: Shared understanding of prognosis is vital for optimal, multidisciplinary, clinical decision making. AIMS: This study aims to determine the frequency and nature of prognostic information in medical oncologists' letters to referring doctors for patients with metastatic cancer. METHODS: We reviewed all consultation letters (to June 2014) for new patients with metastatic cancer presenting to medical oncologists at Concord and Macarthur Cancer Centres between June 2012 and June 2013. We recorded the presence and nature of prognostic information in the letters, patients' characteristics and survival. Characteristics associated with inclusion of prognostic information were explored. RESULTS: We analysed 1344 letters pertaining to 272 patients with a median survival of 13 months. The median number of letters per patient was 4 (interquartile range 1-7), with 50% written by trainees. The terms 'metastatic' or 'stage IV cancer' were included in letters for 253 patients (93%), treatment was described as 'palliative' for 174 patients (64%) and the word 'incurable' was included for 93 (34%). Only 31 patients (11%) had a quantitative estimate of prognosis in any correspondence: median or average survival in 14, general time frame in 12 and, best case, typical and worst case scenarios in 5. Inclusion of quantitative prognostic information was not associated with patient age, cancer type, treatment plan, trainee authoring letter or shorter survival. CONCLUSION: Inclusion of quantitative prognostic information in written correspondence from medical oncologists regarding patients with metastatic cancer was infrequent. Encouraging oncologists to include quantitative prognostic information in their letters could improve communication between oncologists, referring doctors and patients.

Survival times of women with metastatic breast cancer starting first-line chemotherapy in routine clinical practice versus contemporary randomised trials.

BACKGROUND: Survival times of women starting first-line chemotherapy for metastatic breast cancer (MBC) in routine clinical practice were determined and compared with those from a systematic review of randomised clinical trials. METHODS: We identified women with MBC starting first-line chemotherapy from June 2003 to February 2011 and recorded their demographics, tumour and treatment characteristics, and survival times from the start of chemotherapy. Their survival distribution was summarised by the following percentiles (represented scenarios for survival): 90th (worst-case), 75th (lower-typical), 25th (upper-typical) and 10th (best-case), which were compared with the same percentiles from our systematic review of first-line chemotherapy trials. RESULTS: The 273 women had a median age of 56 years, and a median time from diagnosis of MBC of 3 months. Eastern Cooperative Oncology Group performance status was 0-1 in 80%. Tumours were hormone receptor positive in 69%, human epidermal growth factor receptor 2 (HER2)-positive in 27% and triple negative in 13%. Survival times in months in routine clinical practice (vs the systematic review) were: 90th percentile 4 (6); 75th percentile 9 (12); median 20 (22); 25th percentile 36 (36) and 10th percentile 61 (56). Independent predictors of overall survival included HER2-positive disease (hazard ratio (HR) 0.49, P = 0.0002), hormone receptor positive disease (HR 0.51, P = 0.0004), Eastern Cooperative Oncology Group performance status 0-1 (HR 0.36, P < 0.0001) and adjuvant chemotherapy (HR 1.86, P = 0.0002). CONCLUSION: Median and better survival times in routine practice were similar to those from randomised clinical trials; however, survival times worse than the median were shorter, likely reflecting patient selection in trials. Oncologists should adjust trial-based survival estimates for patients not meeting typical trial eligibility criteria.

The efficacy of oral ondansetron and dexamethasone for the prevention of acute chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy - a retrospective audit.

The optimal dose of oral ondansetron for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) resulting from moderately emetogenic chemotherapy (MEC) is unknown. This retrospective audit was conducted to determine the efficacy of 8 mg oral ondansetron plus 8 mg oral dexamethasone as pre-chemotherapy anti-emetic regimen for patients receiving MEC. The efficacy outcomes analysed were the proportion of patients with no acute vomiting, proportion of patients with no acute nausea and the incidence of grade 3 or 4 CINV. A total of 81 patients were identified. The most frequent chemotherapy regimens received in the study population were anthracycline- (48%) and carboplatin-based (28%). No acute vomiting and nausea rates in the study population were 75% and 44% respectively. The incidence of grade 3 CINV was 1%. Patients who received anthracycline-based regimens had a significantly higher incidence of acute emesis (P= 0.001) and nausea (P < 0.0001) when compared with patients who received non-anthracycline-based regimens. In this study, the use of 8 mg oral ondansetron plus 8 mg oral dexamethasone achieved control of acute emesis in 75% of all patients receiving MEC which is comparable to previously reported rates of 70-80%. The benefits of using oral pre-chemotherapy anti-emetics include reduction in the costs of drugs and nursing administration time.

