Platinum chemotherapy for early triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of recurrence. In early TNBC, platinum chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated. METHODS: Randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. RESULTS: From 3972 records, we included 20 published studies. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; adjuvant: HR 0.69, 95% CI 0.54 to 0.88) and OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59). There were no differences seen in examined subgroups. Platinum chemotherapy was associated with reduced dose intensity and increased haematological toxicity. CONCLUSIONS: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. These findings support the use of platinum-based chemotherapy for people with early TNBC.

Platinum-based chemotherapy for early triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of the cancer returning. In early TNBC, platinum-based chemotherapy has been shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated and recommendations to include platinum chemotherapy are not consistent in international guidelines. OBJECTIVES: To evaluate the benefits and harms of platinum-based chemotherapy as adjuvant and neoadjuvant treatment in people with early triple-negative breast cancer. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 4 April 2022. SELECTION CRITERIA: We included randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were disease-free survival (DFS) and overall survival (OS). Our secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life. Prespecified subgroups included BRCA mutation status, homologous recombination deficiency (HRD) status, frequency of chemotherapy, type of platinum agent used, and the presence or absence of anthracycline chemotherapy. We assessed risk of bias using Cochrane's RoB 1 tool and certainty of evidence using the GRADE approach. MAIN RESULTS: From 3972 records, we included 20 published studies involving 21 treatment comparisons, and 25 ongoing studies. For most domains, risk of bias was low across studies. There were 16 neoadjuvant chemotherapy studies (one of which combined neoadjuvant and adjuvant therapy) and four adjuvant chemotherapy trials. Most studies used carboplatin (17 studies) followed by cisplatin (two), and lobaplatin (one). Eight studies had an anthracycline-free intervention arm, five of which had a carboplatin-taxane intervention compared to an anthracycline-taxane control. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS in neoadjuvant and adjuvant settings (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; 7 studies, 8 treatment comparisons, 1966 participants; high-certainty evidence; adjuvant: HR 0.69, 95% CI 0.54 to 0.88; 4 studies, 1256 participants; high-certainty evidence). Platinum chemotherapy in the regimen improved OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; 7 studies, 8 treatment comparisons, 1973 participants; high-certainty evidence; adjuvant: 0.70, 95% CI 0.50 to 0.96; 4 studies, 1256 participants; high-certainty evidence). Median follow-up for survival outcomes ranged from 36 to 97.6 months. Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59; 15 studies, 16 treatment comparisons, 3083 participants; high-certainty evidence). Subgroup analyses showed no evidence of differences in DFS according to BRCA mutation status, HRD status, lymph node status, or whether the intervention arm contained anthracycline chemotherapy or not. Platinum chemotherapy was associated with reduced dose intensity, with participants more likely to require chemotherapy delays (RR 2.23, 95% CI 1.70 to 2.94; 4 studies, 5 treatment comparisons, 1053 participants; moderate-certainty evidence), dose reductions (RR 1.77, 95% CI 1.56 to 2.02; 7 studies, 8 treatment comparisons, 2055 participants; moderate-certainty evidence) and early cessation of treatment (RR 1.20, 95% CI 1.04 to 1.38; 16 studies, 17 treatment comparisons, 4178 participants; moderate-certainty evidence). Increased haematological toxicity occurred in the platinum group who were more likely to experience grade III/IV neutropenia (RR 1.53, 95% CI 1.43 to 1.63; 19 studies, 20 treatment comparisons, 4849 participants; moderate-certainty evidence), anaemia (RR 8.20, 95% CI 5.66 to 11.89; 18 studies, 19 treatment comparisons, 4757 participants; moderate-certainty evidence) and thrombocytopenia (RR 7.59, 95% CI 5.10 to 11.29; 18 studies, 19 treatment comparisons, 4731 participants; moderate-certainty evidence). There was no evidence of a difference between chemotherapy groups in febrile neutropenia (RR 1.16, 95% CI 0.89 to 1.49; 11 studies, 3771 participants; moderate-certainty evidence). Renal impairment was very rare (0.4%, 2 events in 463 participants; note 3 studies reported 0 events in both arms; 4 studies; high-certainty evidence). Treatment-related death was very rare (0.2%, 7 events in 3176 participants and similar across treatment groups; RR 0.58, 95% 0.14 to 2.33; 10 studies, 11 treatment comparisons; note 8 studies reported treatment-related deaths but recorded 0 events in both groups. Thus, the RR and CIs were calculated from 3 studies rather than 11; 3176 participants; high-certainty evidence). Five studies collected quality of life data but did not report them. AUTHORS' CONCLUSIONS: Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity, though serious adverse events including neuropathy, febrile neutropenia or treatment-related death were not increased. These findings support the use of platinum-based chemotherapy for people with early TNBC. The optimal dose and regimen are not defined by this analysis, but there is a suggestion that similar relative benefits result from the addition of carboplatin to either anthracycline-free regimens or those containing anthracycline agents.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

