Development of a key performance indicator for breast cancer in Queensland, Australia.

PURPOSE: Using population-based data for women diagnosed with stage I-III breast cancer, our aim was to examine the impact of time to treatment completion on survival and to identify factors associated with treatment delay. METHODS: This retrospective study used clinical and treatment data from the Queensland Oncology Repository. Time from diagnosis to completing surgery, chemotherapy and radiation therapy identified a cut-off of 37 weeks as the optimal threshold for completing treatment. Logistic regression was used to identify factors associated with the likelihood of completing treatment > 37 weeks. Overall (OS) and breast cancer-specific survival (BCSS) were examined using Cox proportional hazards models. RESULTS: Of 8279 women with stage I-III breast cancer, 31.9% completed treatment > 37 weeks. Apart from several clinical factors, being Indigenous (p = 0.002), living in a disadvantaged area (p = 0.003) and receiving ≥ two treatment modalities within the public sector (p < 0.001) were associated with an increased likelihood of completing treatment > 37 weeks. The risk of death from any cause was about 40% higher for women whose treatment went beyond 37 weeks (HR 1.37, 95%CI 1.16-1.61), a similar result was observed for BCSS. Using the surgery + chemotherapy + radiation pathway, a delay of > 6.9 weeks from surgery to starting chemotherapy was significantly associated with poorer survival (p = 0.001). CONCLUSIONS: Several sociodemographic and system-related factors were associated with a greater likelihood of treatment completion > 37 weeks. We are proposing a key performance indicator for the management of early breast cancer where a facility should have > 90% of patients with a time from surgery to adjuvant chemotherapy < 6.9 weeks.

"I'm a Survivor": Aboriginal and Torres Strait Islander Cancer Survivors' Perspectives of Cancer Survivorship.

BACKGROUND: Disparity in outcomes between Indigenous and non-Indigenous people after cancer diagnosis is multifactorial, including lower cancer screening participation, later diagnosis, reduced access and uptake of cancer treatment, higher rate of comorbidities, and barriers accessing the health system. Little is known about cancer survivorship experiences. OBJECTIVE: The aim of this study was to explore Indigenous Australian cancer survivor's perspectives of cancer survivorship. METHODS: Indigenous people who completed cancer treatment 6 months to 5 years before fieldwork were recruited from a tertiary hospital and remote primary health service for this qualitative study. Data collection was guided by yarning methods, a culturally appropriate method emphasizing storytelling. Data were interpreted using a social constructionist framework. RESULTS: Thirteen women and 6 men were interviewed. Participants' past experiences contributed to their specific identity as survivors. Participants described factors affecting a positive transition from cancer patient to cancer survivor and the importance of ongoing family support in helping to manage survivorship. Finally, participants described a range of community support they received and provided to others and how this improved their cancer survivorship. CONCLUSION: Although a range of experiences are presented, this study provides evidence that the survivorship perspectives of Indigenous cancer survivors may be, in part, shared by non-Indigenous cancer survivors. IMPLICATIONS FOR PRACTICE: Acknowledging Indigenous cancer survivors' past experiences and how these influence their overall well-being is important for providing patient-centered and culturally appropriate care. Nurses and other healthcare professionals may use this knowledge to foster a range of coping strategies to assist Indigenous cancer survivors to live well.

Development and Implementation of a Cancer Quality Index in Queensland, Australia: A Tool for Monitoring Cancer Care.

