Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

BACKGROUND: Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. METHODS: A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). RESULTS: Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. CONCLUSIONS: EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

Cell-free DNA in plasma and ascites as a biomarker of bevacizumab response- a translational research sub-study of the REZOLVE (ANZGOG-1101) clinical trial.

OBJECTIVE: To investigate cell-free DNA (cfDNA) in plasma and ascites and its association with clinical outcomes (paracentesis-free interval, overall survival) and CA125 level in participants with advanced ovarian cancer, treated with palliative intraperitoneal bevacizumab to delay re-accumulation of ascites. METHODS: cfDNA was extracted from 0.3 to 1 mL samples from 20/24 participants of the REZOLVE trial. Standard and methylation-specific PCRs were performed to measure 3 biomarkers: total cfDNA (Alu), tumour-derived cfDNA (ctDNA, methylated IFFO1 promoter) and endothelium-derived cfDNA (ec-cfDNA, unmethylated CDH5 promoter). Values were correlated to clinical outcomes. RESULTS: cfDNA was detected in all samples, with higher yield in ascites (mean 669 ng/mL) than plasma (mean 75 ng/mL, p < 0.0001). Ascites had a higher ctDNA proportion than plasma (74 % vs. 20 %, p < 0.0001) and plasma had a higher ec-cfDNA proportion than ascites (24 % vs. 16 %, p < 0.002). High ctDNA proportion (>75 %) in ascites was associated with a significantly shorter paracentesis-free interval (median interval 47.5 versus 84 days, hazard ratio (HR) 2.21, 95 % confidence interval (CI) 0.85 to 5.73, p = 0.039) and ctDNA presence in plasma was unfavourable for survival (median survival 56 versus 242 days, HR 3.21, 95 % CI 1.15 to 9.00, p = 0.008). A significant positive correlation was observed between ctDNA proportion in plasma and CA125 level (p = 0.012). No significant difference in total cfDNA, ctDNA nor ec-cfDNA was observed between participants who were responders versus non-responders. CONCLUSION: Sufficient cfDNA was detected in both plasma and ascites to study three biomarkers. These samples can provide useful information and should be considered in the design of future ovarian cancer trials.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

Use and outcomes from neoadjuvant chemotherapy in borderline resectable pancreatic ductal adenocarcinoma in an Australasian population.

BACKGROUND: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis. RESULTS: The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p = .01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR) .3, p < .0001). CONCLUSIONS: NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.

Compliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer.

BACKGROUND: Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. AIM: To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS: We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS: Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P < 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P < 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis. CONCLUSION: This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.

Impact of first-line FOLFIRINOX versus Gemcitabine/Nab-Paclitaxel chemotherapy on survival in advanced pancreatic cancer: Evidence from the prospective international multicentre PURPLE pancreatic cancer registry.

BACKGROUND: First-line palliative chemotherapy regimens in advanced pancreatic ductal adenocarcinoma (PDAC) have not been compared in head-to-head phase III randomised controlled trials (RCT). Data on optimum first-line treatment and subsequent sequencing is lacking. OBJECTIVE: To compare overall survival (OS) between first-line treatment regimens in a real-world population to determine if an optimal therapeutic sequence is associated with survival benefit. METHODS: A retrospective analysis of prospectively collated data from the Australasian PURPLE pancreatic cancer registry was undertaken. FINDINGS: From 2016 to 2020, of 1551 pancreatic cancer patients, 615 received palliative-intent chemotherapy. Patients with early-stage resected disease without recurrence (n = 369), radiotherapy alone (n = 43), received supportive care alone (n = 458) or had less than 3 months follow-up (n = 66) were excluded. Median OS was comparable between patients receiving first-line Gemcitabine/Nab-Paclitaxel (n = 376) and those receiving FOLFIRINOX (n = 73) (11.3 versus 12.3 months, P = 0.37), with 38% proceeding to second-line chemotherapy which was associated with longer mOS compared to first-line treatment alone (17.4 versus 8.2 months, P < 0.001). With second-line treatment following prior FOLFIRINOX (n = 29) or Gemcitabine/Nab-Paclitaxel (n = 101), mOS did not differ significantly (17.3 versus 15.9 months, P = 0.92), respectively, whilst median progression-free survival was longer with prior FOLFIRINOX (5.2 versus 2.9 months, P = 0.03). CONCLUSION: There was no significant difference in overall survival between either first-line chemotherapy choice, despite patients receiving FOLFIRINOX being younger, fitter, and more likely to have localised disease. However, FOLFIRINOX was associated with delayed progression. In the absence of phase III RCT data, clinicians should be comfortable using either Gemcitabine/Nab-Paclitaxel or FOLFIRINOX as first-line therapy in advanced PDAC.

Massive hypertriglyceridemia associated with paclitaxel; a case report.