PURPOSE: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. METHODS: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. RESULTS: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. CONCLUSION: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

"Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials.

Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor-negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.

Combination versus sequential single agent chemotherapy for metastatic breast cancer.

BACKGROUND: Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time. OBJECTIVES: To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012). SELECTION CRITERIA: Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available. MAIN RESULTS: Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome. AUTHORS' CONCLUSIONS: Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Identifying and prioritising gaps in colorectal cancer trials research in Australia.

OBJECTIVES: To identify gaps in colorectal cancer clinical trials research in Australia and to suggest and prioritise trials to fill those gaps. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of colorectal cancer trial activity from 1 January 2005 to 1 July 2011 in Australia and internationally, followed by a consensus meeting of consumers, health care professionals, researchers and funding agencies. MAIN OUTCOME MEASURES: Proportion of Phase III and randomised clinical trials in the areas of prevention, screening, surgery, adjuvant therapy, advanced disease and behavioural interventions, and priority areas of research identified by participants at the consensus meeting. RESULTS: The registry search identified 76 colorectal cancer clinical trials (all phases) registered in Australia from 1 January 2005 to 1 July 2011, of which 51 were Phase III or randomised, and 323 Phase III and randomised trials registered worldwide. In Australia, most trials were in advanced colorectal cancer (32), screening (10), and behavioural interventions (9). Worldwide, most Phase III or randomised trials were in advanced disease (94, 29.1%), surgery (64, 19.8%), behavioural interventions (38, 11.8%), and screening (30, 9.3%). At the consensus meeting, all participant groups emphasised the need for research in secondary prevention, screening, individualised treatments and follow-up care after treatment for colorectal cancer. CONCLUSIONS: There is a mismatch between the high proportion of registered trials in advanced colorectal cancer and the areas of priority identified. The development of specific trials in these priority areas depends on the availability of funding and the existence of plausible interventions likely to improve patient outcomes.

Pulmonary metastasectomy for bone and soft tissue sarcoma in Australia: 114 patients from 1978 to 2008.

AIMS: The aim of this study is to analyze the prognostic factors for overall and relapse-free survival that may help select patients for pulmonary metastasectomy and inform their prognosis. METHODS: From 1978 to 2008 130 patients underwent pulmonary metastasectomy for bone (osteosarcoma, chondrosarcoma and Ewing's sarcoma) and soft tissue sarcomas. Outcome measures analyzed were time to death and relapse and Cox regression models analyzed the association of prognostic factors. RESULTS: In total 114 patients were analyzed. The 5-year post-metastasectomy overall survival rate was 43%. The 5-year relapse-free survival rate was 19%. In the multivariate analysis, an incomplete surgical resection (P = 0.02) was associated with an increased risk of death. There was weak evidence that a diameter of the largest resected metastasis ≥ 1.8 cm (P = 0.07) and a disease-free interval of ≤ 18 months (P = 0.08) were associated with an increased risk of death. CONCLUSION: Poor prognostic factors for overall survival after a pulmonary metastasectomy are an incomplete surgical resection, a large diameter of the biggest resected metastasis and a short disease-free interval. The role of perioperative chemotherapy is uncertain.