PURPOSE: Many cancer-specific assessment tools to measure health care performance have been developed. However, reporting on quality indicators at a population level is uncommon. We describe the development and implementation of a Cancer Quality Index (CQI) and examine the sensitivity of the index to detect change over time. METHODS: In developing the CQI, we reviewed existing indices, guidelines, and cancer care pathways. Our choice of indicators was additionally guided by the availability of population-wide data. A series of pilot indicators underwent trial use and were evaluated, and outcomes were discussed before a final set of indicators was established. The process was overseen by a clinician-led quality assurance committee that included hospital administrators and data custodians. RESULTS: The CQI includes five quality dimensions and 16 indicators for public and private cancer services using population-wide information. The following are the five indicators: Effective, Efficient, Safe, Accessible, and Equitable. We demonstrated the sensitivity of the CQI to measure change over time by examining outcomes such as time to first treatment and 30-day surgical mortality, using linked cancer registry and health administrative data for 99,728 patients with cancer diagnosed between 2005 and 2009 and 2010 and 2014. CONCLUSION: The CQI is a valuable tool to track progress in delivering safe, quality cancer care within health care services. Critical to its development and implementation has been the involvement of clinicians from several disciplines and the availability of population-based data. We found the CQI to be a sensitive tool able to detect changes over time.

Pregnancy with successful foetal and maternal outcome in a melanoma patient treated with nivolumab in the first trimester: case report and review of the literature.

Although T-cell checkpoint blockade has revolutionized melanoma therapy, metastatic melanoma in pregnancy remains a challenging area of unmet need. Treatment with anti-PD1 therapy decreases foetal-maternal tolerance and increases the risk of pregnancy loss in animal studies and is considered category D by the Food and Drug Administration. We describe a unique case of conception and pregnancy, with successful maternal and foetal outcomes, in a patient with metastatic melanoma who had received combination anti-CTLA-4 and anti-PD1 therapy. A 32-year-old G0P0 lady, with a 10-year history of infertility of unclear cause, was found to be 7 weeks pregnant after 14 months of nivolumab maintenance therapy, having previously received combination ipilimumab and nivolumab. Nivolumab was ceased upon discovery of pregnancy in the first trimester. The patient had an uneventful pregnancy, followed by spontaneously premature labour, and delivered by caesarean section at 33 weeks' gestation. The foetus had moderate intrauterine growth restriction, as well as congenital hypothyroidism, which possibly constitutes the first documented case of foetal immune-related adverse event from maternal anti-PD1 exposure. No adverse events were noted in the mother. At 6 months of follow-up postpartum, the mother had a sustained complete response to treatment, and the baby had appropriate weight gain with normal developmental milestones. We summarize and discuss the available literature of immune checkpoint inhibitor exposure in pregnancy, which consists of a total of three case reports.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Community-identified recommendations to enhance cancer survivorship for Aboriginal and Torres Strait Islander people.

Indigenous Australians diagnosed with cancer experience higher mortality and lower survival rates compared to non-Indigenous Australians. Reasons are multifaceted and complex. Knowledge about Indigenous cancer survivors' perspectives of positive cancer survivorship is a gap in research evidence. The study explored cancer survivorship perspectives of Indigenous cancer survivors, their support people and healthcare workers with a view to developing recommendations for cancer survivorship. Indigenous Australians who completed cancer treatment in the previous 6 months to 5 years, their support people and primary healthcare workers were recruited from primary healthcare centres and a large tertiary Queensland hospital. Semi-structured interviews and focus groups were conducted with written and informed consent obtained prior. Participants emphasised key action areas and recommendations to enhance cancer survivorship, namely: establishing a community cancer advocate and peer support program, availability and use of a cancer-specific Indigenous primary healthcare worker and hospital-based Indigenous patient navigator, as well as adoption of question prompt lists and cancer survivorship care plans. Existing research suggests significant benefits from implementing the key recommendations identified in this study. Greater support and commitment across health sectors and funding bodies is needed to promote institutional change and health system development.

Identification of Australian Aboriginal and Torres Strait Islander Cancer Patients in the Primary Health Care Setting.