This report describes a patient who developed massive hypertriglyceridemia (12,488 mg/dL or 141 mmol/L) during paclitaxel and carboplatin adjuvant chemotherapy for high grade serous fallopian tube carcinoma. Paclitaxel was thought to be the causative agent and she had normal triglyceride levels following a change to carboplatin and gemcitabine. To our knowledge, this is the highest reported triglyceride level associated with paclitaxel. Measurement of serum lipids should be considered in individuals receiving taxane chemotherapy, especially in those with type 2 diabetes mellitus or a history of dyslipidemia.

Biology and Clinical Implications of Fecal Occult Blood Test Screen-Detected Colorectal Cancer.

BACKGROUND: Fecal occult blood test (FOBT)-based screening for colorectal cancer (CRC) reduces mortality, with earlier stage at diagnosis a prominent feature. Other characteristics of FOBT screen-detected cancers and any implications for clinical management have not been well explored. METHODS: We examined a multisite clinical registry to compare the characteristics and outcomes of FOBT screen-detected CRC via the Australian National Bowel Cancer Screening Program (NBCSP), which is offered biennially to individuals aged 50-74 years, and age-matched non-screen-detected CRC in the same registry. All statistical tests were 2-sided. Odds ratios (ORs) were calculated using the Baptista-Pike method, and hazard ratios via the log-rank method. RESULTS: Of 7153 registry patients diagnosed June 1, 2006, to June 30, 2020, 4142 (57.9%) were aged between 50 and 74 years. Excluding 406 patients with non-NBCSP screen-detected cancers and 35 patients with unknown method of detection, 473 (12.8%) were screen detected via the NBCSP, and 3228 (87.2%) were non-screen detected. Screen-detected patients were younger (mean age = 62.4 vs 64.2 years; P < .001) and more medically fit (OR for ASA score 1-2 = 1.91, 95% confidence interval [CI] = 1.51 to 2.41; P < .001). Pathologic characteristics within each stage favored the screen-detected patients. Stage III screen-detected colon cancers were more likely to receive adjuvant therapy (OR = 3.58, 95% CI = 1.52 to 8.36; P = .002). Screen-detected patients had superior relapse-free (hazard ratio = 0.41, 95% CI = 0.29 to 0.60; P < .001) and overall survival (hazard ratio = 0.22, 95% CI = 0.15 to 0.35; P < .001), which was maintained in matched stage comparisons and multivariable analysis. CONCLUSIONS: Beyond stage at diagnosis, multiple other factors associated with a favorable outcome are observed in FOBT screen-detected CRC. Given the substantial stage-by-stage differences in survival outcomes, if independently confirmed, individualized adjuvant therapy and surveillance strategies could be warranted for FOBT screen-detected cancers.

Impact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer.

BACKGROUND: RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. AIMS: To review routine care RAS testing and results over time. METHODS: A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018. RESULTS: Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). CONCLUSIONS: Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

Use and outcomes of chemotherapy for metastatic pancreatic cancer in Australia.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is highly lethal. Combination chemotherapy regimens improve overall survival (OS). Historically, only one-third of mPDAC patients in Victoria received chemotherapy. AIM: To describe current Australian chemotherapy utilisation and outcomes in patients with mPDAC using the multi-site PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) registry. METHODS: PURPLE collects longitudinal data on consecutive patients with pancreatic cancer seen since January 2016. Data were collated for patients with mPDAC from six Victorian sites, and analysed descriptively. RESULTS: Three hundred and sixty-three patients with mPDAC were identified. Median age was 70 years (range 20-94 years). First-line chemotherapy was administered in 195 (54%) patients. Prevalent regimens included gemcitabine-nab-paclitaxel (71%), gemcitabine alone (10%) and FOLFIRINOX (6%). Sixty-two of 195 (32%) patients who received first line treatment have proceeded to second-line chemotherapy. Chemotherapy-treated patients were younger (69 versus 73 years; P < 0.01), with better Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1 89 vs 66%; P < 0.01) and lower median Charlson comorbidity index (3 vs 4; P < 0.01) compared with untreated patients. Median OS of the entire cohort from diagnosis of metastases was 5.1 months. Median OS was 9.3 months in the chemotherapy treated patients, and 2.5 months in chemotherapy-untreated patients (P < 0.01). CONCLUSIONS: A substantial proportion of patients with mPDAC still do not receive active treatment, which may in part by explained by age, poor performance status and comorbidity. Gemcitabine-nab-paclitaxel was the preferred first-line chemotherapy regimen. Median OS for treated patients in this cohort was comparable to that of recent published clinical trials.

Awareness and perceptions of nutrition support in upper gastrointestinal cancer surgery: A national survey of multidisciplinary clinicians.

