Rachel Wong

Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C)

PURPOSE To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.

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.

Circulating Tumor DNA as an Early Marker of Therapeutic Response in Patients with Metastatic Colorectal Cancer

BACKGROUND Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. PATIENTS AND METHODS This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. RESULTS Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). CONCLUSIONS ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.

Using Predictive Biomarkers to Select Patients With Advanced Colorectal Cancer for Treatment With Epidermal Growth Factor Receptor Antibodies

As a result of the data emerging during the course of 2008, including presentations at the 44th Annual Meeting of the American Society of Oncology, it has generally been accepted that selection of patients with metastatic colorectal cancer (mCRC) for treatment with epidermal growth factor receptor (EGFR) antibodies— cetuximab or panitumumab—is reliant on the KRAS status of the tumor. For some time, KRAS had been suggested as a predictive marker for resistance to EGFR monoclonal antibodies, but Amado et al 1 were the first to publish conclusive data demonstrating the relationship between KRAS status and panitumumab efficacy in their analysis of tumor sections from participants in a randomized phase III trial comparing panitumumab with best supportive care. They found that both response to panitumumab monotherapy and improvement in progression-free survival (PFS) were confined to patients with wildtype (WT) KRAS.KRAS mutations were detected in 43% of patients, none of whom responded to panitumumab. Analyses of KRAS status and response to cetuximab have revealed similar results. For instance, in the first-line treatment of mCRC, a retrospective analysis of the impact of KRAS status on PFS and response rate on patients treated with folinic acid, fluorouracil, and irinotecan with or without cetuximab for mCRC within the Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer trial identifiedKRAS mutations in 35.6% of KRAS-assessable patients. 2 ForKRAS WT patients, both PFS (9.9v 8.7 months; HR, 0.68; P .017) and response rate (59.3% v 43.2%; P .0025) were significantly improved by the addition of cetuximab to folinic acid, fluorouracil, and irinotecan. In contrast, for patients withKRAS mutations, there was no significant difference in either PFS (7.6v 8.1 months; HR, 1.07;P .47) or response rate (40.2%v 36.2%; P .46) with the addition of cetuximab. For patients treated with first-line infused fluorouracil, folinic acid, and oxaliplatin with or without cetuximab in the Oxaliplatin and Cetuximab for First-Line Treatment of Metastatic Colorectal Cancer study, the improved response rate and PFS associated with cetiximab was also limited to those with KRAS WT tumors. 3 In fact, in this study, patients with mutated KRAS receiving cetuximab had poorer outcomes compared with those receiving infusional fluorouracil, leucovorin, and oxaliplatin alone. Based on these results, it is now recommended thatKRAS testing to exclude the presence of mutations should be performed when considering either panitumumab or cetuximab in the treatment of advanced colorectal cancer. Ligand-receptor activation of the EGFR at the cell surface results in homo- or heterodimerization of the receptors and triggers activation of downstream signaling pathways. 4 The incidence ofKRAS mutations in colorectal tumors is approximately 35% to 45%. KRAS mutations can result in constitutive activation of the Ras-Raf-MAPkinase pathway, one of the major EGFR downstream pathways, and therefore confer resistance to EGFR antibodies. 5 Nonmutated KRAS does not, however, guarantee benefit from treatment with EGFR monoclonal antibodies. Consequently, even with routine testing of KRAS status, a significant proportion of patients will be exposed to these drugs and their associated toxicity without deriving any benefit. In this issue ofJournalofClinicalOncology, Di Nicolantonio et al 6 evaluate the role ofBRAF mutations as prognostic or predictive factors for response to cetuximab or panitumumab and explore potential ways to circumvent inherent pathways of resistance. In this hypothesis-generating study, a retrospective analysis of 113 patients treated with either cetuximab or panitumumab was conducted. Additionally, a cellular analysis of the effect of the BRAF V600E allele on response to cetuximab or panitumumab was performed. The presence ofKRAS mutations in this population was 30%. As expected, KRAS mutations were associated with a lack of response to EGFR antibodies (P .011) and shorter PFS (P .0275) compared with KRAS WT tumors. Twenty-eight percent of KRAS WT patients responded to either cetuximab (alone or in combination with irinotecan) or panitumumab. BRAF mutations (BRAF V600E allele) were identified in 11 patients (10% of the population evaluated; 14% of KRAS WT patients). BRAF and KRAS mutations were mutually exclusive, as observed in previous studies. 7 Supporting the authors’ hypothesis that in KRAS WT tumors, BRAF mutations could have predictive value, none of the 11 BRAF-mutated tumors responded to treatment. Similarly, in the laboratory, colorectal cancer cell lines carrying the BRAF V600E allele were highly refractory to cetuximab and panitumumab. Conversely, all 22 patients who responded to KRAS WT also had BRAF WT. BRAF-mutated tumors were also associated with shorter PFS and overall survival irrespective of KRAS status (P .0107 and P .0001, respectively), suggesting a potential role of BRAF as a prognostic biomarker. Interestingly, targeting BRAF-mutated cell lines with the combination of cetuximab and sorafenib resulted in much higher response rates than those observed

Heterogeneity of amiodarone‐induced thyrotoxicosis: evaluation of colour‐flow Doppler sonography in predicting therapeutic response

Abstract

Treatment and outcomes of metastatic colorectal cancer in Australia: defining differences between public and private practice

Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia.

Patterns of care and outcomes for elderly patients with metastatic colorectal cancer in Australia

OBJECTIVES The elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting. MATERIALS AND METHODS Elderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65-74 vs. 75-84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis. RESULTS Of 1439 patients, 363, 352, and 106 were aged 65-74, 75-84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65-74-, 75-84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%). CONCLUSION Chemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.

Multidisciplinary Management of Locally Advanced Rectal Cancer—An Evolving Landscape?

For many years, the multidisciplinary approach of neoadjuvant radiotherapy with or without concurrent chemotherapy followed by total mesorectal excision and adjuvant fluoropyrimidine chemotherapy has remained the accepted standard management for locally advanced rectal cancers. Over this time period, many new systemic treatment options have become available, including: additional chemotherapeutic agents (oxaliplatin) and targeted therapies (vascular endothelial growth factor and epidermal growth factor receptor inhibitors), which can be added to neoadjuvant and adjuvant regimens or given in combination with radiotherapy as radio-sensitizing agents. Here we review the current literature, examining emerging data related to the impact of multiple modifications to the standard approach, including the role of neoadjuvant chemotherapy, the addition of new agents to standard chemoradiation, and postoperative fluoropyrimidine-based treatment, the optimal timing of surgery, and nonoperative approaches to the management of locally advanced rectal cancers.

Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study

Objective For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4–10 weeks after surgery. Somatic mutations in individual patient’s tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.

Survival impact of the Australian National Bowel Cancer Screening Programme.

The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age‐based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50–74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP‐detected tumours.