BACKGROUND: Aboriginal and Torres Strait Islander Australians have poorer cancer outcomes and experience 30% higher mortality rates compared to non-Indigenous Australians. Primary health care (PHC) services are increasingly being recognized as pivotal in improving Indigenous cancer patient outcomes. It is currently unknown whether patient information systems and practices in PHC settings accurately record Indigenous and cancer status. Being able to identify Indigenous cancer patients accessing services in PHC settings is the first step in improving outcomes. METHODS: Aboriginal Medical Centres, mainstream (non-Indigenous specific), and government-operated centers in Queensland were contacted and data were collected by telephone during the period from 2014 to 2016. Participants were asked to (i) identify the number of patients diagnosed with cancer attending the service in the previous year; (ii) identify the Indigenous status of these patients and if this information was available; and (iii) advise how this information was obtained. RESULTS: Ten primary health care centers (PHCCs) across Queensland participated in this study. Four centers were located in regional areas, three in remote areas and three in major cities. All participating centers reported ability to identify Indigenous cancer patients attending their service and utilizing electronic Patient Care Information Systems (PCIS) to manage their records; however, not all centers were able to identify Indigenous cancer patients in this way. Indigenous cancer patients were identified by PHCCs using PCIS (n = 8), searching paper records (n = 1), and combination of PCIS and staff recall (n = 1). Six different types of PCIS were being utilized by participating centers. There was no standardized way to identify Indigenous cancer patients across centers. Health service information systems, search functions and capacities of systems, and staff skill in extracting data using PCIS varied between centers. CONCLUSION: It is crucial to be able to easily identify Indigenous cancer patients accessing health services in the PHC setting to monitor progress, improve and evaluate care, and ultimately improve Indigenous cancer outcomes. It is also important for PHC staff to receive adequate training and support to utilize PCISs efficiently and effectively.

Temporal changes in loss of life expectancy due to cancer in Australia: a flexible parametric approach.

PURPOSE: To evaluate changes in cancer mortality burden over time by assessing temporal trends in life expectation for Australian residents diagnosed with cancer. METHODS: The study cohort consisted of all people diagnosed with cancer in the period 1990-2000 and aged 15-89 years (n = 1,275,978), with mortality follow-up to 31 December 2010. Flexible parametric survival models incorporating background age-sex-year-specific population mortality rates were applied to generate the observed survival curves for all cancers combined and selected major cancer types. Predicted values of loss of life expectancy (LOLE) in years were generated and then averaged across calendar year and age group (15-49, 50-69 and 70-89 years) or spread of disease (localized, regional, distant, unknown). RESULTS: The greatest LOLE burden was for lung cancer (14.3 years per diagnosis) and lowest for melanoma (2.5 years). There was a significant decrease in LOLE over time (-0.13 LOLE per year) for all cancers combined. Decreases were also observed for female breast cancer (-0.21), prostate cancer (-0.17), colorectal cancer (-0.08), melanoma (-0.07) and stomach cancer (-0.02), with slight increases for lung cancer (+0.04). When restricted to the sub-cohort from New South Wales with spread of disease information, these decreases in LOLE were primarily among cancers categorized as localized or regional spread at diagnosis. CONCLUSIONS: In Australia, persons diagnosed with cancer have a steadily improving outlook that exceeds that expected by general improvement in population life expectancy. The overall improvement is observed in persons with localized or regional cancers but not in those with advanced cancers, findings which encourage earlier diagnosis.

The role of the GP in follow-up cancer care: a systematic literature review.

PURPOSE: The purpose of the present study is to explore the role of the general practitioners, family physicians and primary care physicians (GP) in the provision of follow-up cancer care. METHODS: PubMed, MEDLINE and CINAHL were systematically searched for primary research focussing on the role of the GP from the perspective of GPs and patients. Data were extracted using a standardised form and synthesised using a qualitative descriptive approach. RESULTS: The initial search generated 6487 articles: 25 quantitative and 33 qualitative articles were included. Articles focused on patients' and GPs' perspectives of the GP role in follow-up cancer care. Some studies reported on the current role of the GP, barriers and enablers to GP involvement from the perspective of the GP and suggestions for future GP roles. Variations in guidelines and practice of follow-up cancer care in the primary health care sector exist. However, GPs and patients across the included studies supported a greater GP role in follow-up cancer care. This included greater support for care coordination, screening, diagnosis and management of physical and psychological effects of cancer and its treatment, symptom and pain relief, health promotion, palliative care and continuing normal general health care provision. CONCLUSION: While there are variations in guidelines and practice of follow-up cancer care in the primary health care sector, GPs and patients across the reviewed studies supported a greater role by the GP. IMPLICATIONS FOR CANCER SURVIVORS: Greater GP role in cancer care could improve the quality of patient care for cancer survivors. Better communication between the tertiary sector and GP across the cancer phases would enable clear delineation of roles.