BACKGROUND: Patients undergoing surgery for upper gastrointestinal (UGI) cancer are at high risk of malnutrition, and a multidisciplinary approach to management is recommended. This study aimed to determine practices, awareness and perceptions of multi-disciplinary clinicians with regards to malnutrition screening and provision of nutrition support. METHODS: A national survey of dietitians, surgeons, oncologists and nurses was conducted using a 30-item online REDCap survey, including questions regarding self-reported malnutrition screening/nutrition support practices, awareness and perceptions, and barriers and enablers. The survey was distributed via professional organisations/networks between 1st September and 30th November 2020. Results are presented as counts and percentages. RESULTS: There were 130 participants (56% dietitians, 25% surgeons, 11% nurses, 8% oncologists). The majority reported that dietitians and nurses performed malnutrition screening, and dietitians and surgeons prescribed nutrition support. Most participants reported that their health service had dietetics support available overall (98%), however only 41% reported having an outpatient service. Participants (>90%) demonstrated very high awareness of the significance of malnutrition and the importance of early nutrition support. Participants mostly perceived dietitians, nurses and surgeons to be responsible for malnutrition screening, whilst responsibility of prescription of nutrition support was mostly dietitians and surgeons. There were a higher number of barriers for the outpatient setting (48%) than the inpatient setting (38%). CONCLUSIONS: Participants identified a high awareness of the importance of identification and treatment of malnutrition in UGI cancer surgery. However reported practices varied and appear to be lacking in the outpatient setting, with significant barriers identified to providing optimal nutrition care.

Treatment and Outcomes of Oligometastatic Colorectal Cancer Limited to Lymph Node Metastases.

INTRODUCTION: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyze the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. MATERIALS & METHODS: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites. RESULTS: Of 3408 mCRC patients diagnosed 2009 to 2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs. 65.6 years, P = .02), more likely to have metachronous disease (57.0% vs. 38.9%, P < .01), be KRAS wild-type (74.6% vs. 53.9%, P< .01) and BRAF mutant (12.9% vs. 6.2%, P = .01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs. 23.2 months, P = .01). These 24 patients had an overall median survival similar (62.7 months, P = .82) to patients with isolated liver or lung metastases also treated with curative intent. CONCLUSION: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team.

Stage dependent recurrence patterns and post-recurrence outcomes in non-metastatic colon cancer.

BACKGROUND: Multiple meta-analyses have demonstrated that routine surveillance following colorectal cancer surgery improves survival outcomes. There is limited data on how recurrence patterns and post-recurrence outcomes vary by individual tumor stage. METHODS: Using a multi-site community cohort study, we examined the potential impact of primary tumor stage on the sites of recurrence, management of recurrent disease with curative intent, and post-resection survival. We also explored changes over time. RESULTS: Of 4257 new colon cancers diagnosed 2001 through 2016, 789 (21.1%) had stage I, 1584 (42.4%) had stage II, and 1360 (36.4%) had stage III colon cancer. For consecutive 5-year periods (2001-2005, 2006-2010, 2011-2016), recurrence rates have declined (23.4 vs. 17.1 vs. 13.6%, p < 0.001), however, the resection rates of metastatic disease (29.3 vs. 38.6 vs. 35.0%, p = 0.21) and post-resection 5-year survival (52.0 vs. 51.8 vs. 64.2%, p = 0.12) have remained steady. Primary tumor stage impacted recurrence rate (3.8 vs. 12 vs. 28%, p < 0.0001 for stage 1, 2, and 3), patterns of recurrence, resection of metastatic disease, (50 vs. 42 vs. 30%, p < 0.0001) and post-resection 5-year survival (92 vs. 64 vs. 44%, p < 0.001). CONCLUSION: In this community cohort we defined significant differences in recurrence patterns and post-resection survival by tumor stage, with a diminishing rate of recurrence over time. While recurrence rates were lower with stage I and II disease, the high rate of metastatic disease resection and excellent post-resection outcomes help to justify routine surveillance in these patients.

REZOLVE (ANZGOG-1101): A phase 2 trial of intraperitoneal bevacizumab to treat symptomatic ascites in patients with chemotherapy-resistant, epithelial ovarian cancer.