Consumer input into research: the Australian Cancer Trials website.

BACKGROUND: The Australian Cancer Trials website (ACTO) was publicly launched in 2010 to help people search for cancer clinical trials recruiting in Australia, provide information about clinical trials and assist with doctor-patient communication about trials. We describe consumer involvement in the design and development of ACTO and report our preliminary patient evaluation of the website. METHODS: Consumers, led by Cancer Voices NSW, provided the impetus to develop the website. Consumer representative groups were consulted by the research team during the design and development of ACTO which combines a search engine, trial details, general information about trial participation and question prompt lists. Website use was analysed. A patient evaluation questionnaire was completed at one hospital, one week after exposure to the website. RESULTS: ACTO's main features and content reflect consumer input. In February 2011, it covered 1, 042 cancer trials. Since ACTO's public launch in November 2010, until the end of February 2011, the website has had 2, 549 new visits and generated 17, 833 page views. In a sub-study of 47 patient users, 89% found the website helpful for learning about clinical trials and all respondents thought patients should have access to ACTO. CONCLUSIONS: The development of ACTO is an example of consumers working with doctors, researchers and policy makers to improve the information available to people whose lives are affected by cancer and to help them participate in their treatment decisions, including consideration of clinical trial enrolment. Consumer input has ensured that the website is informative, targets consumer priorities and is user-friendly. ACTO serves as a model for other health conditions.

Landscape of cancer clinical trials in Australia: using trial registries to guide future research.

OBJECTIVE: To quantify and describe current cancer clinical trial activity in Australia and help guide future trials research using trial registries. DESIGN AND SETTING: Data from cancer trials recruiting in Australia at 31 March 2009 were extracted from the Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov. A regression model was used to identify factors associated with industry sponsorship. MAIN OUTCOME MEASURES: The proportion of cancer trials compared with estimated burden of disease for each cancer. RESULTS: There were 368 interventional cancer trials open to recruitment. The most-researched cancer was breast cancer, accounting for 17% of trials. Only 7% of trials were in lung cancer, yet lung cancer is responsible for the greatest burden of disease. Industry was the primary sponsor in 43% of trials. Drug treatments were tested in most trials (69%). Trials were more likely to be industry sponsored if they tested systemic rather than local treatments (OR, 16.71; 95% CI, 4.70-59.43), included patients with advanced rather than early disease (OR, 3.76; 95% CI, 1.78-7.94) and used random rather than non-random allocation (OR, 1.78; 95% CI, 1.06-3.00). CONCLUSION: There is variation in the number of trials according to cancer site, with some cancers being underrepresented relative to their burden of disease. Industry sponsorship is more likely for trials that investigate systemic therapy, recruit patients with advanced disease and are randomised.

Factors associated with Australian and New Zealand oncologists' future work preferences.

AIM: To understand the factors associated with oncologists' work preferences to help future workforce planning. METHODS: In May 2008 a questionnaire was e-mailed to members of the Medical Oncology Group of Australia, Fellowship of Radiation Oncologists and the New Zealand Association of Cancer Specialists. Univariate and multivariate analysis were used to determine if gender, age, specialist status or specialty were associated with the intention to work full time or part time or consider weekend or evening work, and with the level of satisfaction with current working hours. RESULTS: In total, 205 medical and radiation oncologists and trainees responded. Overall 77 (38%) oncologists intended to work part time. There was strong evidence (P<0.0001) that women were more likely than men to want to work part time (OR 4.18, 95% CI, 2.12-8.22). Overall 52% of oncologists were not prepared to work on weekends. Women were less willing to consider working on weekends than men (P=0.02, OR 0.48, 95% CI 0.26-0.89). A total of 58% of oncologists felt they were working more than their ideal working hours. There was evidence (P<0.0001) that this was independently associated with oncology specialty; medical oncologists had twice the odds of feeling dissatisfied with their working hours compared with radiation oncologists (OR 2.18, 95% CI 1.20-3.94). CONCLUSION: Female gender was the most important factor associated with wanting to work part time. This should be considered when planning the oncology workforce, particularly because an increasing number of oncologists are women.