Single institution retrospective review of perioperative chemotherapy in adult and adolescent patients with operable osteosarcoma.

AIMS: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. METHODS: This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan-Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. RESULTS: Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. CONCLUSION: The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983).

OBJECTIVE: In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS. METHODS: The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models. RESULTS: After adjustment for identified prognostic factors, moderately (5.1-30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2-4, interaction HR = 0.98). CONCLUSIONS: Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.

Workforce shortages in medical oncology: a looming threat to quality cancer care.

Supply must meet demand to maintain our high standards of cancer care.

The shortage of medical oncologists: the Australian Medical Oncologist Workforce Study.

OBJECTIVE: To determine current and projected supply, demand and shortfall of medical oncologists (MOs) and the Australian chemotherapy utilisation rate. DESIGN, SETTING AND PARTICIPANTS: A 2009 cross-sectional observational study of Australian adult medical oncology practice work patterns. INSTRUMENT: Electronic or paper self-administered questionnaire. MAIN OUTCOME MEASURES: The 2009 and projected (2014) supply, demand and shortfall of full-time equivalent (FTE) MOs, and the chemotherapy utilisation rate. RESULTS: 476 medical oncology positions comprising 234 FTE MOs were identified. Of the 150 medical oncology practices, 117 (78%) were in metropolitan locations and 33 (22%) were in rural locations. The average number of new patients seen per FTE MO was 270 patients (ranging by state from 191 to 343). The demand for FTE MOs was estimated at 326 to 391 in 2009 and 361 to 432 in 2014. The shortfall of FTE MOs was estimated at 92 to 157 in 2009 and 84 to 156 in 2014. The chemotherapy utilisation rate was 19%. CONCLUSIONS: The current shortage of MOs is expected to persist in the future. National strategies are needed to increase the capacity of the medical oncology workforce and the chemotherapy utilisation rate.

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial.

INTRODUCTION: Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction. METHODS: Patients were randomised to receive preoperative CT with cisplatin (80 mg/m(2)) and infusional 5 fluorouracil (1000 mg/m(2)/d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m(2)/d. The radiation dose was 35 Gy in 15 fractions over 3 weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life. RESULTS: Seventy-five patients were enrolled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p = 0.01) and R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively (p = 0.37). The median OS was 29 months for CT compared with 32 months for CRT (p = 0.83). CONCLUSIONS: Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus.

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer.

BACKGROUND: Chemoradiation therapy using regimens containing cisplatin and 5-fluorouracil are most commonly used for inoperable cancer of the esophagus. Cisplatin is relatively toxic and is not suitable for many patients. Little data exists using platinum analogues together with protracted infusion 5-fluorouracil and radiation therapy in the curative setting. METHODS: Fourteen patients with localised oesophageal cancer suitable for curative chemoradiation therapy registered on the study. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout radiation therapy, with oxaliplatin 60 mg/m(2) weekly. The radiation dose was 56 to 60 Gy in 28 to 30 fractions. RESULTS: The median age of the patients was 70.5 years. Therapy was associated with excessive grade 3 and 4 non-hematologic toxicity. There was one treatment related death. The median progression-free survival was 31.5 months and median overall survival 32.6 months. Six patients achieved a prolonged complete endoscopic and radiological response. CONCLUSIONS: Although weekly oxaliplatin in combination with infusional 5 fluorouracil produces durable remissions in esophageal cancer, the regimen used in this trial was not acceptable for routine use. Future protocols should incorporate lower chemotherapy doses.