BACKGROUND: The primary aim of this study was to evaluate the activity of intraperitoneal bevacizumab (IP-bev) in delaying re-accumulation of malignant ascites in women with chemotherapy-resistant epithelial ovarian cancer (CR-EOC) who have ceased chemotherapy. Secondary outcomes were safety and quality of life. METHODS: Women with CR-EOC and malignant ascites that reaccumulated within 28 days of their last paracentesis (P-1) were administered IP-bev 5 mg/kg following their first therapeutic paracentesis on study (P0). Additional doses of IP-bev were allowed at each subsequent paracentesis (P1, P2, etc) provided the interval from the last dose was 42 days or greater (median time from first to second therapeutic ascitic drainage). RESULTS: 24 participants (median age 67 years [range 38-86]; median 4.5 lines prior systemic treatment [range 1-12]; ECOG performance status of 0 in 1, 1 in 8, and 2-3 in 15) were recruited. The doses of IP-bev administered were 1 in 13 participants, 2 in 5, 3 in 2, 4 in 1, and 5 in 1. The proportion with a TTP of >42 days using competing risk analysis was 77% (95% CI 58-92). Median time from P0 to P1 or death was 48 days (range 8-248). Median paracentesis-free interval (P0-P1 or death) was 4.29-fold (95% CI 2.4-5.8) higher following a first dose of IP-bev compared with the time between paracenteses prior to study entry (P-1-P0). CONCLUSION: IP-bev was safe, active, and warrants further study as a palliative intervention for recurrent ascites in CR-EOC patients receiving best supportive care.

Real-World Treatment and Outcomes of Metastatic Colorectal Cancer Patients With a Poor or Very Poor Performance Status.

BACKGROUND: The management of metastatic colorectal cancer patients with a poor performance status (PS) continues to be a clinical dilemma, with the potential activity and safety of treating this population remaining poorly understood. Few of these patients are enrolled onto clinical trials, and poor PS is often multifactorial. PATIENTS AND METHODS: We analyzed the Treatment of Recurrent and Advanced Colorectal Cancer registry to describe treatment practices and outcomes in poor (Eastern Cooperative Oncology Group [ECOG] PS 2) and very poor PS (ECOG PS > 2) patients to explore the relationship between age, tumor burden, comorbidities, and PS, and to evaluate the benefit of systemic therapy. Standard descriptive statistical methods, Kaplan-Meier analysis, and a multivariate Cox regression model were used. RESULTS: Of 2769 registry patients (diagnosed January 2009 to June 2018), 329 (12%) and 182 (7%) patients had a poor and very poor PS, respectively. Good PS patients were more likely to receive systemic therapy than poor and very poor PS patients (85%, 55%, and 21.5%, P < .0001), but clinician assessed response was observed in all subsets (53%, 41%, and 29%, P = .0003). Treatment with chemotherapy was associated with longer median overall survival across PS groups. Exploratory analysis based on comorbidity score and tumor burden subgroups demonstrated a consistently positive overall survival association with treatment. Benefit was observed where poor overall survival was attributable to medical comorbidities and to tumor burden. CONCLUSION: In routine clinical care, a substantial proportion of poor and very poor PS patients receive active treatment, which is often associated with meaningful clinical benefit.

Tumor Response and Symptom Palliation from RAINBOW, a Phase III Trial of Ramucirumab Plus Paclitaxel in Previously Treated Advanced Gastric Cancer.

BACKGROUND: In the intent-to-treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation. MATERIALS AND METHODS: Tumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR. RESULTS: In both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation. CONCLUSION: Treatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. NCT01170663. IMPLICATIONS FOR PRACTICE: Ramucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first-line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits.

CART-WHEEL.org: An Ethically Approved Online Database for Patient-Entered Data to Facilitate Rare Cancer Research.

PURPOSE: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. PATIENTS AND METHODS: Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research. RESULTS: From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL-based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. CONCLUSIONS: Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.

Therapeutic options for mucinous ovarian carcinoma.

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Utilisation of systemic therapy options in routine treatment of metastatic colorectal cancer in Australia.

BACKGROUND: In the treatment of metastatic colorectal cancer (mCRC), exposure to all three active cytotoxic agents, 5-fluorouracil/capecitabine, irinotecan and oxaliplatin, improves overall survival. The addition of biologic agents (bevacizumab and cetuximab/panitumumab) further improves survival. The uptake of available systemic agents for mCRC in routine practice in Australia is poorly described. METHODS: The ACCORD database was interrogated to determine demographics, treatments and outcomes for patients diagnosed with mCRC between 1 January 2011 and 1 January 2016 at six Melbourne centres. RESULTS: About 1130 mCRC patients were identified: median age was 69 years (range 26-105); 61% had synchronous disease. KRAS status was known in 62%, of whom 49% were KRAS wild-type. At the time of analysis, 67% of all patients had commenced systemic treatment, 50% had received two or more lines of therapy and 19% of KRAS wild-type patients had received all five active drugs. Of KRAS-mutated patients, 35% had received all four Pharmaceutical Benefits Scheme-reimbursed active drugs. Patients who had not received chemotherapy included 72 patients who underwent metastasectomy alone. At a median follow up of 34 months, median overall survival was 25 months for all patients and 69 months for those who underwent metastasectomy. CONCLUSION: In this community-based cohort, 33% of patients had not received any systemic therapy for mCRC, and few patients had received all available active systemic agents. As many patients remain alive, these figures will likely increase over time. The overall survival of patients with mCRC in this community-based cohort was 25 months and not dissimilar to that achieved in recent clinical trials.