A systematic review of the role of chemotherapy in retroperitoneal sarcoma by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

BACKGROUND: In primary localised resectable retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether neoadjuvant or adjuvant chemotherapy improve outcomes in adults with primary localised resectable RPS. Medline, Embase and Cochrane Central were queried for publications from 1946 to June 2022 that evaluated recurrence free survival, overall survival, and post operative complications. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Twenty three studies were identified; one meta-analysis of retrospective studies and 22 retrospective studies including three with propensity matched cohorts. Most studies did not analyse outcomes by histology, detail treatment regimens, provide baseline characteristics or selection criteria for those receiving chemotherapy. Evidence of selection bias was illustrated in several studies. Newcastle-Ottawa quality of retrospective cohort studies was good for 12 studies and poor for 10 studies. All studies were assessed as Level III-2 evidence by the Australian NHMRC hierarchy. Overall, the addition of neoadjuvant or adjuvant chemotherapy to surgery was not associated with improvement in local recurrence, metastasis free survival, disease free survival or overall survival in primary localised resectable RPS. There is some evidence of an association of chemotherapy with worse overall survival. One single centre study showed that neoadjuvant chemotherapy was not associated with increased post operative complications compared to surgery alone in primary localised resectable RPS. CONCLUSIONS: There is currently no evidence that demonstrates the addition of chemotherapy to surgery improves outcomes in adult patients with primary localised resectable RPS. Available evidence is limited by its retrospective nature and high likelihood of selection bias with chemotherapy generally administered to patients at higher risk of recurrence and many patients not receiving care in high volume sarcoma centres. Randomised trials are required to conclusively determine the role of chemotherapy in primary localised resectable RPS.

Quantitative proteomic studies addressing unmet clinical needs in sarcoma.

Sarcoma is a rare and complex disease comprising over 80 malignant subtypes that is frequently characterized by poor prognosis. Challenges in clinical management include uncertainties in diagnosis and disease classification, limited prognostic and predictive biomarkers, incompletely understood disease heterogeneity among and within subtypes, lack of effective treatment options, and limited progress in identifying new drug targets and novel therapeutics. Proteomics refers to the study of the entire complement of proteins expressed in specific cells or tissues. Advances in proteomics have included the development of quantitative mass spectrometry (MS)-based technologies which enable analysis of large numbers of proteins with relatively high throughput, enabling proteomics to be studied on a scale that has not previously been possible. Cellular function is determined by the levels of various proteins and their interactions, so proteomics offers the possibility of new insights into cancer biology. Sarcoma proteomics therefore has the potential to address some of the key current challenges described above, but it is still in its infancy. This review covers key quantitative proteomic sarcoma studies with findings that pertain to clinical utility. Proteomic methodologies that have been applied to human sarcoma research are briefly described, including recent advances in MS-based proteomic technology. We highlight studies that illustrate how proteomics may aid diagnosis and improve disease classification by distinguishing sarcoma histologies and identify distinct profiles within histological subtypes which may aid understanding of disease heterogeneity. We also review studies where proteomics has been applied to identify prognostic, predictive and therapeutic biomarkers. These studies traverse a range of histological subtypes including chordoma, Ewing sarcoma, gastrointestinal stromal tumors, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumors, myxofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, osteosarcoma, and undifferentiated pleomorphic sarcoma. Critical questions and unmet needs in sarcoma which can potentially be addressed with proteomics are outlined.

First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors.

BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

Mesenchymal chondrosarcoma: An Australian multi-centre cohort study.

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is an ultra-rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting. METHODS: We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression-free survival (PFS). RESULTS: We identified 22 patients with MCS between 2001-2022. Median age was 28 (range 10-59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow-up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow-up of 50.9  (range 0.4-210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8-182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0-1 compared to 2-3 (p = 0.023) on univariate analysis. CONCLUSIONS: This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies.

Systemic treatments and outcomes in CIC-rearranged Sarcoma: A national multi-centre clinicopathological series and literature review.

