Suzanne Kosmider

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease. Footprints of persistent cancer Stage II colon cancer, which has spread through the wall of the colon but has not metastasized to the lymph nodes, can present a therapeutic dilemma. On one hand, these tumors can usually be completely removed by surgery, and the majority does not recur even without chemotherapy. On the other hand, it is difficult to determine which of these tumors will recur and to identify patients who would benefit from adjuvant chemotherapy after surgery. Tie et al. show that the presence of circulating tumor DNA in a patient’s blood after surgery is a sign of persistent tumor and a greatly increased risk of relapse, suggesting that this group of patients may require chemotherapy to prevent recurrence. Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAFV600E mutation

BRAFV600E mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. Knowledge of the concordance between primary–metastasis pairs and the impact of BRAFV600E on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I–IV) evenly matched for age (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary–metastasis pairs. BRAFV600E, KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right‐sided tumor location (p < 0.0001) were independently associated with BRAFV600E. The prevalence of BRAFV600E was considerably higher in older (age > 70) females with KRAS wild‐type right‐sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC (HR = 2.02; 95% CI 1.26–3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild‐type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAFV600E. Patients with BRAFV600E wild‐type primary tumor do not appear to acquire the mutation in their metastases, and BRAFV600E is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAFV600E inhibitors in CRC.

Chemotherapy Dosing Strategies in the Obese, Elderly, and Thin Patient: Results of a Nationwide Survey

PURPOSE Determining the optimal starting dose of chemotherapy (CHT) presents a considerable challenge when using body-surface area (BSA)-based dosing, particularly in obese, elderly, or thin patients. We sought to document the range of approaches employed when administering CHT to these patients. METHODS A questionnaire was developed by a panel of oncologists and mailed to all members of the Medical Oncology Group of Australia. RESULTS From 315 oncologists, 188 responded (response rate 59.7%). BSA-based dosing is standard practice for 176 (97.2%) of the responding oncologists. In the adjuvant disease setting, 23 (12.7%) use ideal rather than actual body weight (BW) to calculate BSA, or choose whichever is less. When treating obese patients, only 6.1% of respondents routinely use actual BW. Of the remainder, 69.5% either cap the dose at 2 m(2) or use ideal BW. In underweight patients, 95% (n = 171) routinely calculate BSA using actual BW. Forty one respondents (22.7%) routinely reduce dose in the fit elderly. CONCLUSION This analysis of BSA-based CHT dosing methods demonstrates significant variability in practice. Based on evidence from adjuvant studies showing that actual BSA-based dosing is desirable, a substantial number of Australian patients are being underdosed. Further education, together with ongoing research, is required to optimize individualized dosing for efficacy and tolerability.

Radioembolization in Combination with Systemic Chemotherapy as First-line Therapy for Liver Metastases from Colorectal Cancer

PURPOSE To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE. RESULTS Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity. CONCLUSIONS The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

Dose rounding of chemotherapy in colorectal cancer: an analysis of clinician attitudes and the potential impact on treatment costs.

Aim:  The aims of this study were to calculate theoretical cost savings of oxaliplatin dose rounding in colorectal cancer (CRC), and to assess clinician attitudes to chemotherapy dose rounding.

Preoperative investigations for metastatic staging of colon and rectal cancer across multiple centres – what is current practice?

Objective  The optimal strategy for elective distant staging of colorectal carcinoma (CRC) has yet to be defined, with current guidelines based on small and limited series. One specific issue requiring review is the value of routine computerized tomographic (CT) chest examination. Also lacking is data on current routine clinical practice.

Developing a national database for metastatic colorectal cancer management: perspectives and challenges

The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian‐centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed.

TOWARDS ESTABLISHING A NATIONAL COLORECTAL CANCER DATABASE: LESSONS LEARNT FROM BIO21 MOLECULAR MEDICINE INFORMATICS MODEL

Background:  Collecting data regarding treatment and outcomes of patients with cancer, for both audit and research purposes, is a common but challenging goal. Modern technology promises greater ease and sophistication for data collection, linkage and analysis, but many traditional challenges remain.

Preliminary analysis of the cost-effectiveness of the National Bowel Cancer Screening Program: demonstrating the potential value of comprehensive real world data

Background/Aim:  The complexity and cost of treating cancer patients is escalating rapidly and increasingly difficult decisions are being made regarding which interventions provide value for money. BioGrid Australia supports collection and analysis of comprehensive treatment and outcome data across multiple sites. Here, we use preliminary data regarding the National Bowel Cancer Screening Program (NBCSP) and stage‐specific treatment costs for colorectal cancer (CRC) to demonstrate the potential value of real world data for cost‐effectiveness analyses (CEA).

Primary Tumor Resection in Patients With Metastatic Colorectal Cancer Is Associated With Reversal of Systemic Inflammation and Improved Survival

BACKGROUND The true survival benefit of noncurative primary tumor resection in patients with de novo metastatic colorectal cancer (mCRC) remains uncertain. The present study examined the effect of primary tumor resection on systemic inflammation and survival in patients with mCRC. MATERIALS AND METHODS Consecutive patients with de novo mCRC who had undergone primary tumor resection were identified from a prospective database. Patients were excluded if they had undergone resection of metastases, had undergone delayed primary resection, or if blood samples were unavailable. The neutrophil/lymphocyte ratio (NLR) was used as a biomarker of systemic inflammation. Overall survival (OS) was compared between patient groups according to the pre- and postprimary resection NLR. The associations between the reversal of an elevated NLR and primary tumor bulk or performance status were explored. RESULTS A total of 145 eligible patients were identified from the database, with a median age of 70 years. The baseline NLR was elevated (> 5) in 65 patients, 36 (55%) of whom had a low NLR after surgery. The reversal of an elevated NLR was associated with significantly improved OS (hazard ratio, 0.53; P = .017). A similar benefit was seen after excluding patients undergoing emergency primary resection. NLR reversal was more frequent in patients with larger primary tumors or good performance status. CONCLUSION The present study is the first to demonstrate a relationship between the reversal of a systemic inflammatory response and the improved survival after primary resection in those with mCRC. A greater effect was seen in patients with large primary tumors. If validated, these observations could guide clinical decision-making in patients with mCRC at presentation.