Recurrent ovarian cancer: treatment with pegylated liposomal doxorubicin; a Westmead Cancer Care Centre experience.

AIM: To describe the overall survival, progression-free survival, response rate and toxicity of pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer. METHODS: A retrospective study of 45 patients with recurrent or progressive ovarian cancer was conducted at the Westmead Cancer Care Centre. Patients received PLD at a starting dose of 30-50 mg/m(2) every 4 weeks. RESULTS: A total of 43 patients were included for analysis. The starting dose was 40 mg/m(2) in 67% of cases, and 21 % had a dose increase. A median of 2 cycles (mean 3, range 1-7) was given. All patients were assessable for response and 77% stopped treatment due to progressive disease. The overall response rate to PLD assessed by CA-125 criteria was 14 percent (six of 43 patients). Five patients (12 percent) were from the potentially platinum-sensitive group and one (2 percent) was from the platinum-resistant group. The overall median progression-free survival was 52 days (2 months), which was greater in the platinum-sensitive than in the platinum-resistant group (4.4 months vs 1.7 months, respectively, P = 0.030). The median overall survival was 296 days (10.6 months) with a trend for this to be longer in the platinum-sensitive than in the platinum-resistant group (13 vs 9 months, P = 0.393). Overall 25 percent of patients had grade 2 or 3 toxicity. CONCLUSION: The benefit of PLD in platinum-resistant recurrent ovarian cancer is small and the treatment has considerable toxicity. These data support the need to establish whether chemotherapy in this setting has any favorable effect on quality of life. The Australian New Zealand Gynaecological Oncology Group is currently addressing this question in a large prospective study measuring both the subjective and objective benefit (response and survival) of palliative chemotherapy in platinum-resistant or refractory ovarian cancer in Australia. Clinicians are urged to enter their patients in this study to address this important question.

Second opinions in oncology: the experiences of patients attending the Sydney Cancer Centre.

OBJECTIVE: To investigate the frequency, goals and outcomes of second-opinion consultations at the Sydney Cancer Centre. DESIGN, SETTING AND PARTICIPANTS: A questionnaire-based study of patients who registered to see a medical oncologist at the Sydney Cancer Centre between January 2006 and January 2008 and who were seeking a second opinion. MAIN OUTCOME MEASURES: Proportion and demographic characteristics of patients who had previously seen a medical oncologist and who stated they were seeking a second opinion. RESULTS: 123 of 1892 new patients (6.5%) stated that they were seeking a second opinion, of whom 22 declined study participation, were excluded from study participation or had been referred specifically for enrolment in a particular clinical trial. Of the remaining 101 patients, 77 completed a questionnaire; 59 were women and 26 had a university degree. Reasons for seeking second opinions included: to obtain information related to treatment (54 patients), for reassurance about diagnosis or treatment (47), and dissatisfaction with the information given by the first medical oncologist (24). Sixty-four patients reported that they received new information at the second-opinion consultation, with 45 identifying discussion of treatment options and 34 identifying discussion of future or prognosis. Fifty-one patients reported how the second-opinion consultation differed from the first, identifying it as longer (24), and indicating that the oncologist answered concerns (26). Most patients were aware of multidisciplinary teams and treatment guidelines, but fewer had read guidelines. CONCLUSIONS: Patients seeking a second opinion from a medical oncologist are typically more educated, younger and female, probably due to preferences for more detailed information. The most common reasons for seeking a second opinion were to obtain additional information or reassurance about recommended management.