CIC-rearranged sarcoma is a recently established, ultra-rare, molecularly defined sarcoma subtype. We aimed to further characterise clinical features of CIC-rearranged sarcomas and explore clinical management including systemic treatments and outcomes. METHODS: A multi-centre retrospective cohort study of patients diagnosed between 2014-2019. RESULTS: Eighteen patients were identified. The median age was 27 years (range 13-56), 10 patients were male (56%), 11 patients (61%) had localised disease and 7 patients had advanced (metastatic or unresectable) disease at diagnosis. Of 11 patients with localised disease at diagnosis, median overall survival (OS) was 40.6 months and the 1-, 2- and 5-year OS estimates were 82%, 64% and 34% respectively. Nine patients (82%) underwent surgery (all had R0 resections), 8 (73%) patients received radiotherapy to the primary site (median dose 57Gy in 28 fractions), and 8 (73%) patients received chemotherapy (predominantly Ewing-based regimens). Metastases developed in 55% with a median time to recurrence of 10.5 months. In patients with advanced disease at diagnosis, median OS was 12.6 months (95% CI 5.1-20.1), 1-year OS was 57%. Median progression-free survival was 5.8 months (95% CI 4.5-7.2). Durable systemic therapy responses occurred infrequently with a median duration of systemic treatment response of 2.1 months. One durable complete response of metastatic disease to VDC/IE chemotherapy was seen. Responses to pazopanib (n = 1) and pembrolizumab (n = 1) were not seen. CONCLUSION: In this series, CIC-rearranged sarcomas affected young adults and had a high incidence of presenting with, or developing, metastatic disease. The prognosis overall was poor. In advanced disease, durable systemic therapy responses were infrequent.

Pediatric and Adolescent Extracranial Germ Cell Tumors: The Road to Collaboration.

During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.

Deriving a preference-based utility measure for cancer patients from the European Organisation for the Research and Treatment of Cancer's Quality of Life Questionnaire C30: a confirmatory versus exploratory approach.

BACKGROUND: Multi attribute utility instruments (MAUIs) are preference-based measures that comprise a health state classification system (HSCS) and a scoring algorithm that assigns a utility value to each health state in the HSCS. When developing a MAUI from a health-related quality of life (HRQOL) questionnaire, first a HSCS must be derived. This typically involves selecting a subset of domains and items because HRQOL questionnaires typically have too many items to be amendable to the valuation task required to develop the scoring algorithm for a MAUI. Currently, exploratory factor analysis (EFA) followed by Rasch analysis is recommended for deriving a MAUI from a HRQOL measure. AIM: To determine whether confirmatory factor analysis (CFA) is more appropriate and efficient than EFA to derive a HSCS from the European Organisation for the Research and Treatment of Cancer's core HRQOL questionnaire, Quality of Life Questionnaire (QLQ-C30), given its well-established domain structure. METHODS: QLQ-C30 (Version 3) data were collected from 356 patients receiving palliative radiotherapy for recurrent/metastatic cancer (various primary sites). The dimensional structure of the QLQ-C30 was tested with EFA and CFA, the latter informed by the established QLQ-C30 structure and views of both patients and clinicians on which are the most relevant items. Dimensions determined by EFA or CFA were then subjected to Rasch analysis. RESULTS: CFA results generally supported the proposed QLQ-C30 structure (comparative fit index =0.99, Tucker-Lewis index =0.99, root mean square error of approximation =0.04). EFA revealed fewer factors and some items cross-loaded on multiple factors. Further assessment of dimensionality with Rasch analysis allowed better alignment of the EFA dimensions with those detected by CFA. CONCLUSION: CFA was more appropriate and efficient than EFA in producing clinically interpretable results for the HSCS for a proposed new cancer-specific MAUI. Our findings suggest that CFA should be recommended generally when deriving a preference-based measure from a HRQOL measure that has an established domain structure.

Factors delaying chemotherapy for breast cancer in four urban and rural oncology units.

BACKGROUND: Delays in commencing adjuvant chemotherapy for early breast cancer beyond 12 weeks are associated with increased mortality. The aim of this study was to identify factors delaying chemotherapy in an inner metropolitan, outer metropolitan, small rural and large rural cancer centre in New South Wales, Australia. METHODS: We retrospectively reviewed 400 consecutive patients that received adjuvant chemotherapy for stages I-III breast cancer. We evaluated factors affecting time from primary and definitive surgery until commencing chemotherapy. RESULTS: The primary factor associated with chemotherapy delays was the geographic location of the cancer centre. The median time from primary surgery to chemotherapy was longer for the large rural centre (median 58 days), compared with the outer metropolitan (45 days), small rural (39 days) and inner metropolitan centre (33 days). Treatment delays in the large rural centre were associated with higher rates of multiple operations (43% versus 31% elsewhere), mainly because of more staged axillary dissections (34% versus 19%), and longer time from definitive surgery to oncology assessment. CONCLUSION: Patients in the large rural centre, who are served by fly-in medical oncology services, are more likely to experience delays in receiving adjuvant chemotherapy for early breast cancer. Strategies to reduce delays include use of intraoperative frozen section analysis, multidisciplinary meetings, improving efficiency in pathology reporting and employment of a breast cancer care coordinator and an on-site medical oncologist.

Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer.

PURPOSE: We compared oral capecitabine, administered intermittently or continuously, versus classical cyclophosphamide, methotrexate, and fluorouracil (CMF) as first-line chemotherapy for women with advanced breast cancer unsuited to more intensive regimens. PATIENTS AND METHODS: Three hundred twenty-three eligible women were randomly assigned to capecitabine administered intermittently (1,000 mg/m(2) twice daily for 14 of every 21 days; n = 107) or continuously (650 mg/m(2) twice daily for 21 of every 21 days; n = 107), or to classical CMF (oral cyclophosphamide 100 mg/m(2) days 1 to 14 with intravenous methotrexate 40 mg/m(2) and fluorouracil 600 mg/m(2) on days 1 and 8 every 28 days; n = 109). The primary end point was quality-adjusted progression-free survival (PFS); secondary end points included PFS, overall survival (OS), objective tumor response, and adverse events. Intermittent and continuous capecitabine were to be compared first and, if similar (P > .05), combined for definitive comparisons versus CMF. RESULTS: Quality-adjusted PFS (P = .2), objective tumor response rate (20%; P = .8), and PFS (median, 6 months; hazard ratio [HR], 0.86; 95% CI, 0.67 to 1.10; P = .2) were similar in women assigned capecitabine versus CMF. OS was longer in women assigned capecitabine rather than CMF (median, 22 v 18 months; HR, 0.72; 95% CI, 0.55 to 0.94; P = .02). Febrile neutropenia, infection, stomatitis, and serious adverse events were more common with CMF; hand-foot syndrome was more common with capecitabine. CONCLUSION: Capecitabine improved OS by being similarly active, less toxic, and more tolerable than CMF. Capecitabine is a good first-line chemotherapy option for women with advanced breast cancer who are unsuited to more intensive regimens.

Comparison of two standard chemotherapy regimens for good-prognosis germ cell tumors: updated analysis of a randomized trial.

BACKGROUND: The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up. METHODS: Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3B(90)E(500)P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m(2) etoposide on days 1-5; and 20 mg/m(2) cisplatin on days 1-5; n = 83) or 4B(30)E(360)P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m(2) etoposide on days 1-3, and 100 mg/m(2) cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided. RESULTS: The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3B(90)E(500)P than in those assigned to 4B(30)E(360)P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3B(90)E(500)P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3B(90)E(500)P vs 4B(30)E(360)P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P = .15). At the end of treatment, average scores for most side effect scales favored 3B(90)E(500)P. After the completion of treatment, average GLQ-8 scores for numbness (P = .003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3B(90)E(500)P. CONCLUSION: The survival benefit of 3B(90)E(500)P over 4B(30)E(360)P was maintained with long-term follow-up.

Preliminary validation of an optimally weighted patient-based utility index by application to randomized trials in breast cancer.

OBJECTIVES: To optimize, apply, and validate a scoring algorithm that provides a utility index from a cancer-specific quality of life questionnaire called the Utility-Based Questionnaire-Cancer (UBQ-C) using data sets from randomized trials in breast cancer. The index is designed to reflect the perspective of cancer patients in a specific clinical context so as to best inform clinical decisions. METHODS: We applied the UBQ-C scoring algorithm to trials of chemotherapy for advanced (n = 325) and early (n = 126) breast cancer. The algorithm converts UBQ-C subscales into a subset index, and combines it with a global health status item into an overall HRQL index, which is then converted to a utility index using a power transformation. The optimal subscale weights were determined by their correlations with the global scale in the relevant data set. The validity of the utility index was tested against other patient characteristics. RESULTS: Optimal weights (range 0-1) for the subset index in advanced (early) breast cancer were: physical function 0.20 (0.09); social/usual activities 0.23 (0.25); self-care 0.04 (0.01); and distresses 0.53 (0.64). Weights for the overall HRQL index were health status 0.66 (0.63) and subset index 0.34 (0.37). The utility index discriminated between breast cancer that was advanced rather than early (means 0.88 vs. 0.94, P < 0.0001) and was responsive to the toxic effects of chemotherapy in early breast cancer (mean change 0.07, P < 0.0001). CONCLUSIONS: The scoring algorithm for the UBQ-C utility index can be optimized in different clinical contexts to reflect the relative importance of different aspects of quality of life to the patients in a trial. It can be used to generate sensitive and responsive utility scores, and quality-adjusted life-years that can be used within a trial to compare the net benefit of treatments and inform clinical decision-making.