A short outpatient hydration schedule for cisplatin administration.

BACKGROUND: Cisplatin remains a principal chemotherapy agent in the treatment of many solid tumours. However because of its nephrotoxicity, inpatient hydration schedules have been utilized to ensure safe administration. In May 1995, due to significant load on in-patient bed availability, the Medical Oncology Department of the Cancer Therapy Centre, Liverpool Hospital, developed a short, intravenous fluid hydration protocol to be used on an out-patient setting. METHODS: Following an initial pilot program of the abbreviated hydration regimen, a retrospective study of all adult in-patients and out-patients who received cisplatin (60-100 mg/m2) from May 1995 to August 1998 was conducted. Biochemistry was performed prior to the start of chemotherapy, and a repeat serum creatinine level was taken immediately prior to each subsequent cycle of chemotherapy, unless clinically indicated at an earlier time. The in-patient hydration protocol was 6000 ml of normal saline with 60 mmol/L KCL, and 30 mmol/L MgSO4 over 24 to 28 hours, and the out-patient hydration was 4000 ml of normal saline over 6 hours. RESULTS: A total of 145 patients were included, 57 in-patient (39%) and 88 out-patients (61%), 95 males, and 50 females. The mean age was 56 years. The maximum mean percentage change in creatinine from baseline for all cycles of chemotherapy for in-patients was 32.5% ranging from -7% to 288% (95% CI=19.9-45.11), and for outpatients 19.9% ranging from -20% to 154% (95% CI=13.47-26.39). Although the mean increase was higher in the in-patient group by 12.6%, it was not statistically significant (p=0.079). CONCLUSION: In patient's eligible for cis-platinum therapy on the basis of good performance status and normal renal function, this agent can be safely administered in the out-patient setting with an abbreviated duration, moderate volume intravenous hydration regimen.

Assessing outcomes of cancer care: lessons to be learned from a retrospective review of the management of small cell lung cancer at the Cancer Therapy Centre, Liverpool Hospital, January 1996-July 2000.

The purpose of the present paper was to review the outcomes of care of small cell lung cancer (SCLC) at one Sydney teaching hospital. A retrospective cohort study was carried out of patients with SCLC seen between January 1996 and July 2000. The main outcomes were relapse-free and overall survival. Secondary outcomes of interest were the uniformity of staging investigations, initial treatment, use of prophylactic cranial irradiation (PCI), patterns of relapse and treatment received following relapse. One hundred and three patients with SCLC were treated at the Liverpool Hospital Cancer Therapy Centre during this period. There were 58 men (56%) and 45 women (44%). Forty-two patients (41%) had limited stage disease (LD) and 61 (59%) had extensive stage disease (ED). There was considerable variation in staging investigations. There was little variation in systemic treatment of SCLC. Only 32 of 42 patients with limited stage SCLC were candidates for thoracic radiotherapy and only seven patients received PCI. Median relapse-free survival was 11.2 months (95% confidence interval (CI): 7.7-14.8) for patients with LD and 6 months (95%CI: 4.4-7.5) for ED. Median overall survival was 15.1 months (95%CI: 11-19.1) for patients with LD and 8.9 months (95%CI: 7.5-10.2) for ED. Some health outcomes similar to that reported in clinical trials can be achieved in clinical practice. Measuring health outcomes is an important process of maintaining quality of care.

Primary peritoneal carcinoma: a treatable subset of patients with adenocarcinoma of unknown primary.

The syndrome of adenocarcinoma of unknown primary (ACUP) is a frequent problem in both medical and surgical practice. The prognosis is poor, the median lifespan being 4 months. In general, multiple invasive procedures aimed at determining the primary tumour are not warranted due to the low frequency of detecting a tumour for which adequate treatment exists. In this paper we wish to highlight a subset of female patients presenting with malignant ascites and no evidence of a pelvic mass, who on laparotomy were found to have primary peritoneal papillary serous adenocarcinoma. These tumours must be regarded as a potentially treatable subset of patients with ACUP in view of their frequent response to chemotherapy and relatively good prognosis.