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.

BACKGROUND: Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. METHODS: This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0.71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. FINDINGS: In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1-6) preoperative cycles and 115 (63%) patients received a median six (1-8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7.3% (from 28.1% [95.66% CI 21.3-35.5] to 35.4% [28.1-42.7]; HR 0.79 [0.62-1.02]; p=0.058) in randomised patients; 8.1% (from 28.1% [21.2-36.6] to 36.2% [28.7-43.8]; HR 0.77 [0.60-1.00]; p=0.041) in eligible patients; and 9.2% (from 33.2% [25.3-41.2] to 42.4% [34.0-50.5]; HR 0.73 [0.55-0.97]; p=0.025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0.04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. INTERPRETATION: Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma.

Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.

Feasibility of chemoradiation therapy with protracted infusion of 5-fluorouracil for esophageal cancer patients not suitable for cisplatin.

BACKGROUND: Chemoradiation therapy is the standard treatment for esophageal cancer in patients not fit for surgery. The regimen most commonly used includes cisplatin and 5-fluorouracil. Little data exists regarding alternative chemotherapy regimens in patients not suitable for cisplatin. We report on a regimen using protracted infusion 5-fluorouracil alone for both curative and palliative indications. METHODS: Twenty-two patients with localized esophageal cancer suitable for curative chemoradiation therapy and 24 patients suitable for palliative therapy were enrolled. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout the radiation therapy. The radiation dose was 56 to 60 Gy in 28 to 30 fractions (curative patients) and 30 to 35 Gy in 15 fractions (palliative patients). RESULTS: The median age of the patients was 75 years. The regimen was tolerable. Significant grade 3 toxicities experienced were esophagitis (11%) and venous catheter toxicity (9%). The median survival was 17 months for curative patients and 9 months for palliative patients. The complete response rate was 86% endoscopically and 45% radiologically for curative patients. Relief of dysphagia was experienced in 67% of palliative patients. Quality of life was satisfactory in both groups. CONCLUSIONS: This study showed that continuous-infusion 5-fluorouracil given concurrently with radiation therapy is a useful alternative to platinum-based chemoradiation therapy in patients with esophageal carcinoma.

Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial.

BACKGROUND: Resection remains the best treatment for carcinoma of the oesophagus in terms of local control, but local recurrence and distant metastasis remain an issue after surgery. We aimed to assess whether a short preoperative chemoradiotherapy regimen improves outcomes for patients with resectable oesophageal cancer. METHODS: 128 patients were randomly assigned to surgery alone and 128 patients to surgery after 80 mg/m(2) cisplatin on day 1, 800 mg/m(2) fluorouracil on days 1-4, with concurrent radiotherapy of 35 Gy given in 15 fractions. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, tumour response, toxic effects, patterns of failure, and quality of life. Analysis was done by intention to treat. FINDINGS: Neither progression-free survival nor overall survival differed between groups (hazard ratio [HR] 0.82 [95% CI 0.61-1.10] and 0.89 [0.67-1.19], respectively). The chemoradiotherapy-and-surgery group had more complete resections with clear margins than did the surgery-alone group (103 of 128 [80%] vs 76 of 128 [59%], p=0.0002), and had fewer positive lymph nodes (44 of 103 [43%] vs 69 of 103 [67%], p=0.003). Subgroup analysis showed that patients with squamous-cell tumours had better progression-free survival with chemoradiotherapy than did those with non-squamous tumours (HR 0.47 [0.25-0.86] vs 1.02 [0.72-1.44]). However, the trial was underpowered to determine the real magnitude of benefit in this subgroup. INTERPRETATION: Preoperative chemoradiotherapy with cisplatin and fluorouracil does not significantly improve progression-free or overall survival for patients with resectable oesophageal cancer compared with surgery alone. However, further assessment is warranted of the role of chemoradiotherapy in patients with squamous-cell tumours.