Deriving a patient-based utility index from a cancer-specific quality of life questionnaire.

OBJECTIVES: The aim of this study was to derive a scoring algorithm for a validated disease-specific quality of life instrument called the Utility-Based Questionnaire-Cancer (UBQ-C) that provided a utility index designed to inform clinical decisions about cancer treatments. METHODS: The UBQ-C includes a scale for global health status (1 item); and subscales for physical function (3 items), social/usual activities (4 items), self-care (1 item), and distresses because of physical and psychological symptoms (21 items). A scoring algorithm was derived to convert the subscales into a subset index, and combine it with the global scale into an overall health-related quality of life (HRQL) index, which was converted to a utility index with a power transformation. The valuation survey consisted of 204 advanced cancer patients who completed the UBQ-C and assigned time trade-off (TTO) utilities about their own health state. Preliminary validation involved comparing these derived utilities with other measures of HRQL. RESULTS: Weights for the subset index were: physical function 0.28, social/usual activities 0.06, self-care 0.01, and distresses 0.64. Weights for the overall HRQL index were health status 0.65 and subset index 0.35. The mean of the utility index scores was similar to the mean of the TTO utilities (0.92 vs. 0.91, P = 0.6). The utility index was substantially correlated with other measures of HRQL. CONCLUSIONS: Data from a simple, self-rated, disease-specific questionnaire can be converted into a utility index suitable for comparing the net effect of cancer treatments on quality of life, and to evaluate trade-offs between quality and quantity of life in quality-adjusted survival analyses.

Quality of life and adjuvant systemic therapy for early-stage breast cancer.

Adjuvant chemotherapy and hormonal therapy reduce the risk of recurrence and death due to breast cancer, but often at considerable cost to the health-related quality of life (HRQL) of patients. The short-term effects of chemotherapy on HRQL are well known and are accepted by most patients for modest gains in survival. The long-term effects of chemotherapy-induced menopause and hormonal therapy on HRQL are poorly recognized. Vasomotor symptoms and altered sexual function are common, distressing and inadequately treated. HRQL information is helpful in describing likely effects of adjuvant treatment, facilitating informed decision-making, identifying health problems to guide research into potential solutions, guiding treatment strategies for interventions with equivalent survival and guiding resource allocation. New technologies will make HRQL information increasingly available for individual patient care.

Primary pancreatic lymphoma--pancreatic tumours that are potentially curable without resection, a retrospective review of four cases.

BACKGROUND: Primary pancreatic lymphomas (PPL) are rare tumours of the pancreas. Symptoms, imaging and tumour markers can mimic pancreatic adenocarcinoma, but they are much more amenable to treatment. Treatment for PPL remains controversial, particularly the role of surgical resection. METHODS: Four cases of primary pancreatic lymphoma were identified at Prince of Wales Hospital, Sydney, Australia. A literature review of cases of PPL reported between 1985 and 2005 was conducted, and outcomes were contrasted. RESULTS: All four patients presented with upper abdominal symptoms associated with weight loss. One case was diagnosed without surgery. No patients underwent pancreatectomy. All patients were treated with chemotherapy and radiotherapy, and two of four patients received rituximab. One patient died at 32 months. Three patients are disease free at 15, 25 and 64 months, one after successful retreatment. Literature review identified a further 103 patients in 11 case series. Outcomes in our series and other series of chemotherapy and radiotherapy compared favourably to surgical series. CONCLUSION: Biopsy of all pancreatic masses is essential, to exclude potentially curable conditions such as PPL, and can be performed without laparotomy. Combined multimodality treatment, utilising chemotherapy and radiotherapy, without surgical resection is advocated but a cooperative prospective study would lead to further improvement in treatment outcomes.